Coronavirus Disease 2019 (COVID-19) Treatment Guidelines



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Visit https://www.covid19treatmentguidelines.nih.gov/ to access the most up-to-date guideline.

How to Cite the COVID-19 Treatment Guidelines:

COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [insert date].

The COVID-19 Treatment Guidelines Panel regularly updates the recommendations in these guidelines as new information on the management of COVID-19 becomes available. The most recent version of the guidelines can be found on the COVID-19 Treatment Guidelines website (https://www.covid19treatmentguidelines.nih.gov/).

   

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Table of Contents

What’s New in the Guidelines …………………………………………………………………………………….. 4

Introduction ……………………………………………………………………………………………………………… 6

Overview of COVID-19 ………………………………………………………………………………………………. 9 Testing for SARS-CoV-2 Infection………………………………………………………………………….. 14 Prevention and Prophylaxis of SARS-CoV-2 Infection ……………………………………………… 20 Clinical Spectrum of SARS-CoV-2 Infection……………………………………………………………. 30

Outpatient Management of Acute COVID-19……………………………………………………………… 38

Care of Critically Ill Adult Patients With COVID-19 ……………………………………………………… 48 General Considerations ……………………………………………………………………………………….. 50 Infection Control …………………………………………………………………………………………………. 58 Hemodynamics …………………………………………………………………………………………………… 61 Oxygenation and Ventilation …………………………………………………………………………………. 64 Acute Kidney Injury and Renal Replacement Therapy………………………………………………. 71 Pharmacologic Interventions ………………………………………………………………………………… 72 Extracorporeal Membrane Oxygenation …………………………………………………………………. 73

Therapeutic Management of Patients With COVID-19 ………………………………………………… 75

Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19 … 89 Remdesivir …………………………………………………………………………………………………………. 91 Table 2a. Remdesivir: Selected Clinical Data ……………………………………………………… 94 Chloroquine or Hydroxychloroquine With or Without Azithromycin ………………………….. 100

Table 2b. Chloroquine or Hydroxychloroquine With or Without Azithromycin:
Selected Clinical Data ………………………………………………………………………………….. 105

Ivermectin ………………………………………………………………………………………………………… 117 Table 2c. Ivermectin: Selected Clinical Data …………………………………………………….. 122 Lopinavir/Ritonavir and Other HIV Protease Inhibitors ……………………………………………. 133

Table 2d. Characteristics of Antiviral Agents That Are Approved or Under
Evaluation for the Treatment of COVID-19…………………………………………………………….. 138

Anti-SARS-CoV-2 Antibody Products ……………………………………………………………………… 141 Anti-SARS-CoV-2 Monoclonal Antibodies…………………………………………………………….. 142 Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data…………. 149 Convalescent Plasma ………………………………………………………………………………………… 155 Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data……………………… 162 Immunoglobulins: SARS-CoV-2-Specific ……………………………………………………………… 173

Table 3c. Characteristics of SARS-CoV-2 Antibody-Based Products Under
Evaluation for the Treatment of COVID-19…………………………………………………………….. 174

Cell-Based Therapy Under Evaluation for the Treatment of COVID-19 ……………………….. 177

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Immunomodulators Under Evaluation for the Treatment of COVID-19………………………… 180

Colchicine ………………………………………………………………………………………………………… 181

Corticosteroids………………………………………………………………………………………………….. 185 Table 4a. Corticosteroids: Selected Clinical Data ……………………………………………… 190

Fluvoxamine……………………………………………………………………………………………………… 201 Immunoglobulins: Non-SARS-CoV-2-Specific ………………………………………………………. 204 Interferons (Alfa, Beta) …………………………………………………………………………………….. 206 Interleukin-1 Inhibitors ……………………………………………………………………………………….. 210 Interleukin-6 Inhibitors ……………………………………………………………………………………….. 213

Table 4b. Interleukin-6 Inhibitors: Selected Clinical Data ……………………………………. 219

Kinase Inhibitors: Baricitinib and Other Janus Kinase Inhibitors, and Bruton’s
Tyrosine Kinase Inhibitors …………………………………………………………………………………… 231

Table 4c. Characteristics of Immunomodulators Under Evaluation for the
Treatment of COVID-19………………………………………………………………………………………. 238

Antithrombotic Therapy in Patients with COVID-19 ………………………………………………….. 251 Supplements…………………………………………………………………………………………………………. 260 Vitamin C………………………………………………………………………………………………………….. 261 Vitamin D………………………………………………………………………………………………………….. 264 Zinc …………………………………………………………………………………………………………………. 266

Considerations for Certain Concomitant Medications in Patients with COVID-19 ……….. 270

COVID-19 and Special Populations…………………………………………………………………………. 276 Special Considerations in Pregnancy …………………………………………………………………… 277 Special Considerations in Children………………………………………………………………………. 280 Special Considerations in Adults and Children With Cancer……………………………………. 291 Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell

Transplant, and Cellular Therapy Candidates, Donors, and Recipients …………………….. 299 Special Considerations in People With HIV …………………………………………………………… 308 Influenza and COVID-19 …………………………………………………………………………………….. 314

Appendix A, Table 1. COVID-19 Treatment Guidelines Panel Members………………………. 318 Appendix A, Table 2. Panel on COVID-19 Treatment Guidelines Financial Disclosure

for Companies Related to COVID-19 Treatment or Diagnostics …………………………………. 320

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What’s New in the Guidelines

Last Updated: April 21, 2021

The Coronavirus Disease 2019 (COVID-19) Treatment Guidelines is published in an electronic format that can be updated in step with the rapid pace and growing volume of information regarding the treatment of COVID-19.

The COVID-19 Treatment Guidelines Panel (the Panel) is committed to updating this document to ensure that health care providers, patients, and policy experts have the most recent information regarding the optimal management of COVID-19 (see the Panel Roster for a list of Panel members).

New Guidelines sections and recommendations and updates to existing Guidelines sections are developed by working groups of Panel members. All recommendations included in the Guidelines are endorsed by
a majority of Panel members (see the Introduction for additional details on the Guidelines development process).

Major revisions to the Guidelines within the last month are as follows:

April 21, 2021

New Sections of the Guidelines

Outpatient Management of Acute COVID-19

In this section, the Panel provides recommendations for screening, triage, and therapeutic management of patients with mild to moderate COVID-19 who do not require hospitalization. This section also provides recommendations for managing patients with COVID-19 after they are discharged from the emergency department or the hospital.

Colchicine

Based on the results of a large, randomized, placebo-controlled trial in outpatients with COVID-19, the Panel has determined that there are insufficient data to recommend either for or against the use of colchicine in nonhospitalized patients with COVID-19. The Panel recommends against the use of colchicine in hospitalized patients, except in a clinical trial (AIII).

Fluvoxamine

Based on the results of a small randomized controlled trial and an observational study, the Panel has determined that there are insufficient data to recommend either for or against the use of fluvoxamine for the treatment of COVID-19.

Key Updates to the Guidelines

Therapeutic Management of Adults With COVID-19

This section has been updated to incorporate recommendations for when to use combination anti-SARS- CoV-2 monoclonal antibodies and tocilizumab (in combination with dexamethasone) in certain patients with COVID-19. This section also includes a detailed discussion of the rationale behind these recommendations.

Overview of COVID-19

A new subsection has been added to discuss the emerging information on SARS-CoV-2 variants of concern.

Clinical Spectrum of SARS-CoV-2 Infection

A new subsection describes reports of SARS-CoV-2 reinfection in individuals who had previously documented COVID-19. The discussion on patients who experience persistent symptoms or organ

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dysfunction after acute COVID-19 has also been updated.

Anti-SARS-CoV-2 Monoclonal Antibodies

This section now incorporates information and recommendations from the Panel’s Statement on the Emergency Use Authorization of Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19 that was released on April 8, 2021. This section also includes information on the various reported SARS-CoV-2 variants and the potential impact of mutations on in vitro susceptibility to different anti-SARS-CoV-2 monoclonal antibodies.

Convalescent Plasma

High-titer convalescent plasma is available through a Food and Drug Administration Emergency Use Authorization for the treatment of certain hospitalized patients with COVID-19. This section has been updated to include new recommendations regarding the use of convalescent plasma in hospitalized patients with COVID-19 (including those who have impaired humoral immunity) and in nonhospitalized patients with COVID-19. A new clinical data table summarizes the results from several randomized clinical trials and retrospective cohort studies of convalescent plasma use in patients with COVID-19.

Interleukin-6 Inhibitors (With Focus on Tocilizumab)

This section has been updated to incorporate and expand on the Panel’s statements on the use of tocilizumab for the treatment of COVID-19 that were released on February 3 and March 5, 2021. This section includes considerations for using tocilizumab in combination with dexamethasone in certain hospitalized patients who are exhibiting rapid respiratory decompensation due to COVID-19. A new clinical data table summarizes the results from key studies of tocilizumab and sarilumab use in patients with COVID-19 that have had the greatest impact on the Panel’s recommendations.

Special Considerations in Children

This section now includes expanded discussions on treatment considerations for children with acute COVID-19. Additions to the section include updated information on the epidemiology and risk factors for COVID-19 in children, vertical transmission of SARS-CoV-2 infection, and multisystem inflammatory syndrome in children (MIS-C).

Other Updates to the Guidelines

The following sections have been updated to include recommendations and special considerations for SARS-CoV-2 vaccination in specific populations:

• Special Considerations in Adults and Children With Cancer

• Special Considerations in Persons with HIV

• Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell Transplant, and Cellular Therapy Candidates, Donors, and Recipients

The information in the following sections has also been updated:

• Testing for SARS-CoV-2 Infection

• Prevention and Prophylaxis of SARS-CoV-2 Infection

• Oxygenation and Ventilation

• Remdesivir

• Vitamin C

• Vitamin D

• Zinc

• Considerations for Certain Concomitant Medications in Patients With COVID-19
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Introduction

Last Updated: February 11, 2021

The COVID-19 Treatment Guidelines have been developed to provide clinicians with guidance on how to care for patients with COVID-19. Because clinical information about the optimal management of COVID-19 is evolving quickly, these Guidelines will be updated frequently as published data and other authoritative information become available.

Panel Composition

Members of the COVID-19 Treatment Guidelines Panel (the Panel) are appointed by the Panel co-chairs based on their clinical experience and expertise in patient management, translational and clinical science, and/or development of treatment guidelines. Panel members include representatives from federal agencies, health care and academic organizations, and professional societies. Federal agencies and professional societies represented on the Panel include:

• American Association of Critical-Care Nurses

• American Association for Respiratory Care

• American College of Chest Physicians

• American College of Emergency Physicians

• American College of Obstetricians and Gynecologists

• American Society of Hematology

• American Thoracic Society

• Biomedical Advanced Research and Development Authority

• Centers for Disease Control and Prevention

• Department of Defense

• Department of Veterans Affairs

• Food and Drug Administration

• Infectious Diseases Society of America

• National Institutes of Health

• Pediatric Infectious Diseases Society

• Society of Critical Care Medicine

• Society of Infectious Diseases Pharmacists
The inclusion of representatives from professional societies does not imply that their societies have endorsed all elements of these Guidelines.
The names, affiliations, and financial disclosures of the Panel members and ex officio members, as well as members of the Guidelines support team, are provided in the Panel Roster and Financial Disclosure sections of the Guidelines.
Development of the Guidelines
Each section of the Guidelines is developed by a working group of Panel members with expertise in the area addressed in the section. Each working group is responsible for identifying relevant information and published scientific literature and for conducting a systematic, comprehensive review of that information
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and literature. The working groups propose updates to the Guidelines based on the latest published research findings and evolving clinical information.

New Guidelines sections and recommendations are reviewed and voted on by the voting members of the Panel. To be included in the Guidelines, a recommendation statement must be endorsed by a majority of Panel members; this applies to recommendations for treatments, recommendations against treatments, and cases where there are insufficient data to recommend either for or against treatments. Updates to existing sections that do not affect the rated recommendations are approved by Panel co-chairs without a Panel vote. Panel members are required to keep all Panel deliberations and unpublished data considered during the development of the Guidelines confidential.

Method of Synthesizing Data and Formulating Recommendations

The working groups critically review and synthesize the available data to develop recommendations. Aspects of the data that are considered can include, but are not limited to, the source of the data, the type of study (e.g., randomized controlled trial, prospective or retrospective cohort study, case series), the quality and suitability of the methods, the number of participants, and the effect sizes observed.

The recommendations in these Guidelines are based on scientific evidence and expert opinion. Each recommendation includes two ratings: an uppercase letter (A, B, or C) that indicates the strength of the recommendation and a Roman numeral with or without a lowercase letter (I, IIa, IIb, or III) that indicates the quality of the evidence that supports the recommendation (see Table 1).

Table 1. Recommendation Rating Scheme

Strength of Recommendation

Quality of Evidence for Recommendation

. A:  Strong recommendation for the statement

. B:  Moderate recommendation for the statement

. C:  Optional recommendation for the statement

I: One or more randomized trials without major limitations

IIa: Other randomized trials or subgroup analyses of randomized trials

IIb: Nonrandomized trials or observational cohort studies III: Expert opinion

To develop the recommendations in these Guidelines, the Panel uses data from the rapidly growing body of published research on COVID-19. The Panel also relies heavily on experience with other diseases, supplemented with members’ evolving clinical experience with COVID-19.

In general, the recommendations in these Guidelines fall into the following categories:

• The Panel recommends using [blank] for the treatment of COVID-19 (rating).
Recommendations in this category are based on evidence from clinical trials or large cohort studies that demonstrate the clinical or virologic efficacy of a therapy in patients with COVID-19, with the potential benefits outweighing the potential risks.

• There are insufficient data for the Panel to recommend either for or against the use of [blank] for the treatment of COVID-19 (no rating). This statement is used in cases when there are insufficient data to make a recommendation. In this case, rationale for this statement is outlined in the text.

• The Panel recommends against the use of [blank] for the treatment of COVID-19, except in a clinical trial (rating). This recommendation is used for an intervention that has not clearly demonstrated efficacy in the treatment of COVID-19 and/or has potential safety concerns. More clinical trials are needed to further define the role of the intervention.
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• The Panel recommends against the use of [blank] for the treatment of COVID-19 (rating).

This recommendation is used in cases when the available data clearly show a safety concern and/ or the data show no benefit for the treatment of COVID-19.

Evolving Knowledge on Treatment for COVID-19

Currently, remdesivir, an antiviral agent, is the only Food and Drug Administration-approved drug
for the treatment of COVID-19. An array of drugs approved for other indications and multiple investigational agents are being studied for the treatment of COVID-19 in clinical trials around the globe. These trials can be accessed at ClinicalTrials.gov. In addition, providers can access and prescribe investigational drugs or agents that are approved or licensed for other indications through various mechanisms, including Emergency Use Authorizations (EUAs), Emergency Investigational New Drug (EIND) applications, compassionate use or expanded access programs with drug manufacturers, and/or off-label use.

Whenever possible, the Panel recommends that promising, unapproved, or unlicensed treatments for COVID-19 be studied in well-designed, controlled clinical trials. This recommendation also applies
to drugs that have been approved or licensed for indications other than the treatment of COVID-19.
The Panel recognizes the critical importance of clinical research in generating evidence to address unanswered questions regarding the safety and efficacy of potential treatments for COVID-19. However, the Panel also realizes that many patients and providers who cannot access these potential treatments via clinical trials still seek guidance about whether to use them.

A large volume of data and publications from randomized controlled trials, observational cohorts, and case series are emerging at a very rapid pace, some in peer-reviewed journals, others as manuscripts that have not yet been peer reviewed, and, in some cases, press releases. The Panel continuously reviews
the available data and assesses their scientific rigor and validity. These sources of data and the clinical experiences of the Panel members are used to determine whether new recommendations or changes to the current recommendations are warranted.

Finally, it is important to stress that the rated treatment recommendations in these Guidelines should not be considered mandates. The choice of what to do or not to do for an individual patient is ultimately decided by the patient and their provider.



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Overview of COVID-19

Last Updated: April 21, 2021

Epidemiology

The COVID-19 pandemic has exploded since cases were first reported in China in December 2019. As of April 19, 2021, more than 141 million cases of COVID-19—caused by SARS-CoV-2 infection—have been reported globally, including more than 3 million deaths.1

Individuals of all ages are at risk for infection and severe disease. However, the probability of serious COVID-19 disease is higher in people aged ≥60 years, those living in a nursing home or long-term care facility, and those with chronic medical conditions. In an analysis of more than 1.3 million laboratory- confirmed cases that were reported in the United States between January and May 2020, 14% of patients required hospitalization, 2% were admitted to the intensive care unit, and 5% died.2 The percentage

of patients who died was 12 times higher (19.5% vs. 1.6%) and the percentage of patients who were hospitalized was six times higher (45.4% vs. 7.6%) in those with reported medical conditions than in those without medical conditions. The mortality rate was highest in those aged >70 years, regardless of the presence of chronic medical conditions. Among those with available data on health conditions, 32% had cardiovascular disease, 30% had diabetes, and 18% had chronic lung disease. Other conditions that may lead to a high risk for severe COVID-19 include cancer, kidney disease, obesity, sickle cell disease, and other immunocompromising conditions. Transplant recipients and pregnant people are also at a higher risk of severe COVID-19.3-10

Emerging data from the United States suggest that racial and ethnic minorities experience higher rates of COVID-19 and subsequent hospitalization and death.11-15 However, surveillance data that include race and ethnicity are not available for most reported cases of COVID-19 in the United States.4,16 Factors that contribute to the increased burden of COVID-19 in these populations may include over-representation in work environments that confer higher risks of exposure to COVID-19, economic inequality (which limits people’s ability to protect themselves against COVID-19 exposure), neighborhood disadvantage,17 and a lack of access to health care.16 Structural inequalities in society contribute to health disparities for racial and ethnic minority groups, including higher rates of comorbid conditions (e.g., cardiac disease, diabetes, hypertension, obesity, pulmonary diseases), which further increases the risk of developing severe COVID-19.15

SARS-CoV-2 Variants of Concern

Like other RNA viruses, SARS-CoV-2 is constantly evolving through random mutations. Any new mutations can potentially increase or decrease infectiousness and virulence. In addition, mutations can increase the virus’ ability to evade adaptive immune responses from past SARS-CoV-2 infection or vaccination. This may lead to an increased risk of reinfection or decreased efficacy of vaccines.18 There is already evidence that some SARS-CoV-2 variants have reduced susceptibility to plasma from people who were previously infected or immunized, as well as to select monoclonal antibodies that are being considered for prevention and treatment.19

Since December 2020, several variants of concern have been identified. There is emerging evidence that the B.1.1.7 variant first seen in the United Kingdom is more infectious than earlier variants and may
be more virulent.20-22 It has become the predominant variant in the United Kingdom, and it continues to spread across the globe, including throughout many regions of the United States. The B.1.351 variant that was originally identified in South Africa is now the predominant variant in that region and has spread to many other countries, including the United States. The P.1 variant was originally identified

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in Manaus, Brazil, and has now been identified in the United States. Other variants that have emerged in the United States are receiving attention, such as the B.1.427/B.1.429 variants that are circulating throughout California and the B.1.526 variant reported in New York.

The data on the emergence, spread, and clinical relevance of these new variants is rapidly evolving; this is especially true for research on how variants might affect transmission rates, disease progression, vaccine development, and the efficacy of current therapeutics. Because the research on variants
of concern is moving quickly, websites such as the Centers for Disease Control and Prevention’s National Genomic Surveillance Dashboard and CoVariants.org provide regular updates on the data
for SARS-CoV-2 variants. The COVID-19 Treatment Guidelines Panel will review the emerging data on these variants, paying particular attention to research on the impacts of these variants on testing, prevention, and treatment.

Clinical Presentation

The estimated incubation period for COVID-19 is up to 14 days from the time of exposure, with a median incubation period of 4 to 5 days.6,23,24 The spectrum of illness can range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome and death. Among 72,314 persons with COVID-19 in China, 81% of cases were reported to be mild (defined in this study as
no pneumonia or mild pneumonia), 14% were severe (defined as dyspnea, respiratory frequency ≥30 breaths/min, oxygen saturation [SpO2] ≤93%, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2] <300 mm Hg, and/or lung infiltrates >50% within 24 to 48 hours), and 5% were critical (defined as respiratory failure, septic shock, and/or multiorgan dysfunction or failure).25 In a report on more than 370,000 confirmed COVID-19 cases with reported symptoms in the United States, 70% of patients experienced fever, cough, or shortness of breath, 36% had muscle aches, and 34% reported headaches.2 Other reported symptoms have included, but are not limited to, diarrhea, dizziness, rhinorrhea, anosmia, dysgeusia, sore throat, abdominal pain, anorexia, and vomiting.

The abnormalities seen in chest X-rays vary, but bilateral multifocal opacities are the most common. The abnormalities seen in computed tomography of the chest also vary, but the most common are bilateral peripheral ground-glass opacities, with areas of consolidation developing later in the clinical course of COVID-19.26 Imaging may be normal early in infection and can be abnormal in the absence of symptoms.26

Common laboratory findings in patients with COVID-19 include leukopenia and lymphopenia. Other laboratory abnormalities have included elevated levels of aminotransferase, C-reactive protein, D-dimer, ferritin, and lactate dehydrogenase.

While COVID-19 is primarily a pulmonary disease, emerging data suggest that it also leads to cardiac,27,28 dermatologic,29 hematologic,30 hepatic,31 neurologic,32,33 renal,34,35 and other complications. Thromboembolic events also occur in patients with COVID-19, with the highest risk occurring in critically ill patients.36

The long-term sequelae of COVID-19 survivors are currently unknown. Persistent symptoms after recovery from acute COVID-19 have been described (see Clinical Spectrum of SARS-CoV-2 Infection). Lastly, SARS-CoV-2 infection has been associated with a potentially severe inflammatory syndrome
in children (multisystem inflammatory syndrome in children, or MIS-C).37,38 Please see Special Considerations in Children for more information.

References

1. Johns Hopkins. COVID-19 dashboard by the Center for Science and Engineering. 2021. Available at:

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https://coronavirus.jhu.edu/map.html. Accessed March 15, 2021.

2. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States, January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6924e2-H.pdf.

3. Cai Q, Chen F, Wang T, et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China. Diabetes Care. 2020;43(7):1392-1398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409502.

4. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): cases in U.S. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html. Accessed March 31, 2021.

5. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-COVID—NET, 14 states, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32298251.

6. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.

7. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167524.

8. Palaiodimos L, Kokkinidis DG, Li W, et al. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York. Metabolism. 2020;108:154262. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32422233.

9. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): people who are at increased risk for severe illness. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-increased-risk.html. Accessed March 31, 2021.

10. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status – United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(44):1641-1647. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33151921.

11. Azar KMJ, Shen Z, Romanelli RJ, et al. Disparities in outcomes among COVID-19 patients in a large health care system in California. Health Aff (Millwood). 2020;39(7):1253-1262. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32437224.

12. Gold JAW, Wong KK, Szablewski CM, et al. Characteristics and clinical outcomes of adult patients hospitalized with COVID-19—Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69(18):545-550. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32379729.

13. Gross CP, Essien UR, Pasha S, Gross JR, Wang SY, Nunez-Smith M. Racial and ethnic disparities in population-level COVID-19 Mortality. J Gen Intern Med. 2020;35(10):3097-3099. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32754782.

14. Nayak A, Islam SJ, Mehta A, et al. Impact of social vulnerability on COVID-19 incidence and outcomes in the United States. medRxiv. 2020;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32511437.

15. Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and mortality among black patients and white patients with Covid-19. N Engl J Med. 2020;382(26):2534-2543. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459916.

16. Centers for Disease Control and Prevention. Health equity considerations and racial and ethnic minority groups. 2020; https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/racial-ethnic-minorities. html. Accessed November 24, 2020.

17. Kind AJH, Buckingham WR. Making neighborhood-disadvantage metrics accessible—the neighborhood atlas.

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N Engl J Med. 2018;378(26):2456-2458. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29949490.

18. Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 variants of concern in the United States-challenges and
opportunities. JAMA. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33595644.

19. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature.
2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33684923.

20. Leung K, Shum MH, Leung GM, Lam TT, Wu JT. Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill. 2021;26(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33413740.

21. Davies NG, Barnard RC, Jarvis CI, et al. Report: Continued spread of VOC 202012/01 in England. 2020. Available at: https://cmmid.github.io/topics/covid19/reports/uk-novel-variant/2020_12_31_Transmissibility_ and_severity_of_VOC_202012_01_in_England_update_1.pdf.

22. Murugan NA, Javali PA, Pandian CJ, Ali MA, Srivastava V, Jeyaraman J. Computational investigation of increased virulence and pathogenesis of SARS-CoV-2 lineage B.1.1.7. bioRxiv. 2021;preprint. Available at: https://www.biorxiv.org/content/10.1101/2021.01.25.428190v1.

23. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382(13):1199-1207. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31995857.

24. Lauer SA, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150748.

25. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32091533.

26. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32105637.

27. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular system. Circulation. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32293910.

28. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. 2020;5(7):831-840. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32219363.

29. Sachdeva M, Gianotti R, Shah M, et al. Cutaneous manifestations of COVID-19: report of three cases and a review of literature. J Dermatol Sci. 2020;98(2):75-81. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32381430.

30. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7):1021-1028. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32286245.

31. Agarwal A, Chen A, Ravindran N, To C, Thuluvath PJ. Gastrointestinal and liver manifestations of COVID-19. J Clin Exp Hepatol. 2020;10(3):263-265. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32405183.

32. Whittaker A, Anson M, Harky A. Neurological manifestations of COVID-19: a systematic review and current update. Acta Neurol Scand. 2020;142(1):14-22. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32412088.

33. Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699-702. Available at:

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https://www.ncbi.nlm.nih.gov/pubmed/32314810.

34. Pei G, Zhang Z, Peng J, et al. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J Am Soc Nephrol. 2020;31(6):1157-1165. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32345702.

35. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):219-227. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32327202.

36. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32311448.

37. Chiotos K, Bassiri H, Behrens EM, et al. Multisystem inflammatory syndrome in children during the coronavirus 2019 pandemic: a case series. J Pediatric Infect Dis Soc. 2020;9(3):393-398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32463092.

38. Belhadjer Z, Meot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32418446.

     

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Testing for SARS-CoV-2 Infection

Last Updated: April 21, 2021



Summary Recommendations

• To diagnose acute infection of SARS-CoV-2, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using a nucleic acid ampli cation test (NAAT) with a sample collected from the upper respiratory tract (i.e., a nasopharyngeal, nasal, or oropharyngeal specimen) (AIII).

• For intubated and mechanically ventilated adults who are suspected to have COVID-19 but who do not have a con rmed diagnosis:
• The Panel recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial upper respiratory tract sample is negative (BII).
• The Panel recommends obtaining endotracheal aspirates over bronchial wash or bronchoalveolar lavage samples when collecting lower respiratory tract samples to establish a diagnosis of COVID-19 (BII).

• A NAAT should not be repeated in an asymptomatic person within 90 days of a previous SARS-CoV-2 infection, even if the person has had a signi cant exposure to SARS-CoV-2 (AIII).

• SARS-CoV-2 reinfection has been reported in people who have received an initial diagnosis of infection; therefore, a NAAT should be considered for persons who have recovered from a previous infection and who present with symptoms that are compatible with SARS-CoV-2 infection if there is no alternative diagnosis (BIII).

• The Panel recommends against the use of serologic (i.e., antibody) testing as the sole basis for diagnosis of acute SARS-CoV-2 infection (AIII).

• The Panel recommends against the use of serologic (i.e., antibody) testing to determine whether a person is immune to SARS-CoV-2 infection (AIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

Diagnostic Testing for SARS-CoV-2 Infection

Everyone who has symptoms that are consistent with COVID-19, as well as people with known high-risk exposures to SARS-CoV-2, should be tested for SARS-CoV-2 infection. Such testing should employ either a nucleic acid amplification test (NAAT) or an antigen test to detect SARS-CoV-2. Ideally, diagnostic testing should also be performed for people who are likely to be at repeated risk
of exposure to SARS-CoV-2, such as health care workers and first responders. Testing should also be considered for individuals who spend time in heavily populated environments (e.g., teachers, students, food industry workers) and for travelers. Testing requirements may vary by state, local, and employer policies. Travelers may need evidence of a recent negative test result to enter some states or countries; such documentation may be an acceptable alternative to quarantine upon arrival.

A number of diagnostic tests for SARS-CoV-2 infection (e.g., NAATs, antigen tests) have received Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA),1 but no diagnostic test has been approved by the FDA.

Although nasopharyngeal specimens remain the recommended samples for SARS-CoV-2 diagnostic testing, nasal (anterior nares or mid-turbinate) or oropharyngeal swabs are acceptable alternatives.2 Lower respiratory tract samples have a higher yield than upper tract samples, but they are often not obtained because of concerns about aerosolization of the virus during sample collection procedures. Some tests that have received EUAs can also be performed on saliva specimens. Studies are currently evaluating the use of other sample types, including stool samples.

Some tests that have received EUAs allow for self-collection of specimens at home, but these specimens

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must be sent to a laboratory for processing. In addition, some tests allow trained personnel to collect and test specimens in nonclinical settings, such as in the home or in nursing or assisted living facilities. This allows real-time antigen results to be obtained on site.

Nucleic Acid Amplification Testing for SARS-CoV-2 Infection

Reverse transcriptase polymerase chain reaction (RT-PCR)-based diagnostic tests (which detect viral nucleic acids) are considered the gold standard for detecting current SARS-CoV-2 infection. More recently, NAATs have included a variety of additional platforms (e.g., reverse transcriptase loop- mediated isothermal amplification [RT-LAMP]). Clinically, there may be a window period of up to
5 days after exposure before viral nucleic acids can be detected. Diagnostically, some NAATs may produce false negative results if a mutation occurs in the part of the virus’ genome that is assessed
by that test.3 The FDA monitors the potential effects of SARS-CoV-2 genetic variations on NAAT results and issues updates when specific variations could affect the performance of NAATs that have received EUAs. Generally, false negative results are more likely to occur when using NAATs that rely on only one genetic target. Therefore, a single negative test result does not exclude the possibility of SARS-CoV-2 infection in people who have a high likelihood of infection based on their exposure history and/or their clinical presentation.4

Many commercial NAATs that use RT-PCR rely on multiple targets to detect the virus, such that even if a mutation impacts one of the targets, the other RT-PCR targets will still work.5 NAATs that use multiple targets are less likely to be impacted by an increased prevalence of genetic variants. In fact, because each of these tests target multiple locations on the virus’ genome, they can be helpful in identifying new genetic variants before they become widespread in the population. For example, the B.1.1.7 variant that has been associated with increased transmission carries many mutations, including a double deletion at positions 69 and 70 on the spike protein gene (S-gene). This mutation appears to impact the detection of the S-gene but does not impact other genetic targets in certain NAATs. If COVID-19 is still suspected after a patient receives a negative test result, clinicians should consider repeating testing; ideally, they should use a NAAT with different genetic targets.3

SARS-CoV-2 poses several diagnostic challenges, including potentially discordant shedding of virus from the upper versus the lower respiratory tract. However, due to the high specificity of NAATs, a positive result on a NAAT of an upper respiratory tract sample from a patient with recent onset of SARS-CoV-2-compatible symptoms is sufficient to diagnose COVID-19. In patients with COVID-19, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), lower respiratory tract specimens have a higher viral load and thus a higher yield than upper respiratory tract specimens.6-12 For intubated or mechanically ventilated patients with clinical signs and symptoms that are consistent with COVID-19 pneumonia, the COVID-19 Treatment Guidelines Panel (the Panel) recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial upper respiratory tract sample is negative (BII). The Panel recommends obtaining endotracheal aspirates over bronchial wash or bronchoalveolar lavage (BAL) samples when collecting lower respiratory tract samples to establish a diagnosis of COVID-19 (BII).

BAL and sputum induction are aerosol-generating procedures that should be performed only after careful consideration of the risk of exposing staff to infectious aerosols. Endotracheal aspiration appears to carry a lower risk of aerosol-generation than BAL, and some experts consider the sensitivity and specificity of endotracheal aspirates and BAL specimens comparable in detecting SARS-CoV-2.

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Nucleic Acid Amplification Testing for Individuals With a Previous Positive SARS-CoV-2 Test Result

NAATs can detect SARS-CoV-2 RNA in specimens obtained weeks to months after the onset of COVID-19 symptoms.13,14 However, the likelihood of recovering replication-competent virus >10 days from the onset of symptoms in those with mild disease and >20 days in those with severe disease is very low.15,16 Furthermore, both virologic studies and contact tracing of high-risk contacts show a low risk
for SARS-CoV-2 transmission after these intervals.17,18 Based on these results, the Centers for Disease Control and Prevention (CDC) recommends that NAATs should not be repeated in asymptomatic persons within 90 days of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS-CoV-2 (AIII).19 If there are concerns that an immunocompromised health care worker may still be infectious >20 days from the onset of SARS-CoV-2 infection, consultation with local employee health services regarding return-to-work testing policies is advised.

SARS-CoV-2 reinfection has been reported in people who have received an initial diagnosis of infection; therefore, a NAAT should be considered for persons who have recovered from a previous infection and who present with symptoms that are compatible with SARS-CoV-2 infection if there is no alternative diagnosis (BIII). However, it should be noted that persons infected with SARS-CoV-2 may have a negative result on an initial NAAT and then have a positive result on a subsequent test due to intermittent detection of viral RNA and not due to reinfection.13 When the results for an initial and a subsequent test are positive, comparative viral sequence data from both tests are needed to distinguish between the persistent presence of viral fragments and reinfection. In the absence of viral sequence data, the cycle threshold (Ct) value from a positive NAAT result may provide information about whether a newly detected infection is related to the persistence of viral fragments or to reinfection. The Ct value is the number of PCR cycles at which the nucleic acid target in the sample becomes detectable. In general, the Ct value is inversely related to the SARS-CoV-2 viral load. Because the clinical utility of Ct values is an area of active investigation, an expert should be consulted if these values are used to guide clinical decisions.

Antigen Testing for SARS-CoV-2 Infection

Antigen-based diagnostic tests (which detect viral antigens) are less sensitive than RT-PCR-based tests, but they have similarly high specificity. Antigen tests perform best early in the course of symptomatic SARS-CoV-2 infection, when the viral load is thought to be highest. Advantages of antigen-based tests are their low cost and rapid turnaround time. The availability of immediate results makes them an attractive option for point-of-care testing in high-risk congregate settings where preventing transmission is critical. Antigen-based tests also allow for repeat testing to quickly identify persons with SARS-CoV-2 infection.

Increasingly, data are available to guide the use of antigen tests as screening tests to detect or exclude SARS-CoV-2 infection in asymptomatic persons, or to determine whether a person who was previously confirmed to have SARS-CoV-2 infection is still infectious. The CDC has developed an antigen testing algorithm for persons who have symptoms of COVID-19, those who are asymptomatic and have a close contact with COVID-19, and those who are asymptomatic and have no known exposure to a person with COVID-19.20

The CDC testing algorithm recommends additional NAATs when a person who is strongly suspected of having SARS-CoV-2 infection (i.e., a person who is symptomatic) receives a negative result, and when a person who is asymptomatic receives a positive result. Antigen tests can yield false positive results for a variety of reasons, including:

• Incomplete adherence to the instructions for antigen test performance (e.g., reading the results outside the specified time interval or storing test cartridges/cards inappropriately)

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• Test interference due to human antibodies (e.g., rheumatoid factor or other nonspecific antibodies)

• Use in communities that have a low prevalence of SARS-CoV-2 infection
Serologic or Antibody Testing for Diagnosis of SARS-CoV-2 Infection
Unlike NAATs and antigen tests for SARS-CoV-2 that detect the presence of the virus, serologic or antibody tests can detect recent or prior SARS-CoV-2 infection. Because it may take 21 days or longer after symptom onset for seroconversion to occur (i.e., the development of detectable immunoglobulin [Ig] M and/or IgG antibodies to SARS-CoV-2),21-26 the Panel does not recommend serologic testing as the sole basis for diagnosing acute SARS-CoV-2 infection (AIII). Because NAATs and antigen tests for SARS-CoV-2 occasionally yield false negative results, serologic tests have been used in some settings as an additional diagnostic test for patients who are strongly suspected to have SARS-CoV-2 infection. Using a serologic test in combination with a NAAT to detect IgG or total antibodies 3 to 4 weeks after symptom onset maximizes the sensitivity and specificity to detect past infection.
No serologic tests for SARS-CoV-2 are approved by the FDA; some, but not all, commercially available serologic tests for SARS-CoV-2 have received EUAs from the FDA.1 Several professional societies and federal agencies, including the Infectious Diseases Society of America, the CDC, and the FDA, provide guidance on the use of serologic testing for SARS-CoV-2.
Several factors should be considered when using serologic tests for SARS-CoV-2, including:

• Important performance characteristics of many of the commercially available serologic tests have not been fully characterized, including the sensitivity and specificity of these tests (i.e., the rates of true positive and true negative results). Serologic assays that have FDA EUAs should be used for public health and clinical use. Formal comparisons of serologic tests are in progress.

• Two types of serologic tests have received EUAs from the FDA. The first type are antibody tests that detect the presence of binding antibodies, which bind to a pathogen (e.g., a virus). The second type of tests detect neutralizing antibodies from recent or prior SARS-CoV-2 infection. It is unknown whether one type of test is more clinically meaningful than the other.

• Serologic assays may detect IgM, IgG, IgA, and/or total antibodies, or a combination of IgM and IgG antibodies. Serologic assays that detect IgG and total antibodies have higher specificity to detect past infection than assays that detect IgM and/or IgA antibodies or a combination of IgM and IgG antibodies.

• False positive test results may occur due to cross-reactivity from pre-existing antibodies to other coronaviruses.
Serologic Testing and Immunity to SARS-CoV-2 Infection
The Panel recommends against the use of serologic testing to determine whether a person is immune to SARS-CoV-2 infection (AIII).
If SARS-CoV-2 antibodies are detected during a serologic test, the results should be interpreted with caution for the following reasons:

• It is unclear how long antibodies persist following infection; and

• It is unclear whether the presence of antibodies confers protective immunity against future infection.
In communities that have a low prevalence of SARS-CoV-2 infection, the proportion of positive test results that are false positives may be quite high. In these situations, confirmatory testing using a distinct antibody assay, ideally one that uses a different antigenic target (e.g., the nucleocapsid phosphoprotein
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if the first assay targeted the spike protein), can substantially improve the probability that persons with positive test results are antibody positive.

Assuming that the test is reliable, serologic tests that identify recent or prior SARS-CoV-2 infection may be used to:

• Differentiate SARS-CoV-2 antibody responses to natural infection from vaccine-induced antibody responses to the SARS-CoV-2 spike protein antigen. Because nucleocapsid protein is not a constituent of vaccines that are currently available through EUAs or in late-stage clinical trials, serologic tests that detect antibodies by recognizing nucleocapsid protein can be used to distinguish antibody responses to natural infection from vaccine-induced antibody responses.

• Determine who may be eligible to donate convalescent plasma

• Estimate the proportion of the population that has been exposed to SARS-CoV-2
Based on current knowledge, serologic tests should not be used to (AIII):

• Make decisions about how to group persons in congregate settings (e.g., schools, dormitories,
correctional facilities)

• Determine whether persons may return to the workplace

• Assess for prior infection solely to determine whether to vaccinate an individual

• Assess for immunity to SARS-CoV-2 following vaccination, except in clinical trials
References

1. Food and Drug Administration. Coronavirus disease 2019 (COVID-19) emergency use authorizations for medical devices. 2020. Available at: https://www.fda.gov/medical-devices/emergency-situations-medical- devices/emergency-use-authorizations. Accessed February 4, 2021.

2. Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical specimens from persons for coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.cdc.gov/ coronavirus/2019-ncov/lab/guidelines-clinical-specimens.html. Accessed February 4, 2021.

3. Food and Drug Administration. Genetic variants of SARS-CoV-2 may lead to false negative results with molecular tests for detection of SARS-CoV-2—letter to clinical laboratory staff and health care providers. 2021. Available at: https://www.fda.gov/medical-devices/letters-health-care-providers/genetic-variants-sars- cov-2-may-lead-false-negative-results-molecular-tests-detection-sars-cov-2. Accessed March 15, 2021.

4. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med. 2020;173(4):262-267. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32422057.

5. Centers for Disease Control and Prevention. Science brief: emerging SARS-CoV-2 variants. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants. html. Accessed March 15, 2021.

6. Chan PK, To WK, Ng KC, et al. Laboratory diagnosis of SARS. Emerg Infect Dis. 2004;10(5):825-831. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15200815.

7. Tang P, Louie M, Richardson SE, et al. Interpretation of diagnostic laboratory tests for severe acute respiratory syndrome: the Toronto experience. CMAJ. 2004;170(1):47-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14707219.

8. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Respiratory tract samples, viral load, and genome fraction yield in patients with Middle East respiratory syndrome. J Infect Dis. 2014;210(10):1590-1594. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24837403.

9. Centers for Disease Control and Prevention. Overview of testing for SARS-CoV-2 (COVID-19). 2020.

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Available at: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html. Accessed February 4, 2021.

10. Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical specimens from persons under investigation (PUIs) for Middle East respiratory syndrome coronavirus (MERS-CoV)–Version 2.1. 2019. Available at: https://www.cdc.gov/coronavirus/mers/guidelines-clinical- specimens.html. Accessed February 4, 2021.

11. Hase R, Kurita T, Muranaka E, Sasazawa H, Mito H, Yano Y. A case of imported COVID-19 diagnosed by PCR-positive lower respiratory specimen but with PCR-negative throat swabs. Infect Dis (Lond). 2020:1-4. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32238024.

12. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323(18):1843-1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32159775.

13. Xiao AT, Tong YX, Zhang S. Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19 patients. Clin Infect Dis. 2020;71(16):2249-2251. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32306036.

14. Rhee C, Kanjilal S, Baker M, Klompas M. Duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity: when is it safe to discontinue isolation? Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33029620.

15. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med. 2020;382(22):2081-2090. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32329971.

16. Bullard J, Dust K, Funk D, et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis. 2020;71(10):2663-2666. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32442256.

17. Cheng HY, Jian SW, Liu DP, et al. Contact tracing assessment of COVID-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset. JAMA Intern Med. 2020;180(9):1156- 1163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32356867.

18. Korean Disease Control and Prevention Agency. Findings from investigation and analysis of re-positive cases [press release]. 2020. Available at: https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030.

19. Centers for Disease Control and Prevention. Duration of isolation and precautions for adults with COVID-19. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html. Accessed January 7, 2021.

20. Centers for Disease Control and Prevention. Interim guidance for antigen testing for SARS-CoV-2. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html. Accessed January 7, 2021.

21. Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis. 2020;71(15):778-785. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32198501.

22. Haveri A, Smura T, Kuivanen S, et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveill. 2020;25(11). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32209163.

23. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020;26(6):845-848. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32350462.

24. Okba NMA, Muller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease patients. Emerg Infect Dis. 2020;26(7):1478-1488. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32267220.

25. Xiang F, Wang X, He X, et al. Antibody detection and dynamic characteristics in patients with COVID-19. Clin Infect Dis. 2020;71(8):1930-1934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32306047.

26. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020;71(16):2027-2034. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32221519.

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Prevention and Prophylaxis of SARS-CoV-2 Infection

Last Updated: April 21, 2021



Summary Recommendations

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of any drugs for SARS-CoV-2 pre-exposure prophylaxis (PrEP), except in a clinical trial (AIII).

• The Panel recommends against the use of hydroxychloroquine for SARS-CoV-2 post-exposure prophylaxis (PEP) (AI).

• The Panel recommends against the use of other drugs for SARS-CoV-2 PEP, except in a clinical trial (AIII).

• The Panel recommends that health care providers follow recommendations from the Advisory Committee on Immunization Practices when using SARS-CoV-2 vaccines (AI).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

General Prevention Measures

Transmission of SARS-CoV-2 is thought to mainly occur through respiratory droplets transmitted from an infectious person to others within six feet of the person. Less commonly, airborne transmission of small droplets and particles of SARS-CoV-2 to persons further than six feet away can occur, and in
rare cases, people passing through a room that was previously occupied by an infectious person may become infected. SARS-CoV-2 infection via airborne transmission of small particles tends to occur after prolonged exposure (i.e., ≥30 minutes) to an infectious person who is in an enclosed space with poor ventilation.1

The risk of SARS-CoV-2 transmission can be reduced by covering coughs and sneezes and maintaining a distance of at least six feet from others. When consistent distancing is not possible, face coverings may further reduce the spread of infectious droplets from individuals with SARS-CoV-2 infection to others. Frequent handwashing also effectively reduces the risk of infection.2 Health care providers should follow the Centers for Disease Control and Prevention (CDC) recommendations for infection control and appropriate use of personal protective equipment (PPE).3

Vaccines

Currently, no SARS-CoV-2 vaccine has been approved by the Food and Drug Administration (FDA). In December 2020, the FDA issued Emergency Use Authorizations for two mRNA vaccines, BNT162b2 (Pfizer-BioNTech)4 and mRNA-1273 (Moderna).5 In February 2021, FDA issued an EUA for a human adenovirus type 26 (Ad26) vectored vaccine, Ad26.COV2.S (Johnson & Johnson/Janssen).6 BNT162b2 can be administered to individuals aged ≥16 years, whereas mRNA-1273 and Ad26.COV2.S can

be given to individuals aged ≥18 years. Clinical trials for these vaccines in younger age groups are currently underway.

In large, placebo-controlled trials, the mRNA-1273 and BNT162b2 vaccines were 94% and 95% efficacious, respectively, in preventing symptomatic laboratory-confirmed COVID-19 after participants completed a two-dose series. The Ad26.COV2.S vaccine was 66% efficacious in preventing moderate to severe/critical laboratory-confirmed COVID-19 after a single vaccine dose. Cases of COVID-19 were confirmed by the presence of symptoms and a positive result on a SARS-CoV-2 nucleic acid amplification test (NAAT).6-8 All three vaccines also showed high efficacy against severe COVID-19. Local and systemic adverse events are relatively common with these vaccines, especially after the second dose. Most adverse events that occurred in vaccine trials were mild or moderate in severity (i.e.,

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they did not prevent vaccinees from engaging in daily activities). There have been a few reports of severe allergic reactions following SARS-CoV-2 vaccination, including some reports of patients who experienced anaphylaxis after receiving a SARS-CoV-2 mRNA vaccine.6,9 Safety data continue to be collected. Certain populations, such as pregnant and lactating individuals, were not included in the initial vaccine trials. The American College of Obstetricians and Gynecologists has published interim guidance on the use of the SARS-CoV-2 mRNA vaccines in pregnant and lactating people.10

It is not known how long the protective effect of SARS-CoV-2 vaccines will last or whether SARS-CoV-2 vaccines can prevent asymptomatic infection or transmission, whether they will
prevent infection by all current or emergent strains of SARS-CoV-2, whether they will be effective in immunocompromised patients, or whether they will work as well in patients who are at high risk for severe COVID-19 as in those who are at low risk. The efficacy and safety of SARS-CoV-2 vaccines have not been established in children, pregnant people, or immunocompromised patients. Clinical trials for other SARS-CoV-2 vaccine candidates are ongoing.

CDC sets the adult and childhood immunization schedules for the United States based on recommendations from the Advisory Committee on Immunization Practices (ACIP). ACIP considers disease epidemiology, burden of disease, vaccine efficacy and effectiveness, vaccine safety, the quality of the available evidence, and potential vaccination implementation issues. ACIP also sets priorities regarding who receives vaccines in the event of a shortage. ACIP COVID-19 vaccine recommendations are reviewed by CDC’s Director and, if adopted, are published as official CDC recommendations in the Morbidity and Mortality Weekly Report.11

Pre-Exposure Prophylaxis

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of any drugs for SARS-CoV-2 pre-exposure prophylaxis (PrEP), except in a clinical trial (AIII).

Rationale

At present, there is no known agent that can be administered before exposure to SARS-CoV-2 (i.e., as PrEP) to prevent infection. Clinical trials are investigating several agents, including emtricitabine plus tenofovir alafenamide or tenofovir disoproxil fumarate, hydroxychloroquine, ivermectin, and supplements such as zinc, vitamin C, and vitamin D. Studies of monoclonal antibodies that target SARS-CoV-2 are in development. Please check ClinicalTrials.gov for the latest information.

Clinical Trial Data

Randomized Controlled Trial of Hydroxychloroquine for SARS-CoV-2 Pre-Exposure Prophylaxis Among Health Care Workers

This double-blind, placebo-controlled, randomized trial was designed to determine whether hydroxychloroquine 600 mg per day reduced the frequency of SARS-CoV-2 infection over an 8-week period in hospital-based health care workers. The primary outcome was incidence of SARS-CoV-2 infection as determined by reverse transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swabs collected at 4 and 8 weeks or the occurrence of COVID-19 symptoms.12

Study Population

• Participants included health care workers at two Philadelphia hospitals who worked ≥20 hours per week in a hospital-based unit, had no known history of SARS-CoV-2 infection, and had no COVID-19-like symptoms in the 2 weeks before enrollment. The study enrolled workers in the emergency department and in dedicated COVID-19 treatment units.

• The study excluded individuals who were allergic to hydroxychloroquine and those with glucose- 6-phosphate dehydrogenase deficiency, retinal disease, or substantial cardiac disease.
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Results

• The study was based on an assumed 10% infection rate for the planned inclusion of 100 participants per arm.

• Between April 9 and July 14, 2020, community SARS-CoV-2 infection rates declined. At the time of the second interim analysis (when 125 of 132 participants who provided consent were evaluable for the primary endpoint), the Data Safety Monitoring Board recommended early termination of the study for futility.

• Four participants in each group developed SARS-CoV-2 infection (positivity rate of 6.3% vs. 6.6% in the hydroxychloroquine and placebo groups, respectively; P > 0.99). Across the groups, six participants developed symptoms of COVID-19, but none required hospitalization.

• Serologic testing for anti-spike protein immunoglobulin (Ig) M, IgG, and nucleocapsid protein IgG demonstrated more positive results among participants in the hydroxychloroquine group (four participants [7.4%]) than in the placebo group (two participants [3.7%]), although the difference was not statistically significant (P = 0.40).

• Mild adverse events were more common among participants in the hydroxychloroquine group (45%) than in the placebo group (26%; P = 0.04). The greatest difference was the increased frequency of mild diarrhea in the hydroxychloroquine group.

• The rates of treatment discontinuation were similar in the hydroxychloroquine group (19%) and the placebo group (16%).

• There were no cardiac events in either arm and also no significant difference in the median frequency of changes in QTc between the study arms (P = 0.98).
Limitations

• The study was stopped early.

• Due to the low SARS-CoV-2 infection rate among the participants, the study was underpowered to detect a prophylactic benefit of hydroxychloroquine.

• The study population was mostly young, healthy health care workers; therefore, whether the study findings are applicable to other populations is uncertain.
Interpretation
There was no clinical benefit of administering hydroxychloroquine 600 mg per day for 8 weeks as PrEP to health care workers who were exposed to patients with COVID-19. Compared to placebo, hydroxychloroquine was associated with an increased risk of mostly mild adverse events.
Hydroxychloroquine as Pre-Exposure Prophylaxis for COVID-19 in Health Care Workers: A Randomized Trial (COVID PREP Study)
This double-blind, placebo-controlled, randomized clinical trial investigated whether hydroxychloroquine 400 mg given once- or twice-weekly for 12 weeks can prevent SARS-CoV-2 infection in health care workers at high-risk of exposure. The primary outcome was COVID-19-free survival time. Diagnosis of COVID-19 was defined as having laboratory-confirmed SARS-CoV-2 infection or having cough, shortness of breath, or difficulty breathing or having two or more of the following symptoms: fever, chills, rigors, myalgia, headache, sore throat, or new olfactory and taste disorders. COVID-19-compatible illness was included as a primary outcome even if a SARS-CoV-2 PCR test was not performed or if it was performed and the result was negative.13
Study Population

• The study participants had to be working in the emergency department, in the intensive care unit, on a dedicated COVID-19 hospital ward, or as a first responder; alternatively, they had to have a

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job description that included regularly performing aerosol-generating procedures.

• Participants were recruited via social media platforms. Informed consent was obtained remotely, and the study drug was delivered to the participants by couriers.

Results

• The study was powered based on an anticipated 10% event rate of new symptomatic infections. The investigators determined that the study needed to enroll 1,050 participants per arm to have 80% power. However, it became apparent before the first interim analysis that the study would not meet the enrollment target. As a result, enrollment was stopped without unblinding. The investigators attributed the marked decline in enrollment to the negative reports related to the safety of hydroxychloroquine, including a warning from the FDA.

• Among the 1,483 participants who were randomized, baseline characteristics were similar across the study arms.

• The number of individuals who met the primary endpoint of confirmed or suspected SARS-CoV-2 infection was 39 (7.9%) in the placebo group and 29 (5.9%) in both the once- and twice-
weekly hydroxychloroquine groups. Among the 97 participants, only 17 were confirmed to be SARS-CoV-2 PCR positive.

• Compared to placebo, the hazard ratio for the primary endpoint was 0.72 (95% CI, 0.4–1.16; P = 0.18) for the once-weekly hydroxychloroquine arm and 0.74 (95% CI, 0.46–1.19; P = 0.22) for the twice-weekly hydroxychloroquine arm.

• There were no significant differences for any of the secondary efficacy endpoints among the three groups.

• There were significantly more adverse events reported in the once- and twice-weekly hydroxychloroquine arms (occurred in 31% vs. 36% of participants, respectively; P < 0.001 for both groups) than in the placebo group (occurred in 21% of participants). The most common side effects were upset stomach and nausea.

• Drug concentrations were measured in dried whole blood samples from a subset of 180 participants who received hydroxychloroquine. The median hydroxychloroquine concentrations for the twice- and once-weekly hydroxychloroquine groups were 200 ng/mL and 98 ng/mL, respectively; both concentrations are substantially below the in vitro half-maximal effective concentration (EC50) of hydroxychloroquine. The investigators noted that the simulations that were used to determine the hydroxychloroquine dose for the study predicted much higher drug concentrations than the observed levels.
Limitations

• The study was prematurely halted due to poor enrollment; therefore, the study population was insufficient to detect differences in outcomes among the study arms.

• The study only assessed the SARS-CoV-2 inhibitory activity of two doses of hydroxychloroquine, neither of which achieved concentrations that exceeded the in vitro EC50 of the drug.

• Only 17.5% of the participants who met study endpoints had positive SARS-CoV-2 test results; the remainder had COVID-19-compatible symptoms without a confirmatory diagnosis.
Interpretation
Hydroxychloroquine 400 mg once- or twice-weekly did not reduce the incidence of documented SARS-CoV-2 infection or COVID-19-compatible symptoms among health care workers who were at a high risk of infection. These findings suggest that hydroxychloroquine was not effective for SARS-CoV-2 PrEP or that the dose used for PrEP was suboptimal.
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Post-Exposure Prophylaxis

• The Panel recommends against the use of hydroxychloroquine for SARS-CoV-2 post-exposure prophylaxis (PEP) (AI).

• The Panel recommends against the use of other drugs for SARS-CoV-2 PEP, except in a clinical trial (AIII).
Rationale
Several randomized controlled trials have evaluated the use of hydroxychloroquine for SARS-CoV-2 PEP.14-16 None of these studies have reported any evidence of efficacy, and all showed a higher frequency of adverse events among participants who received hydroxychloroquine than among control participants. The results of some of these studies are described below.
A number of agents (e.g., anti-SARS-CoV-2 monoclonal antibodies, hyperimmune gammaglobulin, convalescent plasma, ivermectin, interferons, tenofovir with or without emtricitabine, vitamin D) are currently being investigated for SARS-CoV-2 PEP. The latest clinical trials for SARS-CoV-2 PEP can be found at ClinicalTrials.gov.
Clinical Trial Data
Both chloroquine and hydroxychloroquine have in vitro activity against severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and SARS-CoV-2.17,18 A small cohort study without a control group suggested that hydroxychloroquine might reduce the risk of SARS-CoV-2 transmission to close contacts.19
Household-Randomized, Double-Blind Controlled Trial of SARS-CoV-2 Post-Exposure Prophylaxis With Hydroxychloroquine
A household-randomized, double-blind controlled trial evaluated the use of hydroxychloroquine as PEP to prevent SARS-CoV-2 infection. The study was conducted at seven institutions in the United States between March and August 2020. Participants were recruited using online advertising, social media, and referrals from hospitals, health departments, and individuals with laboratory-confirmed SARS-CoV-2 infection.14
Households were randomized to receive oral hydroxychloroquine 400 mg once daily for 3 days, followed by hydroxychloroquine 200 mg once daily for an additional 11 days, or oral ascorbic acid 500 mg once daily for 3 days, followed by ascorbic acid 250 mg once daily for 11 days. Mid-turbinate nasal swabs were collected daily during the first 14 days, with the primary endpoint being PCR-confirmed SARS-CoV-2 infection within 14 days after enrollment in those who were not infected at baseline.
Study Population

• Eligible participants had close contact with a SARS-CoV-2-infected person, which included household contacts or other close contacts (82%) or health care workers (18%) who cared for an infected person without wearing appropriate PPE. Participants must have come into contact with an index person who had received a diagnosis of SARS-CoV-2 infection within the past 14 days, and high-risk exposure to the index people must have occurred within the previous 96 hours.

• Enrollment included 829 participants from 671 households; 407 participants (in 337 households) received hydroxychloroquine, and 422 participants (in 334 households) received ascorbic acid.
Results

• A total of 98 SARS-CoV-2 infections were detected during the first 14 days of follow-up, with an overall cumulative incidence of 14.3% (95% CI, 11.5% to 17%). Fifty-three events (i.e., PCR-

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confirmed SARS-CoV-2 infection) occurred in the hydroxychloroquine group, and 45 events occurred in the control group (aHR 1.10; 95% CI, 0.73–1.66; P > 0.20)

• In preplanned analyses, hazard ratios were not significantly different within subgroups based on type of contact, time between the most recent contact and the first dose of the study drug, duration of contact, number of contacts enrolled within the household, quarantine status, index case symptoms, or number of adults or children in the household.

• Adverse events that are associated with the use of hydroxychloroquine, including gastrointestinal symptoms and rash, occurred in 112 participants: 66 participants (16.2%) in the hydroxychloroquine group and 46 participants (10.9%) in the control group (P = 0.026).
Limitations

• There was an average window of 2 days between the time of the most recent exposure to the index people and the time the study drugs were administered. The lapse of time between exposure to SARS-CoV-2 and initiation of hydroxychloroquine may have affected the efficacy of the drug as PEP.

• The primary analysis excluded approximately 10% of enrolled people who were shown to have SARS-CoV-2 infection at baseline.
Interpretation
In this study, hydroxychloroquine was ineffective when used as PEP for SARS-CoV-2 infection. Participants who received hydroxychloroquine had an expected greater risk of adverse events than those who received ascorbic acid.
Double-Blind Randomized Controlled Trial of Hydroxychloroquine as Post-Exposure Prophylaxis in Contacts With High-Risk or Moderate-Risk Occupational or Household Exposures
This double-blind randomized controlled trial included 821 participants who self-enrolled in the study using an internet-based survey. Participants were randomized to receive either hydroxychloroquine (hydroxychloroquine 800 mg once, followed by hydroxychloroquine 600 mg 6 to 8 hours later, and then hydroxychloroquine 600 mg once daily for 4 additional days) or placebo. Because enrollment was done online, the study drugs were sent to participants by overnight mail, and consequently, more than 50%
of the participants started the first dose of their assigned treatment 3 to 4 days after exposure to SARS- CoV-2.16
Study Population

• Participants had a high or moderate risk of occupational exposure (66% of participants) or household exposure (34% of participants) to SARS-CoV-2.

• High-risk exposure was defined as being within six feet of an individual with confirmed SARS-CoV-2 infection for more than 10 minutes while not wearing a face mask or eye shield (87.6% of participants). Moderate-risk exposure was defined as exposure from the same distance and for the same duration while wearing a face mask but no eye shield (12.4% of participants).
Results

• A total of 107 participants developed the primary outcome of symptomatic illness. Illness was confirmed by a positive result on a SARS-CoV-2 molecular test. If testing was not available, participants were considered to have symptomatic illness if they developed a compatible COVID- 19-related syndrome based on CDC criteria.

• Due to limited access to molecular diagnostic testing, SARS-CoV-2 infection was confirmed in only 16 of the 107 participants (15%). There was no statistically significant difference in the
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incidence of the primary outcome (symptomatic illness) between the hydroxychloroquine group and the placebo group (11.8% vs. 14.3%, respectively; P = 0.35).

• There were more adverse events in the hydroxychloroquine group (mostly nausea, loose stools, and abdominal discomfort), and no serious adverse reactions or cardiac arrhythmias in either group.

Limitations

• Most participants did not start their assigned therapy until at least 3 days after exposure to SARS-CoV-2.

• Only 15% of participants who reached the primary outcome had SARS-CoV-2 infection confirmed by molecular diagnostics.

• The study participants were young (median age 40 years) and had a relatively low risk of severe COVID-19.
Interpretation
There was no difference in the incidence of observed symptomatic COVID-19 between participants
who received hydroxychloroquine 600 mg once daily and those who received placebo. Although hydroxychloroquine 600 mg per day was associated with an increased frequency of adverse events, these adverse events were mostly mild.
Cluster-Randomized Trial of SARS-CoV-2 Post-Exposure Prophylaxis With Hydroxychloroquine
This open-label, cluster-randomized trial included 2,314 asymptomatic contacts of 672 COVID-19 cases in Spain.15 Participants who were epidemiologically linked to a PCR-positive COVID-19 case were defined as study clusters (called rings). All contacts in a ring were simultaneously cluster-randomized
in a 1:1 ratio to the control arm (usual care) or the intervention arm (hydroxychloroquine 800 mg once daily for 1 day, followed by hydroxychloroquine 400 mg once daily for 6 days). Participants were informed of their allocated study arm after being randomized to the intervention or control arm and signing a consent form.
The primary outcome was onset of laboratory-confirmed COVID-19, which was defined as a positive result on a SARS-CoV-2 PCR test and at least one of the following symptoms: fever, cough, difficulty breathing, myalgia, headache, sore throat, new olfactory and taste disorders, or diarrhea. A secondary outcome was onset of SARS-CoV-2 infection, which was defined as either a positive SARS-CoV-2 PCR test result or the presence of any of the symptoms compatible with COVID-19. An additional secondary outcome was development of serological positivity at Day 14.
Study Population

• Study participants were health care or nursing home workers (60.3%), household contacts (27.1%), or nursing home residents (12.7%) who were documented to have spent >15 minutes within two meters of a PCR-positive COVID-19 case during the 7 days prior to enrollment.

• The baseline characteristics of the participants were similar between the two study arms, including comorbidities, number of days of exposure to SARS-CoV-2 before enrollment and randomization, and type of contact.
Results

• A total of 138 study participants (6.0%) developed PCR-confirmed, symptomatic SARS-CoV-2 infection. There was no statistical difference in the incidence of confirmed infection between the hydroxychloroquine and control arms (5.7% vs. 6.2%, respectively; risk ratio 0.86; 95% CI, 0.52–1.42).

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• There was no statistical difference between the study arms in the incidence of either PCR- confirmed or symptomatically compatible COVID-19, which was 18.2% overall (18.7% in the hydroxychloroquine arm vs. 17.8% in the control arm; risk ratio 1.03; 95% CI, 0.77–1.38).

• There was no statistical difference between the arms in the rate of positivity for SARS-CoV-2 IgM and/or IgG (14.3% in the hydroxychloroquine arm vs. 8.7% in the control arm; risk ratio 1.57; 95% CI, 0.94–2.62).

• There were more adverse events among the hydroxychloroquine-treated participants (56.1%) than among the control participants (5.9%), although most of the adverse events were mild. Common adverse events included gastrointestinal events, nervous system disorders, myalgia, fatigue, and malaise. No serious adverse events were attributed to the study drug.
Limitations

• The study lacked a placebo comparator, which could have had an impact on safety reporting.

• Data regarding the extent of the exposure to the index cases was limited.

• For >50% of the study participants, the time from exposure to the index case to randomization was ≥4 days.
Interpretation
The hydroxychloroquine regimen used for PEP in this study did not prevent SARS-CoV-2 infection in healthy individuals who were exposed to a PCR-positive case.
Ivermectin
High concentrations of ivermectin have been shown to inhibit SARS-CoV-2 replication in vitro.20,21 Population data also indicate that country-wide mass use of prophylactic chemotherapy for parasitic infections, including the use of ivermectin, is associated with a lower incidence of COVID-19.22 At this time, there are limited clinical trials regarding the safety and efficacy of ivermectin for SARS-CoV-2 PrEP or PEP. Although several studies have reported potentially promising results, the findings are limited by the design of the studies, their small sample sizes, and lack of details regarding the safety and efficacy of ivermectin. The results of these trials are described below.
In a descriptive, uncontrolled interventional study of 33 contacts of patients with laboratory-confirmed COVID-19, no cases of SARS-CoV-2 infection were identified within 21 days of initiating ivermectin
for PEP.23 An open-label, randomized controlled trial investigated ivermectin prophylaxis (plus personal protective measures [PPMs]) in health care workers (as PrEP) or in household contacts (as PEP) exposed to patients with laboratory-confirmed COVID-19. The incidence of SARS-CoV-2 infection was lower among the participants who received ivermectin than among control participants who used only PPMs. However, the study provided no data on the characteristics of the study participants, types of exposures, or how endpoints were defined.24 Finally, in a small case-control study in SARS-CoV-2-exposed health care workers, 186 participants who became infected were matched with 186 uninfected controls. Of those who received ivermectin after exposure to SARS-CoV-2, 38 were in the infected group and 77 were in the uninfected group, which led the investigators to conclude that ivermectin reduced the incidence of SARS-CoV-2 infection.25
Additional studies of ivermectin for SARS-CoV-2 are ongoing. Please see ClinicalTrials.gov for the latest information.
References

1. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): scientific brief:

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SARS-CoV-2 and potential airborne transmission. 2020. Available at: https://www.cdc.gov/coronavirus/2019- ncov/more/scientific-brief-sars-cov-2.html. Accessed January 26, 2021.

2. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): how to protect yourself & others. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention. html. Accessed March 29, 2021.

3. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): infection control guidance for healthcare professionals about coronavirus (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed March 29, 2021.

4. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination providers): emergency use authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.fda.gov/media/144413/download.

5. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination providers): emergency use authorization (EUA) of the Moderna COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.fda.gov/media/144637/download.

6. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination providers): emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). 2021. Available at: https://www.fda.gov/media/146304/download.

7. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383(27):2603-2615. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33301246.

8. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403-416. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33378609.

9. Centers for Disease Control and Prevention. Interim considerations: preparing for the potential management of anaphylaxis after COVID-19 vaccination. 2020. Available at: https://www.cdc.gov/vaccines/covid-19/info-by- product/pfizer/anaphylaxis-management.html. Accessed January 6, 2021.

10. The American College of Obstetricians and Gynecologists. Practice advisory: vaccinating pregnant and lactating patients against COVID-19. 2020. Available at: https://www.acog.org/clinical/clinical-guidance/ practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19. Accessed January 6, 2021.

11. Centers for Disease Control and Prevention. Current COVID-19 ACIP vaccine recommendations. 2020. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. Accessed January 6, 2021.

12. Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre- exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med. 2021;181(2):195-202. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33001138.

13. Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial. Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33068425.

14. Barnabas RV, Brown ER, Bershteyn A, et al. Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection: a randomized trial. Ann Intern Med. 2021;174(3):344-352. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33284679.

15. Mitjà O, Corbacho-Monné M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention of COVID-19. N Engl J Med. 2021;384(5):417-427. Available at: https://pubmed.ncbi.nlm.nih.gov/33289973/.

16. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517-525. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492293.

17. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin

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Infect Dis. 2020;71(15):732-739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150618.

18. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection
and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.

19. Lee SH, Son H, Peck KR. Can post-exposure prophylaxis for COVID-19 be considered as an outbreak response strategy in long-term care hospitals? Int J Antimicrob Agents. 2020;55(6):105988. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32305587.

20. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32251768.

21. Belhadjer Z, Meot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142(5):429-436. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32418446.

22. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin. Int J Antimicrob Agents. 2021;57(1):106248. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33259913.

23. Aguirre Chang G, Figueredo ANT. COVID-19: post-exposure prophylaxis with ivermectin in contacts. At homes, places of work, nursing homes, prisons, and others. ResearchGate. 2020;Preprint. Available at: https:// http://www.researchgate.net/publication/344781515_COVID-19_POST-EXPOSURE_PROPHYLAXIS_WITH_ IVERMECTIN_IN_CONTACTS.

24. Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, Eltaweel A. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-100956/v3.

25. Behera P, Patro BK, Singh AK, et al. Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: a matched case-control study. PLoS One. 2021;16(2):e0247163. Available at: https://pubmed.ncbi.nlm.nih.gov/33592050.

          

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Clinical Spectrum of SARS-CoV-2 Infection

Last Updated: April 21, 2021

Patients with SARS-CoV-2 infection can experience a range of clinical manifestations, from no symptoms to critical illness. This section of the Guidelines discusses the clinical presentation of SARS- CoV-2-infected individuals according to illness severity.

In general, adults with SARS-CoV-2 infection can be grouped into the following severity of illness categories. However, the criteria for each category may overlap or vary across clinical guidelines and clinical trials, and a patient’s clinical status may change over time.

Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-CoV-2 using a virologic test (i.e., a nucleic acid amplification test [NAAT] or an antigen test) but who have no symptoms that are consistent with COVID-19.

Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging.

Moderate Illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level.

Severe Illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%.

Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.

Patients with certain underlying comorbidities are at a higher risk of progressing to severe COVID-19. These comorbidities include being aged 65 years or older; having cardiovascular disease, chronic lung disease, sickle cell disease, diabetes, cancer, obesity, or chronic kidney disease; being pregnant; being a cigarette smoker; and being a recipient of transplant or immunosuppressive therapy.1 Health care providers should monitor such patients closely until clinical recovery is achieved.

The optimal pulmonary imaging technique has not yet been defined for people with symptomatic SARS-CoV-2 infection. Initial evaluation for these patients may include chest X-ray, ultrasound, or, if indicated, computed tomography. An electrocardiogram should be performed if indicated. Laboratory testing includes a complete blood count with differential and a metabolic profile, including liver and renal function tests. Although inflammatory markers such as C-reactive protein (CRP), D-dimer, and ferritin are not routinely measured as part of standard care, results from such measurements may have prognostic value.2-4

The definitions for the severity of illness categories listed above also apply to pregnant patients. However, the threshold for certain interventions may be different for pregnant patients and nonpregnant patients. For example, oxygen supplementation is recommended for pregnant patients when SpO2 falls below 95% on room air at sea level to accommodate physiologic changes in oxygen demand during pregnancy and to ensure adequate oxygen delivery to the fetus.5 If laboratory parameters are used for monitoring pregnant patients and making decisions about interventions, clinicians should be aware that normal physiologic changes during pregnancy can alter several laboratory values. In general, leukocyte cell count increases throughout gestation and delivery and peaks during the immediate postpartum period. This increase is mainly due to neutrophilia.6 D-dimer and CRP levels also increase during

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pregnancy and are often higher in pregnant patients than nonpregnant patients.7 Detailed information on treating COVID-19 in pregnant patients can be found in Special Considerations in Pregnancy and in the pregnancy considerations subsection of each individual section of the Guidelines.

In pediatric patients, radiographic abnormalities are common and, for the most part, should not be the only criteria used to determine the severity of illness. The normal values for respiratory rate also vary with age in children; thus, hypoxia should be the primary criterion used to define severe COVID-19, especially in younger children. In a small number of children and in some young adults, SARS-CoV-2 infection may be followed by a severe inflammatory condition called multisystem inflammatory syndrome in children (MIS-C).8,9 This syndrome is discussed in detail in Special Considerations in Children.

Asymptomatic or Presymptomatic Infection

Asymptomatic SARS-CoV-2 infection can occur, although the percentage of patients who remain truly asymptomatic throughout the course of infection is variable and incompletely defined. It is unclear what percentage of individuals who present with asymptomatic infection progress to clinical disease. Some asymptomatic individuals have been reported to have objective radiographic findings that are consistent with COVID-19 pneumonia.10,11 The availability of widespread virologic testing for SARS-CoV-2 and the development of reliable serologic assays for antibodies to the virus will help determine the true prevalence of asymptomatic and presymptomatic infection. See Therapeutic Management of Adults With COVID-19 for recommendations regarding SARS-CoV-2–specific therapy.

Mild Illness

Patients with mild illness may exhibit a variety of signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell). They do not have shortness of breath, dyspnea on exertion, or abnormal imaging. Most mildly ill patients can be managed in an ambulatory setting or at home through telemedicine or telephone visits. No imaging or specific laboratory evaluations are routinely indicated in otherwise healthy patients with mild COVID-19. Older patients and those with underlying comorbidities are at higher risk of disease progression; therefore, health care providers should monitor these patients closely until clinical recovery is achieved. See Therapeutic Management of Adults With COVID-19 for recommendations regarding SARS-CoV-2- specific therapy.

Moderate Illness

Moderate illness is defined as evidence of lower respiratory disease during clinical assessment or imaging, with SpO2 ≥94% on room air at sea level. Given that pulmonary disease can progress rapidly in patients with COVID-19, patients with moderate disease should be closely monitored. If bacterial pneumonia or sepsis is suspected, administer empiric antibiotic treatment, re-evaluate the patient
daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection. See Therapeutic Management of Adults With COVID-19 for recommendations regarding SARS-CoV-2–specific therapy.

Severe Illness

Patients with COVID-19 are considered to have severe illness if they have SpO2 <94% on room air
at sea level, a respiratory rate >30 breaths/min, PaO2/FiO2 <300 mm Hg, or lung infiltrates >50%. These patients may experience rapid clinical deterioration. Oxygen therapy should be administered immediately using a nasal cannula or a high-flow oxygen device. See Therapeutic Management of Adults With COVID-19 for recommendations regarding SARS-CoV-2-specific therapy. If secondary bacterial pneumonia or sepsis is suspected, administer empiric antibiotics, re-evaluate the patient daily,

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and de-escalate or stop antibiotics if there is no evidence of bacterial infection.

Critical Illness

Critically ill patients may have acute respiratory distress syndrome, septic shock that may represent virus-induced distributive shock, cardiac dysfunction, an exaggerated inflammatory response, and/or exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with critical illness may also experience cardiac, hepatic, renal, central nervous system, or thrombotic disease.

As with any patient in the intensive care unit (ICU), successful clinical management of a patient with COVID-19 includes treating both the medical condition that initially resulted in ICU admission and other comorbidities and nosocomial complications.

For more information, see Care of Critically Ill Patients With COVID-19. SARS-CoV-2 Reinfection

As seen with other viral infections, reinfection with SARS-CoV-2 after recovery from prior infection
has been reported.12 The true prevalence of reinfection is not known, although there are concerns that it may occur with increased frequency with the circulation of new variants.13 SARS-CoV-2 can often be detected from nasal swab for weeks to months after initial infection, therefore, repeat testing to evaluate for reinfection should be considered only for those who have recovered from initial infection and present with COVID-19-compatible symptoms with no obvious alternate etiology (AIII).14 Diagnostic testing in this setting is summarized in Testing for SARS-CoV-2 Infection. In addition, if reinfection is suspected, guidelines for the diagnosis and evaluation of suspected SARS-CoV-2 reinfection are provided by the Centers for Disease Control and Prevention (CDC).15

It has been speculated that reinfection may occur more frequently in those with a less robust immune response during the initial infection, as is often reported in those with mild illness. Reinfection may also occur as initial immune responses wane over time. Nevertheless, one review noted that SARS-CoV-2 reinfection occurred after previous severe disease in three cases and as early as 3 weeks after diagnosis of the initial infection.16 A public site posts a variety of published and unpublished reports of reinfection, noting that it has been described to occur from as early as a few weeks to many months after initial infection, and occasionally follows episodes of severe COVID-19.17 Although data are limited, there is no evidence to suggest that the treatment of highly suspected or documented SARS-CoV-2 reinfection should be different from that for initial infection as outlined in Therapeutic Management of Adults With COVID-19.

Persistent Symptoms or Organ Dysfunction After Acute COVID-19

There have been an increasing number of reports of patients who experience persistent symptoms and/ or organ dysfunction after acute COVID-19. Data about the incidence, natural history, and etiology
of these symptoms are emerging. However, these reports have several limitations, including lack of
an agreed-upon case definition and potential bias as most reports included only patients who attended post-COVID-19 clinics and no comparator groups. No specific treatments for the persistent effects

of COVID-19 have yet been identified, although this COVID-19 rapid guideline proposes general management strategies.

The nomenclature for this phenomenon is evolving, and there is no established clinical terminology to date. It has been referred to as post-COVID-19 condition or colloquially, “long COVID,” and affected patients have been referred to as “long haulers.” The term “post-acute sequelae of COVID-19” (PASC) has also been used to describe late sequelae of SARS-CoV-2 infection that include these persistent

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symptoms, as well as other delayed syndromes such as MIS-C and multisystem inflammatory syndrome in adults (MIS-A). To date, no case definition and no specific time frame have been established to define the syndrome of persistent symptoms and/or organ dysfunction after acute COVID-19. However, CDC recently proposed defining late sequelae as sequelae that extend >4 weeks after initial infection.18,19 The Patient-Led Research Collaborative for COVID-19 defines long COVID as a collection of symptoms that develop during or following a confirmed or suspected case of COVID-19 and that continue for >28 days.20 Incidence rates vary widely, from about 10% in some reports to one cohort study in which 87% of patients reported at least one persistent symptom.21

Some of the symptoms overlap with the post-intensive care syndrome (PICS) that has been described in patients without COVID-19, but prolonged symptoms and disabilities after COVID-19 have also been reported in patients with milder illness, including outpatients (see General Considerations for information on PICS).22,23

Despite limitations of the available descriptive data related to these persistent symptoms, some representative studies have suggested that common findings include fatigue, joint pain, chest pain, palpitations, shortness of breath, cognitive impairment, and worsened quality of life.24,25

CDC conducted a telephone survey of a random sample of 292 adult outpatients who had positive polymerase chain reaction results for SARS-CoV-2. Among the 274 respondents who were symptomatic at the time of testing, 35% reported not having returned to their usual state of health 2 weeks or more after testing; 26% among patients aged 18 to 34 years, 32% among those aged 35 to 49 years, and 47% among those aged ≥50 years.23 An age of ≥50 years and the presence of three or more chronic medical conditions were associated with not returning to usual health within 14 to 21 days. Moreover, one in five individuals aged 18 to 34 years who did not have chronic medical conditions had not returned to baseline health when interviewed at a median of 16 days from the testing date.

In a cohort study from Wuhan, China, 1,733 discharged patients with COVID-19 were evaluated for persistent symptoms at a median of 186 days after symptom onset.26 The most common symptoms were fatigue or muscle weakness and sleep difficulties (reported among 63% and 26% of participants, respectively). Anxiety or depression was reported among 23% of patients.

In a longitudinal prospective cohort of mostly outpatients with laboratory-confirmed SARS-CoV-2 infection at the University of Washington, 177 participants completed a follow-up questionnaire between 3 and 9 months after illness onset.27 Overall, 91% of the respondents were outpatients (150 with mild illness and 11 with no symptoms), and only 9.0% had moderate or severe disease requiring hospitalization. Among those reporting symptoms, 33% of the outpatients and 31% of the hospitalized patients reported at least one persistent symptom. Persistent symptoms were reported by 27% of the patients aged 18 to 39 years, 30% aged 40 to 64 years, and 43% aged ≥65 years. The most common persistent symptoms were loss of sense of smell or taste and fatigue (both reported by 14% of participants).

Fatigue

The prevalence of fatigue among 128 individuals from Ireland who had recovered from the acute phase of COVID-19 was examined using the Chalder Fatigue Scale (CFQ11). More than half of patients (67
of 128 patients [52.3%]) reported persistent fatigue at a median of 10 weeks after initial symptoms first appeared. There was no association between illness severity and fatigue.28 An outpatient service for patients recovering from acute COVID-19 developed in Italy reported that 87% of 143 patients surveyed reported persistent symptoms at a mean of 60 days after symptom onset, with the most common symptom being fatigue (which occurred in 53.1% of these patients).21

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Cardiopulmonary

A study from the United Kingdom reported that among 100 hospitalized patients (32 received care in the ICU and 68 received care in hospital wards only), 72% of the ICU patients and 60% of the ward patients experienced fatigue and breathlessness at 4 to 8 weeks after hospital discharge. The authors suggested that posthospital rehabilitation may be necessary for some of these patients.24 A retrospective study from China found that pulmonary function (as measured by spirometry) was still impaired 1 month after hospital discharge in 31 of 57 patients (54.4%).29 In a study from Germany that included 100 patients who had recently recovered from COVID-19, cardiac magnetic resonance imaging (MRI) performed

a median of 71 days after diagnosis revealed cardiac involvement in 78% of patients and ongoing myocardial inflammation in 60% of patients.30 A retrospective study from China of 26 patients who had recovered from COVID-19 and who had initially presented with cardiac symptoms found abnormalities on cardiac MRI in 15 patients (58%).31 The assessment of the prevalence of cardiac abnormalities in people with post-acute COVID-19 syndrome should be viewed with caution, however, as the analysis included only patients with cardiac symptoms.

Neuropsychiatric

Neurologic and psychiatric symptoms have also been reported among patients who have recovered
from acute COVID-19. High rates of anxiety and depression have been reported in some patients using self-report scales for psychiatric distress.25,32 Younger patients have been reported to experience more psychiatric symptoms than patients aged >60 years.24,25 Patients may continue to experience headaches, vision changes, hearing loss, loss of taste or smell, impaired mobility, numbness in extremities, tremors, myalgia, memory loss, cognitive impairment, and mood changes for up to 3 months after diagnosis of COVID-19.33-35 One study in the United Kingdom administered cognitive tests to 84,285 participants who had recovered from suspected or confirmed SARS-CoV-2 infection. These participants had worse performances across multiple domains than would be expected for people with the same ages and demographic profiles; this effect was observed even among those who had not been hospitalized.36 However, the study authors did not report when the tests were administered in relation to the diagnosis of COVID-19.

Persistent symptoms after acute COVID-19 have also been reported in pregnant people.37 Systematic data on persistent symptoms in children following recovery from the acute phase of COVID-19 are not currently available, although case reports suggest that children may experience long-term effects similar to those experienced by adults after clinical COVID-19.38,39 MIS-C is discussed in Special Considerations in Children.

More research and more rigorous observational cohort studies are needed to better understand the pathophysiology and clinical course of these post-acute COVID-19 sequelae and to identify management strategies for patients. More information about ongoing studies can be found at ClinicalTrials.gov.

References

1. Centers for Disease Control and Prevention. COVID-19 (coronavirus disease): people with certain medical conditions. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people- with-medical-conditions.html. Accessed December 7, 2020.

2. Tan C, Huang Y, Shi F, et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol. 2020;92(7):856-862. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32281668.

3. Berger JS, Kunichoff D, Adhikari S, et al. Prevalence and outcomes of D-dimer elevation in hospitalized patients with COVID-19. Arterioscler Thromb Vasc Biol. 2020;40(10):2539-2547. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32840379.

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4. Casas-Rojo JM, Anton-Santos JM, Millan-Nunez-Cortes J, et al. Clinical characteristics of patients hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 Registry. Rev Clin Esp. 2020;220(8):480-494. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32762922.

5. Society for Maternal Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_ COVID_pos_preg_patients_4-30-20_final.pdf.

6. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114(6):1326-1331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19935037.

7. Anderson BL, Mendez-Figueroa H, Dahlke JD, Raker C, Hillier SL, Cu-Uvin S. Pregnancy-induced changes in immune protection of the genital tract: defining normal. Am J Obstet Gynecol. 2013;208(4):321.e1-321.e9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23313311.

8. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32386565.

9. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32410760.

10. Zhang R, Ouyang H, Fu L, et al. CT features of SARS-CoV-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from Wuhan city. Eur Radiol. 2020;30(8):4417-4426. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32279115.

11. Inui S, Fujikawa A, Jitsu M, et al. Chest CT findings in cases from the cruise ship “Diamond Princess” with coronavirus disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging. 2020;2(2). Available at: https://pubs.rsna.org/doi/10.1148/ryct.2020200110.

12. Cohen J, Burbelo PD. Reinfection with SARS-CoV-2: implications for vaccines. Oxford Academic. 2020;Preprint. Available at: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1866/6041697.

13. Nonaka CKV, Franco MM, Graf T, et al. Genomic evidence of SARS-CoV-2 reinfection case with E484K spike mutation, Brazil. Emerg Infect Dis. 2021;27(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33605869.

14. Centers for Disease Control and Prevention. Interim guidance on duration of isolation and precautions for adults with COVID-19. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration- isolation.html. Accessed March 2, 2021.

15. Centers for Disease Control and Prevention. Investigative criteria for suspected cases of SARS-CoV-2 reinfection (ICR). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/php/invest-criteria.html. Accessed March 30, 2021.

16. Kim AY, Gandhi RT. Reinfection with severe acute respiratory syndrome coronavirus 2: what goes around may come back around. 2020;Preprint. Available at: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1541/5920338.

17. BNO News. COVID-19 reinfection tracker. 2020. Available at: https://bnonews.com/index.php/2020/08/ covid-19-reinfection-tracker/. Accessed March 2, 2021.

18. Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324(22):2251-2252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33206133.

19. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ. 2020;370:m3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32784198.

20. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long-COVID: analysis of COVID cases and their symptoms collected by the COVID symptoms study app. Nat Med. 2020. Available at:

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https://www.nature.com/articles/s41591-021-01292-y.

21. Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute
COVID-19. JAMA. 2020;324(6):603-605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32644129.

22. Rawal G, Yadav S, Kumar R. Post-intensive care syndrome: an overview. J Transl Int Med. 2017;5(2):90-92.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28721340.

23. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32730238.

24. Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J Med Virol. 2021;93(2):1013-1022. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32729939.

25. Cai X, Hu X, Ekumi IO, et al. Psychological distress and its correlates among COVID-19 survivors during early convalescence across age groups. Am J Geriatr Psychiatry. 2020;28(10):1030-1039. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32753338.

26. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220-232. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33428867.

27. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open. 2021. Available at: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776560.

28. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15(11):e0240784. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33166287.

29. Huang Y, Tan C, Wu J, et al. Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase. Respir Res. 2020;21(1):163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32600344.

30. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265- 1273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32730619.

31. Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging. 2020;13(11):2330-2339. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32763118.

32. Mazza MG, De Lorenzo R, Conte C, et al. Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors. Brain Behav Immun. 2020;89:594-600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32738287.

33. Lu Y, Li X, Geng D, et al. Cerebral micro-structural changes in COVID-19 patients—an MRI-based 3-month follow-up study. EClinicalMedicine. 2020;25:100484. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32838240.

34. Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020;12(1):69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32498691.

35. Lechien JR, Chiesa-Estomba CM, Beckers E, et al. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. J Intern Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33403772.

36. Hampshire A, Trender W, Chamberlain SR, et al. Cognitive deficits in people who have recovered from COVID-19 relative to controls: an N = 84,285 online study. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1.

37. Afshar Y, Gaw SL, Flaherman VJ, et al. Clinical presentation of coronavirus disease 2019 (COVID-19) in

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pregnant and recently pregnant people. Obstet Gynecol. 2020;136(6):1117-1125. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33027186.

38. Ludvigsson JF. Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19. Acta Paediatr. 2021;110(3):914-921. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33205450.

39. Buonsenso D, Munblit D, De Rose C, et al. Preliminary evidence on long COVID in children. MedRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1.

  

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Outpatient Management of Acute COVID-19

Last Updated: April 21, 2021



Summary Recommendations

Managing Outpatients With COVID-19

• Outpatient management of acute COVID-19 should include providing supportive care, taking steps to reduce the risk of SARS-CoV-2 transmission (including isolating the patient), and advising patients on when to contact a health care provider and seek an in-person evaluation (AIII).

• Patients with symptoms of COVID-19 should be triaged, when possible, via telehealth visits before receiving in-person care. Patients with dyspnea should be referred for an in-person evaluation by a health care provider and should be followed closely during the initial days after the onset of dyspnea to assess for worsening respiratory status (AIII).

• Management plans should be based on a patient’s vital signs, physical exam ndings, risk factors for progression to severe illness, and the availability of health care resources (AIII).
Speci c Therapy for Outpatients With Mild to Moderate COVID-19

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using one of the following combination anti-SARS- CoV-2 monoclonal antibodies to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression, as de ned by the Emergency Use Authorization criteria (treatments are listed in alphabetical order):
• Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or • Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).

• The Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin (AI). There are insuf cient data for the Panel to recommend either for or against the use of other agents for the treatment of outpatients with COVID-19.

• The Panel recommends against the use of dexamethasone or other systemic glucocorticoids in outpatients in the absence of another indication (AIII). There is currently a lack of safety and ef cacy data on the use of these agents in outpatients with COVID-19, and systemic glucocorticoids may cause harm in these patients.

• The Panel recommends against the use of antibacterial therapy (e.g., azithromycin, doxycycline) in the absence of another indication (AIII).

• Health care providers should provide information about ongoing clinical trials of investigational therapies to eligible outpatients with COVID-19 so they can make informed decisions about participating in clinical trials (AIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

Introduction

This section of the Guidelines is intended to provide information to health care providers who are caring for nonhospitalized patients with COVID-19. The COVID-19 Treatment Guidelines Panel (the Panel) recognizes that the distinction between outpatient and inpatient care may be less clear during the COVID-19 pandemic. Patients with COVID-19 may receive care outside traditional ambulatory care or hospital settings amid the rising number of COVID-19 hospitalizations across the country. Settings such as field hospitals and ambulatory surgical centers and programs such as Acute Hospital Care at Home have been implemented to alleviate hospital bed and staffing shortages.1 Patients may enter an Acute Hospital Care at Home program from either an emergency department (ED) or an inpatient hospital setting. Health care providers should use their judgment when deciding whether the guidance offered in this section applies to individual patients.

This section focuses on the evaluation and management of: • Adults with COVID-19 in an ambulatory care setting;

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• Adults with COVID-19 following discharge from the ED; and

• Adults with COVID-19 following inpatient discharge.
Outpatient evaluation and management in each of these settings may include some or all of the following: telemedicine, remote monitoring, in-person visits, and home visits by nurses or other health care providers.
Outpatient Management of Patients With COVID-19 in an Ambulatory Care Setting
Approximately 80% of patients with COVID-19 have mild illness that does not warrant medical intervention or hospitalization.2 Most patients with mild COVID-19 (defined as the absence of viral pneumonia and hypoxemia) can be managed in an ambulatory care setting or at home. Patients with moderate COVID-19 (those with viral pneumonia but without hypoxemia) and severe COVID-19 (those with dyspnea, hypoxemia, or lung infiltrates >50%) need in-person evaluation and close monitoring, as pulmonary disease can progress rapidly and require hospitalization.3
There are limited data to inform outpatient management strategies; current strategies are based mostly
on clinical experience accumulated since the beginning of the pandemic. Management of COVID-19 patients in the outpatient setting should focus on providing supportive care, taking steps to reduce the risk of SARS-CoV-2 transmission (e.g., wearing a mask, isolating the patient),4,5 and advising patients when to seek in-person evaluation.6 Supportive care includes managing symptoms (as described below), assuring that patients are receiving the proper nutrition, and paying attention to the risks of social isolation, particularly in older adults.7 Other unique aspects of care for geriatric patients with COVID-19 include consideration of cognitive impairment, frailty, fall risk, and polypharmacy. Older patients and those
with chronic medical conditions have a higher risk for hospitalization and death; however, SARS-CoV-2 infection may cause severe disease and death in patients of any age, even in the absence of any risk factors. The decision to monitor a patient in the outpatient setting should be made on a case-by-case basis.
Criteria to Determine Whether In-Person Evaluation Is Needed
Patients with suspected or laboratory-confirmed COVID-19 should be triaged via telehealth, when possible, before they receive an in-person evaluation. Outpatient management may include the use
of patient self-assessment tools. During initial triage, clinic staff should determine which patients
are eligible to receive supportive care at home and which patients warrant an in-person evaluation.8 Local emergency medical services, if called by the patient, may also be of help in deciding whether an in-person evaluation is indicated. Patient management plans should be based on the patient’s vital signs, physical exam findings, risk factors for progression to severe illness, and the availability of health care resources (AIII).
All patients with dyspnea, oxygen saturation (SpO2) ≤94% on room air at sea level (if this information
is available), or symptoms that suggest higher acuity (e.g., chest pain or tightness, dizziness, confusion or other mental status changes) should be referred for an in-person evaluation by a health care provider. The criteria used to determine the appropriate clinical setting for an in-person evaluation may vary by location and institution; it may also change over time as new data and treatment options emerge. There should be a low threshold for in-person evaluation of older persons and those with medical conditions associated with risk of progression to severe COVID-19. The individual who performs the initial triage should use their clinical judgement to determine whether a patient requires ambulance transport. There are unique considerations for residents of nursing homes and other long-term care facilities who develop acute COVID-19. Decisions about transferring these patients for an in-person evaluation should be a collaborative effort between the resident (or their health care decision maker), a hospital-based specialist (e.g., an emergency physician or geriatrician), and the clinical manager of the facility.9
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In some settings where clinical evaluation is challenged by geography, health care provider home visits may be used to evaluate patients.10 Patients who are homeless should be provided with housing where they can adequately self-isolate. Providers should be aware of the potential adverse effects of prolonged social isolation, including depression and anxiety.7 All outpatients should receive instructions regarding self-care, isolation, and follow-up, and should be advised to contact a health care provider or a local ED for any worsening symptoms.11,12 Guidance for implementing home care and isolation of outpatients with COVID-19 is provided by the U.S. Centers for Disease Control and Prevention (CDC).

Clinical Considerations When Managing Patients in an Ambulatory Care Setting

Persons who have symptoms that are compatible with COVID-19 or who have been exposed to others with suspected or laboratory-confirmed COVID-19 should undergo diagnostic SARS-CoV-2 testing (see Prevention and Prophylaxis of SARS-CoV-2 Infection). Patients with SARS-CoV-2 infection may be asymptomatic or experience symptoms that are indistinguishable from other acute viral or bacterial infections (e.g., fever, cough, sore throat, malaise, muscle pain, headache, gastrointestinal symptoms). It is important to consider other possible etiologies of symptoms, including other respiratory viral infections (e.g., influenza), community-acquired pneumonia, congestive heart failure, asthma or chronic obstructive pulmonary disease exacerbations, and streptococcal pharyngitis.

In most adult patients, if dyspnea develops, it tends to occur between 4 and 8 days after symptom
onset, although it can also occur after 10 days.13 While mild dyspnea is common, worsening dyspnea and severe chest pain/tightness suggest the development or progression of pulmonary involvement. In studies of patients who developed acute respiratory distress syndrome, progression occurred a median of 2.5 days after the onset of dyspnea.14-16 Adult outpatients with dyspnea should be followed closely with telehealth or in-person monitoring, particularly during the first few days following onset of dyspnea, to monitor for worsening respiratory status (AIII).

If an adult patient has access to a pulse oximeter at home, SpO2 measurements can be used to help
assess overall clinical status. Patients should be advised to use a pulse oximeter on warm fingers rather than cold fingers for better accuracy. Patients should inform their health care provider if the value
is repeatedly below 95% at sea level. Pulse oximetry may not accurately detect occult hypoxemia, especially in Black patients.3,17,18 Additionally, SpO2 readings obtained through a mobile telephone application may not be accurate enough for clinical use.19-21 Importantly, oximetry should only be interpreted within the context of a patient’s entire clinical presentation (i.e., results should be disregarded if a patient is complaining of increasing dyspnea).

Counseling Regarding the Need for Follow-Up

Health care providers should identify patients who are at risk for disease progression and ensure that these patients receive adequate medical follow-up. The frequency and duration of follow-up will depend on the risk for severe disease, the severity of symptoms, and the patient’s ability to self-report worsening symptoms. Health care providers should determine whether a patient has access to a phone, computer, or tablet for telehealth; whether they have adequate transportation for clinic visits; and whether they have regular access to food. The clinician should also confirm that the patient has a caregiver who can assist with daily activities if needed.

All patients and/or their family members or caregivers should be counseled about the warning symptoms that should prompt re-evaluation by a telehealth visit or an in-person evaluation in an ambulatory care setting or ED. These symptoms include new onset of dyspnea, worsening dyspnea (particularly if dyspnea occurs while resting or if it interferes with daily activities), dizziness, and mental status changes such as confusion. Patients should be educated about the time course of these symptoms and the possible

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respiratory decline that may occur, on average, 1 week after the onset of illness.

Symptom Management

Symptomatic treatment includes using over-the-counter antipyretics, analgesics, and antitussives for fever, headache, myalgias, and cough. Patients with dyspnea may benefit from resting in the prone position rather than the supine position.22 Health care providers should consider educating patients about breathing exercises, as severe breathlessness may cause anxiety.23 Patients should be advised to drink fluids regularly to avoid dehydration. Rest is recommended as needed during the acute phase of COVID-19, and ambulation and other forms of activity should be increased according to the patient’s tolerance. Patients should be educated about the variability in time to symptom resolution and complete recovery.

Therapeutic Management

The Panel continues to review the most recent clinical data to provide up-to-date treatment recommendations for clinicians who are caring for patients with COVID-19. Therapeutic Management of Adults With COVID-19 includes recommendations for managing patients with varying severities of disease.

Anti-SARS-CoV-2 Monoclonal Antibodies

The Panel recommends using one of the following combination anti-SARS-CoV-2 monoclonal antibodies to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression as defined by the Emergency Use Authorization (EUA) criteria (treatments are listed in alphabetical order):

• Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or

• Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).
Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen test or a nucleic acid amplification test and within 10 days of symptom onset. For more details on the available clinical trial data for these antibodies, see Anti-SARS-CoV-2 Monoclonal Antibodies.
Two combination anti-SARS-CoV-2 monoclonal antibody products—bamlanivimab plus etesevimab and casirivimab plus imdevimab—have received EUAs from the Food and Drug Administration
(FDA) for the treatment of mild to moderate COVID-19 in outpatients who are at high risk of clinical progression. In laboratory studies, some SARS-CoV-2 variants of concern or interest that harbor certain mutations have markedly reduced susceptibility to bamlanivimab and may have lower sensitivity to etesevimab and casirivimab.24 Reduced in vitro susceptibility to both antibodies in a combination regimen is currently uncommon.
There are no comparative data to determine whether there are differences in clinical efficacy or safety between bamlanivimab plus etesevimab and casirivimab plus imdevimab. There are SARS-CoV-2 variants, particularly those that contain the mutation E484K, that reduce the virus’ susceptibility
to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known. In regions where SARS-CoV-2 variants with reduced in vitro susceptibility to bamlanivimab plus etesevimab are common, some Panel members would preferentially use casirivimab plus imdevimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.
Vaccination with a COVID-19 vaccine should be deferred for at least 90 days in those who have received anti-SARS-CoV-2 monoclonal antibodies. This is a precautionary measure, as the antibody
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treatment may interfere with vaccine-induced immune responses. In people who are vaccinated and then develop COVID-19, prior receipt of vaccine should not affect treatment decisions, including the use of and timing of treatment with monoclonal antibodies.25

Other Therapeutic Agents

The Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 (AI). Health care providers should provide information about ongoing clinical trials of investigational therapies to eligible outpatients with COVID-19 so they can make informed decisions about participating in clinical trials (AIII).

Remdesivir

Remdesivir is currently the only drug approved by the FDA for the treatment of COVID-19. It is recommended for use in hospitalized patients who require supplemental oxygen. In some cases, a hospital bed may not be available for patients who require supplemental oxygen; for these patients, remdesivir should only be administered in health care settings that can provide a similar level of care to an inpatient hospital.

Dexamethasone

The Panel recommends against the use of dexamethasone or other systemic glucocorticoids to treat outpatients with mild to moderate COVID-19 (AIII). There is currently a lack of safety and efficacy data on the use of these agents in outpatients with COVID-19, and systemic glucocorticoids may cause harm in these patients. Patients who are receiving dexamethasone or another corticosteroid for other indications should continue therapy for their underlying conditions as directed by their health care providers (AIII). For more information, see Therapeutic Management of Adults With COVID-19. The use of dexamethasone in outpatients with severe disease is discussed below.

In hospitalized patients with COVID-19, dexamethasone was shown to reduce mortality in patients who required supplemental oxygen. There was no observed benefit of dexamethasone in hospitalized patients who did not receive oxygen support.26 Outpatients with mild to moderate COVID-19 were not included in this trial; thus, the safety and efficacy of corticosteroids in this population have not been established. The Panel recommends against the use of corticosteroids in this population as there are no clinical trial data to support their use (AIII). Moreover, the use of corticosteroids can lead to adverse effects, such

as hyperglycemia, neuropsychiatric symptoms, and secondary infections, all of which may be difficult to detect and monitor in an outpatient setting. In some cases, a hospital bed may not be available for patients who require supplemental oxygen; for these patients, clinicians can consider administering dexamethasone only if the patient is placed in a health care setting that can provide a similar level of care to an inpatient hospital.

Antithrombotic Therapy

Anticoagulants and antiplatelet therapy should not be initiated in the outpatient setting for the prevention of venous thromboembolism (VTE) or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIII). For more information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to ambulate, and activity should be increased according to the patient’s tolerance.

Antibacterial Therapy

The Panel recommends against the use of antibacterial therapy (e.g., azithromycin, doxycycline) for outpatient treatment of COVID-19 in the absence of another indication (AIII).

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Concomitant Medication Management

In general, a patient’s usual medication and/or supplement regimen should be continued after the diagnosis of COVID-19 (see Considerations for Certain Concomitant Medications in Patients With COVID-19). Angiotensin-converting enzyme inhibitors, statin therapy, nonsteroidal anti- inflammatory drugs, and oral, inhaled, and intranasal corticosteroids prescribed for comorbid conditions should be continued as directed (AIII). Patients should be advised to avoid the use of nebulized medications in the presence of others to avoid potential aerosolization of SARS-CoV-2.27
In patients with HIV, antiretroviral therapy should not be switched or adjusted for the purpose of preventing or treating SARS-CoV-2 infection (AIII). For more information, see Special Considerations in People With HIV.

When a patient is receiving an immunomodulating medication, the prescribing clinician should be consulted about the risks and benefits associated with temporary dose reduction or discontinuation; these risks and benefits will depend on the medication’s indication and the severity of the underlying condition.

Patients who use a continuous positive airway pressure (CPAP) device or a bilevel positive airway pressure (BiPAP) device to manage obstructive sleep apnea may continue to use their machine. As with nebulizers, patients should be advised to use the device only when isolated from others.

Outpatient Management of Adults With COVID-19 Following Discharge from the Emergency Department

There are no fixed criteria for hospital admission of patients with COVID-19; the criteria may vary by region and hospital facilities. Patients with severe disease are typically admitted to the hospital, but due to the high prevalence of infection and limited hospital resources, some patients with severe disease may not be admitted. In addition, patients who could receive appropriate care at home but are unable to be adequately managed in their usual residential setting are candidates for temporary shelter in supervised facilities, such as a COVID-19 alternative care facility.28 For example, patients who are living in multigenerational households or who are homeless may not be able to self-isolate and should be provided resources such as dedicated housing units or hotel rooms, when available. Unfortunately, dedicated residential care facilities for COVID-19 patients are not widely available, and community- based solutions for self-care and isolation should be explored.

In the cases where institutional resources (e.g., inpatient beds, staff members) are scarce, it may be necessary to discharge an adult patient home and provide an advanced level of home care, including supplemental oxygen (if indicated), pulse oximetry, and close follow-up. Although early discharge
of those with severe disease is not generally recommended by the Panel, it is recognized that these management strategies are sometimes necessary. In these situations, some institutions are providing frequent telemedicine follow-up visits for these patients or providing a hotline for patients to speak with a clinician if necessary. Home resources should be assessed before a patient is discharged from the ED; outpatients should have a caregiver and access to a device that is suitable for telehealth. Patients and/

or their family members or caregivers should be counseled about the warning symptoms that should prompt re-evaluation by a health care provider.

Both dexamethasone and remdesivir may be appropriate treatment for some patients who are discharged from the ED but require supplemental oxygen, even though they are not hospitalized (see Therapeutic Management of Adults With COVID-19). Since remdesivir can only be administered by intravenous infusion, there may be logistical issues with providing it to an outpatient. If dexamethasone is given, it should be provided for no more than 10 days, and clinicians should consider stopping dexamethasone

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when the patient no longer requires oxygen. It is important that patients on dexamethasone or
other corticosteroids are counseled about potential adverse effects, including hyperglycemia and neuropsychiatric impairment. In-person visits or telehealth visits should be performed to monitor closely for toxicities and/or assist with blood glucose control.

Anticoagulants and antiplatelet therapy should not be initiated for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIII). For more information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to ambulate, and activity should be increased according to the patient’s tolerance.

Outpatient Management of Adults With COVID-19 Following Hospital Discharge

Most patients who are discharged from the hospital setting should have a follow-up visit with a health care provider soon after discharge. Whether an in-person visit or a telehealth visit is most appropriate depends on the clinical and social situation. In some cases, adult patients are deemed to be stable for discharge from the inpatient setting even though they still require supplemental oxygen. When possible, these individuals should receive oximetry monitoring and close follow-up through telehealth, visiting nurse services, or in-person clinic visits.

The pivotal safety and efficacy trials for remdesivir and corticosteroids stopped these treatments at the time of discharge from the hospital; therefore, these therapies are generally discontinued in patients who are discharged from an inpatient setting, even if they are receiving supplemental oxygen. Nevertheless, it is recognized that the practice of discharging inpatients who still require oxygen was likely uncommon in the pivotal trials. The data supporting the use of corticosteroids after discharge in such cases are limited, with the main concerns being the lack of monitoring for toxicities, including, but not limited

to, blood glucose control and neuropsychiatric impairment. As a result, the Panel recommends against administering corticosteroids after discharge as routine practice (BIII). If a patient continues to receive corticosteroids after discharge, it should be for no more than a total of 10 days and only in those who are stable and have shown good tolerance to this therapy prior to discharge.

Hospitalized patients with COVID-19 should not routinely be discharged on VTE prophylaxis unless they have another indication or are participating in a clinical trial (AIII). For more information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to ambulate, and activity should be increased according to the patient’s tolerance.

Considerations in Pregnancy

Managing pregnant outpatients with COVID-19 is similar to managing nonpregnant patients (see Special Considerations in Pregnancy). Clinicians should offer supportive care, take steps to reduce the risk of SARS-CoV-2 transmission, and provide guidance for when to seek an in-person evaluation. The American College of Obstetricians and Gynecologists (ACOG) has developed an algorithm to aid the practitioner in evaluating and managing pregnant outpatients with laboratory-confirmed or suspected COVID-19.29 ACOG has also published recommendations on how to use telehealth for prenatal care and how to modify routine prenatal care when necessary to decrease the risk of SARS-CoV-2 transmission to patients, caregivers, and staff.

In pregnant patients, SpO2 should be maintained at 95% or above at sea level; therefore, the threshold for monitoring pregnant patients in an inpatient setting may be lower than in nonpregnant patients.30 In general, there are no changes to fetal monitoring recommendations in the outpatient setting, and fetal management should be similar to that provided to other pregnant patients with medical illness.31 However, these monitoring strategies can be discussed on a case-by-case basis with an obstetrician. Pregnant and lactating patients should be given the opportunity to participate in clinical trials of

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outpatients with COVID-19 to help inform decision-making in this population.

Considerations in Children

Children and adolescents with acute COVID-19 are less likely than adults to require medical intervention or hospitalization, and most can be managed in an ambulatory care setting or at home. In general, the need for ED evaluation or hospitalization should be based on the patient’s vital signs, physical exam findings (e.g., dyspnea), and risk factors for progression to severe illness. Certain groups, including young infants, children with risk factors, or those with presentations that overlap with multisystem inflammatory syndrome in children (MIS-C), may require hospitalization for more intensive monitoring. However, this should be determined on a case-by-case basis.

Most children with mild or moderate COVID-19, even those with risk factors, will not progress to more severe illness and will recover without specific therapy (see Special Considerations in Children). There are insufficient pediatric data to recommend either for or against the use of anti-SARS-CoV-2 monoclonal antibody products in children with COVID-19 who are not hospitalized but who have
risk factors for severe disease. Based on adult studies, bamlanivimab plus etesevimab or casirivimab plus imdevimab may be considered on a case-by-case basis for nonhospitalized children who meet
the EUA criteria, especially those who meet more than one criterion or are aged ≥16 years. The Panel recommends consulting a pediatric infectious disease specialist in such cases.

In general, pediatric patients should not continue receiving remdesivir, dexamethasone, or other COVID- 19-directed therapies following discharge from an ED or an inpatient setting. Clinicians should refer to the Special Considerations in Children section for more information on the management of children with COVID-19.

References

1. Centers for Medicare & Medicaid Services. CMS announces comprehensive strategy to enhance hospital capacity amid COVID-19 surge. 2020. Available at: https://www.cms.gov/newsroom/press-releases/cms- announces-comprehensive-strategy-enhance-hospital-capacity-amid-covid-19-surge.

2. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States, January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6924e2-H.pdf.

3. Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.

4. Centers for Disease Control and Prevention. COVID-19: how to protect yourself & others. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html.

5. Centers for Disease Control and Prevention. COVID-19: if you are sick or caring for someone. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/.

6. Cheng A, Caruso D, McDougall C. Outpatient management of COVID-19: rapid evidence review. Am Fam Physician. 2020;102(8):478-486. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33064422.

7. Morrow-Howell N, Galucia N, Swinford E. Recovering from the COVID-19 pandemic: a focus on older adults. J Aging Soc Policy. 2020;32(4-5):526-535. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32336225.

8. Centers for Disease Control and Prevention. Coronavirus self-checker. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/coronavirus-self-checker.html.

9. Burkett E, Carpenter CR, Hullick C, Arendts G, Ouslander JG. It’s time: delivering optimal emergency care of residents of aged care facilities in the era of COVID-19. Emerg Med Australas. 2021;33(1):131-137. Available

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at: https://www.ncbi.nlm.nih.gov/pubmed/33131219.
10. Close RM, Stone MJ. Contact tracing for native americans in rural Arizona. N Engl J Med. 2020;383(3):e15.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/32672426.
11. Centers for Disease Control and Prevention. COVID-19: what to do if you are sick. 2020. Available at:

https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/steps-when-sick.html.
12. Centers for Disease Control and Prevention. COVID-19: isolate if you are sick. 2021. Available at:

https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/isolation.html.

13. Cohen PA, Hall LE, John JN, Rapoport AB. The early natural history of SARS-CoV-2 infection: clinical observations from an urban, ambulatory COVID-19 clinic. Mayo Clin Proc. 2020;95(6):1124-1126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32451119.

14. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus- infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32031570.

15. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state. JAMA. 2020;323(16):1612-1614. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32191259.

16. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475- 481. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32105632.

17. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home. Potential pitfalls and practical guidance. Ann Am Thorac Soc. 2020;17(9):1040-1046. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32521167.

18. Sjoding MW, Dickson RP, Iwashyna TJ, Gay SE, Valley TS. Racial bias in pulse oximetry measurement. N Engl J Med. 2020;383(25):2477-2478. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33326721.

19. Modi A, Kiroukas R, Scott JB. Accuracy of smartphone pulse oximeters in patients visiting an outpatient pulmonary function lab for a 6-minute walk test. Respir Care. 2019;64(Suppl 10). Available at: http://rc.rcjournal.com/content/64/Suppl_10/3238714.

20. Tarassenko L, Greenhalgh T. Question: should smartphone apps be used clinically as oximeters? Answer: no. 2020. Available at: https://www.cebm.net/covid-19/question-should-smartphone-apps-be-used-as-oximeters- answer-no/.

21. Jordan TB, Meyers CL, Schrading WA, Donnelly JP. The utility of iPhone oximetry apps: a comparison with standard pulse oximetry measurement in the emergency department. Am J Emerg Med. 2020;38(5):925-928. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31471076.

22. Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375- 378. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32320506.

23. National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. BMJ. 2020;369:m1461. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32312715.

24. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info. html.

25. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/info-by- product/clinical-considerations.html.

26. Recovery Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-704. Available at:

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https://www.ncbi.nlm.nih.gov/pubmed/32678530.

27. Cazzola M, Ora J, Bianco A, Rogliani P, Matera MG. Guidance on nebulization during the current COVID-19
pandemic. Respir Med. 2021;176:106236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33248363.

28. Meyer GS, Blanchfield BB, Bohmer RMJ, Mountford MB, Vanderwagen WC. Alternative care sites for the COVID-19 pandemic: the early U.S. and U.K. experience. NEJM Catalyst. 2020. Available at: https://catalyst.nejm.org/doi/full/10.1056/CAT.20.0224.

29. The American College of Obstetricians and Gynecologists. Outpatient Assessment and Management for Pregnant Women with Suspected or Confirmed Novel Coronavirus (COVID-19). 2020. Available at: https://www.smfm.org/covid19/.

30. The American College of Obstetricians and Gynecologists. COVID-19 FAQs for obstetrician-gynecologists, obstetrics. 2020. Available at: https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob- gyns-obstetrics.

31. Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_ COVID_pos_preg_patients_4-30-20_final.pdf.

       

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Care of Critically Ill Adult Patients With COVID-19

Last Updated: December 17, 2020



Summary Recommendations

Infection Control

• For health care workers who are performing aerosol-generating procedures on patients with COVID-19, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using an N95 respirator (or equivalent or higher-level respirator) rather than surgical masks, in addition to other personal protective equipment (PPE) (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) (AIII).

• The Panel recommends minimizing the use of aerosol-generating procedures on intensive care unit patients with COVID-19 and carrying out any necessary aerosol-generating procedures in a negative-pressure room, also known as an airborne infection isolation room, when available (AIII).

• For health care workers who are providing usual care for nonventilated patients with COVID-19, the Panel recommends using an N95 respirator (or equivalent or higher-level respirator) or a surgical mask in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) (AIIa).

• For health care workers who are performing non-aerosol-generating procedures on patients with COVID-19 who are on closed-circuit mechanical ventilation, the Panel recommends using an N95 respirator (or equivalent or higher-level respirator) in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) because ventilator circuits may become disrupted unexpectedly (BIII).

• The Panel recommends that endotracheal intubation in patients with COVID-19 be performed by health care providers with extensive airway management experience, if possible (AIII).

• The Panel recommends that intubation be performed using video laryngoscopy, if possible (CIIa). Hemodynamics

• For adults with COVID-19 and shock, the Panel recommends using dynamic parameters, skin temperature, capillary re lling time, and/or lactate levels over static parameters to assess uid responsiveness (BIIa).

• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using buffered/balanced crystalloids over unbalanced crystalloids (BIIa).

• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against the initial use of albumin for resuscitation (BIIa).

• The Panel recommends against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (AIIa).

• The Panel recommends norepinephrine as the rst-choice vasopressor (AIIa). The Panel recommends adding either vasopressin (up to 0.03 units/min) (BIIa) or epinephrine (CIIb) to norepinephrine to raise mean arterial pressure to target or adding vasopressin (up to 0.03 units/min) (CIIa) to decrease norepinephrine dosage.

• When norepinephrine is available, the Panel recommends against using dopamine for patients with COVID-19 and shock (AIIa).

• The Panel recommends against using low-dose dopamine for renal protection (BIIa).

• The Panel recommends using dobutamine in patients who show evidence of cardiac dysfunction and persistent
hypoperfusion despite adequate uid loading and the use of vasopressor agents (BIII).

• The Panel recommends that all patients who require vasopressors have an arterial catheter placed as soon as
practical, if resources are available (BIII).

• For adults with COVID-19 and refractory septic shock who are not receiving corticosteroids to treat their COVID-19, the
Panel recommends using low-dose corticosteroid therapy (“shock-reversal”) over no corticosteroid therapy (BIIa). Oxygenation and Ventilation

• For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel recommends high- ow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV) (BIIa).

• In the absence of an indication for endotracheal intubation, the Panel recommends a closely monitored trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure and for whom HFNC is not available (BIIa).

• For patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated, the Panel recommends considering a trial of awake prone positioning to

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improve oxygenation (CIIa).

• The Panel recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid
intubation in patients who otherwise meet the indications for intubation and mechanical ventilation (AIII).

• If intubation becomes necessary, the procedure should be performed by an experienced practitioner in a controlled setting due to the enhanced risk of severe acute respiratory syndrome coronavirus 2 exposure to health care practitioners during intubation (AIII).

• For mechanically ventilated adults with COVID-19 and acute respiratory distress syndrome (ARDS):

• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body weight) over
higher VT ventilation (VT >8 mL/kg) (AI).

• The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).

• The Panel recommends using a conservative uid strategy over a liberal uid strategy (BIIa).

• The Panel recommends against the routine use of inhaled nitric oxide (AIIa).

• For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:

• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a lower PEEP strategy
(BIIa).

• For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel
recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BIIa).

• For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:

• The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents (NMBA) or continuous NMBA infusion to facilitate protective lung ventilation (BIIa).

• In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the Panel recommends using a continuous NMBA infusion for up to 48 hours as long as patient anxiety and pain can be adequately monitored and controlled (BIII).

• For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies:

• The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers (CIIa).

• If recruitment maneuvers are used, the Panel recommends against using staircase (incremental PEEP) recruitment
maneuvers (AIIa).

• The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in
oxygenation is observed, the treatment should be tapered off (CIII). Acute Kidney Injury and Renal Replacement Therapy

• For critically ill patients with COVID-19 who have acute kidney injury and who develop indications for renal replacement therapy, the Panel recommends continuous renal replacement therapy (CRRT), if available (BIII).

• If CRRT is not available or not possible due to limited resources, the Panel recommends prolonged intermittent renal replacement therapy rather than intermittent hemodialysis (BIII).
Pharmacologic Interventions

• In patients with COVID-19 and severe or critical illness, there are insuf cient data to recommend empiric broad- spectrum antimicrobial therapy in the absence of another indication.

• If antimicrobials are initiated, the Panel recommends that their use should be reassessed daily in order to minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).
Extracorporeal Membrane Oxygenation
• There are insuf cient data to recommend either for or against the use of extracorporeal membrane oxygenation in patients with COVID-19 and refractory hypoxemia.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

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General Considerations

Last Updated: April 21, 2021

Severe cases of COVID-19 may be associated with hypoxemic respiratory failure, acute respiratory distress syndrome (ARDS), septic shock, cardiac dysfunction, elevation in multiple inflammatory cytokines, thromboembolic disease, and/or exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with COVID-19 may also experience cardiac, hepatic, renal, and central nervous system disease. Because patients with critical illness are likely to undergo aerosol-generating procedures, they should be placed in airborne infection isolation rooms, when available.

Guidance on diagnostic testing for SARS-CoV-2 can be found in the Testing for SARS-CoV-2 Infection section.

Most of the recommendations for the management of critically ill patients with COVID-19 are extrapolated from experience with other causes of sepsis.1 Currently, there is limited information to suggest that the critical care management of patients with COVID-19 should differ substantially from the management of other critically ill patients; however, special precautions to prevent environmental contamination by SARS-CoV-2 are warranted.

As with any patient in the intensive care unit (ICU), successful clinical management of a patient with COVID-19 includes treating both the medical condition that initially resulted in ICU admission and other comorbidities and nosocomial complications.

Comorbid Conditions

Certain attributes and comorbidities (e.g., older age, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, cancer, renal disease, obesity, sickle cell disease, receipt of a solid organ transplant) are associated with an increased risk of severe illness from COVID-19.2

Bacterial Superinfection of COVID-19-Associated Pneumonia

Limited information exists about the frequency and microbiology of pulmonary coinfections and superinfections in patients with COVID-19, such as hospital-acquired pneumonia (HAP) and ventilator- associated pneumonia (VAP). Some studies from China emphasize the lack of bacterial coinfections in patients with COVID-19, while other studies suggest that these patients experience frequent bacterial complications.3-8 There is appropriate concern about performing pulmonary diagnostic procedures such
as bronchoscopy or other airway sampling procedures that require disruption of a closed airway circuit
in patients with COVID-19. Thus, while some clinicians do not routinely start empiric broad-spectrum antimicrobial therapy for patients with severe COVID-19 disease, other experienced clinicians routinely use such therapy. However, empiric broad-spectrum antimicrobial therapy is the standard of care for the treatment of shock. Antibiotic stewardship is critical to avoid reflexive or continued courses of antibiotics.

Inflammatory Response Due to COVID-19

Patients with COVID-19 may express increased levels of pro-inflammatory cytokines and anti- inflammatory cytokines, which has previously been referred to as “cytokine release syndrome” or “cytokine storm,” although these are imprecise terms. However, these terms are misnomers because the magnitude of cytokine elevation in patients with COVID-19 is modest compared to that in patients with many other critical illnesses, such as sepsis and ARDS.9,10

Patients with COVID-19 and severe pulmonary involvement are well described to also manifest extrapulmonary disease and to exhibit laboratory markers of acute inflammation. Patients with these

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manifestations of severe pulmonary disease typically progress to critical illness 10 to 12 days after the onset of COVID-19 symptoms.

Multisystem Inflammatory Syndrome in Adults

In addition, there are case reports describing patients who had evidence of acute or recent SARS-CoV-2 infection (documented by a nucleic acid amplification test [NAAT] or antigen or antibody testing) with minimal respiratory symptoms, but with laboratory markers of severe inflammation (e.g., elevated C-reactive protein [CRP], ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) and various other symptoms, including fever and shock; and signs of cardiovascular, gastrointestinal, dermatologic, and neurologic disease. This constellation of signs and symptoms has been designated multisystem inflammatory syndrome in adults (MIS-A).11 To date, most adults in whom MIS-A has been described have survived. This syndrome is similar to a syndrome previously described in children (multisystem inflammatory syndrome in children [MIS-C]).

MIS-A is defined by the following criteria:

1. A severe illness requiring hospitalization in an individual aged ≥21 years;

2. Current or past infection with SARS-CoV-2;

3. Severe dysfunction in one or more extrapulmonary organ systems;

4. Laboratory evidence of elevated inflammatory markers (e.g., CRP, ferritin, D-dimer, interleukin [IL]-6);

5. Absence of severe respiratory illness; and

6. Absence of an alternative unifying diagnosis.11

Because there is no specific diagnostic test for MIS-A, diagnosis of this inflammatory syndrome is one of exclusion after other causes (e.g., septic shock) have been eliminated. Although there are currently no controlled clinical trial data in patients with MIS-A to guide treatment of the syndrome, case reports have described the use of intravenous immunoglobulin, corticosteroids, or anti-IL-6 therapy.

COVID-19-Induced Cardiac Dysfunction, Including Myocarditis

A growing body of literature describes cardiac injury or dysfunction in approximately 20% of patients who are hospitalized with COVID-19.4,6,12-15 COVID-19 may be associated with an array of cardiovascular complications, including acute coronary syndrome, myocarditis, arrythmias, and thromboembolic disease.16

Thromboembolic Events and COVID-19

Critically ill patients with COVID-19 have been observed to have a prothrombotic state, which is characterized by the elevation of certain biomarkers, and there is an apparent increase in the incidence of venous thromboembolic disease in this population. In some studies, thromboemboli have been diagnosed in patients who received chemical prophylaxis with heparinoids.17-19 Autopsy studies provide additional evidence of both thromboembolic disease and microvascular thrombosis in patients with COVID-19.20 Some authors have called for routine surveillance of ICU patients for venous thromboembolism.21 See the Antithrombotic Therapy in Patients with COVID-19 section for a more detailed discussion.

Renal and Hepatic Dysfunction Due to COVID-19

Although SARS-CoV-2 is primarily a pulmonary pathogen, renal and hepatic dysfunction are consistently described in patients with severe COVID-19.4 In one case series of patients with critical

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disease, >15% of the patients required continuous renal replacement therapy.6 See the Acute Kidney Injury and Renal Replacement Therapy section for a more detailed discussion.

Considerations in Children

Several large epidemiologic studies suggest that rates of ICU admission are substantially lower for children with COVID-19 than for adults with the disease. However, severe disease does occur in children.22-27 The risk factors for severe COVID-19 in children have not yet been established. Data from studies of adults with COVID-19 and extrapolation from data on other pediatric respiratory viruses suggest that children who are severely immunocompromised and those with underlying cardiopulmonary disease may be at higher risk for severe COVID-19.

MIS-C, the postinfectious complication of COVID-19 seen in some children, has been described.28,29 Certain symptoms of MIS-C often require ICU-level care, including blood pressure and inotropic support. These symptoms include severe abdominal pain, multisystem inflammation, shock, cardiac dysfunction, and, rarely, coronary artery aneurysm. A minority of children with MIS-C meet the criteria for typical or atypical Kawasaki disease. For details on MIS-C clinical features and the treatments that are being investigated, see the Special Considerations in Children section.

Interactions Between Drugs Used to Treat COVID-19 and Drugs Used to Treat Comorbidities

All ICU patients should be routinely monitored for drug-drug interactions. The potential for drug-drug interactions between investigational medications or medications used off-label to treat COVID-19 and concurrent drugs should be considered.

Sedation Management in Patients With COVID-19

International guidelines provide recommendations on the prevention, detection, and treatment of pain, sedation, and delirium.30,31 Sedation management strategies, such as maintaining a light level of sedation (when appropriate) and minimizing sedative exposure, have shortened the duration of mechanical ventilation and the length of stay in the ICU for patients without COVID-19.32,33

The Society of Critical Care Medicine’s (SCCM’s) ICU Liberation Campaign promotes the ICU Liberation Bundle (A-F) to improve post-ICU patient outcomes. The A-F Bundle includes the following elements:

A. Assess, prevent, and manage pain;
B. Both spontaneous awakening and breathing trials; C. Choice of analgesia and sedation;
D. Delirium: assess, prevent, and manage;
E. Early mobility and exercise; and
F. Family engagement and empowerment.

The A-F Bundle also provides frontline staff with practical application strategies for each element.34
The A-F Bundle should be incorporated using an interprofessional team model. This approach helps standardize communication among team members, improves survival, and reduces long-term cognitive dysfunction of patients.35 Despite the known benefits of the A-F Bundle, its impact has not been directly assessed in patients with COVID-19; however, the use of the Bundle should be encouraged, when appropriate, to improve ICU patient outcomes. Prolonged mechanical ventilation of COVID-19 patients, coupled with deep sedation and potentially neuromuscular blockade, increases the workload of ICU

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staff. Additionally, significant drug shortages may force clinicians to use older sedatives with prolonged durations of action and active metabolites, impeding routine implementation of the PADIS Guidelines. This puts patients at additional risk for ICU and post-ICU complications.

Post-Intensive Care Syndrome

Patients with COVID-19 are reported to experience prolonged delirium and/or encephalopathy. Risk factors that are associated with delirium include the use of mechanical ventilation; the use of restraints; the use of benzodiazepine, opioid, and vasopressor infusions; and the use of antipsychotics.36,37 Neurological complications are associated with older age and underlying conditions, such as hypertension and diabetes mellitus.38 Autopsy studies have reported both macrovascular and microvascular thrombosis, with evidence of hypoxic ischemia.39 Adequate management requires careful attention to best sedation practices and vigilance in stroke detection.

Post-intensive care syndrome (PICS) is a spectrum of cognitive, psychiatric, and/or physical disability that affects survivors of critical illness and persists after a patient leaves the ICU.40 Patients with PICS may present with varying levels of impairment; including profound muscle weakness (ICU-acquired weakness); problems with thinking and judgment (cognitive dysfunction); and mental health problems, such as problems sleeping, post-traumatic stress disorder (PTSD), depression, and anxiety. ICU-acquired weakness affects 33% of all patients who receive mechanical ventilation, 50% of patients with sepsis, and ≤50% of patients who remain in the ICU for ≥1 week.41-43 Cognitive dysfunction affects 30% to 80% of patients discharged from the ICU.44-46 About 50% of ICU survivors do not return to work within 1 year after discharge.47 Although no single risk factor has been associated with PICS, there are opportunities

to minimize the risk of PICS through medication management (using the A-F Bundle), physical rehabilitation, follow-up clinics, family support, and improved education about the syndrome. PICS also affects family members who participate in the care of their loved ones. In one study, a third of family members who had main decision-making roles experienced mental health problems, such as depression, anxiety, and PTSD.48

Early reports suggest that some patients with COVID-19 who have been treated in the ICU express manifestations of PICS.49 Although specific therapies for COVID-19-induced PICS are not yet available, physicians should maintain a high index of suspicion for cognitive impairment and other related problems in survivors of severe or critical COVID-19 illness.

Other Intensive Care Unit-Related Complications

Patients who are critically ill with COVID-19 are at risk for nosocomial infections and other complications of critical illness care, such as VAP, HAP, catheter-related bloodstream infections, and venous thromboembolism. When treating patients with COVID-19, clinicians also need to minimize the risk of conventional ICU complications to optimize the likelihood of a successful ICU outcome.

Advance Care Planning and Goals of Care

The advance care plans and the goals of care for all critically ill patients must be assessed at hospital admission and regularly thereafter. This is an essential element of care for all patients. Information on palliative care for patients with COVID-19 can be found at the National Coalition for Hospice and Palliative Care website.

To guide shared decision-making in cases of serious illness, advance care planning should include identifying existing advance directives that outline a patient’s preferences and values. Values and care preferences should be discussed, documented, and revisited regularly for patients with or without prior directives. Specialty palliative care teams can facilitate communication between clinicians and surrogate

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decision makers, support frontline clinicians, and provide direct patient care services when needed.

Surrogate decision makers should be identified for all critically ill patients with COVID-19 at hospital admission. Infection-control policies for COVID-19 often create communication barriers for surrogate decision makers, and most surrogates will not be physically present when discussing treatment options with clinicians. Many decision-making discussions will occur via telecommunication.

Acknowledgments

The Surviving Sepsis Campaign (SSC), an initiative supported by the SCCM and the European Society of Intensive Care Medicine, issued Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) in March 2020.1 The COVID-19 Treatment Guidelines Panel (the Panel) has based the recommendations in this section on the SSC COVID-19 Guidelines with permission, and the Panel gratefully acknowledges the work of the SSC COVID-19 Guidelines Panel. The Panel also acknowledges the contributions and expertise of Andrew Rhodes, MBBS, MD, of St. George’s University Hospitals in London, England, and Waleed Alhazzani, MBBS, MSc, of McMaster University in Hamilton, Canada.

References

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2. Centers for Disease Control and Prevention. Evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from COVID-19. 2020. Available at: https://www.cdc.gov/ coronavirus/2019-ncov/need-extra-precautions/evidence-table.html. Accessed December 8, 2020.

3. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167524.

4. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state. JAMA. 2020;323(16):1612-1614. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/32191259.

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9. Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med. 2020;8(12):1233-1244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33075298.

10. Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med. 2020;180(9):1152-1154. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32602883.

11. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults associated

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with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR Morb Mortal Wkly Rep. 2020;69(40):1450-1456. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33031361.

12. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-810. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/32211816.

13. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.

14. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32171076.

15. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus- infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32031570.

16. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol. 2020;17(9):543-558. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32690910.

17. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020;18(7):1743-1746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32320517.

18. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32367170.

19. Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32291094.

20. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32364264.

21. Tavazzi G, Civardi L, Caneva L, Mongodi S, Mojoli F. Thrombotic events in SARS-CoV-2 patients: an urgent call for ultrasound screening. Intensive Care Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32322918.

22. Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32193831.

23. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179660.

24. Centers for Disease Control and Prevention. Coronavirus disease 2019 in children—United States, February 12–April 2, 2020. 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm. Accessed January 5, 2021.

25. Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (COVID-19) at a tertiary care medical center in New York City. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.

26. Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients with coronavirus disease 2019 (COVID-19) in a children’s hospital in New York City, New York. JAMA Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492092.

27. DeBiasi RL, Song X, Delaney M, et al. Severe COVID-19 in children and young adults in the Washington, DC metropolitan region. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32405091.

28. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory

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multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32511692.

29. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32410760.

30. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23269131.

31. Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30113379.

32. Kress JP, Vinayak AG, Levitt J, et al. Daily sedative interruption in mechanically ventilated patients at risk for coronary artery disease. Crit Care Med. 2007;35(2):365-371. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17205005.

33. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371(9607):126-134. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18191684.

34. Society of Critical Care Medicine. ICU Liberation Bundle (A-F). Available at: https://www.sccm.org/ICULiberation/ABCDEF-Bundles. Accessed January 5, 2021.

35. Barnes-Daly MA, Phillips G, Ely EW. Improving hospital survival and reducing brain dysfunction at seven California community hospitals: implementing PAD guidelines via the ABCDEF bundle in 6,064 patients. Crit Care Med. 2017;45(2):171-178. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27861180.

36. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020;382(23):2268-2270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32294339.

37. Pun BT, Badenes R, Heras La Calle G, et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study. Lancet Respir Med. 2021;9(3):239-250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33428871.

38. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/32275288.

39. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of COVID-19. N Engl J Med. 2020;383(10):989-992. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32530583.

40. Society of Critical Care Medicine. Post-intensive care syndrome. 2013. Available at: https://www.sccm.org/MyICUCare/THRIVE/Post-intensive-Care-Syndrome. Accessed September 22, 2020.

41. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. Crit Care Med. 2014;42(4):849-859. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24247473.

42. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002;288(22):2859-2867. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/12472328.

43. Ali NA, O’Brien JM, Jr., Hoffmann SP, et al. Acquired weakness, handgrip strength, and mortality in critically ill patients. Am J Respir Crit Care Med. 2008;178(3):261-268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18511703.

44. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306-1316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24088092.

45. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794. Available at:

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https://www.ncbi.nlm.nih.gov/pubmed/20978258.

46. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012;185(12):1307-1315. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22492988.

47. Kamdar BB, Sepulveda KA, Chong A, et al. Return to work and lost earnings after acute respiratory distress syndrome: a 5-year prospective, longitudinal study of long-term survivors. Thorax. 2018;73(2):125-133. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28918401.

48. Azoulay E, Pochard F, Kentish-Barnes N, et al. Risk of post-traumatic stress symptoms in family members of intensive care unit patients. Am J Respir Crit Care Med. 2005;171(9):987-994. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15665319.

49. Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603-605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32644129.

    

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Infection Control

Last Updated: October 9, 2020

Health care workers should follow the infection control policies and procedures issued by their health care institutions.

Recommendation

• For health care workers who are performing aerosol-generating procedures on patients with COVID-19, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using an N95 respirator (or equivalent or higher-level respirator) rather than surgical masks, in addition to other personal protective equipment (PPE) (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) (AIII).

• Aerosol-generating procedures include endotracheal intubation and extubation, sputum induction, bronchoscopy, mini-bronchoalveolar lavage, open suctioning of airways, manual ventilation, unintentional or intentional ventilator disconnections, noninvasive positive pressure ventilation (NIPPV) (e.g., bilevel positive airway pressure [BiPAP], continuous positive airway pressure [CPAP]), cardiopulmonary resuscitation, and, potentially, nebulizer administration and high-flow oxygen delivery. Caution regarding aerosol generation is appropriate in situations such as tracheostomy and proning, where ventilator disconnections are likely to occur.

Rationale

During the severe acute respiratory syndrome (SARS) epidemic, aerosol-generating procedures increased the risk of infection among health care workers.1,2 N95 respirators block 95% to 99% of aerosol particles; however, medical staff must be fit-tested for the type used.3 Surgical masks block large particles, droplets, and sprays, but are less effective in blocking small particles (<5 μm) and aerosols.4

Recommendation

• The Panel recommends minimizing the use of aerosol-generating procedures on intensive care unit patients with COVID-19 and carrying out any necessary aerosol-generating procedures
in a negative-pressure room, also known as an airborne infection isolation room (AIIR), when available (AIII).

• The Panel recognizes that aerosol-generating procedures are necessary to perform in some patients, and that such procedures can be carried out with a high degree of safety if infection control guidelines are followed.

Rationale

AIIRs lower the risk of cross-contamination among rooms and lower the risk of infection for staff and patients outside the room when aerosol-generating procedures are performed. AIIRs were effective
in preventing virus spread during the SARS epidemic.2 If an AIIR is not available, a high-efficiency particulate air (HEPA) filter should be used, especially for patients on high-flow nasal cannula or noninvasive ventilation. HEPA filters reduce virus transmission in simulations.5

Recommendations

• For health care workers who are providing usual care for nonventilated patients with COVID-19, the Panel recommends using an N95 respirator (or equivalent or higher-level respirator) or a surgical mask, in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield

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or safety goggles) (AIIa).

• For health care workers who are performing non-aerosol-generating procedures on patients with COVID-19 who are on closed-circuit mechanical ventilation, the Panel recommends using an N95 respirator (or equivalent or higher-level respirator) in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) because ventilator circuits may become disrupted unexpectedly (BIII).

Rationale

There is evidence from viral diseases, including SARS, that both surgical masks and N95 masks reduce transmission of infection.6 Current evidence suggests that surgical masks are probably not inferior
to N95 respirators for preventing transmission of laboratory-confirmed, seasonal respiratory viral infections (e.g., influenza).7,8 A recent systematic review and meta-analysis of randomized controlled trials that compared the protective effect of medical masks with N95 respirators demonstrated that the use of medical masks did not increase laboratory-confirmed viral (including coronavirus) respiratory infection or clinical respiratory illness.9

Recommendations

• The Panel recommends that endotracheal intubation in patients with COVID-19 be performed by health care providers with extensive airway management experience, if possible (AIII).

• The Panel recommends that intubation be performed using video laryngoscopy, if possible (CIIa). Rationale
Practices that maximize the chances of first-pass success and minimize aerosolization should be used when intubating patients with suspected or confirmed COVID-19.10,11 Thus, the Panel recommends that the health care worker with the most experience and skill in airway management be the first to attempt intubation. The close facial proximity of direct laryngoscopy can expose health care providers to higher concentrations of viral aerosols. It is also important to avoid having unnecessary staff in the room during intubation procedures.
References

1. Yam LY, Chen RC, Zhong NS. SARS: ventilatory and intensive care. Respirology. 2003;8 Suppl:S31-35. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15018131.

2. Twu SJ, Chen TJ, Chen CJ, et al. Control measures for severe acute respiratory syndrome (SARS) in Taiwan. Emerg Infect Dis. 2003;9(6):718-720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12781013.

3. Centers for Disease Control and Prevention. The National Personal Protective Technology Laboratory (NPPTL): respirator trusted-source information. 2020. Available at: https://www.cdc.gov/niosh/npptl/topics/ respirators/disp_part/respsource1quest2.html. Accessed September 23, 2020.

4. Milton DK, Fabian MP, Cowling BJ, Grantham ML, McDevitt JJ. Influenza virus aerosols in human exhaled breath: particle size, culturability, and effect of surgical masks. PLoS Pathog. 2013;9(3):e1003205. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23505369.

5. Qian H, Li Y, Sun H, Nielsen PV, Huang X, Zheng X. Particle removal efficiency of the portable HEPA air cleaner in a simulated hospital ward. Building Simulation. 2010;3:215-224. Available at: https://link.springer.com/article/10.1007/s12273-010-0005-4.

6. Offeddu V, Yung CF, Low MSF, Tam CC. Effectiveness of masks and respirators against respiratory infections in halthcare workers: a systematic review and meta-analysis. Clin Infect Dis. 2017;65(11):1934-1942. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29140516.

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7. World Health Organization. Infection prevention and control during health care when novel coronavirus (nCoV) infection is suspected. 2020. Available at: https://www.who.int/publications-detail/infection- prevention-and-control-during-health-care-when-novel-coronavirus-(ncov)-infection-is-suspected-20200125. Accessed April 8, 2020.

8. Centers for Disease Control and Prevention. Interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (COVID-19) in healthcare settings. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/infection-control/control-recommendations.html. Accessed September 28, 2020.

9. Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb M. Medical masks vs N95 respirators for preventing COVID-19 in healthcare workers: a systematic review and meta-analysis of randomized trials. Influenza Other Respir Viruses. 2020;14(4):365-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32246890.

10. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One. 2012;7(4):e35797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22563403.

11. Lewis SR, Butler AR, Parker J, Cook TM, Schofield-Robinson OJ, Smith AF. Videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation: a Cochrane Systematic Review. Br J Anaesth. 2017;119(3):369-383. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28969318.

     

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Hemodynamics

Last Updated: October 9, 2020

Most of the hemodynamic recommendations below are similar to those previously published in the

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Ultimately, patients with COVID-19 who require fluid resuscitation or hemodynamic management of shock should be treated and managed identically to patients with septic shock.1

COVID-19 patients who require fluid resuscitation or hemodynamic management of shock should be treated and managed for septic shock in accordance with other published guidelines, with the following exceptions.

Recommendation

• For adults with COVID-19 and shock, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using dynamic parameters, skin temperature, capillary refilling time, and/or lactate levels over static parameters to assess fluid responsiveness (BIIa).

Rationale

No direct evidence addresses the optimal resuscitation strategy for patients with COVID-19 and shock. In a systematic review and meta-analysis of 13 non-COVID-19 randomized clinical trials (n = 1,652),2 dynamic assessment to guide fluid therapy reduced mortality (risk ratio 0.59; 95% CI, 0.42–0.83), intensive care unit (ICU) length of stay (weighted mean difference -1.16 days; 95% CI, -1.97 to -0.36), and duration of mechanical ventilation (weighted mean difference -2.98 hours; 95% CI, -5.08 to -0.89). Dynamic parameters used in these trials included stroke volume variation (SVV), pulse pressure variation (PPV), and stroke volume change with passive leg raise or fluid challenge. Passive leg raising, followed by PPV and SVV, appears to predict fluid responsiveness with the highest accuracy.3 The static parameters included components of early goal-directed therapy (e.g., central venous pressure, mean arterial pressure).

Resuscitation of non-COVID-19 patients with shock based on serum lactate levels has been summarized in a systematic review and meta-analysis of seven randomized clinical trials (n = 1,301). Compared with central venous oxygen saturation-guided therapy, early lactate clearance-directed therapy was associated with a reduction in mortality (relative ratio 0.68; 95% CI, 0.56–0.82), shorter length of ICU stay (mean difference -1.64 days; 95% CI, -3.23 to -0.05), and shorter duration of mechanical ventilation (mean difference -10.22 hours; 95% CI, -15.94 to -4.50).4

Recommendation

• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using buffered/balanced crystalloids over unbalanced crystalloids (BIIa).

Rationale

A pragmatic randomized trial that compared balanced and unbalanced crystalloids in 15,802 critically ill adults found that the rate of the composite outcome of death, new renal-replacement therapy, or persistent renal dysfunction was lower in the balanced crystalloids group (OR 0.90; 95% CI, 0.82–0.99; P = 0.04).5 A secondary analysis compared outcomes in a subset of patients with sepsis (n = 1,641). Among the sepsis patients in the balanced crystalloids group, there were fewer deaths (aOR 0.74; 95% CI, 0.59–0.93; P = 0.01), as well as fewer days requiring vasopressors and renal replacement therapy.6

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A subsequent meta-analysis of 21 randomized controlled trials (n = 20,213) that included the pragmatic trial cited above compared balanced crystalloids to 0.9% saline for resuscitation of critically ill adults and children and reported nonsignificant differences in hospital mortality (OR 0.91; 95% CI, 0.83–1.01) and acute kidney injury (OR 0.92; 95% CI, 0.84–1.00).7

Recommendation

• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against the initial use of albumin for resuscitation (BIIa).

Rationale

A meta-analysis of 20 non-COVID-19 randomized controlled trials (n = 13,047) that compared the use of albumin or fresh-frozen plasma to crystalloids in critically ill patients found no difference in all-cause mortality,8 whereas a meta-analysis of 17 non-COVID-19 randomized controlled trials (n = 1,977) that compared the use of albumin to crystalloids specifically in patients with sepsis observed a reduction in mortality (OR 0.82; 95% CI, 0.67–1.0; P = 0.047).9 Given the higher cost of albumin and the lack of a definitive clinical benefit, the Panel recommends against the routine use of albumin for initial acute resuscitation of patients with COVID-19 and shock.

Additional Recommendations Based on General Principles of Critical Care

• The Panel recommends against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (AIIa).

• The Panel recommends norepinephrine as the first-choice vasopressor (AIIa). The Panel recommends adding either vasopressin (up to 0.03 units/min) (BIIa) or epinephrine (CIIb) to norepinephrine to raise mean arterial pressure to target or adding vasopressin (up to 0.03 units/ minute) (CIIa) to decrease norepinephrine dosage.

• When norepinephrine is available, the Panel recommends against using dopamine for patients with COVID-19 and shock (AIIa).

• The Panel recommends against using low-dose dopamine for renal protection (BIIa).

• The Panel recommends using dobutamine in patients who show evidence of cardiac dysfunction and persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (BIII).

• The Panel recommends that all patients who require vasopressors have an arterial catheter placed as soon as practical, if resources are available (BIII).

• For adults with COVID-19 and refractory septic shock who are not receiving corticosteroids to treat their COVID-19, the Panel recommends using low-dose corticosteroid therapy (“shock- reversal”) over no corticosteroid therapy (BIIa).

• A typical corticosteroid regimen in septic shock is intravenous hydrocortisone 200 mg per day administered either as an infusion or in intermittent doses. The duration of hydrocortisone therapy is usually a clinical decision.

• Patients who are receiving corticosteroids for COVID-19 are receiving sufficient replacement therapy such that they do not require additional hydrocortisone.
References

1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. Available at:

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https://www.ncbi.nlm.nih.gov/pubmed/28098591.

2. Bednarczyk JM, Fridfinnson JA, Kumar A, et al. Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45(9):1538-1545. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28817481.

3. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27673307.

4. Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore). 2019;98(8):e14453. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30813144.

5. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29485925.

6. Brown RM, Wang L, Coston TD, et al. Balanced crystalloids versus saline in sepsis. A secondary analysis of the SMART clinical trial. Am J Respir Crit Care Med. 2019;200(12):1487-1495. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31454263.

7. Antequera Martin AM, Barea Mendoza JA, Muriel A, et al. Buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children. Cochrane Database Syst Rev. 2019;7:CD012247. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31334842.

8. Lewis SR, Pritchard MW, Evans DJ, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8:CD000567. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30073665.

9. Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39(2):386-391. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21248514.

        

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Oxygenation and Ventilation

Last Updated: December 17, 2020

The COVID-19 Treatment Guidelines Panel’s (the Panel’s) recommendations below emphasize recommendations from the Surviving Sepsis Campaign Guidelines for adult sepsis, pediatric sepsis, and COVID-19.

Nonmechanically Ventilated Adults With Hypoxemic Respiratory Failure

Recommendations

• For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel recommends high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV) (BIIa).

• In the absence of an indication for endotracheal intubation, the Panel recommends a closely monitored trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure and for whom HFNC is not available (BIIa).

• For patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated, the Panel recommends considering a trial of awake prone positioning to improve oxygenation (CIIa).

• The Panel recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients who otherwise meet the indications for intubation and mechanical ventilation (AIII).

• If intubation becomes necessary, the procedure should be performed by an experienced practitioner in a controlled setting due to the enhanced risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure to health care practitioners during intubation (AIII).
Rationale
Severe illness in COVID-19 typically occurs approximately 1 week after the onset of symptoms.
The most common symptom is dyspnea, which is often accompanied by hypoxemia. Patients with severe disease typically require supplemental oxygen and should be monitored closely for worsening respiratory status because some patients may progress to acute respiratory distress syndrome (ARDS).
Goal of Oxygenation
The optimal oxygen saturation (SpO2) in adults with COVID-19 is uncertain. However, a target SpO2 of 92% to 96% seems logical considering that indirect evidence from experience in patients without COVID-19 suggests that an SpO2 <92% or >96% may be harmful.
Regarding the potential harm of maintaining an SpO2 <92%, a trial randomly assigned ARDS patients without COVID-19 to either a conservative oxygen strategy (target SpO2 of 88% to 92%) or a liberal oxygen strategy (target SpO2 ≥96%). The trial was stopped early due to futility after enrolling 205 patients, but in the conservative oxygen group there was increased mortality at 90 days (between- group risk difference of 14%; 95% CI, 0.7% to 27%) and a trend toward increased mortality at 28-days (between-group risk difference of 8%; 95% CI, -5% to 21%).1
Regarding the potential harm of maintaining an SpO2 >96%, a meta-analysis of 25 randomized trials involving patients without COVID-19 found that a liberal oxygen strategy (median SpO2 of 96%) was associated with an increased risk of in-hospital mortality compared to a lower SpO2 comparator (relative
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risk 1.21; 95% CI, 1.03–1.43).2

Acute Hypoxemic Respiratory Failure

In adults with COVID-19 and acute hypoxemic respiratory failure, conventional oxygen therapy may be insufficient to meet the oxygen needs of the patient. Options for providing enhanced respiratory support include HFNC, NIPPV, intubation and invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

High-Flow Nasal Cannula and Noninvasive Positive Pressure Ventilation

HFNC is preferred over NIPPV in patients with acute hypoxemic respiratory failure based on data from an unblinded clinical trial in patients without COVID-19 who had acute hypoxemic respiratory failure. Study participants were randomized to HFNC, conventional oxygen therapy, or NIPPV. The patients in the HFNC group had more ventilator-free days (24 days) than those in the conventional oxygen therapy group (22 days) or NIPPV group (19 days) (P = 0.02), and 90-day mortality was lower in the HFNC group than in either the conventional oxygen therapy group (HR 2.01; 95% CI, 1.01–3.99) or the NIPPV group (HR 2.50; 95% CI, 1.31–4.78).3 In the subgroup of more severely hypoxemic patients (PaO2/FiO2 mm Hg ≤200), the intubation rate was lower for HFNC than for conventional oxygen therapy or NIPPV (HR 2.07 and 2.57, respectively).

The trial’s findings were corroborated by a meta-analysis of eight trials with 1,084 patients conducted to assess the effectiveness of oxygenation strategies prior to intubation. Compared to NIPPV, HFNC reduced the rate of intubation (OR 0.48; 95% CI, 0.31–0.73) and ICU mortality (OR 0.36; 95% CI, 0.20–0.63).4

NIPPV may generate aerosol spread of SARS-CoV-2 and thus increase nosocomial transmission of the infection.5,6 It remains unclear whether HFNC results in a lower risk of nosocomial SARS-CoV-2 transmission than NIPPV.

Prone Positioning for Nonintubated Patients

Although prone positioning has been shown to improve oxygenation and outcomes in patients with moderate-to-severe ARDS who are receiving mechanical ventilation,7,8 there is less evidence regarding the benefit of prone positioning in awake patients who require supplemental oxygen without mechanical ventilation. In a case series of 50 patients with COVID-19 pneumonia who required supplemental oxygen upon presentation to a New York City emergency department, awake prone positioning improved the overall median oxygen saturation of the patients. However, 13 patients still required intubation due to respiratory failure within 24 hours of presentation to the emergency department.9 Other case series of patients with COVID-19 requiring oxygen or NIPPV have similarly reported that awake prone positioning is well-tolerated and improves oxygenation,10-12 with some series also reporting low intubation rates after proning.10,12

A prospective feasibility study of awake prone positioning in 56 patients with COVID-19 receiving HFNC or NIPPV in a single Italian hospital found that prone positioning for ≤3 hours was feasible in 84% of the patients. There was a significant improvement in oxygenation during prone positioning (PaO2/FiO2 181 mm Hg in supine position vs. PaO2/FiO2 286 mm Hg in prone position). However, when compared with baseline oxygenation before initiation of prone positioning, this improvement in oxygenation was not sustained (PaO2/FiO2 of 181 mm Hg and 192 mm Hg at baseline and 1 hour after resupination, respectively). Among patients put in the prone position, there was no difference in intubation rate between patients who maintained improved oxygenation (i.e., responders) and nonresponders.9

A prospective, multicenter observational cohort study in Spain and Andorra evaluated the effect of prone positioning on the rate of intubation in COVID-19 patients with acute respiratory failure receiving

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HFNC. Of the 199 patients requiring HFNC, 55 (27.6%) were treated with prone positioning. Although the time to intubation was 1 day (IQR 1.0–2.5) in patients receiving HFNC and prone positioning versus 2 days [IQR 1.0–3.0] in patients receiving only HFNC (P = 0.055), the use of awake prone positioning did not reduce the risk of intubation (RR 0.87; 95% CI, 0.53–1.43; P = 0.60).13

Overall, despite promising data, it is unclear which hypoxemic, nonintubated patients with COVID-19 pneumonia benefit from prone positioning, how long prone positioning should be continued, or whether the technique prevents the need for intubation or improves survival.10

Appropriate candidates for awake prone positioning are those who can adjust their position independently and tolerate lying prone. Awake prone positioning is contraindicated in patients who are in respiratory distress and who require immediate intubation. Awake prone positioning is also contraindicated in patients who are hemodynamically unstable, patients who recently had abdominal surgery, and patients who have an unstable spine.14 Awake prone positioning is acceptable and feasible for pregnant patients and can be performed in the left lateral decubitus position or the fully prone position.15

Intubation for Invasive Mechanical Ventilation

It is essential to monitor hypoxemic patients with COVID-19 closely for signs of respiratory decompensation. To ensure the safety of both patients and health care workers, intubation should be performed in a controlled setting by an experienced practitioner.

Mechanically Ventilated Adults

Recommendations

For mechanically ventilated adults with COVID-19 and ARDS:

• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body
weight) over higher VT ventilation (VT >8 mL/kg) (AI).

• The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).

• The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).

• The Panel recommends against the routine use of inhaled nitric oxide (AIIa).
Rationale
There is no evidence that ventilator management of patients with hypoxemic respiratory failure due to COVID-19 should differ from ventilator management of patients with hypoxemic respiratory failure due to other causes.
Positive End-Expiratory Pressure and Prone Positioning in Mechanically Ventilated Adults With Moderate to Severe Acute Respiratory Distress Syndrome
Recommendations
For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:

• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a
lower PEEP strategy (BIIa).

• For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BIIa).
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Rationale

PEEP is beneficial in patients with ARDS because it prevents alveolar collapse, improves oxygenation, and minimizes atelectotrauma, a source of ventilator-induced lung injury. A meta-analysis of individual patient data from the three largest trials that compared lower and higher levels of PEEP in patients without COVID-19 found lower rates of ICU mortality and in-hospital mortality with higher PEEP in those with moderate (PaO2/FiO2 100–200 mm Hg) and severe ARDS (PaO2/FiO2 <100 mm Hg).16

Although there is no clear standard as to what constitutes a high level of PEEP, one conventional threshold is >10 cm H2O.17 Recent reports have suggested that, in contrast to patients with non-COVID- 19 causes of ARDS, some patients with moderate or severe ARDS due to COVID-19 have normal static lung compliance and thus, in these patients, higher PEEP levels may cause harm by compromising hemodynamics and cardiovascular performance.18,19 Other studies reported that patients with moderate to severe ARDS due to COVID-19 had low compliance, similar to the lung compliance seen in patients with conventional ARDS.20-23 These seemingly contradictory observations suggest that COVID-19 patients with ARDS are a heterogeneous population and assessment for responsiveness to higher PEEP should be individualized based on oxygenation and lung compliance. Clinicians should monitor patients for known side effects of higher PEEP, such as barotrauma and hypotension.

Neuromuscular Blockade in Mechanically Ventilated Adults With Moderate to Severe Acute Respiratory Distress Syndrome

Recommendations

For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:

• The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents
(NMBA) or continuous NMBA infusion to facilitate protective lung ventilation (BIIa).

• In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the Panel recommends using a continuous NMBA infusion for up to 48 hours as long as patient anxiety and pain can be adequately monitored and controlled (BIII).
Rationale
The recommendation for intermittent boluses of NMBA or continuous infusion of NMBA to facilitate lung protection may require a health care provider to enter the patient’s room frequently for close clinical monitoring. Therefore, in some situations, the risks of SARS-CoV-2 exposure and the need
to use personal protective equipment for each entry into a patient’s room may outweigh the benefit of NMBA treatment.
Rescue Therapies for Mechanically Ventilated Adults With Acute Respiratory Distress Syndrome
Recommendations
For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies:

• The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers (CIIa).

• If recruitment maneuvers are used, the Panel recommends against using staircase (incremental PEEP) recruitment maneuvers (AIIa).
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• The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off (CIII).

Rationale

There are no studies to date assessing the effect of recruitment maneuvers on oxygenation in severe ARDS due to COVID-19. However, a systematic review and meta-analysis of six trials of recruitment maneuvers in non-COVID-19 patients with ARDS found that recruitment maneuvers reduced mortality, improved oxygenation 24 hours after the maneuver, and decreased the need for rescue therapy.24 Because recruitment maneuvers can cause barotrauma or hypotension, patients should be closely monitored during recruitment maneuvers. If a patient decompensates during recruitment maneuvers, the maneuver should be stopped immediately. The importance of properly performing recruitment maneuvers was illustrated by an analysis of eight randomized controlled trials in non-COVID-19 patients (n = 2,544) which found that recruitment maneuvers did not reduce hospital mortality (RR 0.90; 95% CI, 0.78–1.04). Subgroup analysis found that traditional recruitment maneuvers significantly reduced hospital mortality (RR 0.85; 95% CI, 0.75–0.97), whereas incremental PEEP titration recruitment maneuvers increased mortality (RR 1.06; 95% CI, 0.97–1.17).25

Although there are no published studies of inhaled nitric oxide in patients with COVID-19, a Cochrane review of 13 trials of inhaled nitric oxide use in patients with ARDS found no mortality benefit.26 Because the review showed a transient benefit in oxygenation, it is reasonable to attempt inhaled nitric oxide as a rescue therapy in COVID patients with severe ARDS after other options have failed. However, if there

is no benefit in oxygenation with inhaled nitric oxide, it should be tapered quickly to avoid rebound pulmonary vasoconstriction that may occur with discontinuation after prolonged use.

References

1. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020;382(11):999-1008. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32160661.

2. Chu DK, Kim LH, Young PJ, et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693- 1705. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29726345.

3. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-2196. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25981908.

4. Ni YN, Luo J, Yu H, Liu D, Liang BM, Liang ZA. The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-analysis. Am J Emerg Med. 2018;36(2):226-233. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28780231.

5. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One. 2012;7(4):e35797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22563403.

6. Yu IT, Xie ZH, Tsoi KK, et al. Why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? Clin Infect Dis. 2007;44(8):1017-1025. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17366443.

7. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-2168. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23688302.

8. Fan E, Del Sorbo L, Goligher EC, et al. An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice guideline: mechanical ventilation in adult

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patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(9):1253-1263. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28459336.

9. Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-378. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32320506.

10. Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020;10(1):33. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32189136.

11. Elharrar X, Trigui Y, Dols AM, et al. Use of prone positioning in nonintubated patients With COVID-19 and hypoxemic acute respiratory failure. JAMA;2020;323(22):2336-2338. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32412581.

12. Sartini C, Tresoldi M, Scarpellini P, et al. Respiratory parameters in patients with COVID-19 after using noninvasive ventilation in the prone position outside the intensive care unit. JAMA. 2020;323(22):2338-2340. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32412606.

13. Ferrando C, Mellado-Artigas R, Gea A, et al. Awake prone positioning does not reduce the risk of intubation in COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, adjusted cohort study. Crit Care. 2020;24(1):597. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33023669.

14. Bamford P, Bentley A, Dean J, Whitmore D, Wilson-Baig N. ICS guidance for prone positioning of the conscious COVID patient. Intensive Care Society. 2020. Available at: https://emcrit.org/wp-content/ uploads/2020/04/2020-04-12-Guidance-for-conscious-proning.pdf. Accessed December 8, 2020.

15. Society for Maternal Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_COVID_ pos_preg_patients_4-30-20_final.pdf. Accessed December 8, 2020.

16. Briel M, Meade M, Mercat A, et al. Higher vs. lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865-873. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20197533.

17. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32224769.

18. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32329799.

19. Tsolaki V, Siempos I, Magira E, Kokkoris S, Zakynthinos GE, Zakynthinos S. PEEP levels in COVID-19 pneumonia. Crit Care. 2020;24(1):303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32505186.

20. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. COVID-19 in critically ill patients in the Seattle region – case series. N Engl J Med. 2020;382(21):2012-2022. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32227758.

21. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32442528.

22. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study. Am J Respir Crit Care Med. 2020;201(12):1560-1564. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32348678.

23. Schenck EJ, Hoffman K, Goyal P, et al. Respiratory mechanics and gas exchange in COVID-19 associated respiratory failure. Ann Am Thorac Soc. 2020;17(9):1158-1161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32432896.

24. Goligher EC, Hodgson CL, Adhikari NKJ, et al. Lung recruitment maneuvers for adult patients with acute respiratory distress syndrome. a systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(Supplement 4):S304-S311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29043837.

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25. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-887. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32222812.

26. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016(6):CD002787. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27347773.

 

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Acute Kidney Injury and Renal Replacement Therapy

Last Updated: December 17, 2020

Recommendations

• For critically ill adults with COVID-19 who have acute kidney injury (AKI) and who develop indications for renal replacement therapy (RRT), the COVID-19 Treatment Guidelines Panel (the Panel) recommends continuous renal replacement therapy (CRRT), if available (BIII).

• If CRRT is not available or not possible due to limited resources, the Panel recommends prolonged intermittent renal replacement therapy (PIRRT) rather than intermittent hemodialysis (IHD) (BIII).
Rationale
AKI that requires RRT occurs in approximately 22% of patients with COVID-19 who are admitted to the intensive care unit.1 Evidence pertaining to RRT in patients with COVID-19 is scarce. Until additional evidence is available, the Panel suggests using the same indications for RRT in patients with COVID-19 as those used for other critically ill patients.2
RRT modalities have not been compared in COVID-19 patients; the Panel’s recommendations are motivated by the desire to minimize the risk of viral transmission to health care workers. The Panel considers CRRT to be the preferred RRT modality. CRRT is preferable to PIRRT because medication dosing for CRRT is more easily optimized and CRRT does not require nursing staff to enter the patient’s room to begin and end dialysis sessions. CRRT and PIRRT are both preferable to IHD because neither requires a dedicated hemodialysis nurse.3 Peritoneal dialysis has also been used during surge situations in patients with COVID-19.
In situations where there may be insufficient CRRT machines or equipment to meet demand, the Panel advocates performing PIRRT instead of CRRT, and then using the machine for another patient after appropriate cleaning.
References

1. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5,700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32320003.

2. American Society of Nephrology. Recommendations on the care of hospitalized patients with COVID-19 and kidney failure requiring renal replacement therapy. 2020. Available at: https://www.asn-online.org/g/blast/ files/AKI_COVID-19_Recommendations_Document_03.21.2020.pdf. Accessed November 20, 2020.

3. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): considerations for providing hemodialysis to patients with suspected or confirmed COVID-19 in acute care settings. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/dialysis/dialysis-in-acute-care.html. Accessed November 19, 2020.

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Pharmacologic Interventions

Last Updated: October 9, 2020

Antiviral Therapy

See Therapeutic Management of Patients with COVID-19 for recommendations on the use of remdesivir with or without corticosteroids.

Immune-Based Therapy

Several immune-based therapies that are expected to modify the course of COVID-19, including corticosteroids, are currently under investigation or are already in use. These agents may target the virus (e.g., convalescent plasma) or modulate the immune response (e.g., corticosteroids, interleukin [IL]-1 or IL-6 inhibitors). Recommendations regarding immune-based therapy can be found in Immunomodulators Under Evaluation for the Treatment of COVID-19.

Corticosteroids

See Therapeutic Management of Patients with COVID-19 for recommendations on the use of dexamethasone with or without remdesivir.

Adjunctive Therapy

Recommendations for using adjunctive therapy in a critical care setting can be found in the Antithrombotic Therapy and Vitamin C sections.

Empiric Broad-Spectrum Antimicrobial Therapy

Recommendations

• In patients with COVID-19 and severe or critical illness, there are insufficient data to recommend empiric broad-spectrum antimicrobial therapy in the absence of another indication.

• If antimicrobials are initiated, the Panel recommends that their use should be reassessed daily in order to minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).
Rationale
There are no reliable estimates of the incidence or prevalence of copathogens with severe acute respiratory syndrome coronavirus 2 at this time.
Some experts routinely administer broad-spectrum antibiotics as empiric therapy for bacterial pneumonia to all patients with COVID-19 and moderate or severe hypoxemia. Other experts administer antibiotics only for specific situations, such as the presence of a lobar infiltrate on a chest X-ray, leukocytosis, an elevated serum lactate level, microbiologic data, or shock.
Gram stain, culture, or other testing of respiratory specimens is often not available due to concerns about aerosolization of the virus during diagnostic procedures or when processing specimens.
There are no clinical trials that have evaluated the use of empiric antimicrobial agents in patients with COVID-19 or other severe coronavirus infections.
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Extracorporeal Membrane Oxygenation

Last Updated: December 17, 2020

Recommendation

• There are insufficient data to recommend either for or against the use of extracorporeal membrane oxygenation (ECMO) in adults with COVID-19 and refractory hypoxemia.

Rationale

ECMO has been used as a short-term rescue therapy in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 and refractory hypoxemia. However, there is no conclusive evidence that ECMO is responsible for better clinical outcomes regardless of the cause of hypoxemic respiratory failure.1-4

The clinical outcomes for patients with ARDS who are treated with ECMO are variable and depend
on multiple factors, including the etiology of hypoxemic respiratory failure, the severity of pulmonary and extrapulmonary illness, the presence of comorbidities, and the ECMO experience of the individual center.5-7 A recent case series of 83 COVID-19 patients in Paris reported a 60-day mortality of 31%
for patients on ECMO.8 This mortality was similar to the mortality observed in a 2018 study of non- COVID-19 patients with ARDS who were treated with ECMO during the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial; that study reported a mortality of 35% at Day 60.3

The Extracorporeal Life Support Organization (ELSO) Registry provides the largest multicenter outcome dataset of patients with confirmed COVID-19 who received ECMO support and whose data were voluntarily submitted. A recent cohort study evaluated ELSO Registry data for 1,035 COVID-19 patients who initiated EMCO between January 16 and May 1, 2020, at 213 hospitals in 36 countries. This study reported an estimated cumulative in-hospital mortality of 37.4% in these patients 90 days after they initiated ECMO (95% CI; 34.4% to 40.4%).9 Without a controlled trial that evaluates the use of ECMO in patients with COVID-19 and hypoxemic respiratory failure (e.g., ARDS), the benefits of ECMO cannot be clearly defined for this patient population.

Ideally, clinicians who are interested in using ECMO should try to enter their patients into clinical trials or clinical registries so that more informative data can be obtained. The following resources provide more information on the use of ECMO in patients with COVID-19:

• The ELSO ECMO in COVID-19 website

• A list of clinical trials that are evaluating ECMO in patients with COVID-19 on ClinicalTrials.gov
References

1. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19762075.

2. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)- induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am J Respir Crit Care Med. 2013;187(3):276-285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23155145.

3. Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018;378(21):1965-1975. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29791822.

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4. Munshi L, Walkey A, Goligher E, Pham T, Uleryk EM, Fan E. Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir Med. 2019;7(2):163-172. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30642776.

5. Bullen EC, Teijeiro-Paradis R, Fan E. How I select which patients with ARDS should be treated with venovenous extracorporeal membrane oxygenation. Chest. 2020;158(3):1036-1045. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32330459.

6. Henry BM, Lippi G. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports. J Crit Care. 2020;58:27-28. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32279018.

7. Mustafa AK, Alexander PJ, Joshi DJ, et al. Extracorporeal membrane oxygenation for patients with COVID-19 in severe respiratory failure. JAMA Surg. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32780089.

8. Schmidt M, Hajage D, Lebreton G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32798468.

9. Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet. 2020;396(10257):1071-1078. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32987008.

     

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Therapeutic Management of Patients With COVID-19

Last Updated: April 21, 2021

Executive Summary

Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course, the disease is primarily driven by replication of SARS-CoV-2. Later in the clinical course, the disease appears to be driven by a dysregulated immune/inflammatory response to SARS-CoV-2 that leads to tissue damage. Based on this understanding, it is anticipated that antiviral therapies would have the greatest effect early in the course of the disease, while immunosuppressive/anti-inflammatory therapies are likely to be more beneficial in the later stages of COVID-19.

No therapy has been proven to be beneficial in outpatients with mild to moderate COVID-19 who
are not at high risk for disease progression. The COVID-19 Treatment Guidelines Panel (the Panel) recommends providing supportive care and symptomatic management to outpatients with COVID-19; steps should also be taken to reduce the risk of SARS-CoV-2 transmission to others.1,2 Patients should be advised about when to seek in-person evaluation. See Outpatient Management of Acute COVID-19 for more information.

In outpatients with mild to moderate COVID-19 who are at high risk for disease progression, anti- SARS-CoV-2 antibody-based therapies may have the greatest potential for clinical benefit during the earliest stages of infection. For these patients, the Panel recommends administering bamlanivimab plus etesevimab (AIIa) or casirivimab plus imdevimab (AIIa), both of which are available through Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA). See Anti- SARS-CoV-2 Monoclonal Antibodies for more information about using these combinations and other monoclonal antibodies.

Remdesivir, an antiviral agent, is currently the only drug that is approved by the FDA for the treatment of COVID-19. It is recommended for use in hospitalized patients who require supplemental oxygen. However, it is not routinely recommended for patients who require mechanical ventilation due to the lack of data showing benefit at this advanced stage of the disease.3-6

Dexamethasone, a corticosteroid, has been found to improve survival in hospitalized patients who require supplemental oxygen, with the greatest benefit observed in patients who require mechanical ventilation. Therefore, the use of dexamethasone is strongly recommended in this setting.7-10

Adding tocilizumab, a recombinant humanized anti-interleukin-6 receptor monoclonal antibody, to dexamethasone therapy was found to improve survival among patients who were exhibiting rapid respiratory decompensation due to COVID-19.11,12

The Panel continues to review the most recent clinical data to provide up-to-date treatment recommendations for clinicians who are caring for patients with COVID-19. Figure 1 summarizes the Panel’s recommendations for managing patients with varying severities of disease.

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For definitions of the clinical severity categories for patients with COVID-19, please see Clinical Spectrum of SARS-CoV-2 Infection.

Patients With Mild to Moderate COVID-19 Who Are Not Hospitalized

Recommendations

For patients who are not at high risk of disease progression:
• The Panel recommends providing supportive care and symptomatic management (AIII).

For patients who are at high risk of disease progression, as defined by the EUA criteria for treatment with anti-SARS-CoV-2 monoclonal antibodies:

• The Panel recommends using one of the following combination anti-SARS-CoV-2 monoclonal antibodies (treatments are listed in alphabetical order):

• Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or

• Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).

• Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen test or a nucleic acid amplification test and within 10 days of symptom onset.
Additional Considerations

• There are no comparative data to determine whether there are differences in clinical efficacy or safety between bamlanivimab plus etesevimab and casirivimab plus imdevimab.

• There are SARS-CoV-2 variants, particularly those that contain the mutation E484K, that reduce the virus’ susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known.

• In regions where SARS-CoV-2 variants with reduced in vitro susceptibility to bamlanivimab plus etesevimab are common, some Panel members would preferentially use casirivimab plus imdevimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.
Rationale for Recommending Supportive Care and Symptomatic Management for Patients Who Are Not at High Risk of Disease Progression
No specific therapy has been proven to be beneficial in outpatients with mild to moderate COVID-19
who are not at high risk for disease progression. The Panel recommends supportive care and symptomatic management (AIII), with close monitoring for worsening symptoms and clinical deterioration for patients.
Rationale for the Use of Combination Anti-SARS-CoV-2 Monoclonal Antibodies
Two anti-SARS-CoV-2 combination products—bamlanivimab plus etesevimab and casirivimab plus imdevimab—have received EUAs from the FDA for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of disease progression (as defined by the EUA). The FDA had previously issued an EUA for bamlanivimab alone. Due to the increase in circulating variants that have the potential for resistance to bamlanivimab, that EUA has since been revoked.
Several circulating SARS-CoV-2 variants, particularly those that contain the mutation E484K, are associated with reduced susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro. However, the clinical impact of these mutations is not known. Reduced in vitro susceptibility to both antibodies in a combination regimen is currently uncommon. Please see Anti-
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SARS-CoV-2 Monoclonal Antibodies for more information regarding the circulating SARS-CoV-2 variants of concern and interest and the susceptibility of these variants to anti-SARS-CoV-2 monoclonal antibodies.

The clinical trial data that demonstrate the clinical benefit of these anti-SARS-CoV-2 monoclonal antibody combinations for the treatment of outpatients with mild to moderate COVID-19 are outlined below. It is worth noting that these studies were conducted before the widespread circulation of the variants of concern.

Clinical Data

Bamlanivimab Plus Etesevimab

The EUA for bamlanivimab plus etesevimab was based on data from several studies, including the Blocking Viral Attachment and Cell Entry With SARS-CoV-2 Neutralizing Antibodies (BLAZE)-1 and BLAZE-4 trials.

In the Phase 3 BLAZE-1 trial, a randomized trial that included 1,035 high-risk participants, the primary endpoint was the proportion of participants who had a COVID-19-related hospitalization (defined as
≥24 hours of acute care) or who died from any cause by Day 29. Compared to those who received placebo, participants who received bamlanivimab 2,800 mg plus etesevimab 2,800 mg had a 5% absolute reduction and a 70% relative reduction in COVID-19-related hospitalizations or death from any cause; endpoint events occurred in 11 of 518 participants (2.1%) in the bamlanivimab plus etesevimab arm

and in 36 of 517 participants (7.0%) in the placebo arm (P = 0.0004). There were no deaths in the bamlanivimab plus etesevimab arm, and 10 deaths occurred in the placebo arm.13,14

Of note, the doses authorized in the EUA (bamlanivimab 700 mg plus etesevimab 1,400 mg) are different from the doses studied in the Phase 3 BLAZE-1 study. The available data suggest that the antiviral activity of this lower dose is similar to that of bamlanivimab 2,800 mg plus etesevimab 2,800 mg.14

Casirivimab Plus Imdevimab

The recommendation for the use of casirivimab plus imdevimab is based on Phase 3 results from the R10933-10987-COV-2067 study (the information from this study is currently available only in a press release, and there is no peer-reviewed preprint or publication).15 This trial compared 1,355 participants who received casirivimab 1,200 mg plus imdevimab 1,200 mg to 1,341 participants who received placebo.

The modified full analysis set included participants who were aged ≥18 years and had a positive SARS-CoV-2 polymerase chain reaction result from a nasopharyngeal swab at randomization and one or more risk factors for severe COVID-19. COVID-19-related hospitalizations or death from any cause were reported in 18 of 1,355 participants (1.3%) in the casirivimab plus imdevimab arm and in 62 of 1,341 participants (4.6%) in the placebo arm (P < 0.0001). This represents a 3.3% absolute reduction and a 71% relative reduction in hospitalization or death in the casirivimab plus imdevimab treatment participants.

Patients Who Are Hospitalized With Moderate COVID-19 but Who Do Not Require Supplemental Oxygen

Recommendations

• The Panel recommends against the use of dexamethasone or other corticosteroids (AIIa). Patients who are receiving dexamethasone or another corticosteroid for other indications should continue therapy for their underlying conditions as directed by their health care provider.

• There are insufficient data to recommend either for or against the routine use of remdesivir in these patients. The use of remdesivir may be appropriate in patients who have a high risk of disease progression.
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Rationale for Recommending Against the Use of Dexamethasone or Other Corticosteroids

In the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, a multicenter, open-label trial in the United Kingdom, hospitalized patients with COVID-19 were randomized to receive either dexamethasone plus standard of care or standard of care alone (control arm).7 In the subgroup of participants who did not require supplemental oxygen at enrollment, no survival benefit was observed for dexamethasone: 17.8% of participants in the dexamethasone arm and 14% in the control arm died within 28 days of enrollment (rate ratio 1.19; 95% CI, 0.91–1.55). Please see Table 4a for additional information. Based on these data, the Panel recommends against the use of dexamethasone (AIIa) or other corticosteroids (AIII) for the treatment of COVID-19 in this subgroup, unless the patient has another indication for corticosteroid therapy.

Rationale for the Panel’s Assessment That There Are Insufficient Data to Recommend Either for or Against the Use of Remdesivir

The Adaptive COVID-19 Treatment Trial (ACTT-1) was a multinational randomized controlled trial that compared remdesivir to placebo in hospitalized patients with COVID-19. Remdesivir showed no significant benefit in patients with mild to moderate disease, which was defined as oxygen saturation >94% on room air or a respiratory rate <24 breaths/min without supplemental oxygen (rate ratio for recovery 1.29; 95% CI, 0.91–1.83); however, there were only 138 patients in this group.3

In a manufacturer-sponsored, open-label randomized trial of 596 patients with moderate COVID-19, patients who received 5 days of remdesivir had higher odds of having a better clinical status on Day 11 (based on distribution on a seven-point ordinal scale) than those who received standard of care (OR 1.65; 95% CI, 1.09–2.48; P = 0.02). However, the difference between the groups was of uncertain clinical importance.5

The Solidarity trial was a large, multinational, open-label randomized controlled trial in which a 10-day course of remdesivir was compared to standard of care. About 25% of hospitalized patients in the remdesivir and control arms did not require supplemental oxygen at study entry. The primary outcome of in-hospital mortality occurred in 11 of 661 patients (2%) in the remdesivir arm and in 13 of 664 patients (2.1%) in the control arm (rate ratio 0.90; 99% CI, 0.31–2.58).16 The open-label design of this study makes it difficult to determine whether remdesivir affects recovery time as determined by duration of hospitalization, because patient discharge may have been delayed in order to complete remdesivir therapy. Please see Table 2a for additional information.

Because these trials produced conflicting results regarding the benefits of remdesivir, the Panel finds
the available data insufficient to recommend either for or against routine treatment with remdesivir for all hospitalized patients with moderate COVID-19. However, the Panel recognizes that there may be situations in which a clinician judges that remdesivir is an appropriate treatment for a hospitalized patient with moderate disease (e.g., a person who is at a particularly high risk for clinical deterioration).

For Hospitalized Patients With COVID-19 Who Require Supplemental Oxygen but Who Do Not Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or Extracorporeal Membrane Oxygenation

Recommendations

The Panel recommends one of the following options for these patients:

• Remdesivir (e.g., for patients who require minimal supplemental oxygen) (BIIa);

• Dexamethasone plus remdesivir (e.g., for patients who require increasing amounts of oxygen) (BIII); or
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• Dexamethasone (e.g., when combination therapy with remdesivir cannot be used or is not available) (BI).

Additional Considerations

• If dexamethasone is not available, an alternative corticosteroid such as prednisone, methylprednisolone, or hydrocortisone can be used (BIII). See Corticosteroids for dosing recommendations.

• In the rare circumstances when corticosteroids cannot be used, baricitinib plus remdesivir can be used (BIIa). Baricitinib should not be used without remdesivir.

• There is insufficient evidence to determine which patients in this group would benefit from adding tocilizumab to dexamethasone treatment. Some Panel members would add tocilizumab to a patient’s dexamethasone treatment in cases where the patient has rapidly increasing oxygen needs and C-reactive protein (CRP) levels ≥75 mg/L but does not yet require oxygen through high-flow nasal canula (HFNC) or noninvasive ventilation.
Rationale for the Use of Remdesivir
In ACTT-1, remdesivir was associated with improved time to recovery in the subgroup of participants
(n = 435) who required oxygen supplementation but not high-flow oxygen, noninvasive ventilation, or mechanical ventilation (7 days for remdesivir vs. 9 days for placebo; recovery rate ratio 1.45; 95% CI, 1.18–1.79). A lower percentage of patients in the remdesivir arm than in the placebo arm progressed to requiring high-flow oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) among those who were not using these methods of oxygen delivery at baseline (17% vs. 24%). In a post hoc analysis of deaths by Day 29, remdesivir appeared to confer a substantial survival benefit in this subgroup (HR for death 0.30; 95% CI, 0.14–0.64).3
The Solidarity trial reported no difference in the rate of in-hospital deaths between patients who received remdesivir and those who received standard of care (rate ratio for death in the overall study population 0.95; 95% CI, 0.81–1.11; rate ratio for death in patients who did not require mechanical ventilation at entry 0.86; 99% CI, 0.67–1.11). There was no difference between patients who received remdesivir and those who received standard of care in the percentage of patients who progressed to invasive mechanical ventilation (11.9% vs. 11.5%) or in length of hospital stay.16 However, an open-label trial like Solidarity is less well-suited to assess time to recovery than a placebo-controlled trial. In Solidarity, because both clinicians and patients knew that remdesivir was being administered, it is possible that the hospital discharge could have been delayed in order to complete the 10-day course of therapy.
Based on the results of ACTT-1, the Panel recommends remdesivir (without dexamethasone) as a treatment option for certain patients who require supplemental oxygen (e.g., those who require minimal supplemental oxygen) (BIIa). In these individuals, the hyperinflammatory state where corticosteroids might be most beneficial may not yet be present or fully developed. For more information, please see Table 2a.
Rationale for the Use of Remdesivir Plus Dexamethasone
The safety and efficacy of using remdesivir plus dexamethasone for the treatment of COVID-19 have
not been rigorously evaluated in clinical trials. Despite the lack of clinical trial data, there is a theoretical rationale for combining remdesivir and dexamethasone (see the discussion of clinical trial data for remdesivir above and the discussion for dexamethasone below). Patients with severe COVID-19 may develop a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The potent anti-inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory effects. Thus, the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent, such as dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory response
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that is a consequence of the infection.

Based on these theoretical considerations, the Panel recommends the combination of dexamethasone plus remdesivir as a treatment option for patients in this group (e.g., those who require increasing amounts of supplemental oxygen) (BIII).

Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among participants who required supplemental oxygen at enrollment. In the dexamethasone group, 23.3% of participants died within 28 days of enrollment compared with 26.2% in the standard of care arm (rate ratio 0.82; 95% CI, 0.72–0.94).7 However, the amount of supplemental oxygen that participants were receiving and the proportions of participants who required oxygen delivery through a high-flow device or noninvasive ventilation were not reported. It is possible that the benefit of dexamethasone was greatest in those who required more respiratory support. It should be noted that <0.1% of patients in the RECOVERY trial received concomitant remdesivir. For more information, please see the Corticosteroids section.

However, some experts prefer not to use dexamethasone monotherapy in this group because of the theoretical concern that corticosteroids might slow viral clearance when they are administered without an antiviral drug. Corticosteroids have been associated with delayed viral clearance and/or worse clinical outcomes in patients with other viral respiratory infections.17-19 Some studies have suggested that corticosteroids slow SARS-CoV-2 clearance, but the results to date are inconclusive.20-24

Rationale for the Use of Baricitinib Plus Remdesivir When Corticosteroids Cannot Be Administered

In ACTT-2, 1,033 hospitalized patients with COVID-19 were randomized to receive baricitinib (a Janus kinase inhibitor) plus remdesivir or placebo plus remdesivir. Among all participants, the median time to recovery was shorter with baricitinib plus remdesivir (7 days) than with remdesivir alone (8 days; rate ratio 1.16; 95% CI, 1.01–1.32; P = 0.03). New use of oxygen or mechanical ventilation was less likely with baricitinib plus remdesivir than with remdesivir alone, as were serious adverse events and new infections.

In a subgroup analysis of participants who required supplemental oxygen but who did not receive it through a high-flow device or invasive mechanical ventilation, the rate ratio for recovery was 1.17 (95% CI, 0.98–1.39). There was no statistically significant difference in mortality by Day 28 between the baricitinib and placebo arms in this subgroup (OR 0.4; 95% CI, 0.14–1.14) or in the overall population. Baseline corticosteroid use was an exclusion criterion, and the trial enrolled most participants prior to the public release of RECOVERY data.

Because dexamethasone has been shown to reduce mortality among patients who required supplemental oxygen, clinicians should prioritize the use of dexamethasone in this subgroup. The Panel therefore reserves baricitinib plus remdesivir for the rare circumstances in which corticosteroids are contraindicated (BIIa). It is unknown whether baricitinib would have an additive benefit or adverse effects when given in combination with corticosteroids. Therefore, the Panel recommends against using the combination of baricitinib, dexamethasone, and remdesivir, except in a clinical trial (BIII). It is also unknown whether baricitinib would have an additive benefit or adverse effects when given

in combination with tocilizumab. Therefore, the Panel recommends against using the combination of baricitinib and tocilizumab, except in a clinical trial (BIII).

Rationale for the Panel’s Assessment That There Are Insufficient Data to Determine Which Patients Would Benefit From Dexamethasone Plus Tocilizumab

Early trials that evaluated the use of tocilizumab in patients who were hospitalized with COVID-19 did

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not show a treatment effect for tocilizumab. These trials included a high proportion of patients who were receiving conventional oxygen therapy; however, many of these trials were underpowered, and only
a small proportion of patients were also receiving corticosteroids.25-29 Although the RECOVERY trial reported a mortality benefit for tocilizumab, the study did not identify a particular subgroup of hospitalized patients on conventional oxygen therapy who benefited most from receiving the drug.12 Among 21,550 participants who were randomized into the RECOVERY platform trial, only 4,116 of the participants (19%) underwent a second randomization into the tocilizumab intervention arm, suggesting that the study results are generalizable only to a restricted subset of hospitalized patients. The Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the RECOVERY trial suggests that patients with clinical evidence of progressive COVID-19 were preferentially selected for the tocilizumab study.

The Panel recognizes that there may be some hospitalized patients who are receiving conventional oxygen therapy who may have progressive hypoxemia associated with significant systemic inflammation. The addition of tocilizumab to their standard treatment may provide a modest benefit. Nevertheless, there is insufficient evidence to clearly characterize the subgroups within this patient population who would benefit from receiving tocilizumab.

For Hospitalized Patients With COVID-19 Who Require Delivery of Oxygen Through a High-Flow Device or Noninvasive Ventilation but Not Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation

Recommendations

• The Panel recommends one of the following options for these patients:

• Dexamethasone alone (AI); or

• A combination of dexamethasone plus remdesivir (BIII).

• For patients who were recently hospitalized and who have rapidly increasing oxygen needs and systemic inflammation, add tocilizumab to one of the two options above (BIIa).
Additional Considerations

• The combination of dexamethasone and remdesivir has not been rigorously studied in clinical trials. Because there are theoretical reasons for combining these drugs, the Panel considers both dexamethasone alone and the combination of remdesivir and dexamethasone to be acceptable options for treating COVID-19 in this group of patients.

• The Panel recommends against the use of remdesivir alone because it is not clear whether remdesivir confers a clinical benefit in this group of patients (AIIa).

• For patients who initially received remdesivir monotherapy and progressed to requiring high-flow oxygen or noninvasive ventilation, dexamethasone should be initiated and remdesivir should be continued until the treatment course is completed.

• If dexamethasone is not available, equivalent doses of other corticosteroids such as prednisone, methylprednisolone, or hydrocortisone may be used (BIII). See Corticosteroids for more information.

• In the rare circumstances where corticosteroids cannot be used, baricitinib plus remdesivir can be used (BIIa). Baricitinib should not be used without remdesivir.

• Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at an equivalent dose).

• Some clinicians may choose to assess a patient’s clinical response to dexamethasone before deciding whether tocilizumab is needed.
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• Although some patients in the Randomised, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) and RECOVERY trials received a second dose of tocilizumab at the discretion of their treating physicians, there are insufficient data to determine which patients, if any, would benefit from an additional dose of the drug.

• The combination of dexamethasone and tocilizumab may increase the risk of opportunistic infections or reactivation. Prophylactic treatment with ivermectin should be considered for patients who are from areas where strongyloidiasis is endemic.
Rationale for the Use of Dexamethasone
In the RECOVERY study, treatment with dexamethasone conferred a survival benefit among participants who required supplemental oxygen without invasive mechanical ventilation at enrollment: 23.3% of the participants in the dexamethasone group died within 28 days of enrollment compared with 26.2% in the standard of care arm (rate ratio 0.82; 95% CI, 0.72–0.94).7
Rationale for the Use of Remdesivir Plus Dexamethasone
The combination of remdesivir and dexamethasone has not been rigorously studied in clinical trials; therefore, the safety and efficacy of this combination are unknown. The Panel recognizes that there are theoretical reasons to use the combination of remdesivir and dexamethasone, as described above. Based on these theoretical considerations, the Panel considers the combination of dexamethasone plus remdesivir a treatment option for patients in this group (e.g., in those who require delivery of oxygen through a high-flow device or noninvasive ventilation).
Rationale for Not Recommending Remdesivir Monotherapy
In ACTT-1, there was no observed difference in time to recovery between the remdesivir and placebo groups (recovery rate ratio 1.09; 95% CI, 0.76–1.57) in the subgroup of participants who required high-flow oxygen or noninvasive ventilation at enrollment (n = 193). A post hoc analysis did not show
a survival benefit for remdesivir at Day 29.3 However, the trial was not powered to detect differences in outcomes within subgroups. The Panel does not recommend using remdesivir monotherapy in these patients because there is uncertainty regarding whether remdesivir alone confers a clinical benefit in this subgroup (AIIa). Dexamethasone or remdesivir plus dexamethasone are better treatment options for COVID-19 in this group of patients.
For patients who start remdesivir monotherapy and then progress to requiring oxygen delivery through
a high-flow device or noninvasive ventilation, the Panel recommends initiating dexamethasone and continuing remdesivir until the treatment course is completed. Clinical trials that evaluated the use of remdesivir categorized patients based on their severity of illness at the start of treatment with remdesivir; therefore, patients may benefit from remdesivir even if their clinical course progresses to a severity of illness for which the benefits of remdesivir are less certain.
Rationale for Recommending the Combination Use of Tocilizumab and Dexamethasone in Certain Hospitalized Patients
The REMAP-CAP and RECOVERY studies, the two largest randomized controlled tocilizumab
trials to date, have both reported a mortality benefit for tocilizumab among patients with rapid respiratory decompensation who require oxygen delivery through HFNC or noninvasive ventilation.11,12 Corticosteroids were given to a majority of patients in both studies. In REMAP-CAP, a narrowly defined population of patients who were admitted to an intensive care unit (ICU) with severe to
critical COVID-19 and who were exhibiting rapid respiratory decompensation were randomized to receive open-label tocilizumab or usual care alone. Compared to usual care, the use of tocilizumab reduced in-hospital mortality (28% vs. 36%) and increased the number of days free of respiratory and
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cardiovascular organ support (10 days vs. 0 days; OR 1.64; 95% CI, 1.25–2.14). Enrollment occurred within 24 hours of ICU admission and within a median of 1.2 days of hospitalization (IQR 0.8–2.8 days), suggesting that the benefit of tocilizumab occurs specifically in patients who are experiencing rapid respiratory decompensation. In REMAP-CAP, the evidence for therapeutic benefit was strongest among recipients who had recently started oxygen supplementation through HFNC or noninvasive ventilation, though the lack of subgroup analyses by oxygen requirement is a notable limitation of this study.

The RECOVERY trial also suggested a mortality benefit for tocilizumab plus dexamethasone in patients who specifically required noninvasive ventilation or HFNC. In this study, a subset of participants with hypoxemia and CRP levels ≥75 mg/L were offered enrollment into a second randomization to receive tocilizumab or usual care. Tocilizumab reduced all-cause mortality in these patients; 29% of participants in the tocilizumab arm had died by Day 28 compared to 33% of participants in the usual care arm (rate ratio 0.86; 95% CI, 0.77–0.96).

The Panel recommends against using tocilizumab without concomitant corticosteroids, as multiple trials have reported that the clinical benefit of tocilizumab is seen among patients who are receiving tocilizumab plus a corticosteroid (see Table 4b).

Rationale for Using Baricitinib Plus Remdesivir When Corticosteroids Are Contraindicated

During ACTT-2, the median time to recovery was shorter in the baricitinib plus remdesivir arm (7
days) than in the placebo plus remdesivir arm (8 days) in the overall study population (rate ratio 1.16; 95% CI, 1.01–1.32; P = 0.03). In a subgroup analysis of participants who required high-flow oxygen
or noninvasive ventilation (n = 216), the median time to recovery was 10 days in the baricitinib plus remdesivir arm and 18 days in the remdesivir alone arm (rate ratio 1.51; 95% CI, 1.10–2.08). There was no statistically significant difference in mortality by Day 28 between the baricitinib and placebo arms (OR 0.65; 95% CI, 0.39–1.09) in the overall population.

Baseline corticosteroid use was an exclusion criterion, and the trial enrolled most participants prior to
the public release of RECOVERY data. It is unknown whether baricitinib would have an additive benefit
to treatment with corticosteroids, or whether baricitinib is safer or more efficacious than corticosteroids. Because dexamethasone has been shown to reduce mortality in patients with COVID-19 who required supplemental oxygen, clinicians should prioritize the use of dexamethasone over the use of baricitinib in
this group of patients. The Panel therefore reserves baricitinib in combination with remdesivir for the rare circumstance in which corticosteroids are contraindicated for this subgroup (BIIa). It is unknown whether baricitinib would have an additive benefit or adverse effects when given in combination with corticosteroids. Therefore, the Panel recommends against using the combination of baricitinib, dexamethasone, and remdesivir, except in a clinical trial (BIII). It is also unknown whether baricitinib would have an additive benefit or adverse effects when given in combination with tocilizumab. Therefore, the Panel recommends against using the combination of baricitinib and tocilizumab, except in a clinical trial (BIII).

For Hospitalized Patients With COVID-19 Who Require Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation

Recommendations

• The Panel recommends the use of dexamethasone in hospitalized patients with COVID-19 who require invasive mechanical ventilation or ECMO (AI).

Additional Considerations

• If dexamethasone is not available, equivalent doses of alternative corticosteroids such as prednisone, methylprednisolone, or hydrocortisone may be used (BIII).

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• For patients who initially received remdesivir monotherapy and progressed to requiring invasive mechanical ventilation or ECMO, dexamethasone should be initiated and remdesivir should be continued until the treatment course is completed.

• The Panel recommends against the use of remdesivir monotherapy (AIIa).

• Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at
an equivalent dose).

• Although some patients in the REMAP-CAP and RECOVERY trials received a second dose of tocilizumab at the discretion of their treating physicians, there are insufficient data to determine which patients, if any, would benefit from an additional dose of the drug.

• The combination of dexamethasone and tocilizumab may increase the risk of opportunistic infections or reactivation. Prophylactic treatment with ivermectin should be considered for patients who are from areas where strongyloidiasis is endemic.
Rationale for the Use of Dexamethasone Monotherapy
As the disease progresses in patients with COVID-19, a systemic inflammatory response may lead to multiple organ dysfunction syndrome. The anti-inflammatory effects of corticosteroids mitigate the inflammatory response, and the use of corticosteroids has been associated with improved outcomes in people with COVID-19 and critical illness.
Dexamethasone reduces mortality in critically ill patients with COVID-19 according to a meta-analysis that aggregated seven randomized trials and included data on 1,703 critically ill patients.30 The largest trial in the meta-analysis was the RECOVERY trial, whose subgroup of mechanically ventilated patients was included.7 For details about the meta-analysis and the RECOVERY trial, see the Corticosteroids section. Because the benefits outweigh the potential harms, the Panel recommends the use of dexamethasone in hospitalized patients with COVID-19 who require invasive mechanical ventilation or ECMO (AI).
Considerations Related to the Use of Dexamethasone Plus Remdesivir Combination Therapy
Dexamethasone plus remdesivir combination therapy has not been evaluated in controlled studies; therefore, there is insufficient information to make a recommendation either for or against the use of this combination therapy. There is, however, a theoretical reason to administer dexamethasone plus remdesivir to patients who have recently been intubated. Antiviral therapy may prevent a steroid-related delay in viral clearance. This delay has been reported in the setting of other viral infections.17,18
Some studies have suggested that corticosteroids slow SARS-CoV-2 clearance, but the studies to date are not definitive. For example, an observational study in people with non-severe COVID-19 suggested that viral clearance was delayed in patients who received corticosteroids,31 whereas a more recent study in patients with moderate to severe COVID-19 found no relationship between the use of corticosteroids and the rate of viral clearance.24 Given the conflicting results from observational studies and the absence of clinical trial data, some Panel members would coadminister dexamethasone and remdesivir in patients who have recently been placed on mechanical ventilation (CIII) until more conclusive evidence becomes available, based on their concerns about delayed viral clearance in patients who received corticosteroids. Other Panel members would not coadminister these drugs due to uncertainties about the benefit of using remdesivir in critically ill patients.
Rationale for Recommending the Use of Tocilizumab Plus Dexamethasone in Patients Within 24 Hours of Admission to the Intensive Care Unit
The REMAP-CAP and RECOVERY studies, the two largest randomized controlled tocilizumab trials to date, have both reported a mortality benefit for tocilizumab among patients who were recently admitted
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to the ICU with rapid respiratory decompensation, including those who required invasive mechanical ventilation.11,12 REMAP-CAP enrolled patients within 24 hours of admission to the ICU. Prior trials
that enrolled patients later in the ICU course and/or who received oxygen support >24 hours after ICU admission have failed to show consistent clinical benefits from tocilizumab (see Table 4b). Thus, it is unclear whether there is a clinical benefit for tocilizumab in patients who received invasive mechanical ventilation more than 24 hours after ICU admission. Findings from RECOVERY suggest a clinical benefit for tocilizumab among patients with rapid clinical progression who received invasive mechanical ventilation, tocilizumab, and corticosteroids. See the section above for additional details on the clinical trial data and rationale for using tocilizumab in this situation.

Rationale for Recommending Against the Use of Remdesivir Monotherapy

A clear benefit of remdesivir monotherapy has not been demonstrated in patients who require invasive mechanical ventilation or ECMO. During ACTT-1, remdesivir did not improve the recovery rate in this subgroup of participants (recovery rate ratio 0.98; 95% CI, 0.70–1.36), and in a post hoc analysis of deaths by Day 29, remdesivir did not improve survival among participants in this subgroup (HR 1.13; 95% CI, 0.67–1.89).3 In the Solidarity trial, there was a trend toward increased mortality among patients who received mechanical ventilation and who were randomized to receive remdesivir rather than standard of care (rate ratio 1.27; 95% CI, 0.99–1.62).16 Taken together, these results do not demonstrate a clear benefit of remdesivir in critically ill patients.

For patients who start remdesivir monotherapy and then progress to requiring invasive mechanical ventilation or ECMO, the Panel recommends initiating dexamethasone and continuing remdesivir until the treatment course is completed. Clinical trials that evaluated remdesivir categorized patients based
on their severity of illness at the start of treatment with remdesivir; therefore, patients may benefit from receiving remdesivir even if their clinical course progresses to a severity of illness for which the benefits of remdesivir are less certain.

References

1. Centers for Disease Control and Prevention. COVID-19: how to protect yourself & others. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed March 15, 2021.

2. Centers for Disease Control and Prevention. COVID-19: if you are sick or caring for someone. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/. Accessed March 15, 2021.

3. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813-1826. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.

4. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32423584.

5. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32821939.

6. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020;383(19):1827-1837. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459919.

7. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.

8. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, Phase IIb, placebo-controlled trial. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32785710.

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9. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-1316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876695.

10. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-1329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876697.

11. Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.

12. Horby PW, Pessoa-Amorim G, Peto L, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021;preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.

13. Dougan M, Nirula A, Gottlieb RL, et al. Bamlanivimab+etesevimab for treatment of COVID-19 in high-risk ambulatory patients. Virtual Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Available at: https://www.croiconference.org/wp-content/uploads/sites/2/resources/2021/vCROI-2021- Abstract-eBook.pdf.

14. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download. Accessed February 17, 2021.

15. Regeneron. COV-2067 Phase 3 trial in high-risk outpatients shows that REGEN-COV (2400 mg and 1200 mg IV doses) significantly reduces risk of hospitalization or death while also shortening symptom duration. 2021. Available at: https://newsroom.regeneron.com/index.php/static-files/a7173b5a-28f3-45d4-bede- b97370bd03f8. Accessed April 5, 2021.

16. Pan H, Peto R, Henao-Restrepo A, et al. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity Trial results. N Engl J Med. 2020;384(6):497-511. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33264556.

17. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29161116.

18. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16968120.

19. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26950335.

20. Chen Y, Li L. Influence of corticosteroid dose on viral shedding duration in patients with COVID-19. Clin Infect Dis. 2020;72(7):1298-1300. Available at: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ ciaa832/5863026.

21. Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19. Clin Infect Dis. 2020;72(7):1297-1298. Available at: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa829/5863128.

22. Ding C, Feng X, Chen Y, et al. Effect of corticosteroid therapy on the duration of SARS-CoV-2 clearance in patients with mild COVID-19: a retrospective cohort study. Infect Dis Ther. 2020;9(4):943-952. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32986226.

23. Liu J, Zhang S, Dong X, et al. Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome. J Clin Invest. 2020;130(12):6417-6428. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33141117.

24. Spagnuolo V, Guffanti M, Galli L, et al. Viral clearance after early corticosteroid treatment in patients with moderate or severe covid-19. Sci Rep. 2020;10(1):21291. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33277573.

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25. Veiga VC, Prats J, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33472855.

26. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332779.

27. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333-2344. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33085857.

28. Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24-31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080005.

29. Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32-40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080017.

30. Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876694.

31. Li Q, Li W, Jin Y, et al. Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther. 2020;9(4):823-836. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32880102.

      

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Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19
Last Updated: February 11, 2021



Summary Recommendations

Remdesivir is the only Food and Drug Administration-approved drug for the treatment of COVID-19. In this section, the COVID-19 Treatment Guidelines Panel (the Panel) provides recommendations for using antiviral drugs to treat COVID-19 based on the available data. As in the management of any disease, treatment decisions ultimately reside with the patient and their health care provider. For more information on these antiviral agents, see Table 2d.

Remdesivir

• See Therapeutic Management of Patients with COVID-19 for recommendations on using remdesivir with or without dexamethasone.

Chloroquine or Hydroxychloroquine With or Without Azithromycin

• The Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the
treatment of COVID-19 in hospitalized patients (AI).

• In nonhospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or
without azithromycin for the treatment of COVID-19, except in a clinical trial (AIIa).

• The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment
of COVID-19 (AI).
Lopinavir/Ritonavir and Other HIV Protease Inhibitors

• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in hospitalized patients (AI).

• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in nonhospitalized patients (AIII).
Ivermectin
• There are insuf cient data for the Panel to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more speci c, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.

 

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

Antiviral Therapy

Because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication leads to many of the clinical manifestations of COVID-19, antiviral therapies are being investigated for the treatment of COVID-19. These drugs inhibit viral entry (via the angiotensin-converting enzyme 2 [ACE2] receptor and transmembrane serine protease 2 [TMPRSS2]), viral membrane fusion and endocytosis, or the activity of the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) and the RNA-dependent RNA polymerase.1 Because viral replication may be particularly active early in the course of COVID-19, antiviral therapy may have the greatest impact before the illness progresses to the hyperinflammatory state that can characterize the later stages of disease, including critical illness.2 For this reason, it is necessary to understand the role of antiviral medications in treating mild, moderate, severe, and critical illness in order to optimize treatment for people with COVID-19.

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The following sections describe the underlying rationale for using different antiviral medications, provide the COVID-19 Treatment Guidelines Panel’s recommendations for using these medications to treat COVID-19, and summarize the existing clinical trial data. Additional antiviral therapies will be added to this section of the Guidelines as new evidence emerges.

References

1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for Coronavirus Disease 2019 (COVID-19): a review. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32282022.

2. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-407. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32362390.

 

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Remdesivir

Last Updated: April 21, 2021

Remdesivir is an intravenous nucleotide prodrug of an adenosine analog. Remdesivir binds to the viral RNA-dependent RNA polymerase and inhibits viral replication through premature termination of RNA transcription. It has demonstrated in vitro activity against SARS-CoV-2.1 In a rhesus macaque model of SARS-CoV-2 infection, remdesivir treatment was initiated soon after inoculation; the remdesivir-treated animals had lower virus levels in the lungs and less lung damage than the control animals.2

Remdesivir is approved by the Food and Drug Administration (FDA) for the treatment of COVID-19
in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). It is also available through an FDA Emergency Use Authorization (EUA) for the treatment of COVID-19 in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg. Remdesivir should be administered in a hospital or a health care setting that can provide a similar level of care to an inpatient hospital.

Remdesivir has been studied in several clinical trials for the treatment of COVID-19. The recommendations from the COVID-19 Treatment Guidelines Panel (the Panel) are based on the results of these studies. See Table 2a for more information.

The safety and efficacy of combination therapy of remdesivir with corticosteroids have not been rigorously studied in clinical trials; however, there are theoretical reasons that combination therapy
may be beneficial in some patients with severe COVID-19. For the Panel’s recommendations on using remdesivir with or without dexamethasone in certain hospitalized patients, see Therapeutic Management of Adults With COVID-19.

Monitoring and Adverse Effects

Remdesivir can cause gastrointestinal symptoms (e.g., nausea), elevated transaminase levels, an increase in prothrombin time (without a change in the international normalized ratio), and hypersensitivity reactions.

Liver function tests and prothrombin time should be obtained in all patients before remdesivir is administered and during treatment as clinically indicated. Remdesivir may need to be discontinued if alanine transaminase (ALT) levels increase to >10 times the upper limit of normal and should be discontinued if an increase in ALT level and signs or symptoms of liver inflammation are observed.3

Considerations in Patients With Renal Insufficiency

Each 100 mg vial of remdesivir lyophilized powder contains 3 g of sulfobutylether beta-cyclodextrin sodium (SBECD), whereas each 100 mg/20 mL vial of remdesivir solution contains 6 g of SBECD.3 SBECD is a vehicle that is primarily eliminated through the kidneys. A patient with COVID-19 who receives a loading dose of remdesivir 200 mg would receive 6 g to 12 g of SBECD, depending on the formulation. This amount of SBECD is within the safety threshold for patients with normal renal function.4 Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities. Clinicians may consider preferentially using the lyophilized powder formulation (which contains less SBECD) in patients with renal impairment.

Because both remdesivir formulations contain SBECD, patients with an estimated glomerular filtration rate (eGFR) of <50 mL/min were excluded from some clinical trials of remdesivir; other trials had an eGFR cutoff of <30 mL/min. Remdesivir is not recommended for patients with an eGFR <30 mL/min

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due to lack of data.5 Renal function should be monitored before and during remdesivir treatment as clinically indicated.3

In two observational studies that evaluated the use of remdesivir in hospitalized patients with COVID-19, no significant differences were reported in the incidences of adverse effects or acute kidney injury between patients with an estimated creatinine clearance (CrCl) <30 mL/min and those with an estimated CrCl ≥30 mL/min.6,7 One of these studies evaluated patients who primarily received the solution formulation of remdesivir (20 patients had an estimated CrCl <30 mL/min and 115 had an estimated CrCl ≥30 mL/min);6 the other study evaluated patients who received the lyophilized powder formulation (40 patients had an estimated CrCl <30 mL/min and 307 had an estimated CrCl ≥30 mL/min).7

Drug-Drug Interactions

Clinical drug-drug interaction studies of remdesivir have not been conducted. In vitro, remdesivir is
a substrate of cytochrome P450 (CYP) 3A4 and of the drug transporters organic anion-transporting polypeptide (OATP) 1B1 and P-glycoprotein. It is also an inhibitor of CYP3A4, OATP1B1, OATP1B3, and multidrug and toxin extrusion protein 1 (MATE1).3

Minimal to no reduction in remdesivir exposure is expected when remdesivir is coadministered with dexamethasone, according to information provided by Gilead Sciences (written communication, July 2020). Chloroquine or hydroxychloroquine may decrease the antiviral activity of remdesivir; coadministration of these drugs is not recommended.3 Remdesivir is not expected to have any significant interactions with oseltamivir or baloxavir, according to information provided by Gilead Sciences (written communications, August and September 2020).

See Table 2d for more information. Considerations in Pregnancy

• Pregnant patients were excluded from the clinical trials that evaluated the safety and efficacy of remdesivir for the treatment of COVID-19, but preliminary reports of remdesivir use in pregnant patients from the remdesivir compassionate use program are reassuring.

• Among 86 pregnant and postpartum hospitalized patients with severe COVID-19 who received compassionate use remdesivir, the therapy was well tolerated, with a low rate of serious adverse events.8

• Remdesivir should not be withheld from pregnant patients if it is otherwise indicated.
Considerations in Children

• The safety and effectiveness of using remdesivir to treat COVID-19 have not been evaluated in pediatric patients aged <12 years or weighing <40 kg.

• Remdesivir is available through an FDA EUA for the treatment of COVID-19 in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.

• A clinical trial is currently evaluating the pharmacokinetics of remdesivir in children (ClinicalTrials.gov Identifier NCT04431453).
Clinical Trials
Several clinical trials that are evaluating the use of remdesivir for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.
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References

1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.

2. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020;585(7824):273-276. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32516797.

3. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf.

4. Committee for Human Medicinal Products. Background review for cyclodextrins used as excipients. 2014. Available at: https://www.ema.europa.eu/en/documents/report/background-review-cyclodextrins-used- excipients-context-revision-guideline-excipients-label-package_en.pdf.

5. Adamsick ML, Gandhi RG, Bidell MR, et al. Remdesivir in patients with acute or chronic kidney disease and COVID-19. J Am Soc Nephrol. 2020;31(7):1384-1386. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32513665.

6. Pettit NN, Pisano J, Nguyen CT, et al. Remdesivir use in the setting of severe renal impairment: a theoretical concern or real risk? Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33315065.

7. Ackley TW, McManus D, Topal JE, Cicali B,Shah S. A valid warning or clinical lore: an evaluation of safety outcomes of remdesivir in patients with impaired renal function from a multicenter matched cohort. Antimicrob Agents Chemother. 2021;65(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33229428.

8. Burwick RM, Yawetz S, Stephenson KE, et al. Compassionate use of remdesivir in pregnant women with severe covid-19. Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33031500.

        

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Table 2a. Remdesivir: Selected Clinical Data

Last Updated: February 11, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for RDV. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.



Study Design

Methods

Results

Limitations and Interpretation

Adaptive COVID-19 Treatment Trial (ACTT-1)1

Multinational, placebo- controlled, double-blind RCT in hospitalized patients (n = 1,062)

Key Inclusion Criteria:

• Aged ≥18 years
• Laboratory-con rmed SARS-CoV-2 infection • At least 1 of the following conditions:

• Pulmonary in ltrates, as determined by radiographic imaging

• SpO2 ≤94% on room air

• Required supplemental oxygen

• Required mechanical ventilation

• Required ECMO
Key Exclusion Criteria:
• ALT or AST >5 times ULN
• eGFR <30 mL/min
• Pregnancy or breastfeeding
Interventions:
• IV RDV 200 mg on Day 1, then 100 mg daily for up to 9 more days
• Placebo for 10 days
Primary Endpoint:
• Time to clinical recovery
Ordinal Scale De nitions:
1. Not hospitalized, no limitations
2. Not hospitalized, with limitations
3. Hospitalized, no active medical problems

Number of Participants:

• RDV (n = 541) and placebo (n = 521)

Participant Characteristics:

• Median time from symptom onset to randomization was 9 days (IQR 6–12 days).

Outcomes

Overall Results:

• RDV reduced time to recovery compared to placebo (10 days vs. 15 days; RRR 1.29; 95% CI, 1.12–1.49; P < 0.001).

• Clinical improvement based on ordinal scale was higher at Day 15 in RDV arm (OR 1.5; 95% CI, 1.2–1.9; P < 0.001).

• No statistically signi cant difference in mortality by Day 29 between RDV and placebo arms (HR 0.73; 95% CI, 0.52–1.03; P = 0.07).

• Bene t of RDV was greatest in patients randomized during the rst 10 days after symptom onset.
Results by Disease Severity at Enrollment:

• No difference in median time to recovery between arms among patients who had mild to moderate disease at enrollment.

• Bene t of RDV for reducing time to recovery was clearest in patients who required supplemental oxygenation at enrollment (n = 435; RRR 1.45; 95% CI, 1.18–1.79), and RDV appeared to confer

Limitations:

• Wide range of disease severity; study was not powered to detect differences within subgroups

• Powered to detect differences in clinical improvement, not mortality

• No data collected on longer-term morbidity
Interpretation:

• In patients with severe COVID-19, RDV reduced time to clinical recovery.

• Bene t of RDV was most apparent in hospitalized patients on supplemental oxygen.

• No observed bene t in those on high- ow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO, but the study was not powered to detect differences within subgroups.

• No observed bene t of RDV in patients with mild or moderate COVID-19, but the number of participants in these categories was relatively small.

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Study Design

Methods

Results

Limitations and Interpretation

Adaptive COVID-19 Treatment Trial (ACTT-1)1, continued

4. Hospitalized, not on oxygen

5. Hospitalized, on oxygen

6. Hospitalized, on high- ow oxygen or noninvasive mechanical ventilation

7. Hospitalized, on mechanical ventilation or ECMO

8. Death

a survival bene t in this subgroup (HR for death by Day 29 0.30; 95% CI, 0.14–0.64).

• No observed difference in time to recovery between arms in patients on high- ow oxygen
or noninvasive ventilation at enrollment (RRR 1.09; 95% CI, 0.76–1.57). No evidence that RDV affected mortality rate in this subgroup (HR 1.02; 95% CI, 0.54–1.91).

• No observed difference in time to recovery between arms in patients on mechanical ventilation or ECMO at enrollment (RRR 0.98; 95% CI, 0.70–1.36). No evidence that RDV affected mortality rate in this subgroup (HR 1.13; 95% CI, 0.67–1.89).
Safety Results:
• Percentages of patients with SAEs were similar between arms (25% vs. 32%).
• Transaminase elevations: 6% of RDV recipients, 10.7% of placebo recipients

Remdesivir Versus Placebo for Severe COVID-19 in China2

Multicenter, placebo- controlled, double-blind RCT in hospitalized patients with severe COVID-19 (n = 237)

Key Inclusion Criteria:

• Aged ≥18 years

• Laboratory-con rmed SARS-CoV-2 infection

• Time from symptom onset to randomization <12 days

• SpO2 ≤94% on room air or PaO2/FiO2 <300 mm Hg

• Radiographically con rmed pneumonia
Key Exclusion Criteria:
• ALT or AST >5 times ULN
• eGFR <30 mL/min
• Pregnancy or breastfeeding

Number of Participants:

• ITT analysis: RDV (n = 158) and placebo (n = 78)

• Study stopped before reaching target enrollment of 453 patients due to control of the COVID-19 outbreak in China.

Participant Characteristics:

• Median time from symptom onset to randomization: 9 days for RDV arm, 10 days for placebo arm

• Receipt of corticosteroids: 65% of patients in RDV arm, 68% in placebo arm

• Receipt of LPV/RTV: 28% of patients in RDV arm, 29% in placebo arm

Limitations:

• Sample size did not have suf cient power to detect differences in clinical outcomes.

• Use of concomitant medications (i.e., corticosteroids, LPV/RTV, IFNs) may have obscured effects of RDV.
Interpretation:

• No difference in time to clinical improvement, 28-day mortality, or rate of SARS-CoV-2 clearance between RDV-treated and placebo-treated patients;

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Study Design

Methods

Results

Limitations and Interpretation

Remdesivir Versus Placebo for Severe COVID-19 in China2, continued

Interventions:

• IV RDV 200 mg on Day 1, then 100 mg daily for 9 days

• Saline placebo for 10 days

Primary Endpoint:

• Time to clinical improvement, de ned as improvement on an ordinal scale or being discharged alive from the hospital

• Receipt of IFN alfa-2b: 29% of patients in RDV arm, 38% in placebo arm

Outcomes:

• No difference in time to clinical improvement between RDV and placebo arms (median time 21 days vs. 23 days; HR 1.23; 95% CI, 0.87–1.75).

• For patients who started RDV or placebo within 10 days of symptom onset, faster time to clinical improvement was seen with RDV (median
time 18 days vs. 23 days; HR 1.52; 95% CI, 0.95–2.43); however, this was not statistically signi cant.

• 28-day mortality was similar between arms (14% of patients in RDV arm, 13% in placebo arm).

• No difference between arms in SARS-CoV-2 viral load at baseline, and rate of decline over time was similar.

• Percentage of patients with AEs: 66% in RDV arm, 64% in placebo arm

• Discontinuations due to AEs: 12% of patients in RDV arm, 5% in placebo arm

however, study was underpowered to detect differences in these outcomes between arms.

World Health Organization Solidarity Trial3

International, open- label, adaptive RCT with multiple treatment arms that enrolled hospitalized patients with COVID-19 (n = 11,330). In 1 arm, patients received RDV.

Key Inclusion Criteria:

• Aged ≥18 years

• Not known to have received any study drug

• Not expected to be transferred elsewhere within 72 hours

• Physician reported no contraindications to study drugs
Interventions:
• IV RDV 200 mg on Day 0, then 100 mg daily on Days 1–9
• Local SOC

Number of Participants:

• ITT analysis: RDV (n = 2,743) and SOC (n = 2,708)

Participant Characteristics:

• Percentage of patients aged 50–69 years: 47% in RDV arm, 48% in SOC arm

• Percentage of patients aged ≥70 years: 18% in RDV arm, 17% in SOC arm

• 67% of patients in both arms were on supplemental oxygen at entry.

• 9% of patients in both arms were mechanically ventilated at entry.

Limitations:

• Open-label study design limits the ability to assess time to recovery; clinicians and patients were aware of treatment assignment, so RDV may have been continued to complete the treatment course even if the patient had improved.

• No data on time from symptom onset to enrollment

• No assessment of outcomes post hospital discharge

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Study Design

Methods

Results

Limitations and Interpretation

World Health Organization Solidarity Trial3, continued

Primary Endpoint:

• In-hospital mortality

Secondary Endpoints:

• Initiation of mechanical ventilation • Duration of hospitalization

• Percentage of patients hospitalized for ≥2 days at entry: 40% in RDV arm, 39% in SOC arm

• Percentages of patients with comorbid conditions were similar between RDV and SOC arms: diabetes (26% and 25%), heart disease (21% both groups), and chronic lung disease (6% and 5%).

• 48% of patients in both arms received corticosteroids.
Primary Outcomes:
• In-hospital mortality: 301 deaths (11.0%) in RDV arm, 303 deaths (11.2%) in SOC arm
• Rate ratios for in-hospital death:

• Overall: 0.95 (95% CI, 0.81–1.11)

• No mechanical ventilation at entry: 0.86 (99% CI, 0.67–1.11)

• Mechanical ventilation at entry: 1.20 (99% CI, 0.80–1.80)
Secondary Outcomes:
• Initiation of mechanical ventilation: 295 patients (10.8%) in RDV arm, 284 patients (10.5%) in SOC arm

Interpretation:

• RDV did not decrease in-hospital mortality in hospitalized patients when compared to local SOC.

Remdesivir Versus Standard of Care in Hospitalized Patients with Moderate COVID-194

Open-label randomized trial in hospitalized patients (n = 596)

Key Inclusion Criteria:

• Laboratory-con rmed SARS-CoV-2 infection

• Moderate pneumonia, de ned as radiographic evidence of pulmonary in ltrates and SpO2 >94% on room air

Key Exclusion Criteria:

• ALT or AST >5 times ULN • CrCl <50 mL/min

Number of Participants:

• 584 patients began treatment: 10-day RDV (n = 193), 5-day RDV (n = 191), and SOC (n = 200)

Participant Characteristics:

• Demographic and baseline disease characteristics were similar across all arms.

Outcomes:

• 5-day RDV had signi cantly higher odds of better clinical status distribution on Day 11 than SOC (OR 1.65; 95% CI, 1.09–2.48; P = 0.02).

Limitations:

• Open-label design may have affected decisions related to concomitant medication use and hospital discharge.

• Greater proportion of patients in SOC arm received HCQ, LPV/ RTV, or AZM, which may cause AEs and have not shown clinical bene ts in hospitalized patients with COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Remdesivir Versus Standard of Care in Hospitalized Patients with Moderate COVID-194, continued

Interventions:

• IV RDV 200 mg on Day 1, then 100 mg daily for 9 days

• IV RDV 200 mg on Day 1, then 100 mg daily for 4 days

• Local SOC
Primary Endpoint:
• Clinical status on Day 11, as measured by a 7-point ordinal scale

• Clinical status distribution on Day 11 was not signi cantly different between the 10-day RDV and SOC arms (P = 0.18).

• By Day 28, there were more hospital discharges among patients who received RDV (89% in 5-day arm and 90% in 10-day arm) than those who received SOC (83%).

• Mortality was low in all arms (1% to 2%).

• Percentages of patients with AEs in RDV arms vs. SOC arm: nausea (10% vs. 3%), hypokalemia (6% vs. 2%), and headache (5% vs. 3%)

• No data on time to return to activity for discharged patients

Interpretation:

• Hospitalized patients with moderate COVID-19 who received 5 days of RDV had better outcomes than those who received SOC; however, difference between arms was of uncertain clinical importance.

Different Durations of Remdesivir Treatment in Hospitalized Patients5

Manufacturer- sponsored, multinational, randomized, open-label trial in hospitalized patients with COVID-19 (n = 402)

Key Inclusion Criteria:

• Aged ≥12 years

• Laboratory-con rmed SARS-CoV-2 infection

• Radiographic evidence of pulmonary in ltrates

• SpO2 ≤94% on room air or receipt of supplemental oxygen
Key Exclusion Criteria:
• Receipt of mechanical ventilation or ECMO • Multiorgan failure
• ALT or AST >5 times ULN
• Estimated CrCl <50 mL/min
Interventions:
• IV RDV 200 mg on Day 1, then 100 mg daily for 4 days
• IV RDV 200 mg on Day 1, then 100 mg daily for 9 days
Primary Endpoint:
• Clinical status at Day 14, as measured by a 7-point ordinal scale

Number of Participants:

• 397 participants began treatment: 5-day RDV (n = 200) and 10-day RDV (n = 197)

Participant Characteristics:

• At baseline, patients in 10-day arm had
worse clinical status (based on ordinal scale distribution) than those in 5-day arm (P = 0.02)

Outcomes:

• After adjusting for imbalances in baseline clinical status, Day 14 distribution in clinical status on the ordinal scale was similar between arms (P = 0.14).

• Time to achieve clinical improvement of at least 2 levels on the ordinal scale (median day of 50% cumulative incidence) was similar between arms (10 days vs. 11 days).

• Median durations of hospitalization among patients discharged on or before Day 14 were similar between 5-day (7 days; IQR 6–10 days) and 10-day arms (8 days; IQR 5–10 days).

• Percentages of patients with SAEs: 35% in 10- day arm, 21% in 5-day arm

Limitations:

• This was an open-label trial without a placebo control
arm, so clinical bene t of RDV (compared with no RDV) could not be assessed.

• There were baseline imbalances in clinical status of patients in the 5-day and 10-day arms.
Interpretation:

• In hospitalized patients with severe COVID-19 who were not on mechanical ventilation or ECMO, RDV treatment for 5 or 10 days had a similar clinical bene t.

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Study Design

Methods

Results

Limitations and Interpretation

Different Durations of Remdesivir Treatment in Hospitalized Patients5, continued

• Discontinuations due to AEs: 4% of patients in 5-day arm, 10% in 10-day arm

Key: AE = adverse effects; ALT = alanine transaminase; AST = aspartate aminotransferase; AZM = azithromycin; CrCl = creatinine clearance; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular ltration rate; HCQ = hydroxychloroquine; IFN = interferon; ITT = intention to treat; IV = intravenous; LPV/ RTV = lopinavir/ritonavir; the Panel = the COVID-19 Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; RCT = randomized controlled trial; RDV = remdesivir; RRR = recovery rate ratio; SAE = serious adverse effects; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SOC = standard of care; SpO2 = saturation of oxygen; ULN = upper limit of normal

References

1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.

2. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32423584.

3. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity Trial results. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33264556.

4. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32821939.

5. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459919.

    

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Chloroquine or Hydroxychloroquine With or Without Azithromycin
Last Updated: October 9, 2020

Chloroquine is an antimalarial drug that was developed in 1934. Hydroxychloroquine, an analogue of chloroquine, was developed in 1946. Hydroxychloroquine is used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, in addition to malaria. In general, hydroxychloroquine has fewer and less severe toxicities (including less propensity to prolong the QTc interval) and fewer drug-drug interactions than chloroquine.

Both chloroquine and hydroxychloroquine increase the endosomal pH, inhibiting fusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host cell membranes.1 Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 receptor, which may interfere with binding of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) to the cell receptor.2 In vitro studies have suggested that both chloroquine and hydroxychloroquine may block the transport of SARS-CoV-2 from early endosomes to endolysosomes, possibly preventing the release of the viral genome.3 Both chloroquine and hydroxychloroquine also have immunomodulatory effects. It has been hypothesized that these effects are other potential mechanisms of action for the treatment of COVID-19. However, despite demonstrating antiviral activity in some in vitro systems, hydroxychloroquine with or without azithromycin did not reduce upper or lower respiratory tract viral loads or demonstrate clinical efficacy in a rhesus macaque model.4

Chloroquine and hydroxychloroquine, with or without azithromycin, have been studied in multiple clinical trials for the treatment of COVID-19. The recommendations below are based on an assessment of the collective evidence from these studies.

Recommendations

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 in hospitalized patients (AI).

• In nonhospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19, except in a clinical trial (AIIa).

• The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI).
Rationale
The safety and efficacy of chloroquine and hydroxychloroquine with or without azithromycin have been evaluated in randomized clinical trials, observational studies, and single-arm studies. Please see Table 2b for more information.
In a large randomized controlled trial of hospitalized patients in the United Kingdom, hydroxychloroquine did not decrease 28-day mortality when compared to the usual standard of care. Participants who were randomized to receive hydroxychloroquine had a longer median hospital stay than those who received the standard of care. In addition, among patients who were not on invasive mechanical ventilation at the time of randomization, those who received hydroxychloroquine were
more likely to subsequently require intubation or die during hospitalization than those who received the standard of care.5
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In another randomized controlled trial that was conducted in Brazil, neither hydroxychloroquine alone nor hydroxychloroquine plus azithromycin improved clinical outcomes among hospitalized patients with mild to moderate COVID-19. More adverse events occurred among patients who received hydroxychloroquine or hydroxychloroquine plus azithromycin than among those who received the standard of care.6 Data from another randomized study of hospitalized patients with severe COVID-19 do not support using hydroxychloroquine plus azithromycin over hydroxychloroquine alone.7

In addition to these randomized trials, data from large retrospective observational studies do not consistently show evidence of a benefit for hydroxychloroquine with or without azithromycin in hospitalized patients with COVID-19. For example, in a large retrospective observational study of patients who were hospitalized with COVID-19, hydroxychloroquine use was not associated with a reduced risk of death or mechanical ventilation.8 Another multicenter retrospective observational study evaluated the use of hydroxychloroquine with and without azithromycin in a random sample of a large cohort of hospitalized patients with COVID-19.9 Patients who received hydroxychloroquine with or without azithromycin did not have a decreased risk of in-hospital mortality when compared to those who received neither hydroxychloroquine nor azithromycin.

Conversely, a large retrospective cohort study reported a survival benefit among hospitalized patients who received either hydroxychloroquine alone or hydroxychloroquine plus azithromycin, compared
to those who received neither drug.10 However, patients who did not receive hydroxychloroquine had
a lower rate of admission to the intensive care unit, which suggests that patients in this group may
have received less-aggressive care. Furthermore, a substantially higher percentage of patients in the hydroxychloroquine arms also received corticosteroids (77.1% of patients in the hydroxychloroquine arms vs. 36.5% of patients in the control arm). Given that the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial showed that corticosteroids improve the survival rate of patients with COVID-19 (see Corticosteroids), it is possible that the findings in this study were confounded by this imbalance in corticosteroid use.11 These and other observational and single-arm studies are summarized in Table 2b.

Many of the observational studies that have evaluated the use of chloroquine or hydroxychloroquine in patients with COVID-19 have attempted to control for confounding variables. However, study arms may be unbalanced in some of these studies, and some studies may not account for all potential confounding factors. These factors limit the ability to interpret and generalize the results from observational studies; therefore, results from these studies are not as definitive as those from large randomized trials. Given the lack of a benefit seen in the randomized clinical trials and the potential for toxicity, the Panel recommends against using hydroxychloroquine or chloroquine with or without azithromycin to treat COVID-19 in hospitalized patients (AI).

The Panel also recommends against using high-dose chloroquine to treat COVID-19 (AI). High-dose chloroquine (600 mg twice daily for 10 days) has been associated with more severe toxicities than lower-dose chloroquine (450 mg twice daily for 1 day, followed by 450 mg once daily for 4 days).
A randomized clinical trial compared the use of high-dose chloroquine and low-dose chloroquine in hospitalized patients with severe COVID-19. In addition, all participants received azithromycin, and 89% of the participants received oseltamivir. The study was discontinued early when preliminary results showed higher rates of mortality and QTc prolongation in the high-dose chloroquine group.12

Several randomized trials have not shown a clinical benefit for hydroxychloroquine in nonhospitalized patients with COVID-19. However, other clinical trials are still ongoing.13,14 In nonhospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19, except in a clinical trial (AI).

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The combination of hydroxychloroquine and azithromycin is associated with QTc prolongation
in patients with COVID-19. Given the long half-lives of both azithromycin (up to 72 hours) and hydroxychloroquine (up to 40 days), caution is warranted even when the two drugs are used sequentially instead of concomitantly.15

Please see Table 2b for additional details. Adverse Effects

Chloroquine and hydroxychloroquine have a similar toxicity profile, although hydroxychloroquine is better tolerated and has a lower incidence of toxicity than chloroquine.

Cardiac Adverse Effects

• QTc prolongation, Torsade de Pointes, ventricular arrythmia, and cardiac deaths.16 If chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse events, especially prolonged QTc interval (AIII).

• The risk of QTc prolongation is greater for chloroquine than for hydroxychloroquine.

• Concomitant medications that pose a moderate to high risk for QTc prolongation (e.g., antiarrhythmics, antipsychotics, antifungals, macrolides [including azithromycin],16 fluoroquinolone antibiotics)17 should be used only if necessary. Consider using doxycycline rather than azithromycin as empiric therapy for atypical pneumonia.

• Multiple studies have demonstrated that concomitant use of hydroxychloroquine and azithromycin can prolong the QTc interval;18-20 in an observational study, the use of hydroxychloroquine plus azithromycin was associated with increased odds of cardiac arrest.9 The use of this combination warrants careful monitoring.

• Baseline and follow-up electrocardiograms are recommended when there are potential drug interactions with concomitant medications (e.g., azithromycin) or underlying cardiac diseases.21

• The risk-benefit ratio should be assessed for patients with cardiac disease, a history of ventricular arrhythmia, bradycardia (<50 bpm), or uncorrected hypokalemia and/or hypomagnesemia.
Other Adverse Effects

• Hypoglycemia, rash, and nausea. Divided doses may reduce nausea.

• Retinopathy. Bone marrow suppression may occur with long-term use, but this is not likely with short-term use.
Drug-Drug Interactions
Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 (CYP) 2D6, and these drugs are also P-glycoprotein (P-gp) inhibitors. Use caution when administering these drugs with medications that are metabolized by CYP2D6 (e.g., certain antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, methadone) or transported by P-gp (e.g., certain direct-acting oral anticoagulants, digoxin).22 Chloroquine and hydroxychloroquine may decrease the antiviral activity of remdesivir; coadministration of these drugs is not recommended.23
Considerations in Pregnancy

• Antirheumatic doses of chloroquine and hydroxychloroquine have been used safely in pregnant women with SLE.

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• Hydroxychloroquine exposure has not been associated with adverse pregnancy outcomes in ≥300 human pregnancies.

• A lower dose of chloroquine (500 mg once a week) is used for malaria prophylaxis during pregnancy.

• No dose changes are necessary for chloroquine or hydroxychloroquine during pregnancy.
Considerations in Children

• Chloroquine and hydroxychloroquine have been routinely used in pediatric populations for the treatment and prevention of malaria and for rheumatologic conditions.

Drug Availability

• Hydroxychloroquine, chloroquine, and azithromycin are not approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.

• Hydroxychloroquine is approved by the FDA for the treatment of malaria, lupus erythematosus, and rheumatoid arthritis. Chloroquine is approved for the treatment of malaria and extraintestinal amebiasis. Azithromycin is commonly used for the treatment and/or prevention of nontuberculous mycobacterial infection, various sexually transmitted infections, and various bacterial infections.
References

1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.

2. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.

3. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194981.

4. Maisonnasse P, Guedj J, Contreras V, et al. Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates. Nature. 2020;585(7826):584-587. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32698191.

5. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.15.20151852v1.

6. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to- moderate COVID-19. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32706953.

7. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32896292.

8. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32379955.

9. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):2493-2502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392282.

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10. Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32623082.

11. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.

12. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. Available at: https://pubmed.ncbi.nlm.nih.gov/32330277/.

13. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32673060.

14. Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial. Clin Infect Dis. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674126.

15. Institute for Safe Medication Practices. Special Edition: Medication Safety Alert! 2020. Available at: https://ismp. org/acute-care/special-edition-medication-safety-alert-april-9-2020/covid-19. Accessed September 24, 2020.

16. Nguyen LS, Dolladille C, Drici MD, et al. Cardiovascular toxicities associated with hydroxychloroquine and azithromycin: an analysis of the World Health Organization pharmacovigilance database. Circulation. 2020;142(3):303-305. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32442023.

17. CredibleMeds. Combined list of drugs that prolong QT and/or cause torsades de pointes (TDP). 2020. Available at: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.

18. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature Medicine. 2020. Available at: https://doi.org/10.1038/s41591-020-0888-2.

19. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(9):1036-1041. Available at: https://pubmed.ncbi.nlm.nih.gov/32936252/.

20. Bessiere F, Roccia H, Deliniere A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) Infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. 2020;5(9):1067-1069. Available at: https://pubmed.ncbi.nlm.nih.gov/32936266/.

21. American College of Cardiology. Ventricular arrhythmia risk due to hydroxychloroquine-
azithromycin treatment for COVID-19. 2020. Available at: https://www.acc.org/latest-in-cardiology/ articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for- covid-19. Accessed September 24, 2020.

22. University of Liverpool. COVID-19 drug interactions. 2020. Available at: https://www.covid19-druginteractions.org/. Accessed September 24, 2020.

23. Food and Drug Administration. Remdesivir by Gilead Sciences: FDA warns of newly discovered potential drug interaction that may reduce effectiveness of treatment. 2020. Available at: https://www.fda.gov/safety/ medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug- interaction-may-reduce. Accessed July 2, 2020.

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Table 2b. Chloroquine or Hydroxychloroquine With or Without Azithromycin:

Selected Clinical Data

Last Updated: October 9, 2020

The information in this table may include data from preprints or articles that have not been peer reviewed. This section will be updated as new information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating CQ, HCQ, and AZM.

The Panel has reviewed other clinical studies of HCQ with or without AZM and studies of CQ for the treatment of COVID-19.1-11 These studies have limitations that make them less definitive and informative than the studies discussed here. The Panel’s summaries and interpretations of some of those studies are available in the archived versions of the COVID-19 Treatment Guidelines.

  

Study Design

Methods

Results

Limitations and Interpretation

Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial12

Open-label RCT with multiple arms, including a control arm; in 1 arm, hospitalized patients received HCQ (n = 11,197)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Clinically suspected or laboratory- con rmed SARS-CoV-2 infection

Key Exclusion Criteria:

• Patients with prolonged QTc intervals were excluded from HCQ arm.

Interventions:

• HCQ 800 mg at entry and at 6 hours, then HCQ 400 mg every 12 hours for 9 days or until discharge

• Usual SOC
Primary Endpoint:
• All-cause mortality at Day 28 after randomization

Number of Participants:

• HCQ (n = 1,561) and SOC (n = 3,155)

• Study enrollment ended early after investigators and trial- steering committee concluded that the data showed no bene t for HCQ.

Participant Characteristics:

• Mean age was 65 years in both arms; 41% of patients were aged ≥70 years.

• 90% of patients had laboratory-con rmed SARS-CoV-2 infection.

• 57% of patients had ≥1 major comorbidity: 27% had diabetes mellitus, 26% had heart disease, and 22% had chronic lung disease.

• At randomization, 17% of patients were receiving invasive mechanical ventilation or ECMO, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.

• Use of AZM or another macrolide during the follow-up period was similar in both arms, as was use of dexamethasone.

Limitations:

• Not blinded

• Information on occurrence of new major cardiac arrythmia was not collected throughout the trial.

Interpretation:

• HCQ does not decrease 28-
day all-cause mortality when compared to the usual SOC
in hospitalized patients with clinically suspected or laboratory- con rmed SARS-CoV-2 infection.

• Patients who received HCQ had a longer median length of hospital stay, and those who were not on invasive mechanical ventilation at the time of randomization were more likely to require intubation or die during hospitalization if they received HCQ.

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Study Design

Methods

Results

Limitations and Interpretation

Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial12, continued

Outcomes:

• No signi cant difference in 28-day mortality between the 2 arms; 418 patients (26.8%) in HCQ arm and 788 patients (25.0%) in SOC arm had died by Day 28 (RR 1.09; 95% CI, 0.96–1.23; P = 0.18).

• A similar 28-day mortality for HCQ patients was reported during the post hoc exploratory analysis that was restricted to the 4,234 participants (90%) who had a positive SARS-CoV-2 test result.

• Patients in HCQ arm were less likely to survive hospitalization and had a longer median time to discharge than patients in SOC arm.

• Patients who received HCQ and who were not on invasive mechanical ventilation at baseline had an increased risk of requiring intubation and an increased risk of death.

• At the beginning of the study, the researchers did not record whether a patient developed a major cardiac arrhythmia after study enrollment; however, these data were later collected for 698 patients (44.7%) in HCQ arm and 1,357 patients (43.0%) in SOC arm.

• No differences between the arms in the frequency of supraventricular tachycardia, ventricular tachycardia or brillation, or instances of AV block that required intervention.

Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin for Mild or Moderate COVID-1913

Open-label, 3-arm RCT in hospitalized patients (n = 667)

Key Inclusion Criteria:

• Aged ≥18 years

• Clinically suspected or laboratory-
con rmed SARS-CoV-2 infection

• Mild or moderate COVID-19

• Duration of symptoms ≤14 days

Number of Participants:

• Modi ed ITT analysis included patients with laboratory- con rmed SARS-CoV-2 infection (n = 504).

Participant Characteristics:

• Mean age was 50 years.

• 58% of patients were men.

• At baseline, 58.2% of patients were ordinal level 3; 41.8% were ordinal level 4.

• Median time from symptom onset to randomization was 7 days.

Limitations:

• Not blinded

• Follow-up period was restricted to 15 days.

Interpretation:

• Neither HCQ alone nor HCQ plus AZM improved clinical outcomes at Day 15 after randomization among hospitalized patients with mild or moderate COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin for Mild or Moderate COVID-1913, continued

Key Exclusion Criteria:

• Need for >4 L of supplemental oxygen or ≥40% FiO2 by face mask

• History of ventricular tachycardia

• QT interval ≥480 ms
Interventions:

• HCQ 400 mg twice daily for 7 days plus SOC

• HCQ 400 mg twice daily plus AZM 500 mg daily for 7 days plus SOC

• SOC alone
Primary Endpoint:
• Clinical status at Day 15, as assessed by a 7-point ordinal scale among the patients with con rmed SARS-CoV-2 infection
Ordinal Scale De nitions:

1. Not hospitalized, no limitations

2. Not hospitalized, with limitations

3. Hospitalized, not on oxygen

4. Hospitalized, on oxygen

5. Hospitalized, oxygen administered by HFNC or noninvasive ventilation

6. Hospitalized, on mechanical ventilation

7. Death

• 23.3% to 23.9% of patients received oseltamivir.

Outcomes:

• No signi cant difference between the odds of worse clinical status at Day 15 for patients in HCQ arm (OR 1.21; 95% CI, 0.69–2.11; P = 1.00) and patients in HCQ plus AZM arm (OR 0.99; 95% CI, 0.57–1.73; P = 1.00).

• No signi cant differences in secondary outcomes of the 3 arms, including progression to mechanical ventilation during the rst 15 days and mean number of days “alive and free of respiratory support.”

• A greater proportion of patients in HCQ plus AZM arm (39.3%) and HCQ arm (33.7%) experienced AEs than those in SOC arm (22.6%).

• QT prolongation was more common in patients who received HCQ plus AZM or HCQ alone than in patients who received SOC alone, but fewer patients in SOC arm had serial electrocardiographic studies performed during the follow-up period.

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Study Design

Methods

Results

Limitations and Interpretation

Hydroxychloroquine Versus Standard of Care for Mild or Moderate COVID-1914

Multicenter, randomized, open-label trial (n = 150)

Key Inclusion Criteria:

• Aged ≥18 years
• Laboratory-con rmed SARS-

CoV-2 infection

Key Exclusion Criteria:

• Severe conditions, including heart, liver, or kidney disease

• Inability to take oral medications • Pregnancy or breastfeeding

Interventions:

• HCQ 1,200 mg once daily for 3 days, then HCQ 800 mg once daily for 2 weeks (in patients with mild or moderate COVID-19) or 3 weeks (in patients with severe disease)

• SOC
Primary Endpoint:
• Negative conversion of SARS- CoV-2 by Day 28

Number of Participants:

• HCQ (n = 75) and SOC (n = 75)

Participant Characteristics:

• Patients were randomized at a mean of 16.6 days after symptom onset.

• 99% of patients had mild or moderate COVID-19.

Outcomes:

• HCQ arm and SOC arm had similar negative PCR conversion rates within 28 days (85.4% of participants vs. 81.3% of participants) and similar times to negative PCR conversion (median of 8 days vs. 7 days).

• No difference in the probability of symptom alleviation between the arms in the ITT analysis.

Limitations:

• Unclear how the overall rate of symptom alleviation was calculated

• Study did not reach target sample size.

Interpretation:

• This study demonstrated no difference in the rate of viral clearance between HCQ and SOC.

High-Dose Chloroquine Versus Low-Dose Chloroquine15

Randomized, double- blind, Phase 2b study in hospitalized adults (n = 81)

Key Inclusion Criteria:

• Aged ≥18 years

• Clinically suspected COVID-19

• At least 1 of the following conditions:

• Respiratory rate >24 rpm • Heart rate >125 bpm
• SpO2 <90% on room air • Shock

Number of Participants:

• High-dose CQ (n = 41) and low-dose CQ (n = 40)

• Planned study sample size was 440 participants, but study was stopped by the study’s DSMB.

Participant Characteristics:

• All patients also received ceftriaxone plus AZM. • 89.6% of patients received oseltamivir.

Limitations:

• More older patients and more patients with a history of heart disease were randomized into the high-dose arm than into the low-dose arm.

Interpretation:

• Despite the small number of patients enrolled, this study raises concerns about an increased risk of mortality when high-dose CQ is administered in combination with AZM and oseltamivir.

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Study Design

Methods

Results

Limitations and Interpretation

High-Dose Chloroquine Versus Low-Dose Chloroquine15, continued

Interventions:

• CQ 600 mg twice daily for 10 days (high dose)

• CQ 450 mg twice daily for 1 day, then CQ 450 mg for 4 days (low dose)
Primary Endpoint:
• Mortality by Day 28

Outcomes:

• Overall fatality rate was 27.2%.

• Mortality by Day 13 was higher in high-dose arm than in low-dose arm (death occurred in 16 of 41 patients [39%] vs. in 6 of 40 patients [15%]; P = 0.03). This difference was no longer signi cant after controlling for age (OR 2.8; 95% CI, 0.9–8.5).

• Overall, QTcF >500 ms occurred more frequently in high-dose arm (18.9% of patients) than in low-dose arm (11.1%).

• In the high-dose arm, 2 patients experienced ventricular tachycardia before death.

Hydroxychloroquine in Nonhospitalized Adults with Early COVID-1916

Randomized, placebo- controlled trial in the United States and Canada (n = 491)

Key Inclusion Criteria:

• ≤4 days of symptoms that were compatible with COVID-19

• Either laboratory-con rmed SARS-CoV-2 infection or high-risk exposure within the previous 14 days

Key Exclusion Criteria:

• Aged <18 years
• Hospitalized
• Receipt of certain medications

Interventions:

• HCQ 800 mg once, then HCQ 600 mg in 6 to 8 hours, then HCQ 600 mg once daily for 4 days

• Placebo

Number of Participants:

• Contributed to primary endpoint data: HCQ (n = 212) and placebo (n = 211)

Participant Characteristics:

• 241 patients were exposed to people with COVID-19 through their position as health care workers (57%), 106 were exposed through household contacts (25%), and 76 had other types of exposure (18%).

• Median age was 40 years.

• 56% of patients were women.

• Only 3% of patients were Black.

• Very few patients had comorbidities: 11% had hypertension, 4% had diabetes, and 68% had no chronic medical conditions.

• 56% of patients were enrolled on Day 1 of symptom onset.

• 341 participants (81%) had either a positive PCR result or a high-risk exposure to a PCR-positive contact.

Limitations:

• This study enrolled a highly heterogenous population.

• Only 227 of 423 participants (53.7%) were con rmed PCR-positive for SARS-CoV-2.

• Changing the primary endpoint without a new power calculation makes it dif cult to assess whether the study is powered to detect differences in outcomes between the study arms.

• This study used surveys for screening, symptom assessment, and adherence reporting.

• Visual analog scales are not commonly used, and their ability to assess acute viral respiratory infections in clinical trials has not been validated.

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Study Design

Methods

Results

Limitations and Interpretation

Hydroxychloroquine in Nonhospitalized Adults with Early COVID-1916, continued

Primary Endpoints:

• Planned primary endpoint was ordinal outcome by Day 14 in
4 categories: not hospitalized, hospitalized, ICU stay, or death.

• Because event rates were lower than expected, a new primary endpoint was de ned: change in overall symptom severity over 14 days, assessed on a 10-point, self-reported, visual analog scale

Outcomes:

• Compared to the placebo recipients, HCQ recipients had a nonsigni cant 12% difference in improvement in symptoms between baseline and Day 14 (-2.60 vs. -2.33 points; P = 0.117).

• Ongoing symptoms were reported by 24% of those in HCQ arm and 30% of those in the placebo arm at Day 14 (P = 0.21).

• No difference in the incidence of hospitalization (4 patients in the HCQ arm vs. 10 patients in placebo arm); 2 of 10 placebo participants were hospitalized for reasons that were unrelated to COVID-19.

• A higher percentage of patients in HCQ arm experienced AEs than patients in placebo arm (43% vs. 22%; P < 0.001).

Interpretation:

• The study has some limitations,
and it did not nd evidence that
early administration of HCQ reduced symptom severity in patients with mild COVID-19.

Hydroxychloroquine in Nonhospitalized Adults with Mild COVID-1917

Open-label RCT in Spain (n = 353)

Key Inclusion Criteria:

• Laboratory-con rmed SARS- CoV-2 infection

• <5 days of mild COVID-19 symptoms

Key Exclusion Criteria:

• Moderate to severe COVID-19 • Severe liver or renal disease
• History of cardiac arrhythmia • QT prolongation

Interventions:

• HCQ 800 mg on Day 1, then HCQ 400 mg once daily for 6 days

• No antiviral treatment

Number of Participants:

• ITT analysis: HCQ (n = 136) and control (n = 157)

• 60 patients were excluded from the ITT analysis due to negative baseline RT-PCR, missing RT-PCR at follow-up visits, or consent withdrawal.

Participant Characteristics:

• Mean age was 41.6 years.

• 67% of patients were woman.

• Majority of patients were health care workers (87%).

• 53% of patients reported chronic health conditions.

• Median time from symptom onset to enrollment was 3 days (IQR 2–4 days).

• Most common COVID-19 symptoms were fever, cough, and sudden olfactory loss.

Limitations:

• Open-label, non-placebo-controlled trial

• Study design allowed for the possibility of drop-outs in control arm and over- reporting of AEs in HCQ arm.

• The intervention changed during the study; the authors initially planned to include HCQ plus DRV/COBI.

• The majority of the participants were relatively young health care workers.
Interpretation:

• Early administration of HCQ to patients with mild COVID-19 did not result in improvement in virologic clearance,
a lower risk of disease progression,

or a reduced time to symptom improvement.

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Study Design

Methods

Results

Limitations and Interpretation

Hydroxychloroquine in Nonhospitalized Adults with Mild COVID-1917, continued

Primary Endpoint:

• Reduction in SARS-CoV-2
viral load, assessed using nasopharyngeal swabs on Days 3 and 7

Secondary Endpoints:

• Disease progression up to Day 28

• Time to complete resolution of symptoms

Outcomes:

• No signi cant difference in viral load reduction between control arm and HCQ arm at Day 3 (-1.41 vs. -1.41 log10 copies/mL; difference of 0.01; 95% CI, -0.28 to 0.29), or at Day 7 (-3.37 vs. -3.44 log10 copies/mL; difference of -0.07; 95% CI, -0.44 to 0.29).

• No difference in the risk of hospitalization between control arm and HCQ arm (7.1% vs. 5.9%; risk ratio 0.75; 95% CI, 0.32–1.77).

• No difference in the median time from randomization to the resolution of COVID-19 symptoms between the 2 arms (12.0 days in control arm vs. 10.0 days in HCQ arm; P = 0.38).

• A higher percentage of participants in the HCQ arm than in the control arm experienced AEs during the 28-day follow-up period (72% vs. 9%). Most common AEs were GI disorders and “nervous system disorders.”

• SAEs were reported in 12 patients in control arm and 8 patients in HCQ arm. SAEs that occurred among patients in HCQ arm were not deemed to be related to the drug.

Observational Study on Hydroxychloroquine With or Without Azithromycin18

Retrospective, multicenter, observational study
in a random sample
of inpatients with COVID-19 from the New York Department of Health (n = 1,438)

Key Inclusion Criteria:

• Laboratory-con rmed SARS- CoV-2 infection

Interventions:

• HCQ plus AZM • HCQ alone
• AZM alone
• Neither drug

Primary Endpoint:

• In-hospital mortality

Number of Participants:

• HCQ plus AZM (n = 735), HCQ alone (n = 271), AZM alone (n = 211), and neither drug (n = 221)

Participant Characteristics:

• Patients in the treatment arms had more severe disease at baseline than those who received neither drug.

Outcomes:

• In adjusted analyses, patients who received 1 of the 3 treatment regimens did not show a decreased in-hospital mortality rate when compared with those who received neither drug.

Limitations:

• This study has the inherent limitations of an observational study, including residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.

Interpretation:

• Despite the limitations discussed above, these ndings suggest that although HCQ and AZM are not associated with an increased risk of

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Study Design

Methods

Results

Limitations and Interpretation

Observational Study on Hydroxychloroquine With or Without Azithromycin18, continued

Secondary Endpoint:

• Cardiac arrest and arrhythmia or QT prolongation on an ECG

• Patients who received HCQ plus AZM had a greater risk of cardiac arrest than patients who received neither drug (OR 2.13; 95% CI, 1.12–4.05).

in-hospital death, the combination of HCQ and AZM may be associated with an increased risk of cardiac arrest.

Observational Study of Hydroxychloroquine Versus No Hydroxychloroquine in New York City19

Observational study in hospitalized adults with COVID-19 at a large medical center (n = 1,376)

Key Inclusion Criteria:

• Laboratory-con rmed SARS- CoV-2 infection

Key Exclusion Criteria:

• Intubation, death, or transfer to another facility within 24 hours of arriving at the emergency department

Interventions:

• HCQ 600 mg twice daily on Day 1, then HCQ 400 mg once daily for 4 days

• No HCQ

Primary Endpoint:

• Time from study baseline (24 hours after patients arrived at the emergency department) to intubation or death

Number of Participants:

• Received HCQ (n = 811) and did not receive HCQ (n = 565)

Participant Characteristics:

• HCQ recipients were more severely ill at baseline than those who did not receive HCQ.

Outcomes:

• Using propensity scores to adjust for major predictors of respiratory failure and inverse probability weighting, the study demonstrated that HCQ use was not associated with intubation or death (HR 1.04; 95% CI, 0.82–1.32).

• No association between concomitant use of AZM and the composite endpoint of intubation or death (HR 1.03; 95% CI, 0.81–1.31).

Limitations:

• This study has the inherent limitations of an observational study, including residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.

Interpretation:

• The use of HCQ for treatment of COVID-19 was not associated with harm or bene t in a large observational study.

Observational Cohort Study of Hydroxychloroquine Versus No Hydroxychloroquine in France20

Retrospective, observational cohort study in hospitalized adults with severe COVID-19 pneumonia at 4 tertiary care centers (n = 181)

Key Inclusion Criteria:

• Aged 18 to 80 years

• Laboratory-con rmed SARS- CoV-2 infection

• Required supplemental oxygen

Key Exclusion Criteria:

• Started HCQ before hospital admission

Number of Participants:

• Received HCQ within 48 hours (n = 84), received HCQ beyond 48 hours (n = 8), and did not receive HCQ (n = 89)

Participant Characteristics:

• In the HCQ arm, 18% of patients received concomitant AZM.

Limitations:

• This was a retrospective, nonrandomized study.

Interpretation:

• There was no difference in the rates of clinically important outcomes between patients who received HCQ within 48 hours of hospital admission and those who did not.

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Study Design

Methods

Results

Limitations and Interpretation

Observational Cohort Study of Hydroxychloroquine Versus No Hydroxychloroquine in France20, continued

• Received tocilizumab, LPV/ RTV, or RDV within 48 hours of admission

• Organ failure requiring immediate ICU admission

• ARDS
Interventions:
• HCQ 600 mg once daily • No HCQ
Primary Endpoint:
• Survival without transfer to the ICU at Day 21
Secondary Endpoints:

• Overall survival rate at Day 21

• Survival rate without ARDS at Day 21

• Weaning from oxygen by Day 21

• Discharge from hospital to home or rehabilitation by Day 21

Outcomes:

• In the inverse probability of treatment-weighted analysis, there was no difference in survival rates without ICU transfer at Day 21 between the HCQ arm (76% of participants) and the non-HCQ arm (75%).

• No difference between the arms in the secondary outcomes of overall survival rate and survival rate without ARDS at Day 21.

Retrospective Cohort Study of Hydroxychloroquine Versus No Hydroxychloroquine in Detroit, Michigan21

Comparative, retrospective cohort study in hospitalized patients with COVID-19 in the Henry Ford Health System in Michigan (n = 2,541)

Key Inclusion Criteria:

• Laboratory-con rmed SARS- CoV-2 infection

Interventions:

• HCQ 400 mg twice daily for 1 day, then 200 mg twice daily for 4 days

• AZM 500 mg for 1 day, then 250 mg once daily for 4 days

• HCQ plus AZM, at the above doses

• Neither drug

Number of Participants:

• HCQ alone (n = 1,202), AZM alone (n = 147), HCQ plus AZM (n = 783), and neither drug (n = 409)

Participant Characteristics:

• HCQ plus AZM was reserved for patients with severe COVID-19 and minimal cardiac risks.

• Median patient age was 64 years (IQR 53–76 years); 51% of patients were men, 56% were African American, and 52% had a BMI ≥30.

• Median time to follow-up was 28.5 days (IQR 3–53 days).

Limitations:

• This study evaluated 1 health care system with an institutional protocol for HCQ and AZM use.

• Because the study was not randomized and not blinded, there is a possibility of residual confounding.

• There was a lower rate of ICU admission among patients who did not receive HCQ, which suggests that this group may have received less aggressive care.

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Study Design

Methods

Results

Limitations and Interpretation

Retrospective Cohort Study of Hydroxychloroquine Versus No Hydroxychloroquine in Detroit, Michigan21, continued

Primary Endpoint:

• In-hospital mortality

• The mSOFA score was not available for 25% of patients.

• Corticosteroids were given to 79% of patients in the HCQ alone arm, 74% of patients in the HCQ plus AZM arm, and 35.7% of those on neither drug.

Outcomes:

• Overall, crude mortality was 18.1%. When broken down by the different arms, mortality was 13.5% in HCQ alone arm, 20.1% in HCQ plus AZM arm, 22.4% in AZM alone arm, and 26.4% in the arm that received neither drug
(P < 0.001).

• Mortality HRs were analyzed using a multivariable Cox regression model; the arm that received neither drug was used as the reference. HCQ alone decreased the mortality HR by 66% (P < 0.001). HCQ plus AZM decreased the mortality HR by 71% (P < 0.001).

• Other predictors of mortality were age ≥65 years (HR 2.6; 95% CI, 1.9–3.3); White race (HR 1.7; 95% CI, 1.4–2.1); chronic kidney disease (HR 1.7; 95% CI, 1.4–2.1); reduced O2 saturation level on admission (HR 1.6; 95% CI, 1.1–2.2); and ventilator use at admission (HR 2.2; 95% CI, 1.4–3.0).

• A propensity-matched Cox regression result suggested a mortality HR of 0.487 for patients who received HCQ (95% CI, 0.285–0.832, P = 0.009).

• Given that the RECOVERY trial showed that dexamethasone use conferred
a survival bene t, it is possible that the ndings were confounded by the imbalance in corticosteroid use among the arms.

Interpretation:

• This study reported a mortality bene t in hospitalized patients with COVID-19 who received either HCQ alone or HCQ plus AZM compared to patients who received neither drug. However, there were substantial imbalances in corticosteroid use among the arms, which may have affected mortality.

• Because the study was retrospective and observational, it cannot control for confounders.

Key: AE = adverse effect; ARDS = acute respiratory distress syndrome; AV = atrioventricular; AZM = azithromycin; BMI = body mass index; bpm = beats per minute; CQ = chloroquine; DRV/COBI = darunavir/cobicistat; DSMB = data safety monitoring board; ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; FiO2 = fraction of inspired oxygen; GI = gastrointestinal; HCQ = hydroxychloroquine; HFNC = high- ow nasal cannula; ICU = intensive care unit; ITT = intention to treat; LPV/RTV = lopinavir/ritonavir; mSOFA = modi ed sequential organ failure assessment; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; QTcF = Fridericia’s correction formula; RCT = randomized controlled trial; RDV = remdesivir; RR = rate ratio; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse effect; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SOC = standard of care

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References

1. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med. 2020;26(6):808-809. Available at: https://pubmed.ncbi.nlm.nih.gov/32488217.

2. Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis. 2020:101663. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32289548.

3. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32205204.

4. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020;12(4):322-325. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32236562.

5. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med (N Y). 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32838355.

6. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32240719.

7. Satlin MJ, Goyal P, Magleby R, et al. Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019 disease. PLoS One. 2020;15(7):e0236778. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32701969.

8. Mikami T, Miyashita H, Yamada T, et al. Risk factors for mortality in patients with COVID-19 in New York City. J Gen Intern Med. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32607928.

9. Catteau L, Dauby N, Montourcy M, et al. Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants. Int J Antimicrob Agents. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32853673.

10. COVID-19 RISK and Treatments (CORIST) Collaboration. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: findings from the observational multicentre Italian CORIST study. Eur J Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32859477.

11. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32896292.

12. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.15.20151852v1.

13. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32706953.

14. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409561.

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15. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32339248.

16. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32673060.

17. Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial. Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674126.

18. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):2493-2502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392282.

19. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32379955.

20. Mahevas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409486.

21. Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32623082.

      

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Ivermectin

Last Updated: February 11, 2021

Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies.1 It is also being evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on treated humans and livestock.2 For these indications, ivermectin has been widely used and is generally well tolerated.1,3 Ivermectin is not approved by the FDA for the treatment of any viral infection.

Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19

Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host’s antiviral response.4,5 In addition, ivermectin docking may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to the human cell membrane.6 Ivermectin is thought to be a host-directed agent, which may be the basis for its broad-spectrum activity in vitro against the viruses that cause dengue, Zika, HIV,

and yellow fever.4,7-9 Despite this in vitro activity, no clinical trials have reported a clinical benefit for ivermectin in patients with these viruses. Some studies of ivermectin have also reported potential anti- inflammatory properties, which have been postulated to be beneficial in people with COVID-19.10-12

Some observational cohorts and clinical trials have evaluated the use of ivermectin for the prevention and treatment of COVID-19. Data from some of these studies can be found in Table 2c.

Recommendation

• There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.

Rationale

Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in cell cultures.13 However, pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.14,15 Even though ivermectin appears to accumulate in

the lung tissue, predicted systemic plasma and lung tissue concentrations are much lower than 2 μM,
the half-maximal inhibitory concentration (IC50) against SARS-CoV-2 in vitro.16-19 Subcutaneous administration of ivermectin 400 μg/kg had no effect on SARS-CoV-2 viral loads in hamsters. However, there was a reduction in olfactory deficit (measured using a food-finding test) and a reduction in the interleukin (IL)-6:IL-10 ratio in lung tissues.20

Since the last revision of this section of the Guidelines, the results of several randomized trials and retrospective cohort studies of ivermectin use in patients with COVID-19 have been published in peer- reviewed journals or have been made available as manuscripts ahead of peer review. Some clinical studies showed no benefits or worsening of disease after ivermectin use,21-24 whereas others reported shorter time to resolution of disease manifestations that were attributed to COVID-19,25-28 greater reduction in inflammatory marker levels,26,27 shorter time to viral clearance,21,26 or lower mortality rates in patients who received ivermectin than in patients who received comparator drugs or placebo.21,26,28

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However, most of these studies had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias. These limitations include:

• The sample size of most of the trials was small.

• Various doses and schedules of ivermectin were used.

• Some of the randomized controlled trials were open-label studies in which neither the participants nor the investigators were blinded to the treatment arms.

• Patients received various concomitant medications (e.g., doxycycline, hydroxychloroquine, azithromycin, zinc, corticosteroids) in addition to ivermectin or the comparator drug. This confounded the assessment of the efficacy or safety of ivermectin.

• The severity of COVID-19 in the study participants was not always well described.

• The study outcome measures were not always clearly defined.
Table 2c includes summaries of key studies. Because most of these studies have significant limitations, the Panel cannot draw definitive conclusions on the clinical efficacy of ivermectin for the treatment
of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide further guidance on the role of ivermectin in the treatment of COVID-19.
Monitoring, Adverse Effects, and Drug-Drug Interactions

• Ivermectin is generally well tolerated. Adverse effects may include dizziness, pruritis, nausea, or diarrhea.

• Neurological adverse effects have been reported with the use of ivermectin for the treatment of onchocerciasis and other parasitic diseases, but it is not clear whether these adverse effects were caused by ivermectin or the underlying conditions.29

• Ivermectin is a minor cytochrome P 3A4 substrate and a p-glycoprotein substrate.

• Ivermectin is generally given on an empty stomach with water; however, administering ivermectin with food increases its bioavailability.

• The FDA issued a warning in April 2020 that ivermectin intended for use in animals should not be used to treat COVID-19 in humans.

• Please see Table 2c for additional information. Considerations in Pregnancy
In animal studies, ivermectin was shown to be teratogenic when given in doses that were maternotoxic. These results raise concerns about administering ivermectin to people who are in the early stages of pregnancy (prior to 10 weeks gestation).30 A 2020 systematic review and meta-analysis reviewed the incidence of poor maternal and fetal outcomes after ivermectin was used for its antiparasitic properties during pregnancy. However, the study was unable to establish a causal relationship between ivermectin use and poor maternal or fetal outcomes due to the quality of evidence. There are numerous reports of inadvertent ivermectin use in early pregnancy without apparent adverse effects.31-33 Therefore, there is insufficient evidence to establish the safety of using ivermectin in pregnant people, especially those in the later stages of pregnancy.
One study reported that the ivermectin concentrations secreted in breastmilk after a single oral dose were relatively low. No studies have evaluated the ivermectin concentrations in breastmilk in patients who received multiple doses.
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Considerations in Children

Ivermectin is used in children weighing >15 kg for the treatment of helminthic infections, pediculosis, and scabies. The safety of using ivermectin in children weighing <15 kg has not been well established. Ivermectin is generally well tolerated in children, with a side effect profile similar to the one seen in adults. Currently, there are no available pediatric data from clinical trials to inform the use of ivermectin for the treatment or prevention of COVID-19 in children.

Clinical Trials

Several clinical trials that are evaluating the use of ivermectin for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.

References

1. Omura S, Crump A. Ivermectin: panacea for resource-poor communities? Trends Parasitol. 2014;30(9):445- 455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25130507.

2. Fritz ML, Siegert PY, Walker ED, Bayoh MN, Vulule JR, Miller JR. Toxicity of bloodmeals from ivermectin- treated cattle to Anopheles gambiae s.l. Ann Trop Med Parasitol. 2009;103(6):539-547. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19695159.

3. Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 years of clinical experience with ivermectin: an overview of safety for an increasing number of indications. J Drugs Dermatol. 2016;15(3):325-332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26954318.

4. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32135219.

5. Arévalo AP, Pagotto R, Pórfido J, et al. Ivermectin reduces coronavirus infection in vivo: a mouse experimental model. bioRxiv. 2020;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2020.11.02.363242v1.

6. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In Vivo. 2020;34(5):3023-3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32871846.

7. Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res. 2013;99(3):301-306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23769930.

8. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851-856. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22417684.

9. Barrows NJ, Campos RK, Powell ST, et al. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe. 2016;20(2):259-270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27476412.

10. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57(11):524-529. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19109745.

11. DiNicolantonio JJ, Barroso J, McCarty M. Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. Open Heart. 2020;7(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32895293.

12. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol. 2009;23(4):449-455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19453757.

13. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the

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replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32251768.

14. Chaccour C, Hammann F, Ramon-Garcia S, Rabinovich NR. Ivermectin and COVID-19: keeping rigor in times of urgency. Am J Trop Med Hyg. 2020;102(6):1156-1157. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32314704.

15. Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122-1133. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12362927.

16. Arshad U, Pertinez H, Box H, et al. Prioritization of anti-SARS-CoV-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther. 2020;108(4):775-790. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32438446.

17. Bray M, Rayner C, Noel F, Jans D, Wagstaff K. Ivermectin and COVID-19: a report in antiviral research, widespread interest, an FDA warning, two letters to the editor and the authors’ responses. Antiviral Res. 2020;178:104805. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32330482.

18. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens. Biotechnology & Biotechnological Equipment. 2020;34(1):469-474. Available at: https://www.tandfonline.com/doi/full/10.1080/13102818.2020.1775118.

19. Jermain B, Hanafin PO, Cao Y, Lifschitz A, Lanusse C, Rao GG. Development of a minimal physiologically- based pharmacokinetic model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug repurposing. J Pharm Sci. 2020;109(12):3574-3578. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32891630.

20. de Melo GD, Lazarini F, Larrous F, et al. Anti-COVID-19 efficacy of ivermectin in the golden hamster. bioRxiv. 2020;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2020.11.21.392639v1.

21. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020;103:214-216. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278625.

22. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in SARS-COV-2/COVID-19 Patients. Int J of Sci. 2020;9:31-35. Available at: https://www.ijsciences.com/pub/article/2378.

23. Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Guo D, He S. A randomized trial of ivermectin- doxycycline and hydroxychloroquine-azithromycin therapy on COVID19 patients. Research Square. 2020;Preprint. Available at: https://assets.researchsquare.com/files/rs-38896/v1/3ee350c3-9d3f-4253-85f9-1f17f3af9551.pdf.

24. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.

25. Hashim HA, Maulood MF, Rasheed AW, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.

26. Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, Eltaweel A. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-100956/v2.

27. Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-109670/v1.

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28. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Arch Bronconeumol. 2020;56(12):828-830. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293006.

29. Chandler RE. Serious neurological adverse events after ivermectin—do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg. 2018;98(2):382-388. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29210346.

30. Ivermectin [package insert]. DailyMed. 2017. Available at: https://dailymed.nlm.nih.gov/dailymed/fda/ fdaDrugXsl.cfm?setid=847a1dd7-d65b-4a0e-a67d-d90392059dac&type=display.

31. Pacque M, Munoz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution. Lancet. 1990;336(8729):1486-1489. Available at: https://www.ncbi.nlm.nih.gov/pubmed/1979100.

32. Chippaux JP, Gardon-Wendel N, Gardon J, Ernould JC. Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg. 1993;87(3):318. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8236406.

33. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health. 2003;8(12):1093- 1101. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14641844.

34. Ogbuokiri JE, Ozumba BC, Okonkwo PO. Ivermectin levels in human breastmilk. Eur J Clin Pharmacol. 1993;45(4):389-390. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8299677.

       

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Table 2c. Ivermectin: Selected Clinical Data

Last Updated: February 11, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for IVM. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.



Study Design

Methods

Results

Limitations and Interpretation

Ivermectin Versus Ivermectin Plus Doxycycline Versus Placebo for Treatment of COVID-191

Randomized, double-blind, placebo-controlled trial of hospitalized adults in Dhaka, Bangladesh (n = 72)

Key Inclusion Criteria:

• Aged 18–65 years

• Laboratory-con rmed SARS- CoV-2 infection with fever, cough, or sore throat

• Admitted to hospital within previous 7 days
Key Exclusion Criteria:
• Chronic cardiac, renal, or liver disease
Interventions:

• IVM 12 mg PO once daily for 5 days

• Single dose of IVM 12 mg PO plus DOX 200 mg PO on Day 1, then DOX 100 mg every 12 hours for 4 days

• Placebo
Primary Endpoints:

• Time to virologic clearance, measured by obtaining an NP swab for SARS-CoV-2 PCR on Days 3, 7, and 14, then weekly until PCR result was negative

• Resolution of fever and cough within 7 days

Number of Participants:

• IVM (n = 24; 2 withdrew), IVM plus DOX (n = 24; 1 withdrew), and placebo (n = 24; 1 withdrew)

Participant Characteristics:

• Mean age was 42 years.
• 54% of participants were female.
• Mean time from symptom onset to assessment was 3.83 days. • No patients required supplemental oxygen.

Primary Outcomes:

• Shorter mean time to virologic clearance with IVM than placebo (9.7 days vs. 12.7 days; P = 0.02), but not with IVM plus DOX (11.5 days; P = 0.27).

• Rates of virologic clearance were greater in IVM arm at Day 7 (HR 4.1; 95% CI, 1.1–14.7; P = 0.03) and at Day 14 (HR 2.7; 95% CI, 1.2–6.0; P = 0.02) compared to placebo, but not in the IVM plus DOX arm (HR 2.3; 95% CI, 0.6–9.0; P = 0.22 and HR 1.7; 95% CI, 0.8–4.0; P = 0.19).

• No statistically signi cant difference in time to resolution of fever, cough, or sore throat between IVM and placebo arms (P = 0.35, P = 0.18, and P = 0.35, respectively) or IVM plus DOX and placebo arms (P = 0.09, P = 0.23, and P = 0.09, respectively).
Other Outcomes:

• Mean values of CRP, LDH, procalcitonin, and ferritin declined in all arms from baseline to Day 7, but there were no between-arm comparisons of the changes.

• No between-arm differences in duration of hospitalization (P = 0.93).

• No SAEs recorded.

Limitations:

• Small sample size

• Not clear whether both IVM and DOX placebos were used.

• Patients with chronic diseases were excluded.

• Disease appears to have been mild in all participants; thus, the reason for hospitalization is unclear.

• Absolute changes in in ammatory markers are not presented but were reportedly signi cant.

• PCR results are not a validated surrogate marker for clinical ef cacy.
Interpretation:

• A 5-day course of IVM resulted in faster virologic clearance than placebo, but not a faster time to resolution of symptoms (fever, cough, and sore throat). Because time to virologic clearance is not

a validated surrogate marker for clinical ef cacy, the clinical ef cacy of IVM is unknown.

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Study Design

Methods

Results

Limitations and Interpretation

Ivermectin Versus Placebo for Outpatients With Mild COVID-192

Open-label RCT of adult outpatients in Lahore, Pakistan (n = 50)

Key Inclusion Criteria:

• SARS-CoV-2 PCR positive • Mild disease

Key Exclusion Criteria:

• Severe symptoms likely related to cytokine storm

• Malignancy, chronic kidney disease, or cirrhosis

• Pregnancy
Interventions:
• IVM 12 mg PO immediately, followed by 12 mg doses at 12 and 24 hours, plus symptomatic treatment
• Symptomatic treatment
Primary Endpoint:
• Symptoms reported on Day 7. Patients were strati ed as asymptomatic or symptomatic.

Number of Participants:

• IVM (n = 25) and control (n = 25)

Participant Characteristics:

• Mean age was 40.6 years.

• 62% of participants were male.

• 40% of participants had diabetes, 30% were smokers, 26% had hypertension, 8% had cardiovascular disease, and 12% had obesity.
Outcomes:
• Proportion of asymptomatic patients at Day 7 was similar in IVM and control arms (64% vs. 60%; P = 0.500).
• AEs were attributed to IVM in 8 patients (32%).

Limitations:

• Small sample size

• Open-label study

• Authors reported the proportions of participants
with certain symptoms and comorbidities but did not provide objective assessment of disease severity. This precludes the ability to compare outcomes between arms.

• Study classi ed outcomes at Day 7 as “symptomatic” and “asymptomatic,” but did not account for symptom worsening or improvement.
Interpretation:
• IVM showed no effect on symptom resolution in patients with mild COVID-19.

Ivermectin Plus Doxycycline Versus Hydroxychloroquine Plus Azithromycin for Asymptomatic Patients and Patients with Mild to Moderate COVID-193

RCT of outpatients with SARS-CoV-2 infection with or without symptoms in Bangladesh (n = 116)

This is a preliminary report that has
not yet been peer reviewed.

Key Inclusion Criteria:

• Laboratory-con rmed SARS-CoV-2 infection by RT-PCR

• SpO2 ≥95%

• Normal or near-normal CXR

• No unstable comorbidities
Interventions
Group A:
• A single dose of IVM 200 μg/kg plus DOX 100 mg twice daily for 10 days

Number of Participants:

• Group A (n = 60) and Group B (n = 56)

Participant Characteristics:

• Mean age was 33.9 years.
• 72% of participants were male.
• 91 of 116 participants (78.5%) were symptomatic.

Outcomes:

• In Group A, PCR became negative in 60 of 60 patients (100%). Mean time to negative PCR result was 8.93 days (range 8–13 days).

Limitations:

• Small sample size

• Open-label study

• No SOC alone group

• Study enrolled young patients without major risk factors for disease progression.

• None of the comparative outcome measures were statistically signi cant.

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Study Design

Methods

Results

Limitations and Interpretation

Ivermectin Plus Doxycycline Versus Hydroxychloroquine Plus Azithromycin for Asymptomatic Patients and Patients with Mild to Moderate COVID-193, continued

Group B:

• HCQ 400 mg on Day 1, then HCQ 200 mg twice daily for 9 days plus AZM 500 mg once daily for 5 days

Primary Endpoints:

• Time to negative PCR result. Asymptomatic patients were tested starting on Day 5, then every other day until a negative result occurred. Symptomatic patients were tested on their second symptom-free
day, then every other day until a negative result occurred.

• Time to resolution of symptoms

• In Group B, PCR became negative in 54 of 56 patients (96.4%). Mean time to negative PCR result was 9.33 days (range 5–15 days).

• Difference between groups in time from recovery to negative PCR result was not statistically signi cant (P = 0.2314).

• In a subgroup analysis of patients who were symptomatic at baseline, the mean durations to negative PCR for Groups A and B were 9.06 days and 9.74 days, respectively (P = 0.0714).

• In the subgroup analysis, the mean symptom recovery durations for Groups A and B were 5.93 days (range 5–10 days) and 6.99 days (range 4–12 days), respectively (P = 0.071).

• Patients receiving IVM plus DOX had fewer AEs than those receiving HCQ plus AZM (31.7% vs. 46.4%) in the subgroup analysis.

Interpretation:

• In this small study with a young population, the authors suggested that IVM plus DOX was superior to HCQ plus AZM despite no statistically signi cant difference in time from recovery to negative PCR result and symptom recovery between patients who received IVM plus DOX and those who received HCQ plus AZM.

Effect of Early Treatment With Ivermectin Versus Placebo on Viral Load, Symptoms, and Humoral Response in Patients With Mild COVID-194

A single-center, randomized, double- blind, placebo- controlled pilot trial in Spain (n = 24)

Key Inclusion Criteria:

• Laboratory-con rmed SARS-CoV-2 infection

• ≤72 hours of symptoms
• No risk factors for severe disease

or COVID-19 pneumonia

Interventions:

• Single dose of IVM 400 μg/kg

• Nonmatching placebo tablet administered by a nurse who did not participate in the patient’s care

Primary Endpoint:

• Positive SARS-CoV-2 PCR result from an NP swab at Day 7 post- treatment

Number of Participants:

• IVM (n = 12) and placebo (n = 12)

Participant Characteristics:

• Mean age was 26 years (range 18–54 years).

• 50% of participants were male.

• All participants had symptoms at baseline; 70% had headache, 66% had fever, 58% had malaise, and 25% had cough.

• Median onset of symptoms was 24 hours in IVM arm and 48 hours in placebo arm.
Outcomes:

• At Day 7, 12 patients (100%) in both groups had a positive PCR (for gene N), and 11 of 12 who received IVM (92%) and 12 of 12 who received placebo (100%) had a positive PCR (for gene E); P = 1.0 for both comparisons.

• In a post hoc analysis, the authors reported fewer patient- days of cough and anosmia in the IVM-treated patients, but no differences in the patient-days for fever, general malaise, headache, and nasal congestion.

Limitations:

• Small sample size

• PCR is not a validated surrogate marker for clinical ef cacy.

• PCR cycle threshold values were higher for patients who received IVM than those who received placebo at some time points, but these comparisons are not statistically signi cant.

• Symptom results were not a prespeci ed outcome and are of unclear statistical and clinical signi cance.
Interpretation:
• Patients who received IVM showed no difference in viral clearance compared to those who received placebo.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Early Treatment With Ivermectin Versus Placebo on Viral Load, Symptoms, and Humoral Response in Patients With Mild COVID-194, continued

• The small sample size and large number of comparisons make it dif cult to assess the clinical ef cacy of IVM in this population.

Ivermectin Plus Doxycycline Plus Standard Therapy Versus Standard Therapy Alone in Patients With Mild to Moderate COVID-195

Randomized, unblinded, single-center study of patients with laboratory- con rmed SARS- CoV-2 infection in Baghdad, Iran (n = 140)

This is a preliminary report that has
not yet been peer reviewed.

Key Inclusion Criteria:

• Diagnosis by clinical, radiological, and PCR testing

• Outpatients had mild or moderate COVID-19, while inpatients had severe and critical COVID-19.
Interventions:

• IVM 200 μg/kg PO daily for 2 days. If patient required more time to recover, a third dose was given 7 days after the rst dose, plus DOX 100 mg twice daily for 5–10 days plus standard therapy (based on clinical condition).

• Standard therapy was based on clinical condition and included AZM, acetaminophen, vitamin C, zinc, vitamin D3, dexamethasone 6 mg daily or methylprednisolone 40 mg twice daily if needed, and oxygen or mechanical ventilation if needed.

• All critically ill patients were assigned to receive IVM plus DOX.

Number of Participants:

• IVM plus DOX plus standard therapy (n = 70) and standard therapy alone (n = 70)

Participant Characteristics:

• Median age was 50 years in IVM arm and 47 years in standard therapy arm.

• 50% of patients were male in IVM arm and 53% were male in standard therapy arm.

• In IVM arm, 48 patients had mild or moderate COVID-19, 11 had severe COVID-19, and 11 had critical COVID-19.

• In standard therapy arm, 48 patients had mild or moderate COVID-19, 22 had severe COVID-19, and no patients had critical COVID-19.
Outcomes:

• Mean recovery time in IVM arm was 10.1 days (SD 5.3 days) vs. 17.9 days (SD 6.8 days) for standard therapy arm (P < 0.0001). This result was only signi cant for those with mild to moderate disease.

• Disease progression occurred in 3 of 70 patients (4.3%) in IVM arm and 7 of 70 (10.0%) in standard therapy arm (P = 0.19)

• 2 of 70 patients (2.85%) in IVM arm and 6 of 70 (8.57%) in standard therapy arm died (P = 0.14)

Limitations:

• Not blinded

• Patient deaths prevent an accurate comparison of mean recovery time between arms in this study, and the authors did not account for competing mortality risks.

• Relies heavily on post hoc subgroup comparisons.

• Substantial imbalance in disease severity at baseline

• Authors noted that critical patients were not assigned to standard therapy arm; thus, the arms were not truly randomized.

• Unclear how many patients required corticosteroids.
Interpretation:

• IVM may shorten the time to recovery for patients with mild or moderate disease, but the lack of control for competing mortality causes in the study limits the ability to interpret the results.

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Study Design

Methods

Results

Limitations and Interpretation

Ef cacy and Safety of Ivermectin Versus Hydroxychloroquine for Treatment of COVID-196

Multicenter RCT that compared the use of IVM and HCQ in patients with mild, moderate, or severe COVID-19 in hospital settings (n = 400)

This is a preliminary report that has
not yet been peer reviewed.

Key Inclusion Criteria:

• Positive RT-PCR result

• Mild, moderate, or severe cases of COVID-19

Key Exclusion Criteria:

• Contraindications for HCQ
• Critical cases of COVID-19
• Chronic kidney, liver, or heart disease

Interventions

All Patients:

• SOC, which included AZM 500 mg once daily for 6 days, vitamin C 1
gm once daily, zinc 50 mg once
daily, lactoferrin 100 mg twice daily, acetylcysteine 200 mg 3 times
daily, prophylactic or therapeutic anticoagulation if D-dimer >1,000, and paracetamol as needed.

Group 1 (Mild or Moderate) and Group 3 (Severe):

• IVM 400 μg/kg once daily for 4 days (maximum of IVM 24 mg per day)

Group 2 (Mild or Moderate) and Group 4 (Severe):

• HCQ 400 mg every 12 hours on Day 1, then HCQ 200 mg every 12 hours for 5 days

Primary Endpoints:

• Clinical laboratory improvement and/ or 2 consecutive negative PCR results ≥48 hours apart

• Length of hospital stay

Number of Participants:

• All 4 arms (n = 100 in each arm)

Participant Characteristics:

• Mean age was 53.8–59.6 years.

• 67% to 72% of patients were male.

• Fatigue and dyspnea reported in 36% to 38% of patients with mild or moderate disease and 86% to 88% of those with severe disease.
Primary Outcomes:

• In those with mild or moderate disease, patients who received IVM had signi cant differences in improvement compared to those who received HCQ (99% vs. 74%), progression of disease (1% vs. 22%), death (0% vs. 4%), and mean number of hospital days (5±1 vs. 15±8) (P < 0.001 for all parameters except death).

• For those with severe disease, patients who received
IVM had signi cant differences compared to those who received HCQ in improvement (94% vs. 50%), progression of disease (4% vs. 30%), death (2% vs. 20%), and mean number of hospital days (6±8 vs. 18±8) (P < 0.001 for all parameters).

• For all patients, those treated with IVM had signi cant improvement in TLC, CRP, ferritin, D-dimer, and RT-PCR conversion days by Week 1 (P < 0.001) compared to those who received HCQ.

• In addition to the markers listed above, patients with severe disease showed greater improvement in hemoglobin in IVM arm than in HCQ arm.

Limitations:

• Unclear whether the study team and patients were blinded.

• The role of SOC therapy in clinical and laboratory responses is unknown.

• Cannot rule out potential harm from HCQ. It is unknown whether using AZM plus
HCQ could have led to worse outcomes.

• No SOC alone group

• Laboratory results are only reported after 1 week of treatment. Length of follow up for clinical outcomes and mortality is unclear.
Interpretation:

• Compared to those who received HCQ, IVM recipients had improved in ammatory markers and time to RT-PCR conversion after 1 week. Improvement in clinical status and decreased mortality was also observed in the IVM arm.

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Study Design

Methods

Results

Limitations and Interpretation

Antiviral Effect of High-Dose Ivermectin in Adults with COVID-197

Multicenter, randomized, open- label, blinded trial of hospitalized adults with mild to moderate COVID-19 (n = 45)

This is a preliminary report that has not yet been peer- reviewed.

Key Inclusion Criteria:

• Laboratory-con rmed SARS- CoV-2 infection

• Hospitalized with WHO Stage 3 to 5 COVID-19

• ≤5 days of symptoms Key Exclusion Criteria:

• Use of any agent with potential anti-SARS-CoV-2 activity or immunomodulators prior to enrollment

• Poorly controlled comorbidities
Interventions:
• IVM 600 μg/kg once daily plus SOC for 5 days
• SOC for 5 days
Primary Endpoint:
• VL reduction at Day 5. VL was quanti ed by NP swab at baseline, then at 24, 48, and 72 hours and Day 5.
PK Sampling:
• Performed 4 hours after dose on Days 1, 2, 3, 5, and 7 to assess elimination

Number of Participants:

• IVM (n = 30) and SOC (n = 15)

• After excluding patients with poor sample quality, those without a detectable VL at baseline, and those who withdrew, 32 patients (20 IVM, 12 SOC) were included in the viral ef cacy analysis population.
Participant Characteristics:
• Mean age was 40.9 years ± 12.5 years. • 56% of patients were male.
Primary Outcomes:

• Nonstatistically signi cant difference in baseline VL between arms. The baseline median VL was 3.74 log10 copies/mL (range 2.8–5.79) in IVM arm and 5.59 log10 copies/mL in SOC arm (P = 0.08).

• By Day 5, a similar magnitude of viral reduction was seen in both arms.
Other Outcomes:

• A signi cant positive correlation was found after analysis of mean plasma IVM concentration in relation to VL reduction. Participants with higher IVM concentrations had greater reductions in VL (r 0.44; P < 0.04). This correlation was stronger when reduction in VL was related to the IVM exposure corrected by baseline VL (r 0.60; P < 0.004).

• Treated patients were divided into 2 groups based on IVM Cmax: IVM >160 ng/mL (median of 202 ng/mL) and ≤160 ng/mL (median of 109 ng/mL).

• Median percentage of VL reduction by Cmax concentration vs. control (P = 0.0096) was 72% (IQR 59% to 77%) in >160 ng/ mL group (n = 9), 40% (IQR 21% to 46%) in ≤160 ng/mL group (n = 11), and 42% (IQR 31% to 73%) in SOC arm.

• Median viral decay rate (P = 0.041) was 0.64 d-1 in >160 ng/mL group, 0.14 d-1 in ≤160 ng/mL group, and 0.13 d-1 in SOC arm.

• Percentages of AEs were similar between the arms (43% in IVM arm, 33% in SOC arm), and AEs were mostly mild. No correlation was found between IVM concentration and the occurrence of AEs.

Limitations:

• Small sample size

• No clinical response data reported.

• The Cmax level of 160 ng/mL used in the analysis appears to be arbitrary.
Interpretation:

• Concentration-dependent virologic response was seen using a higher-than-usual dose of IVM (600 μg/kg vs. 200 or 400 μg/kg once daily), with minimal associated toxicities.

• The study results showed large interpatient variation of IVM Cmax. Larger sample sizes are needed to further assess the safety and ef cacy of using higher doses of IVM to treat COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Ivermectin as Adjunctive Therapy to Hospitalized Patients With COVID-198

Randomized, double-blind, placebo-controlled multicenter Phase 2 clinical trial

of hospitalized adults with mild
to severe SARS- CoV-2 infection in 5 facilities in Iran (n = 180)

This is a preliminary report that has not yet been peer- reviewed.

Key Inclusion Criteria:

• Symptoms suggestive of COVID-19 pneumonia, with chest CT compatible with mild to severe COVID-19 or positive RT-PCR result for SARS-CoV-2

Key Exclusion Criteria:

• Severe immunosuppression, malignancy, or chronic kidney disease

• Pregnancy

Interventions:

• HCQ 200 mg/kg twice daily alone as SOC (standard arm)

• SOC plus 1 of the following:

• Placebo

• Single dose of IVM 200 μg/kg

• IVM 200 μg/kg on Days 1, 3, and 5

• Single dose of IVM 400 μg/kg

• IVM 400 μg/kg on Day 1, then IVM 200 μg/kg on Days 3 and 5
Primary Endpoint:
• Clinical recovery within 45 days of enrollment (de ned as normal temp, respiratory rate, and SpO2 >94% for 24 hours)

Number of Participants:

• All 6 arms (n = 30 in each arm)

Participant Characteristics:

• Average age was 56 years (range 45–67 years).

• 50% of patients were male.

• Disease strati cation (based on CT ndings): negative (1%), mild (14%), moderate (73%), and severe (12%)

• Mean SpO2 at baseline was 89%.
Primary Outcomes:

• Durations of hypoxemia (P = 0.025) and hospitalization (P = 0.006) were shorter in the IVM arms compared to placebo arm, and mortality was lower in the IVM arms (P = 0.001).

• There was no difference in number of days of tachypnea (P = 0.584) or return to normal temperature (P = 0.102).

• Signi cant differences in change from baseline to Day 5 in absolute lymphocyte count, platelet count, erythrocyte sedimentation rate, and CRP.

• Higher mortality was reported in standard and placebo arm than IVM arms.

Limitations:

• Small study

• Power estimation is confusing.

• Mortality was not listed as the primary or secondary outcome.

• It is unclear whether IVM patients also received HCQ.

• It is unclear whether the between-group comparisons are between combined IVM group and placebo plus SOC.

• Participants were strati ed by disease severity based on CT ndings. These categorizations are unclear and were not
taken into account in outcome comparisons.

• The post hoc grouping of randomized arms raises risk of false positive ndings.
Interpretation:

• IVM appeared to improve laboratory outcomes and some clinical outcomes (shorter duration of hypoxemia and hospitalization) and lowered mortality.

• The small size of the study,
the unclear treatment arm assignments, and the lack of accounting of disease severity at baseline make it dif cult to draw conclusions about the ef cacy of using IVM to treat patients with mild COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Retrospective Analysis of Ivermectin in Hospitalized Patients With COVID-199

Retrospective analysis of consecutive patients with laboratory- con rmed SARS- CoV-2 infection who were admitted to 4 Florida hospitals (n = 276)

Key Inclusion Criteria:

• Positive NP swab with SARS- CoV-2 RNA

Interventions:

• Single dose of IVM 200 μg/kg, repeated on Day 7 at the doctors’ discretion; 90% percent of patients also received HCQ.

• Usual care: 97% of patients received HCQ and most also received AZM.
Primary Endpoint:
• All-cause, in-hospital mortality

Number of Participants:

• IVM (n = 173; 160 participants received a single dose, 13 participants received a second dose) and usual care (n = 103)

Participant Characteristics:

• Mean age was 60.2 years in IVM arm and 58.6 years in the usual care arm.

• 51.4% of patients were male in IVM arm and 58.8% were male in usual care arm.

• 56.6% of patients were Black in IVM arm and 51.4% were Black in usual care arm.
Outcomes:

• All-cause mortality was lower in IVM arm than in usual care arm (OR 0.27; 95% CI, 0.09–0.80; P = 0.03); the bene t appeared to be limited to the subgroup of patients with severe disease.

• No difference in median length of hospital stay between arms (7 days for both) or proportion of mechanically ventilated patients who were successfully extubated (36% in IVM arm vs. 15% in usual care arm; P = 0.07).

Limitations:

• Not randomized

• Little to no information on oxygen saturation or radiographic ndings

• Timing of therapeutic interventions was not standardized.

• Ventilation and hospitalization duration analyses do not appear to account for death as a competing risk.

• No virologic assessments were performed.
Interpretation:

• IVM use was associated with lower mortality than usual care. However, the limitations of this retrospective analysis make it dif cult to draw conclusions about the ef cacy of using IVM to treat patients with COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Observational Study on the Effectiveness of Hydroxychloroquine, Azithromycin, and Ivermectin Among Hospitalized Patients With COVID-1910

Retrospective cohort study of hospitalized adults with COVID-19 in Peru (n = 5,683)

This is a preliminary report that has not yet been peer- reviewed.

Key Inclusion Criteria:

• Aged ≥18 years

• Symptomatic

• Laboratory-con rmed SARS- CoV-2 infection

• No life-threatening illness at admission
Key Exclusion Criteria:
• Required oxygen at admission
• Use of tocilizumab, LPV/RTV, or RDV
Interventions:
• One of the following interventions administered within 48 hours of admission:

• HCQ or CQ alone

• IVM alone

• AZM alone

• HCQ or CQ plus AZM

• IVM plus AZM

• SOC (e.g., supportive care, antipyretics, hydration)
Primary Endpoint:
• All-cause mortality
Secondary Endpoint:
• All-cause mortality and/or transfer to ICU

Number of Participants:

• HCQ or CQ alone (n = 200), IVM alone (n = 203), AZM alone (n = 1,600), HCQ or CQ plus AZM (n = 692), IVM plus AZM (n = 358), and SOC (n = 2,630)

Participant Characteristics:

• 63% of patients were male.
• Mean age was 59.4 years (range 18–104 years). • All patients had mild or moderate disease.

Outcomes:

• Median follow-up time was 7 days. Mortality rate was 18.9% at the end of follow up.

• IVM alone was associated with increased risk of death and/or ICU transfer compared to SOC (wHR 1.58; 95% CI, 1.11–2.25).

• IVM plus AZM did not have an effect on deaths or any secondary outcomes (all-cause death and/or ICU transfer, all- cause death and/or oxygen prescription) compared to SOC.

• HCQ or CQ plus AZM was associated with a higher risk of death (wHR 1.84; 95% CI, 1.12–3.02), death and/or ICU transfer (wHR 1.49; 95% CI, 1.01–2.19), and death and/or oxygen prescription (wHR 1.70; 95% CI, 1.07–2.69) compared to SOC.

Limitations:

• Not randomized

• Unclear whether all patients received IVM or other medications according to Peruvian guidelines referred to in the manuscript.

• Dosing and timing of administration are unclear.
Interpretation:

• Compared to SOC, IVM
alone was associated with increased risk of death and/
or ICU admission. Using IVM
in combination with AZM was not associated with effects on mortality, ICU transfer, or oxygen prescription compared to SOC.

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Study Design

Methods

Results

Limitations and Interpretation

Retrospective Study of Ivermectin Versus Standard of Care in Patients With COVID-1911

Retrospective study of consecutive adult patients hospitalized in Bangladesh

with laboratory- con rmed SARS- CoV-2 infection (n = 248)

Key Inclusion Criteria:

• Aged ≥18 years

• Positive NP swab with SARS-
CoV-2 RNA

• “Free from any other serious pathological conditions”
Interventions:
• Single dose of IVM 12 mg within 24 hours of hospital admission
• SOC
Primary Outcome:
• Not speci ed

Number of Participants:

• IVM (n = 115) and SOC (n = 133)

Participant Characteristics:

• Median age in IVM arm was 34 years; 70% of participants were male.

• Median age in SOC arm was 35 years; 52% of participants were male.

• All participants had mild or moderate disease.

• 12% of participants had hypertension in both arms.

• 17% of participants in IVM arm and 12% in SOC arm had diabetes mellitus.
Outcomes:

• Fewer patients in IVM arm had evidence of disease progression compared to SOC arm (P < 0.001): moderate respiratory distress (2.6% vs. 15.8%), pneumonia (0% vs. 9.8%), ischemic stroke (0% vs. 1.5%).

• Fewer patients in IVM arm required intensive care management compared to SOC arm (0.9% vs. 8.8%; P < 0.001).

• Fewer patients in IVM arm required antibiotic therapy (15.7% vs. 60.2%; P < 0.001) or supplemental oxygen (9.6% vs. 45.9%; P < 0.001) compared to SOC arm.

• Shorter median duration of viral clearance in IVM arm compared to SOC arm (4 vs. 15 days; P < 0.001).

• Shorter median duration of hospital stay in IVM arm compared to SOC arm (9 vs. 15 days; P < 0.001)

• Lower mortality in IVM arm compared to SOC arm (0.9% vs. 6.8%; P < 0.05)

Limitations:

• Not randomized

• Disease severity at admission was reported as mild or moderate, but 12% of patients in IVM arm and 9% in SOC arm had SpO2 <94%

• Even though only 10% of patients developed pneumonia, 60% received antibiotics.

• Possibility of harm from concomitant medications
Interpretation:

• Compared to SOC, IVM use was associated with faster rates of viral clearance and better clinical outcomes, including shorter hospital stay and lower mortality

Key: AE = adverse event; AZM = azithromycin; Cmax = maximum concentration; CQ = chloroquine; CRP = C-reactive protein; CT = computed tomography; CXR = chest X-ray; DOX = doxycycline; HCQ = hydroxychloroquine; ICU = intensive care unit; IVM = ivermectin; LDH = lactose dehydrogenase; LPV/RTV = lopinavir/ritonavir;
NP = nasopharyngeal; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PK = pharmacokinetic; PO = orally; r = correlation coef cient; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcriptase polymerase chain reaction; SAE = severe adverse event; SARS- CoV-2 = severe acute respiratory syndrome coronavirus 2; SD = standard deviation; SOC = standard of care; SpO2 = oxygen saturation; TLC = total lymphocyte count; VL = viral load; WHO = World Health Organization; wHR = weighted hazard ratio

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References

1. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020;103:214-216. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278625.

2. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in SARS-COV-2/COVID-19 Patients. Int J of Sci. 2020;9:31-35. Available at: https://www.ijsciences.com/pub/article/2378.

3. Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Guo D, He S. A randomized trial of ivermectin-doxycycline and hydroxychloroquine- azithromycin therapy on COVID19 patients. Research Square. 2020;Preprint. Available at: https://assets.researchsquare.com/files/rs-38896/v1/3ee350c3-9d3f-4253-85f9-1f17f3af9551.pdf.

4. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. Lancet. 2021. Available at: https://www.thelancet.com/action/showPdf?pii=S2589-5370%2820%2930464-8.

5. Hashim HA, Maulood MF, Rasheed AW, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.

6. Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, Eltaweel A. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-100956/v3.

7. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: a pilot, randomised, controlled, open label, multicentre trial. Preprints with the Lancet. 2020;Preprint. Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3714649.

8. Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-109670/v1.

9. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ICON study. Chest. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33065103.

10. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.

11. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Arch Bronconeumol. 2020;56(12):828-830. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293006.

          

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Lopinavir/Ritonavir and Other HIV Protease Inhibitors

Last Updated: February 11, 2021

The replication of SARS-CoV-2 depends on the cleavage of polyproteins into an RNA-dependent RNA polymerase and a helicase.1 Two proteases are responsible for this cleavage: 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).

Lopinavir/ritonavir and darunavir/cobicistat have been studied in patients with COVID-19. The clinical trials discussed below have not demonstrated a clinical benefit for protease inhibitors in patients with COVID-19.

Recommendations

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in hospitalized patients (AI).

• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in nonhospitalized patients (AIII).
Rationale
The pharmacodynamics of lopinavir/ritonavir raise concerns about whether it is possible to achieve drug concentrations that can inhibit the SARS-CoV-2 proteases.2,3 In addition, lopinavir/ritonavir did not show efficacy in two large randomized controlled trials in hospitalized patients with COVID-19.4,5
There is currently a lack of data on the use of lopinavir/ritonavir in nonhospitalized patients with COVID-19. However, the pharmacodynamic concerns and the lack of evidence for a clinical benefit among hospitalized patients with COVID-19 undermine confidence that lopinavir/ritonavir has a clinical benefit at any stage of SARS-CoV-2 infection.
Adverse Events
The adverse events for lopinavir/ritonavir include:

• Nausea, vomiting, diarrhea (common)

• QTc prolongation

• Hepatotoxicity
Drug-Drug Interactions
Lopinavir/ritonavir is a potent inhibitor of cytochrome P450 3A. Coadministering lopinavir/ritonavir with medications that are metabolized by this enzyme may increase the concentrations of those medications, resulting in concentration-related toxicities. Please refer to the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV for a list of potential drug interactions.
Summary of Clinical Data for COVID-19

• The plasma drug concentrations achieved using typical doses of lopinavir/ritonavir are far below the levels that may be needed to inhibit SARS-CoV-2 replication.3

• Lopinavir/ritonavir did not demonstrate a clinical benefit in hospitalized patients with COVID-19 during a large randomized trial in the United Kingdom.4
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• In a large international randomized trial, lopinavir/ritonavir did not reduce the mortality rate among hospitalized patients with COVID-19.5

• A moderately sized randomized trial (n = 199) failed to find a virologic or clinical benefit of lopinavir/ritonavir over standard of care.6

• Results from a small randomized controlled trial showed that darunavir/cobicistat was not effective for the treatment of COVID-19.7

• There are no data from clinical trials that support using other HIV protease inhibitors to treat COVID-19.

• Please see Clinical Data for COVID-19 below for more information.
Clinical Data for COVID-19
The information presented in this section may include data from preprints or articles that have not been peer reviewed. This section will be updated as new information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating lopinavir/ritonavir.
Lopinavir/Ritonavir in Hospitalized Patients With COVID-19: The RECOVERY Trial
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an ongoing, open-label, randomized controlled trial with multiple arms, including a control arm; in one arm, participants received lopinavir/ritonavir. The trial was conducted across 176 hospitals in the United Kingdom and enrolled hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 infection.4
Patients were randomized into several parallel treatment arms; this included randomization in a 2:1 ratio to receive either the usual standard of care only or the usual standard of care plus lopinavir 400 mg/ritonavir 100 mg orally every 12 hours for 10 days or until hospital discharge. Patients who had severe hepatic insufficiency or who were receiving medications that had potentially serious or life- threatening interactions with lopinavir/ritonavir were excluded from randomization into either of these arms. Mechanically ventilated patients were also underrepresented in this study because it was difficult to administer the oral tablet formulation of lopinavir/ritonavir to patients who were on mechanical ventilation. The primary outcome was all-cause mortality at Day 28 after randomization.
The lopinavir/ritonavir arm was discontinued on June 29, 2020, after the independent data monitoring committee concluded that the data showed no clinical benefit for lopinavir/ritonavir.
Patient Characteristics

• Of the 7,825 participants who were eligible to receive lopinavir/ritonavir, 1,616 were randomized to receive lopinavir/ritonavir and 3,424 were randomized to receive standard of care only. The remaining participants were randomized to other treatment arms in the study.

• In both the lopinavir/ritonavir arm and the standard of care arm, the mean age was 66 years; 44% of patients were aged ≥70 years.

• Test results for SARS-CoV-2 infection were positive for 88% of patients. The remaining 12% had a negative test result.

• Comorbidities were common; 57% of patients had at least one major comorbidity. Of those patients, 28% had diabetes mellitus, 26% had heart disease, and 24% had chronic lung disease.

• At randomization, 4% of patients were receiving invasive mechanical ventilation, 70% were receiving oxygen only (with or without noninvasive ventilation), and 26% were receiving neither.

• The percentages of patients who received azithromycin or another macrolide during the follow-up
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period were similar in both arms (23% in the lopinavir/ritonavir arm vs. 25% in the standard of care arm). In addition, 10% of patients in both arms received dexamethasone.

Results

• There was no significant difference in the primary outcome of 28-day mortality between the two arms; 374 patients (23%) in the lopinavir/ritonavir arm and 767 patients (22%) in the standard of care arm had died by Day 28 (rate ratio 1.03; 95% CI, 0.91–1.17; P = 0.60).

• A similar 28-day mortality was reported for patients who received lopinavir/ritonavir in an analysis that was restricted to the 4,423 participants who had positive SARS-CoV-2 test results (rate ratio 1.05; 95% CI, 0.92–1.19; P = 0.49).

• Patients in the lopinavir/ritonavir arm and patients in the standard of care arm had similar median times to discharge (11 days in both arms) and similar probabilities of being discharged alive within 28 days (69% vs. 70%).

• Among participants who were not on invasive mechanical ventilation at baseline, patients who received lopinavir/ritonavir and those who received standard of care only had similar risks of progression to intubation or death.

• Results were consistent across subgroups defined by age, sex, ethnicity, or respiratory support at baseline.
Limitations

• The study was not blinded.

• No laboratory or virologic data were collected.
Interpretation
Lopinavir/ritonavir did not decrease 28-day all-cause mortality when compared to the usual standard of care in hospitalized persons with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants who received lopinavir/ritonavir and those who received standard of care only had similar median lengths of hospital stay. Among the patients who were not on invasive mechanical ventilation at the time of randomization, those who received lopinavir/ritonavir were as likely to require intubation or die during hospitalization as those who received standard of care.
Lopinavir/Ritonavir in Hospitalized Patients with COVID-19: The Solidarity Trial
The Solidarity trial was an open-label, randomized controlled trial that enrolled hospitalized patients
with COVID-19 in 405 hospitals across 30 countries. The study included multiple arms; in one arm, participants received lopinavir/ritonavir. The control group for this arm included people who were randomized at the same site and time who could have received lopinavir/ritonavir but received standard of care instead. Lopinavir 400 mg/ritonavir 100 mg was administered orally twice daily for 14 days or until hospital discharge. Only the oral tablet formulation of lopinavir/ritonavir was available, which precluded administration to those on mechanical ventilation. The primary outcome was in-hospital mortality.5
After the results of the RECOVERY trial prompted a review of the Solidarity data, the lopinavir/ ritonavir arm ended enrollment on July 4, 2020. At that time, 1,411 patients had been randomized to receive lopinavir/ritonavir, and 1,380 patients received standard of care.
Patient Characteristics

• In both the lopinavir/ritonavir arm and the standard of care arm, 20% of the participants were aged ≥70 years and 37% were aged <50 years.

• Comorbidities were common. Diabetes mellitus was present in 24% of patients, heart disease in
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21%, and chronic lung disease in 7%.

• At randomization, 8% of patients were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 53% were receiving oxygen only (with or without noninvasive ventilation), and 39% were receiving neither.

• Similar percentages of patients received corticosteroids in the lopinavir/ritonavir arm and the standard of care arm (23% vs. 24%). Other nonstudy treatments were administered less often, and the use of these treatments was balanced between arms.
Results

• There was no significant difference in in-hospital mortality between the two arms; 148 patients (9.7%) in the lopinavir/ritonavir arm and 146 patients (10.3%) in the standard of care arm had died by Day 28 (rate ratio 1.00; 95% CI, 0.79–1.25; P = 0.97).

• Progression to mechanical ventilation among those who were not ventilated at randomization occurred in 126 patients in the lopinavir/ritonavir arm and 121 patients in the standard of care arm.

• In-hospital mortality results appeared to be consistent across subgroups.
Limitations

• The study was not blinded.

• Those who were on mechanical ventilation were unable to receive lopinavir/ritonavir.

• The study includes no data on time to recovery.
Interpretation
Among hospitalized patients, lopinavir/ritonavir did not decrease in-hospital mortality or the number of patients who progressed to mechanical ventilation compared to standard of care.
Lopinavir/Ritonavir Pharmacokinetics in Patients With COVID-19
In a case series, eight patients with COVID-19 were treated with lopinavir 400 mg/ritonavir 100 mg orally twice daily and had plasma trough levels of lopinavir drawn and assayed by liquid chromatography-tandem mass spectrometry.3
Results

• The median plasma lopinavir concentration was 13.6 μg/mL.

• After correcting for protein binding, trough levels would need to be approximately 60-fold to 120-fold higher to achieve the in vitro half-maximal effective concentration (EC50) for SARS-CoV-2.
Limitations

• Only the trough levels of lopinavir were quantified.

• The concentration of lopinavir required to effectively inhibit SARS-CoV-2 replication in vivo is currently unknown.
Interpretation
The plasma drug concentrations that were achieved using typical doses of lopinavir/ritonavir are far below the levels that may be needed to inhibit SARS-CoV-2 replication.
Other Reviewed Studies
The Panel has reviewed other clinical studies that evaluated the use of protease inhibitors for the
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treatment of COVID-19.6,8,9 These studies have limitations that make them less definitive and informative than larger randomized clinical trials. The Panel’s summaries and interpretations of some of these studies are available in the archived versions of the Guidelines.

References

1. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses – drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327-347. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26868298.

2. Marzolini C, Stader F, Stoeckle M, et al. Effect of systemic inflammatory response to SARS-CoV-2 on lopinavir and hydroxychloroquine plasma concentrations. Antimicrob Agents Chemother. 2020;64(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32641296.

3. Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of lopinavir and ritonavir in patients hospitalized with coronavirus disease 2019 (COVID-19). Ann Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32422065.

4. Group RC. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33031764.

5. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity Trial results. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33264556.

6. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;382(19):1787-1799. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32187464.

7. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa241. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32671131.

8. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial. Lancet. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.

9. Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/ moderate COVID-19: an exploratory randomized controlled trial. Med. 2020:[In Press]. Available at: https://www.sciencedirect.com/science/article/pii/S2666634020300015.

         

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Table 2d. Characteristics of Antiviral Agents That Are Approved or Under Evaluation for the Treatment of COVID-19
Last Updated: April 21, 2021

• The information in this table is derived from data on the use of these drugs for FDA-approved indications or in investigational trials, and it is supplemented with data on their use in patients with COVID-19, when available.

• Information on CQ, HCQ, and LPV/RTV are available in the archived versions of the Guidelines. However, the Panel recommends against using these agents to treat COVID-19.

• There are limited or no data on dose modifications for patients with organ failure or those who require extracorporeal devices. Please refer to product labels, when available.

• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the treatment of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.

• The potential additive, antagonistic, or synergistic effects and the safety of using combination therapies for the treatment of COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.

• For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.

• For the Panel’s recommendations on using the drugs listed in this table, please refer to the individual drug sections or Therapeutic
Management of Adults With COVID-19.

    

Dosing Regimens

The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Events

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Remdesivir

For Hospitalized Adult and Pediatric Patients (Aged ≥12 Years and Weighing ≥40 kg)

For Patients Who Are Not Mechanically Ventilated and/or on ECMO:

• RDV 200 mg IV over 30–120 minutes on Day 1, followed by RDV 100 mg IV on Day 2 through Day 5

• Nausea

• ALT and AST elevations

• Hypersensitivity

• Increases in prothrombin time

• Drug vehicle is SBECD, which has been associated with renal and liver toxicity. SBECD accumulation may occur in patients with moderate or severe renal impairment.

• Infusion reactions

• Renal function, hepatic function, and prothrombin time should be monitored before and during treatment as clinically indicated.

• RDV is not recommended if eGFR is <30 mL/min.

• Clinical drug-drug interaction studies of RDV have not been conducted.

• In vitro, RDV is a substrate of CYP3A4, OATP1B1, and P-gp and an inhibitor of CYP3A4, OATP1B1, OATP1B3, and MATE1.1

• RDV should be administered in a hospital or a health care setting that can provide a similar level of care to an inpatient hospital.

• RDV is approved by the FDA for the treatment of COVID-19 in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg).

• An EUAa is available for hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.

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Dosing Regimens

The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Events

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Remdesivir, continued

• Treatment may be extended to up to 10 days in patients who do not show clinical improvement after 5 days of therapy.

For Mechanically Ventilated Patients and/or Patients on ECMO:

• RDV 200 mg IV over 30–120 minutes on Day 1, followed by RDV 100 mg IV on Day 2 through Day 10

Suggested Dose in EUAa for Hospitalized Pediatric Patients Weighing 3.5 kg to <40 kg or Aged <12 Years and Weighing ≥3.5 kg

For Patients Weighing 3.5 kg to <40 kg:

• RDV 5 mg/kg IV over 30–120 minutes on Day 1, followed by RDV 2.5 mg/kg IV once daily starting on Day 2

• For patients who are not mechanically ventilated and/or on ECMO, the recommended treatment duration is 5 days. If patients have not shown clinical improvement after 5 days of therapy, treatment may be extended to up to 10 days.

• For mechanically ventilated patients and/or patients on ECMO, the recommended treatment duration is 10 days.
For Patients Aged <12 Years and Weighing ≥40 kg:
• Same dose as for adults and children aged ≥12 years and weighing >40 kg

• Each 100 mg vial of RDV lyophilized powder contains 3 g of SBECD, and each 100 mg/20 mL vial of RDV solution contains 6 g of SBECD.

• Clinicians may consider preferentially using
the lyophilized powder formulation (which contains less SBECD) in patients with renal impairment.

• RDV may need to
be discontinued if ALT level increases to >10 times the ULN and should be discontinued if there is an increase in ALT level and signs or symptoms of liver in ammation are observed.1

• Minimal to no reduction in RDV exposure is expected when RDV is coadministered with dexamethasone (Gilead
Sciences, written communication, July 2020).

• CQ or HCQ may decrease the antiviral activity of RDV; coadministration of these drugs is not recommended.1

• No signi cant interaction is expected between RDV and oseltamivir or baloxavir
(Gilead Sciences, personal and written communications, August and September 2020).

• A list of clinical trials is available here:

Remdesivir



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Dosing Regimens

The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Events

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Ivermectin

Adults:

• The dose most commonly used in clinical trials is IVM 0.2–0.6 mg/kg given as a single dose or as a once- daily dose for up to 5 days.

• Generally well tolerated

• Dizziness

• Pruritis

• GI effects (e.g., nausea, diarrhea)

• Neurological AEs have been reported with
the use of IVM for the treatment of parasitic diseases, but it is not clear whether these AEs were caused by IVM or the underlying conditions.

• Monitor for potential AEs.

• Minor CYP3A4 substrate

• P-gp substrate

• Generally given on an empty stomach with water; however, administering IVM with food increases its bioavailability.2

• A list of clinical trials is available here:
Ivermectin



a The FDA EUA permits the emergency use of RDV for the treatment of suspected COVID-19 or laboratory-con rmed SARS-CoV-2 infection in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.3

Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; CQ = chloroquine; CYP = cytochrome P; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular ltration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI = gastrointestinal;
HCQ = hydroxychloroquine; IV = intravenous; IVM = ivermectin; LPV/RTV = lopinavir/ritonavir; MATE = multidrug and toxin extrusion protein; OATP = organic
anion transporter polypeptide; the Panel = the COVID-19 Treatment Guidelines Panel; P-gp = P-glycoprotein; RDV = remdesivir; SBECD = sulfobutylether-beta- cyclodextrin; ULN = upper limit of normal

References

1. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf.

2. Ivermectin (Stromectol) [package insert]. Food and Drug Administration. 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s024s025lbl.pdf.

3. Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of remdesivir (GS-5734TM). 2020. Available at: https://www.fda.gov/media/137566/download.

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Anti-SARS-CoV-2 Antibody Products

Last Updated: April 21, 2021



Summary Recommendations

Anti-SARS-CoV-2 Monoclonal Antibodies

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using one of the following anti-SARS-CoV-2 monoclonal antibody combinations (listed in alphabetical order) to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression, as de ned by the Emergency Use Authorization (EUA) criteria for the products:
• Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or • Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).

• Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen or nucleic acid ampli cation test and within 10 days of symptom onset.

• There are no comparative data to determine whether there are differences in clinical ef cacy or safety between bamlanivimab plus etesevimab and casirivimab plus imdevimab.

• There are SARS-CoV-2 variants, particularly those that contain the mutation E484K, that reduce the virus’ susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known.

• In regions where SARS-CoV-2 variants with reduced in vitro susceptibility to bamlanivimab plus etesevimab are common, some Panel members would preferentially use casirivimab plus imdevimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.

• The Panel recommends against the use of anti-SARS-CoV-2 monoclonal antibodies for patients who are hospitalized because of COVID-19, except in a clinical trial (AIIa). However, their use should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 but who otherwise meet the EUA criteria.
COVID-19 Convalescent Plasma

• The Panel recommends against the use of low-titer COVID-19 convalescent plasma for the treatment of COVID-19
(AIIb). Low-titer COVID-19 convalescent plasma is no longer authorized through the convalescent plasma EUA.

• For hospitalized patients with COVID-19 who do not have impaired immunity:

• The Panel recommends against the use of COVID-19 convalescent plasma for the treatment of COVID-19 in mechanically ventilated patients (AI).

• The Panel recommends against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients who do not require mechanical ventilation, except in a clinical trial (AI).

• For hospitalized patients with COVID-19 who have impaired immunity:
• There are insuf cient data for the Panel to recommend either for or against the use of high-titer COVID-19
convalescent plasma for the treatment of COVID-19.

• For nonhospitalized patients with COVID-19:
• There are insuf cient data for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in patients who are not hospitalized.
Anti-SARS-CoV-2 Speci c Immunoglobulin
• There are insuf cient data for the Panel to recommend either for or against the use of anti-SARS-CoV-2 speci c immunoglobin for the treatment of COVID-19.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

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Anti-SARS-CoV-2 Monoclonal Antibodies

Last Updated: April 21, 2021

Background

The SARS-CoV-2 genome encodes four major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), as well as nonstructural and accessory proteins. The S protein is further divided into two subunits, S1 and S2, that mediate host cell attachment and invasion. Through its receptor-binding domain (RBD), S1 attaches to angiotensin-converting enzyme 2 (ACE2) on the host cell; this initiates a conformational change in S2 resulting in virus-host cell membrane fusion and viral entry.1

Many individuals with COVID-19 produce neutralizing antibodies to SARS-CoV-2 about 10 days after disease onset, with higher antibody levels observed in those with severe disease.2 The neutralizing activity of COVID-19 patients’ plasma was correlated with the magnitude of antibody responses to SARS-CoV-2 S and N proteins. Monoclonal antibodies targeting the S protein have the potential to prevent SARS-CoV-2 infection and to alleviate symptoms and limit progression to severe disease

in patients with mild to moderate COVID-19, particularly in those who have not yet developed an endogenous antibody response.3

Anti-SARS-CoV-2 Monoclonal Antibodies That Received Emergency Use Authorizations From the Food and Drug Administration

Bamlanivimab (also known as LY-CoV555 and LY3819253) is a neutralizing monoclonal antibody that targets the RBD of the S protein of SARS-CoV-2. Etesevimab (also known as LY-CoV016 and LY3832479) is another neutralizing monoclonal antibody that binds to a different but overlapping epitope in the RBD of the SARS-CoV-2 S protein. Casirivimab (previously REGN10933) and imdevimab (previously REGN10987) are recombinant human monoclonal antibodies that bind to nonoverlapping epitopes of the S protein RBD of SARS-CoV-2.

Two combination products, bamlanivimab plus etesevimab and casirivimab plus imdevimab, are available through Food and Drug Administration (FDA) Emergency Use Authorizations (EUAs) for
the treatment of mild to moderate COVID-19 in nonhospitalized patients with laboratory confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization. The issuance of an EUA does not constitute FDA approval. Because of an increasing number of reports of SARS-CoV-2 variants that are resistant to bamlanivimab alone, FDA has recently revoked the EUA for bamlanivimab, and the product will no longer be distributed in the United States.4

Recommendations

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using one of the following anti-SARS-CoV-2 monoclonal antibody combinations (listed in alphabetical order) to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression, as defined by the EUA criteria:

• Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or

• Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).

• Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test (NAAT) and within 10 days of symptom onset.
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• There are SARS-CoV-2 variants, particularly those that contain the mutation E484K (see below), that reduce the virus’ susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known.

• In regions where SARS-CoV-2 variants with reduced in vitro susceptibility to bamlanivimab
plus etesevimab are common, some Panel members would preferentially use casirivimab plus imdevimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.

• The Panel recommends against the use of anti-SARS-CoV-2 monoclonal antibodies for patients who are hospitalized because of COVID-19, except in a clinical trial (AIIa). However, their use should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 but who otherwise meet the EUA criteria.
For additional information on the rationale for the Panel’s recommendations regarding anti-SARS- CoV-2 monoclonal antibodies for nonhospitalized patients with mild to moderate COVID-19, see Therapeutic Management of Patients with COVID-19.
SARS-CoV-2 Variants of Concern or Interest and Their Susceptibility to Anti-SARS- CoV-2 Monoclonal Antibodies
In laboratory studies, some SARS-CoV-2 variants of concern or interest that harbor certain mutations have markedly reduced susceptibility to bamlanivimab and may have lower sensitivity to etesevimab and casirivimab.5 However, the impact of these mutations on the clinical response to anti-SARS-CoV-2 monoclonal antibody combinations is uncertain, and the prevalence of these variants in different regions may vary. Of note:

• The B.1.1.7 variant of concern, which is increasing in frequency in the United States, retains in vitro susceptibility to the anti-SARS-CoV-2 monoclonal antibodies that are currently available through EUAs.6,7

• The B.1.351 variant of concern has been infrequently detected among SARS-CoV-2 samples sequenced in the United States to date. This variant includes the E484K mutation, which results
in a marked reduction in in vitro susceptibility to bamlanivimab.8,9 In vitro studies suggest that bamlanivimab plus etesevimab has markedly reduced activity against the B.1.351 variant.6 In vitro studies also suggest that the K417N mutation, which is present in the B.1.351 variant along with the E484K mutation, reduces casirivimab activity, although the combination of casirivimab and imdevimab appears to retain activity.7

• The P.1 variant of concern has been infrequently detected among SARS-CoV-2 samples sequenced in the United States to date. This variant includes the E484K mutation, which results in a marked reduction in in vitro susceptibility to bamlanivimab.6,10 In vitro studies suggest that bamlanivimab plus etesevimab also has markedly reduced activity against the P.1 variant.6,8,10 In vitro studies
also suggest that the K417T mutation, which is present in the P.1 variant along with the E484K mutation, reduces casirivimab activity, although the combination of casirivimab and imdevimab appears to retain activity.7

• The B.1.429/B.1.427 variants of concern (also called 20C/CAL.20C) that are circulating in parts of the United States, including California, Arizona, and Nevada, have the L452R mutation. This mutation is associated with a marked reduction in in vitro susceptibility to bamlanivimab. There appears to be a modest in vitro decrease in susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not known.6

• The B.1.526 variant of interest is circulating in parts of the United States, such as New York.
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It commonly has the E484K mutation, which is associated with a marked reduction in in vitro susceptibility to bamlanivimab. There appears to also be reduced in vitro susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not known.6 In vitro studies suggest that the E484K mutation may reduce casirivimab activity, although the combination of casirivimab and imdevimab appears to retain activity.7

Ongoing population-based genomic surveillance of the types and frequencies of circulating SARS-CoV-2 variants, as well as studies on the susceptibility of different variants to available anti- SARS-CoV-2 monoclonal antibodies, will be important in defining the utility of specific monoclonal antibodies in the future.

Use of Anti-SARS-CoV-2 Monoclonal Antibodies in Patients Hospitalized for COVID-19

The FDA EUAs do not authorize the use of anti-SARS-CoV-2 monoclonal antibodies for patients who are hospitalized for COVID-19 or for the following patients:

• Those who require oxygen therapy due to COVID-19; or

• Those who are on chronic oxygen therapy due to an underlying non-COVID-19-related
comorbidity and, because of COVID-19, require an increase in oxygen flow rate from baseline.
The FDA EUAs do permit the use of these monoclonal antibodies for patients who are hospitalized for an indication other than COVID-19 provided they have mild to moderate COVID-19 and are at high risk for progressing to severe disease and/or hospitalization.11,12
Anti-SARS-CoV-2 monoclonal antibodies may be available through expanded access programs for the treatment of immunocompromised patients who are hospitalized because of COVID-19. It is not yet known whether these antibodies provide clinical benefits in people with B-cell immunodeficiency or other immunodeficiencies.
Anti-SARS-CoV-2 monoclonal antibodies have not been shown to be beneficial in hospitalized
patients with severe COVID-19.7,12 A substudy of A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (ACTIV-3) randomized patients hospitalized with COVID-19 to receive bamlanivimab 7,000 mg or placebo, each in addition to remdesivir. On October 26, 2020, following a prespecified interim futility analysis, enrollment into this study was stopped due to lack of clinical benefit.13 Among 314 hospitalized adults (163 in the bamlanivimab arm and 151 in the placebo arm), pulmonary outcomes were similar at Day 5 (OR of being in a more favorable category in the bamlanivimab arm than in the placebo arm 0.85; 95% CI, 0.56–1.29; P = 0.45). The time to hospital discharge was also similar in the two arms (rate ratio 0.97; 95% CI, 0.78–1.20).14
Clinical Trial Data
See Table 3a for information on the clinical trials evaluating the safety and efficacy of anti-SARS-CoV-2 monoclonal antibodies.
Monitoring

• These anti-SARS-CoV-2 monoclonal antibodies are to be given as intravenous infusions and should only be administered in health care settings by qualified health care providers who have immediate access to medications to treat severe infusion reactions and to emergency medical services.

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• Patients should be monitored during the infusion and for at least 1 hour after the infusion is completed.

• No dosage adjustments are required for body weight, renal impairment, or mild hepatic impairment.
Adverse Effects

• In the Phase 2 Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial, the most common adverse events associated with bamlanivimab were nausea, diarrhea, dizziness, headache, pruritis, and vomiting. The safety profile of bamlanivimab at all three doses was reportedly like that of the placebo.

• According to the EUA fact sheet for bamlanivimab plus etesevimab, the following adverse events were reported: nausea, dizziness, rash, pruritis, and pyrexia. In the Phase 3 BLAZE-1 study, 1% of the participants experienced hypersensitivity events, including infusion-related reactions, rash, and pruritis. All events resolved.

• Hypersensitivity, including anaphylaxis and infusion reactions, may occur. According to the EUA for bamlanivimab, among >850 participants in ongoing trials who have received bamlanivimab, one anaphylactic reaction and one serious infusion-related reaction occurred, and both required treatment, which in one case included epinephrine.

• According to the EUA fact sheet for casirivimab plus imdevimab, among the 533 participants who received casirivimab plus imdevimab in the R10933-10987-COV-2067 trial, one participant had an anaphylaxis reaction that required treatment with epinephrine, and four participants who received casirivimab 4,000 mg plus imdevimab 4,000 mg had an infusion reaction of grade 2 severity or higher, which, in two cases, resulted in permanent discontinuation of the infusion.
Drug-Drug Interactions

• Drug-drug interactions are unlikely between bamlanivimab plus etesevimab or casirivimab plus imdevimab and medications that are renally excreted or that are cytochrome P450 substrates, inhibitors, or inducers.

• Please see Table 3c for more information. Vaccination

• SARS-CoV-2 vaccination should be deferred for ≥90 days in people who have received anti- SARS-CoV-2 monoclonal antibodies. This is a precautionary measure, as the antibody treatment may interfere with vaccine-induced immune responses.15

• For people who develop COVID-19 after receiving SARS-CoV-2 vaccination, prior vaccination should not affect treatment decisions, including the use of and timing of treatment with monoclonal antibodies.15
Considerations in Pregnancy

• As immunoglobulin (Ig) G monoclonal antibodies, bamlanivimab plus etesevimab, casirivimab plus imdevimab, and bamlanivimab alone would be expected to cross the placenta. There are no available data on the use of these anti-SARS-CoV-2 monoclonal antibodies during pregnancy; however, IgG products are generally not withheld because of pregnancy when their use is indicated.

• Anti-SARS-CoV-2 monoclonal antibodies should not be withheld from a pregnant individual with
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COVID-19 who has a condition that poses a high risk of progression to severe COVID-19, and the patient and provider determine that the potential benefit of the drug outweighs the potential risk (see the EUA criteria for the use of these products below).

• Inclusion of pregnant people in clinical trials should be encouraged to inform decisions on whether to use anti-SARS-CoV-2 monoclonal antibody therapy in this population.

Considerations in Children

• There are insufficient pediatric data to recommend either for or against the use of anti-SARS- CoV-2 monoclonal antibody products for children with COVID-19 who are not hospitalized but who have risk factors for severe disease. Based on adult studies, bamlanivimab plus etesevimab or casirivimab plus imdevimab may be considered for nonhospitalized children who meet EUA criteria, especially those who meet more than one criterion or are aged ≥16 years, on a case-by- case basis in consultation with a pediatric infectious disease specialist. Additional guidance on the use of anti-SARS-CoV-2 monoclonal antibodies for the treatment of COVID-19 in children is provided in a recent publication endorsed by the Pediatric Infectious Diseases Society.16

• Most children with mild or moderate COVID-19, even those with risk factors specified in the EUAs for bamlanivimab plus etesevimab or casirivimab plus imdevimab, will not progress to more severe illness and will recover without specific therapy.

• Risk factors for hospitalization have not been as clearly defined in children with COVID-19 as in adults with the disease, making it difficult to identify those children at the highest risk of hospitalization and those who would be likely to benefit from monoclonal antibody therapy.

• Additional data on clinical outcomes in children who receive monoclonal antibodies for the treatment of COVID-19, including in those with specific risk factors, are needed.

• Please see Special Considerations in Children for more information. Clinical Trials

• Health care providers are encouraged to discuss participation in anti-SARS-CoV-2 monoclonal antibody clinical trials with patients who have mild to moderate COVID-19.

Drug Availability

• Bamlanivimab plus etesevimab and casirivimab plus imdevimab are available through FDA EUAs.17

• Given the possibility of a limited supply of bamlanivimab plus etesevimab and casirivimab plus imdevimab, as well as challenges of distributing and administering the drugs, patients who are at highest risk for COVID-19 progression based on the EUA criteria should have priority access to the drugs.18,19

• Efforts should be made to ensure that communities most affected by COVID-19 have equitable access to these monoclonal antibodies.
High-Risk Criteria in the Emergency Use Authorizations for Anti-SARS-CoV-2 Monoclonal Antibodies
The FDA EUAs for all available anti-SARS-CoV-2 monoclonal antibodies and combinations have the same criteria for use: they allow for the use of the monoclonal antibodies for the treatment of COVID-19 in nonhospitalized adults and children aged ≥12 years and weighing ≥40 kg who are at high risk for progressing to severe COVID-19 and/or hospitalization.
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High-risk individuals as specified in the EUA are those who meet at least one of the following criteria:

• Body mass index (BMI) ≥35

• Chronic kidney disease

• Diabetes mellitus

• Immunocompromising condition

• Currently receiving immunosuppressive treatment

• Aged ≥65 years

• Aged ≥55 years and have:

• Cardiovascular disease, or

• Hypertension, or

• Chronic obstructive pulmonary disease or another chronic respiratory disease.

• Aged 12 to 17 years and have:

• BMI ≥85th percentile for their age and gender based on the Centers for Disease Control and
Prevention growth charts; or

• Sickle cell disease; or

• Congenital or acquired heart disease; or

• Neurodevelopmental disorders (e.g., cerebral palsy); or

• A medical-related technological dependence that is not related to COVID-19 (e.g., tracheostomy, gastrostomy, positive pressure ventilation); or

• Asthma or a reactive airway or other chronic respiratory disease that requires daily medication for control.
References

1. Jiang S, Hillyer C, Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. 2020;41(5):355-359. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32249063.

2. Wang Y, Zhang L, Sang L, et al. Kinetics of viral load and antibody response in relation to COVID-19 severity. J Clin Invest. 2020;130(10):5235-5244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32634129.

3. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332778.

4. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for monoclonal antibody bamlanivimab. News release. Food and Drug Administration. 2021. Available at: https://www.fda.gov/ news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization- monoclonal-antibody-bamlanivimab. Accessed April 19, 2021.

5. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info. html. Accessed April 5, 2021.

6. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download. Accessed February 17, 2021.

7. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of

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REGEN-COV (casirivimab and imdevimab). 2020. Available at: https://www.fda.gov/media/145611/download.

8. Wang P, Liu L, Iketani S, et al. Increased resistance of SARS-CoV-2 variants B.I.315 and B.I.I.7 to antibody neutralization. bioRxiv. 2021;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2021.01.25.428137v2.

9. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33684923.

10. Wang P, Wang M, Yu J, et al. Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization. bioRxiv. 2021;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2021.03.01.433466v1.

11. Food and Drug Administration. Frequently asked questions on the emergency use authorization of casirivimab + imdevimab. 2020. Available at: https://www.fda.gov/media/143894/download. Accessed January 20, 2021.

12. Food and Drug Administration. Frequently asked questions on the emergency use authorization for bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145808/download. Accessed February 17, 2021.

13. National Institute of Allergy and Infectious Diseases. Statement—NIH-sponsored ACTIV-3 trial closes LY-CoV555 sub-study. 2020. Available at: https://www.niaid.nih.gov/news-events/statement-nih-sponsored-activ-3-trial-closes-ly-cov555-sub-study.

14. Activ-Tico Ly- CoV555 Study Group, Lundgren JD, Grund B, et al. A neutralizing monoclonal antibody for hospitalized patients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33356051.

15. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/info-by- product/clinical-considerations.html. Accessed February 17, 2021.

16. Wolf J, Abzug MJ, Wattier RL, et al. Initial guidance on use of monoclonal antibody therapy for treatment of COVID-19 in children and adolescents. J Pediatric Infect Dis Soc. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33388760.

17. Public Health Emergency. Outpatient monoclonal antibody treatment for COVID-19 made available under emergency use authorization. March 24, 2021, update on COVID-19 variants and impact on bamlanivimab distribution. 2021. Available at: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/ Bamlanivimab/Pages/default.aspx. Accessed April 5, 2021.

18. Kim L, Garg S, O’Halloran A, et al. Risk factors for intensive care unit admission and in-hospital mortality among hospitalized adults identified through the U.S. coronavirus disease 2019 (COVID-19)-associated hospitalization surveillance network (COVID-NET). Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674114.

19. Ko JY, Danielson ML, Town M, et al. Risk factors for COVID-19-associated hospitalization: COVID-19- associated hospitalization surveillance network and behavioral risk factor surveillance system. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32945846.

              

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Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data

Last Updated: April 21, 2021



Study Design

Methods

Results

Limitations and Interpretation

Bamlanivimab Plus Etesevimab Versus Placebo in Outpatients With COVID-19 (BLAZE-1)1,2

Double-blind, Phase
3 RCT in outpatients
with mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization as de ned in the BAM plus ETE EUA (n = 1,035)

Note: These data are from the FDA EUA for BAM plus ETE and from a conference abstract presentation.

Key Inclusion Criteria:

• Aged ≥12 years

• Not currently hospitalized

• ≥1 mild or moderate COVID-19 symptom

• At high risk for progressing to severe COVID-19 and/or hospitalization

Key Exclusion Criteria:

• SpO2 ≤93% on room air, or
• Respiratory rate ≥30 breaths/min, or • Heart rate ≥125 bpm

Interventions:

• Single IV infusion of:
• BAM 2,800 mg plus ETE 2,800 mg, or • Placebo

• Administered within 3 days after receiving a positive result on a SARS- CoV-2 virologic test

Primary Endpoint:

• Proportion of participants with COVID-19 related hospitalization (de ned as ≥24 hours of acute care) or death by any cause by Day 29

Secondary Endpoints:

• Proportion of participants with persistently high VL (de ned as SARS- CoV-2 level >5.27 log10 copies/mL) at Day 7

• Mean change in VL from baseline to Days 3, 5, and 7

Number of Participants:

• BAM plus ETE (n = 518) and placebo (n = 517)

Participant Characteristics:

• Median age was 56 years; 31% of the participants were aged ≥65 years.

• 48% of the participants were men.

• 87% of the participants were White; 8% were Black or African American; and 29% were Hispanic/Latinx.

• Mean duration of symptoms was 4 days.

• 77% of the participants had mild COVID-19.
Primary Outcomes:
• Proportion of participants with COVID-19 related hospitalization or death by any cause by Day 29:
• 11 of 518 participants (2.1%) in the BAM plus ETE arm vs. 36 of 517 (7.0%) in the placebo arm (P = 0.0004)
• Relative reduction: 70%
• Proportion of participants who had died from any cause by Day 29:
• 0 of 518 participants (0%) in the BAM plus ETE arm vs. 10 of 517 (1.9%) in the placebo arm (P < 0.001).
Secondary Outcome:
• The proportion of participants with persistently high VLs at Day 7 was 10% in the BAM plus ETE arm vs. 29% in the placebo arm (P < 0.000001).

Limitation:

• Trial data have not yet been peer reviewed and published.

Interpretation:

• There was a 5% absolute reduction and a 70% relative reduction in COVID-19-related hospitalizations or deaths from any cause among the participants who received BAM plus ETE compared to those who received placebo.

• Data are for a BAM plus ETE dose which is not the dose authorized in the EUA.

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39.

Study Design

Methods

Results

Limitations and Interpretation

REGN10933 and REGN10987 (Casirivimab Plus Imdevimab) Versus Placebo in Outpatients with COVID-19 (Modi ed Full Analysis of R10933-10987-COV-2067 Trial)3

Double-blind, Phase
3 RCT in outpatients with mild to moderate COVID-19 (n = 4,180 for modi ed full analysis subset of the Phase 3 trial)

These data are publicly available but have not been peer reviewed or published.

Key Inclusion Criteria:

• Onset of COVID-19 symptoms ≤7 days before randomization

• SARS-CoV-2 PCR positive at baseline

• Criteria only for the modi ed full analysis:
• Aged ≥18 years
• ≥1 risk factor for severe COVID-19
Interventions:
• Single IV infusion of:
• CAS 600 mg plus IMD 600 mg,
• CAS 1,200 mg plus IMD 1,200 mg, or • Placebo
Endpoint:
• Proportion of participants with COVID- 19-related hospitalization or all-cause death through Day 29

Number of Participants:

• CAS 600 mg plus IMD 600 mg (n = 736) vs. placebo (n = 748)

• CAS 1,200 mg plus IMD 1,200 mg (n = 1,355) vs. placebo (n = 1,341)

Participant Characteristics:

• Median age was 50 years.

• 35% of the participants were Hispanic/Latinx and 5% were Black or African American.

• Median duration of symptoms prior to enrollment was 3 days (IQR 2–5 days).4
Outcomes:
• Percentage of participants with COVID-19-related hospitalization or all-cause death through Day 29 (based on participants in the modi ed cohort):

• 7 of 736 (1.0%) in the CAS 600 mg plus IMD 600 mg arm vs. 24 of 748 (3.2%) in the placebo arm (P = 0.0024)

• 18 of 1,355 (1.3%) in the CAS 1,200 mg plus IMD 1,200 mg arm vs. 62 of 1,341 (4.6%) in the placebo arm (P < 0.0001)
• Percentage of participants who died (based on all study participants):

• 1 of 827 (0.1%) in the CAS 600 mg plus IMD 600 mg arm

• 1 of 1,849 (0.05%) in the CAS 1,200 mg plus IMD 1,200 mg arm

• 5 of 1,843 (0.3%) in the placebo arm

Limitations:

• The modi ed full analysis data have not been peer reviewed or published.

• Details of the study design, follow- up, and full methods are limited.
Interpretation:

• There was a 2.2% absolute reduction and a 70% relative risk reduction in COVID-19-related hospitalizations or all-cause deaths in participants who received CAS 600 mg plus IMD 600 mg compared to those who received placebo.

• There was a 3.3% absolute reduction and a 71% relative risk reduction in COVID-19 related hospitalizations and all-cause deaths in participants who received CAS 1,200 mg plus IMD 1,200 mg compared to those who received placebo.

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Study Design

Methods

Results

Limitations and Interpretation

REGN10933 and REGN10987 (Casirivimab Plus Imdevimab) Versus Placebo in Outpatients With COVID-19 (R10933-10987-COV-2067 Trial)5

Double-blind, Phase 1 and 2 RCT in outpatients with mild to moderate COVID-19 (n = 799)

Note: These data are from the FDA EUA for CAS plus IMD.

Key Inclusion Criteria:

• Onset of COVID-19 symptoms ≤7 days before randomization

• SpO2 ≥93% on room air Key Exclusion Criteria:

• Hospitalization before or at randomization due to COVID-19

• Prior, current, or planned future use of any of the treatments speci ed in the protocol (e.g., COVID-19 CP, IVIG for any indication)
Interventions:
• Single IV infusion of:

• CAS plus IMD 2,400 mg (CAS 1,200 mg and IMD 1,200 mg),

• CAS plus IMD 8,000 mg (CAS 4,000 mg and IMD 4,000 mg), or

• Placebo
• Administered ≤3 days after receiving a positive result on a SARS-CoV-2 virologic test
Primary Endpoint:
• TWA change in NP VL from baseline to Day 7
Secondary Endpoints:

• COVID-19-related medical visits including hospitalization or ED, urgent care, or physician of ce/telemedicine visit within 28 days of treatment

• Safety

• Symptom improvement

Number of Participants:

• CAS plus IMD (n = 533):
• CAS plus IMD 2,400 mg (n = 266) • CAS plus IMD 8,000 mg (n = 267)

• Placebo (n = 266)

Participant Characteristics:

• Median age was 42 years; 7% of the participants were aged ≥65 years.

• 34% of the participants had risk factors for severe COVID-19.

• Median duration of symptoms was 3 days.
Primary Outcome:

• The primary endpoint was evaluated in the modi ed full analysis set of participants with detectable virus at baseline (n = 665).

• TWA change in NP VL at Day 7 was greater among the CAS plus IMD-treated participants overall than among the placebo-treated participants (-0.36 log10 copies/mL; P < 0.0001).
Secondary Outcomes:
• The proportion of participants who had COVID-19- related medical visits within 28 days of treatment was lower in the combined CAS plus IMD arms than in the placebo arm:
• Combined CAS plus IMD arms: 2.8% of patients
• Placebo arm: 6.5% of patients
• In a post hoc analysis, percentage of participants who were hospitalized or had a medical visit within 28 days of treatment:
• All CAS plus IMD doses: 8 of 434 (2%) • CAS plus IMD 2,400 mg: 4 of 215 (2%) • CAS plus IMD 8,000 mg: 4 of 219 (2%) • Placebo: 10 of 231 (4%)

Limitations:

• Relatively small number of participants in each arm

• Low number of hospitalizations or ED visits

Interpretation:

• Compared to placebo, a single infusion of CAS plus IMD showed a reduction in NP VL at Day 7 among outpatients with mild or moderate COVID-19.

• The combined hospitalization or ED visit rate was lower in the CAS plus IMD arms than in the placebo arm, but the number of events in each arm was small.

• Because of the small number of clinical events, it is dif cult to draw de nitive conclusions about the clinical bene t of CAS plus IMD from this study. Additional data from a follow-up trial have been reported but remain unpublished.

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Study Design

Methods

Results

Limitations and Interpretation

REGN10933 and REGN10987 (Casirivimab Plus Imdevimab) Versus Placebo in Outpatients With COVID-19 (R10933-10987-COV-2067 Trial)5, continued

• In a post hoc analysis, percentage of participants at high-risk for progression to severe COVID-19 and/or hospitalization who required hospitalization or ED visit:

• All CAS plus IMD doses: 4 of 151 (3%)

• Placebo: 7 of 78 (9%)
• Median time to symptom improvement:

• Combined CAS plus IMD arms: 5 days

• Placebo arm: 6 days

• The safety pro le of CAS plus IMD was similar to the pro le for the placebo.

• 4 infusion related reactions of grade 2 severity or higher were reported in the CAS plus IMD 8,000 mg arm resulting in permanent discontinuation of the infusion in 2 participants; 1 participant had an anaphylactic reaction that resolved with treatment.

REGN10933 (Casirivimab) Plus REGN10987 (Imdevimab) Versus Placebo in Outpatients With COVID-19 (R10933-10987-COV-2067 Interim Analysis)6 Note: The data presented in this published interim analysis represent a subset of participants described in the CAS plus IMD EUA (see study above).

Double-blind, Phase 1 and 2 RCT in outpatients with mild to moderate COVID-19 (n = 275)

Key Inclusion Criteria:

• Onset of COVID-19 symptoms ≤7 days before randomization

• SpO2 ≥93% on room air Key Exclusion Criteria:

• Hospitalization before or at randomization due to COVID-19

• Prior, current, or planned future use of any of the treatments speci ed in the protocol (e.g., COVID-19 CP, IVIG for any indication)
Interventions:
• Single IV infusion of:
• CAS plus IMD 2,400 mg (CAS 1,200 mg and IMD 1,200 mg),

Number of Participants:

• All CAS plus IMD doses (n = 182): • CAS plus IMD 2,400 mg (n = 92) • CAS plus IMD 8,000 mg (n = 90)

• Placebo (n = 93)

Participant Characteristics:

• Median age was 44 years (range 35–52 years).

• Median time from symptom onset to randomization was 3 days.

• Baseline serum antibody status: • Positive: 45% of participants
• Negative: 41% of participants • Unknown: 14% of participants

Limitations:

• No formal hypothesis testing

• Interim analysis

• Relatively small number of participants in each arm

• These data represent only a subset of participants described in the CAS plus IMD EUA (see the study above).

• Low number of medical visits
Interpretation:
• Compared to placebo, a single infusion of CAS plus IMD showed a reduction in VL at Day 7 among outpatients with mild or moderate COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

REGN10933 (Casirivimab) Plus REGN10987 (Imdevimab) Versus Placebo in Outpatients With COVID-19 (R10933-10987-COV-2067 Interim Analysis)6, continued

• CAS plus IMD 8,000 mg (CAS 4,000 mg and IMD 4,000 mg), or

• Placebo

• Administered ≤3 days after receiving a positive result on a SARS-CoV-2 virologic test

Primary Endpoint:

• TWA change in NP VL from baseline to Day 7 in participants with negative serum antibody status at baseline

Secondary Endpoints:

• COVID-19-related medical visits, including hospitalization or ED, urgent care, or physician of ce/telemedicine visit within 28 days of treatment

• Safety

• Symptom improvement

Primary Outcomes:

• Primary endpoint evaluated in modi ed full analysis set of participants with detectable virus at baseline (n = 221).

• TWA change in NP VL at Day 7 was greater among the participants who received CAS plus IMD (-1.74 ± 0.11 log10 copies/mL; 95% CI, -1.95 to -1.53) than among those who received placebo (-1.34 ± 0.13 log10 copies/ mL; 95% CI, -1.60 to -1.08).

• Among the participants with a negative serum antibody status at baseline, TWA change in VL was greater among those who received CAS plus IMD (-1.94 ± 0.13 log10 copies/mL; 95% CI, -2.20 to -1.67) than among those who received placebo (-1.37 ± 0.20 log10 copies/ mL; 95% CI, -1.76 to -0.98).
Secondary Outcomes:
• The percentage of participants who had COVID-19- related medical visits within 28 days of treatment was lower in the CAS plus IMD arms than in the placebo arm:
• All CAS plus IMD doses: 6 of 182 (3%)
• Placebo: 6 of 93 (6%)
• Among participants with negative serum antibody status at baseline, the percentage of those who had COVID-19-related medical visits within 28 days of treatment was lower in the CAS plus IMD arms:
• All CAS plus IMD doses: 5 of 80 (6%)
• Placebo: 5 of 33 (15%)

• The safety pro le of CAS plus IMD was similar to the pro le of the placebo; 2 hypersensitivity or infusion related reactions of grade 2 severity or higher were reported in both the CAS plus IMD 8,000 mg arm and the placebo arm.

• The mean half-life for both CAS and IMD antibodies ranged from 25–37 days.

• The percentage of participants with medical visits was lower in the CAS plus IMD arms than in the placebo arm, but the number of events in each arm was small.

• CAS plus IMD may have a greater effect in patients who are serum antibody negative but further investigation is needed.

• Because of the small number of clinical events, it is dif cult to draw de nitive conclusions about the clinical bene t of CAS plus IMD from this study.

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Key: ACTIV-3/TICO = A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Ef cacy of Investigational Therapeutics for Hospitalized Patients With COVID-19; AE = adverse event; BAM = bamlanivimab; BLAZE-1 = Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies; BMI = body mass index; CAS = casirivimab; CP = convalescent plasma; ED = emergency department; ETE = etesevimab; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; IMD = imdevimab; IV = intravenous; IVIG = intravenous immunoglobulin; NP = nasopharyngeal; PCR = polymerase chain reaction; RCT = randomized controlled trial; RDV = remdesivir; SpO2 = saturation of oxygen; TWA = time-weighted average; VL = viral load

References

1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download.

2. Dougan M, Nirula A, Gottlieb RL, et al. Bamlanivimab+etesevimab for treatment of COVID-19 in high-risk ambulatory patients. Presented at: Conference on Retroviruses and Opportunistic Infections. 2021. Virtual. Available at: https://www.croiconference.org/wp-content/uploads/sites/2/ resources/2021/vCROI-2021-Abstract-eBook.pdf.

3. Regeneron. COV-2067 Phase 3 trial in high-risk outpatients shows that REGEN-COV (2400 mg and 1200 mg IV doses) significantly reduces risk of hospitalization or death while also shortening symptom duration. 2021. Available at: https://newsroom.regeneron.com/index.php/static-files/a7173b5a- 28f3-45d4-bede-b97370bd03f8. Accessed April 5, 2021.

4. Phase 3 trial shows REGEN-COV (casirivimab with imdevimab) antibody cocktail reduced hospitalization or death by 70% in non-hospitalized COVID-19 patients. News release. Regeneron. 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-trial- shows-regen-covtm-casirivimab-imdevimab-antibody. Accessed April 5, 2021.

5. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of casirivimab and imdevimab. 2020. Available at: https://www.fda.gov/media/143892/download.

6. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332778.

        

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Convalescent Plasma

Last Updated: April 21, 2021

Plasma from donors who have recovered from COVID-19 may contain antibodies to SARS-CoV-2 that may help suppress the virus and modify the inflammatory response.1 The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for convalescent plasma for the treatment of certain hospitalized patients with COVID-19.

Recommendation

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of low-titer COVID-19 convalescent plasma for the treatment of COVID-19 (AIIb).

• Low-titer COVID-19 convalescent plasma is no longer authorized through the convalescent plasma EUA.

For Hospitalized Patients With COVID-19 Who Do Not Have Impaired Immunity

• The Panel recommends against the use of COVID-19 convalescent plasma for the treatment of COVID-19 in mechanically ventilated patients (AI).

• The Panel recommends against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients who do not require mechanical ventilation, except in a clinical trial (AI).
For Hospitalized Patients With COVID-19 Who Have Impaired Immunity

• There are insufficient data for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19.

• Observational data including data from case reports, case series, and a retrospective case control study suggest a benefit of COVID-19 convalescent plasma in patients with various primary and secondary humoral immunodeficiencies.2-16

• Several case reports indicate that patients with impaired humoral immunity may experience persistent SARS-CoV-2 viral replication and therefore, may be at risk for developing viral resistance to SARS-CoV-2 antibodies after treatment with COVID-19 convalescent plasma.17-19

• High-titer convalescent plasma is authorized under the EUA for the treatment of hospitalized patients with COVID-19 and impaired immunity.
For Nonhospitalized Patients With COVID-19

• There are insufficient data for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in patients who are not hospitalized, except in a clinical trial.

• Convalescent plasma is not authorized for nonhospitalized patients with COVID-19 under the EUA.

• Results from additional adequately powered, well-designed, and well-conducted randomized clinical trials are needed to provide more specific, evidence-based guidance on the role of COVID-19 convalescent plasma in the treatment of nonhospitalized patients with COVID-19.
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Rationale for Recommendation

On August 23, 2020, the FDA issued an EUA for convalescent plasma for the treatment of hospitalized patients with COVID-19 based on retrospective, indirect evaluations of efficacy generated from a large Expanded Access Program (EAP). The EAP allowed for the use of convalescent plasma regardless of titer. The Panel reviewed the EAP analyses and determined that the data were not sufficient to establish the efficacy or safety of COVID-19 convalescent plasma due to potential confounding, the lack of randomization, and the lack of an untreated control group.

On February 4, 2021, the FDA revised the convalescent plasma EUA to limit the authorization to high-titer COVID-19 convalescent plasma and only for the treatment of hospitalized patients with COVID-19 early in the disease course or hospitalized patients who have impaired humoral immunity.

Use of Convalescent Plasma in Hospitalized Patients With COVID-19 and Without Impaired Humoral Immunity

An updated retrospective analysis of data collected through the EAP indicated that patients who received high-titer plasma had a lower relative risk of death within 30 days after transfusion than patients who received low-titer plasma (relative risk 0.82; 95% CI, 0.67–1.00).20

• Among the patients who were on mechanical ventilation before transfusion, no effect of high-titer plasma versus low-titer plasma was observed (relative risk 1.02; 95% CI, 0.78–1.32).

• Among the patients who were not on mechanical ventilation before transfusion, mortality was lower among patients who received high-titer plasma than among those who received low-titer plasma (relative risk 0.66; 95% CI, 0.48–0.91).20
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an open-label, randomized controlled platform trial evaluating potential treatments for COVID-19. In the convalescent plasma portion of the trial, 11,558 patients were randomized to receive either convalescent plasma (n = 5,795) or usual care (n = 5,763) before enrollment was stopped due to futility.21
The trial results demonstrated no significant differences in the primary endpoint of 28-day mortality between the convalescent plasma arm (24%) and the usual care arm (24%; risk ratio 1.00; 95% CI, 0.93–1.07). Additionally, the trial did not meet its two secondary endpoints: time to hospital discharge and, for those not on mechanical ventilation at randomization, receipt of invasive mechanical ventilation or death. The proportion of patients discharged within 28 days was similar in the convalescent plasma
arm and the usual care arm (66% vs. 67%; rate ratio 0.98; 95% CI, 0.94–1.03). Among those not requiring invasive mechanical ventilation at baseline, the proportion of those progressing to invasive mechanical ventilation or death was also similar in the convalescent plasma arm and the usual care arm (28% vs. 29%; risk ratio 0.99; 95% CI, 0.93–1.05). The 28-day mortality rate ratio was similar in all prespecified patient subgroups, including in those patients without detectable SARS-CoV-2 antibodies at randomization
(32% in the convalescent plasma arm vs. 34% in the usual care arm; rate ratio 0.94; 95% CI, 0.84–1.06). Subgroup analyses suggested a slight trend towards benefit of convalescent plasma in certain subgroups (e.g., those with symptom onset ≤7 days, no requirement for supplemental oxygen at baseline, no concomitant use of corticosteroids). See Table 3b for additional details.
Data from several other randomized clinical trials, all of which were underpowered, have not demonstrated the efficacy of convalescent plasma for the treatment of hospitalized patients with COVID- 19.22-29 See Table 3b for details.
Additionally, two large, randomized trials evaluating convalescent plasma in hospitalized patients have been paused or have limited enrollment due to futility.
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• The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial, which evaluated convalescent plasma versus usual care, was stopped after an interim analysis of 614 patients met the predefined threshold for futility.30

• The Randomised, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), which evaluated convalescent plasma in hospitalized patients, paused enrollment for patients in intensive care units after a preliminary analysis that included 912 participants indicated that convalescent plasma was unlikely to benefit this patient group.31 REMAP-CAP continues to recruit hospitalized patients who do not require intensive care support into the trial’s convalescent plasma evaluation domain.
Results from adequately powered, well-designed, and well-conducted randomized clinical trials are needed to provide more specific, evidence-based guidance on the role of convalescent plasma in the treatment of hospitalized patients with COVID-19 who do not have impaired humoral immunity.
Use of Convalescent Plasma in Hospitalized Patients With COVID-19 and Impaired Humoral Immunity
Data from case reports, case series, and a retrospective case-control study suggest a benefit of convalescent plasma in patients with primary and secondary humoral immunodeficiencies, including patients with hematologic malignancy, common variable immune deficiency, and agammaglobulinemia, and those who have received a transplanted solid organ.2-13,15,16 Several case reports indicate that
patients with impaired humoral immunity may experience persistent SARS-CoV-2 viral replication and, therefore, may be at risk for developing viral resistance to SARS-CoV-2 antibodies after treatment with convalescent plasma.
Results from adequately powered, well-designed, and well-conducted randomized clinical trials are needed to provide more specific, evidence-based guidance on the role of convalescent plasma in the treatment of patients with COVID-19 who have impaired humoral immunity.17-19
Use of Convalescent Plasma in Nonhospitalized Patients With COVID-19
Current data are insufficient to establish the safety or efficacy of convalescent plasma in outpatients with COVID-19.

• Data from a double-blind, placebo-controlled randomized trial of high-titer convalescent plasma in elderly outpatients with <72 hours of mild COVID-19 symptoms suggested a potential for benefit.32 However, the trial included relatively few participants, and only a small number of clinical events related to COVID-19 occurred. See Table 3b for details.

• The Clinical Trial of COVID-19 Convalescent Plasma of Outpatients (C3PO) evaluated convalescent plasma for the treatment of nonhospitalized patients with ≤7 days of mild or moderate COVID-19 symptoms and at least one risk factor for severe COVID-19. The trial was halted after an interim analysis indicated no benefit of convalescent plasma for this group of patients. The trial enrolled 511 of the planned 900 participants before the study was halted.
Convalescent plasma is not authorized for nonhospitalized patients with COVID-19 under the EUA.
Clinical Data to Date
Table 3b includes a summary of key studies of convalescent plasma for the treatment of COVID-19. Considerations in Pregnancy
The safety and efficacy of using COVID-19 convalescent plasma during pregnancy have not been
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evaluated. Pathogen-specific immunoglobulins are used clinically during pregnancy to prevent infection from varicella zoster virus and rabies virus and have been used in clinical trials of congenital cytomegalovirus infection.33 Some ongoing clinical trials that are evaluating COVID-19 convalescent plasma include pregnant individuals.34

Considerations in Children

The safety and efficacy of COVID-19 convalescent plasma have not been evaluated in pediatric patients outside of evaluations described in single-center reports. Clinical trials of COVID-19 convalescent plasma in children are ongoing. There are insufficient data for the Panel to recommend either for or against the use of convalescent plasma for the treatment of COVID-19 in hospitalized children who do not require mechanical ventilation. The Panel recommends against the use of convalescent plasma for the treatment of COVID-19 in mechanically ventilated pediatric patients (AIII). In consultation with a pediatric infectious disease specialist, high-titer convalescent plasma may be considered on a case-by- case basis for children with COVID-19 who meet the EUA criteria.

Adverse Effects

Available data suggest that serious adverse reactions following the administration of COVID-19 convalescent plasma are infrequent and consistent with the risks associated with plasma infusions for other indications. These risks include transfusion-transmitted infections (e.g., HIV, hepatitis B, hepatitis C), allergic reactions, anaphylactic reactions, febrile nonhemolytic reactions, transfusion-related
acute lung injury, transfusion-associated circulatory overload, and hemolytic reactions. Hypothermia, metabolic complications, and post-transfusion purpura have also been described.21,35,36

Additional risks of COVID-19 convalescent plasma transfusion include a theoretical risk of antibody-dependent enhancement of SARS-CoV-2 infection and a theoretical risk of long-term immunosuppression.

The Panel recommends consulting a transfusion medicine specialist when considering convalescent plasma for patients with a history of severe allergic or anaphylactic transfusion reactions.

Product Availability

On February 4, 2021, the FDA revised the convalescent plasma EUA to limit the authorization to high-titer COVID-19 convalescent plasma.37

• The revised EUA Letter of Authorization provides an expanded list of anti-SARS-CoV-2 antibody tests and corresponding qualifying results that may be used to determine the suitability of donated convalescent plasma.

• Please refer to the FDA’s Recommendations for Investigational COVID-19 Convalescent Plasma webpage for guidance on the transfusion of investigational convalescent plasma while blood establishments develop the necessary operating procedures to manufacture COVID-19 convalescent plasma in accordance with the Conditions of Authorization described in the EUA.38
Clinical Trials
Randomized clinical trials that are evaluating convalescent plasma for the treatment of COVID-19 are underway. Please see ClinicalTrials.gov for the latest information.
References

1. Wang X, Guo X, Xin Q, et al. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32497196.

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2. Ferrari S, Caprioli C, Weber A, Rambaldi A, Lussana F. Convalescent hyperimmune plasma for chemo- immunotherapy induced immunodeficiency in COVID-19 patients with hematological malignancies. Leuk Lymphoma. 2021:1-9. Available at: https://www.tandfonline.com/doi/full/10.1080/10428194.2021.1872070.

3. Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood. 2020;136(20):2290-2295. Available at: https://ashpublications.org/blood/ article/136/20/2290/463806/Convalescent-plasma-therapy-for-B-cell-depleted.

4. Rahman F, Liu STH, Taimur S, et al. Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: experience at large transplant center in New York City. Clin Transplant. 2020;34(12):e14089. Available at: https://onlinelibrary.wiley.com/doi/10.1111/ctr.14089.

5. Mira E, Yarce OA, Ortega C, et al. Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(8):2793-2795. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345404/.

6. Fung M, Nambiar A, Pandey S, et al. Treatment of immunocompromised COVID-19 patients with convalescent plasma. Transpl Infect Dis. 2020; 2020/09/30:e13477. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537112/pdf/TID-9999-na.pdf. Accessed March 23, 2021.

7. Quinti I, Lougaris V, Milito C, et al. A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J Allergy Clin Immunol. 2020;146(1):211-213 e214. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0091674920305571?via%3Dihub.

8. Jin H, Reed JC, Liu STH, et al. Three patients with X-linked agammaglobulinemia hospitalized for COVID-19 improved with convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(10):3594-3596 e3593. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490621/.

9. Betrains A, Godinas L, Woei AJF, et al. Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies. 2020. Available at: https://onlinelibrary.wiley.com/doi/10.1111/bjh.17266.

10. Balashov D, Trakhtman P, Livshits A, et al. SARS-CoV-2 convalescent plasma therapy in pediatric patient after hematopoietic stem cell transplantation. Transfus Apher Sci. 2021;60(1):102983. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33153902.

11. Thompson MA, Henderson JP, Shah PK, et al. Convalescent plasma and improved survival in patients with hematologic malignancies and COVID-19. MedRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.05.21250953v1.

12. Senefeld JW, Klassen SA, Ford SK, et al. Therapeutic use of convalescent plasma in COVID-19 patients with immunodeficiency. 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.11.08.20224790v1.full. pdf. Accessed March 24, 2021.

13. Clark E, Guilpain P, Filip IL, et al. Convalescent plasma for persisting COVID-19 following therapeutic lymphocyte depletion: a report of rapid recovery. Br J Haematol. 2020;190(3):e154-e156. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32593180.

14. Iaboni A, Wong N, Betschel SD. A patient with X-linked agammaglobulinemia and COVID-19 infection treated with remdesivir and convalescent plasma. J Clin Immunol. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33547548.

15. Van Damme KFA, Tavernier S, Roy NV, et al. Case report: convalescent plasma, a targeted therapy for patients with CVID and severe COVID-19. Front Immunol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714937/.

16. Tremblay D, Seah C, Schneider T, et al. Convalescent plasma for the treatment of severe COVID-19 infection in cancer patients. Cancer Medicine. 2020. Available at: https://onlinelibrary.wiley.com/doi/10.1002/cam4.3457.

17. Choi B, Choudhary MC, Regan J, et al. Persistence and Evolution of SARS-CoV-2 in an

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Immunocompromised Host. N Engl J Med. 2020;383(23):2291-2293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33176080.

18. Kemp SA, Collier DA, Datir RP, et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021. Available at: https://www.nature.com/articles/s41586-021-03291-y.

19. Tarhini H, Recoing A, Bridier-Nahmias A, et al. Long term SARS-CoV-2 infectiousness among three immunocompromised patients: from prolonged viral shedding to SARS-CoV-2 superinfection. The Journal of Infectious Diseases. 2021. Available at: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/ jiab075/6131370.

20. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med. 2021. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2031893.

21. The RECOVERY Collaborative Group, Horby PW, Estcourt L, et al. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.09.21252736v1.

22. Simonovich VA, Pratx LDB, Scibona P, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2021. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2031304.

23. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371. Available at: https://www.bmj.com/content/bmj/371/bmj.m3939.full.pdf.

24. Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492084.

25. Gharbharan A, Jordans CCE, GeurtsvanKessel C, et al. Convalescent plasma for COVID-19: a randomized clinical trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.01.20139857v1.

26. Avendano-Sola C, Ramos-Martinez A, Muñez-Rubio E, et al. Convalescent plasma for COVID-19: a multicenter, randomized clinical trial. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.full.pdf. Accessed March 23, 2021.

27. AlQahtani M, Abdulkarim A, Almadani A, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. MedRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.02.20224303v1.full.

28. Ray Y, Paul SR, Bandopadhyay P, et al. Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. MedRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.25.20237883v1.

29. O’Donnell MR, Grinsztejn B, Cummings MJ, et al. A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19. MedRxiv. 2021. Available at: https://www.medrxiv.org/ content/10.1101/2021.03.12.21253373v1?%25253fcollection=.

30. CONCOR-1. Welcome to CONCOR-1 clinical trial website. Available at: https://concor1.ca/. Accessed March 25, 2021.

31. REMAP-CAP PR. International Trial of SARS-CoV-2 Convalescent Plasma Pauses Enrollment of Critically Ill COVID-19 Patients. 2021. Available at: https://www.recover-europe.eu/press-release-international-trial-of- sars-cov-2-convalescent-plasma-pauses-enrollment-of-critically-ill-covid-19-patients/. Accessed March 25, 2021.

32. Libster R, Perez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med. 2021;384(7):610-618. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2033700.

33. Centers for Disease Control and Prevention. Updated recommendations for use of VariZIG—United States, 2013. MMWR Morb Mortal Wkly Rep. 2013;62(28):574-576. Available at:

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https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6228a4.htm. Accessed March 26, 2021.

34. University of Pennsylvania. COVID-19 convalescent plasma for mechanically ventilated population. 2020.
Available at: https://clinicaltrials.gov/ct2/show/NCT04388527. Accessed March 26, 2021.

35. Food and Drug Administration. EUA of COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients: fact sheet for health care providers. 2020. Available at: https://www.fda.gov/media/141478/download. Accessed September 22, 2020.

36. Nguyen FT, van den Akker T, Lally K, et al. Transfusion reactions associated with COVID-19 convalescent plasma therapy for SARS-CoV-2. Transfusion. 2021;61(1):78-93. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33125158.

37. Food and Drug Administration. Convalescent Plasma Letter of Authorization. 2020. Available at: https://www.fda.gov/media/141477/download. Accessed August 31, 2020.

38. Food and Drug Administration. Recommendations for investigational COVID-19 convalescent plasma. 2021. Available at: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device- exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma. Accessed March 26, 2021.

      

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Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data

Last Updated: April 21, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for COVID-19 CP. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.



Study Design

Methods

Results

Limitations and Interpretation

Convalescent Plasma in Hospitalized Patients With COVID-19 (RECOVERY Trial)1

Open-label, platform RCT evaluating potential treatments, including high-titer CP, in hospitalized patients with COVID-19 in the United Kingdom (n = 11,558)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Clinically suspected or laboratory-con rmed SARS- CoV-2 infection

• CP available at study site

Key Exclusion Criteria:

• CP contraindicated (e.g., known allergy to blood components)

Interventions:

• One 275 mL (+/- 75 mL) unit of CP immediately and another unit the next day (≥12 hours after the rst unit)

• CP was selected by sample to cut-off IgG SARS-CoV-2 spike protein ratio ≥6.0.

• Usual care

Primary Endpoint:

• All-cause mortality at Day 28

Secondary Endpoints:

• Time to hospital discharge

• Among patients not receiving IMV at randomization, receipt of IMV or death by Day 28

Number of Participants:

• ITT analysis: CP (n = 5,795) and usual care (n = 5,763)

Participant Characteristics:

• Mean age was 63.5 years.

• 63% of patients in the CP arm and 66% in the usual care arm were men.

• 5% of patients in each arm were on IMV.

• At baseline, 52% of the patients in the CP arm and 48% in the usual care arm were SARS-CoV-2 antibody seropositive.

• 93% of the patients in the CP arm and 92% in the usual care arm received corticosteroids.
Outcomes:

• No difference in 28-day mortality between the CP arm and the usual care arm (24% vs. 24%; rate ratio 1.00; 95% CI, 0.93–1.07).

• No difference in the proportion of patients discharged within 28 days (66% in CP arm vs. 67% in usual care arm; rate ratio 0.98; 95% CI, 0.94–1.03; P = 0.50).

• 28-day mortality rate ratio was consistent across prespeci ed patient subgroups, including subgroups by SARS-CoV-2 antibody presence
at randomization. In particular, among patients without detectable SARS-CoV-2 antibodies, there was no evidence of a mortality difference between those who received CP and those who received usual care (32% vs. 34%; rate ratio 0.94; 95% CI, 0.84–1.06).

• Among those not receiving IMV at baseline, the percentage of patients who progressed to IMV or died was similar in the CP arm and the usual care arm (28% vs. 29%; rate ratio 0.99; 95% CI, 0.93–1.05; P = 0.79).

• Severe allergic reactions were rare (occurred in 16 patients in the CP arm and 2 in the usual care arm).

Limitations:

• The study was not blinded.

• >90% of participants received corticosteroids. There is uncertainty about the effect of
CP in hospitalized patients who do not require supplemental oxygen and for whom corticosteroids are not recommended.
Interpretation:
• The trial did not demonstrate a bene t of CP in hospitalized patients with COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Convalescent Plasma in Hospitalized Adults With COVID-19 (PLACID Trial)2

Multicenter, open- label, Phase 2 RCT in hospitalized adults with severe COVID-19 in India (n = 464)

Key Inclusion Criteria:

• Aged ≥18 years

• Positive SARS-CoV-2 RT-PCR

• PaO2/FiO2 = 200–300 mm Hg or respiratory rate >24 breaths/ min with SpO2 ≤93% on room air
Key Exclusion Criteria:
• Critical illness
Interventions:
• 2 doses of 200 mL CP, transfused 24 hours apart
• SOC
Primary Endpoint:

• Composite of progression to severe disease (de ned as PaO2/FiO2 <100 mm Hg) any time within 28 days

of enrollment or all-cause mortality at 28 days

Number of Participants:

• CP (n = 235) and SOC (n = 229)

Participant Characteristics:

• Median age was 52 years.

• 75% of participants in the CP arm and 77% in the SOC arm were men.

• Higher prevalence of diabetes in the CP arm (48%) than in SOC arm (38%).

Outcomes:

• No difference between the arms in the primary outcome of progression to severe disease or death (occurred in 18.7% of participants in CP arm and 17.9% in SOC arm).

• A post hoc analysis evaluating outcomes among patients without detectable SARS-CoV-2 neutralizing antibody titers at baseline also revealed no bene t of CP.

Limitations:

• The study was not blinded.

• SARS-CoV-2 antibody testing was not used to select donated CP units; therefore, many participants may have received CP units with low titers of SARS- CoV-2 neutralizing antibodies.
Interpretation:

• This trial did not demonstrate a bene t of CP in hospitalized patients with severe COVID-19.

Convalescent Plasma in COVID-19 Severe Pneumonia (PlasmAr Study)3

Double-blind, placebo- controlled, multicenter RCT in hospitalized adults with severe COVID-19 in Argentina (n = 333)

Key Inclusion Criteria:

• Aged ≥18 years
• Positive SARS-CoV-2 RT-PCR • Severe COVID-19

Key Exclusion Criteria:

• Critical illness

Interventions

2:1 Randomization:

• Single dose (median volume

Number of Participants:

• CP (n = 228) and placebo (n = 105)

Participant Characteristics:

• Median age was 62 years.

• 67.6% of the participants were men.

• 64.9% of the participants had a coexisting condition at trial entry.

• Median time from symptom onset to enrollment was 8 days.

• Of 215 participants tested, 46% had no detectable SARS-CoV-2 antibodies at baseline. Median SARS-CoV-2 antibody titer in both the CP arm and placebo arm was 1:50.

Limitations:

• The majority of participants in
both arms received concomitant glucocorticoid treatment, potentially masking subtle differences in clinical outcomes between the study arms.

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Study Design

Methods

Results

Limitations and Interpretation

Convalescent Plasma in COVID-19 Severe Pneumonia (PlasmAr Study)3, continued

500 mL) of CP pooled from 2–5 donors. Only plasma units with a SARS-CoV-2 viral spike- RBD IgG titer ≥1:800 were transfused.

• Placebo

Primary Endpoint:

• Change in clinical status 30 days after intervention measured using a 6-point ordinal scale

Outcomes:

• No signi cant differences between the arms in the distribution of outcomes according to the categories on the 6-point ordinal scale (OR 0.83; 95% CI, 0.52–1.35).

• 30-day mortality was similar in CP arm (11.0%) and placebo arm (11.4%).

• Infusion-related AEs were more frequent in the CP arm than in the placebo arm (occurred in 4.8% vs. 1.9% of participants).

Interpretation:

• This trial did not demonstrate a bene t of CP in hospitalized patients with severe COVID-19.

Convalescent Plasma in Adults With Severe COVID-194

Double-blind, Phase
2 RCT in hospitalized adults with severe COVID-19 (n = 223) in the United States (n = 73) and Brazil (n = 150)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Aged ≥18 years

• COVID-19 pneumonia

• SpO2 ≤94% on room air or requirement for supplemental oxygen, IMV, or ECMO
Key Exclusion Criteria:
• >5 days on IMV or ECMO • Severe multiorgan failure
Interventions
2:1 Randomization:

• Single dose of SARS-CoV-2 CP (approximately 250 mL). Only units with a SARS-CoV-2 viral spike-RBD IgG titer ≥1:400 were transfused.

• Non-SARS-CoV-2 plasma (normal control plasma)

Number of Participants:

• CP (n = 150) and normal control plasma (n = 73)

• Enrollment initiated in New York City in April 2020 and in Brazil in August 2020

Participant Characteristics:

• Median age was 61 years.

• 66% of the participants were men.

• Median duration of symptoms prior to randomization was 9 days.

• 57% of the participants required supplemental oxygen at baseline, 25% required high- ow oxygen or noninvasive ventilation, and 13% required IMV or ECMO.

• There were some imbalances between the study arms at baseline. The CP arm included more women; the participants were younger and had slightly longer symptom durations.

• 81% of the participants received corticosteroids.
Outcomes:
• No difference in clinical status on Day 28 was observed between the CP arm and the control arm (OR 1.5 for being in a better category with CP vs. control plasma; 95% CI, 0.83–2.68; P = 0.18).

Limitations:

• The intervention in the control group arm was blood plasma without SARS-CoV-2 antibodies. This ensured blinded administration; however, because the trial was not placebo controlled; it is not possible to identify potential harm due to plasma infusion.

• Low sample size and number of events

• There were
imbalances in baseline characteristics between the study arms that may have impacted study outcomes. After adjustment for the imbalances, the

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Study Design

Methods

Results

Limitations and Interpretation

Convalescent Plasma in Adults With Severe COVID-194, continued

Primary Endpoint:

• Clinical status on Day 28, measured using an ordinal scale (initially with 7 categories, but modi ed to 6).

Secondary Endpoints:

• Time to clinical improvement

• In-hospital and 28-day mortality

• Time to discontinuation of supplemental oxygen

• Time to hospital discharge

• In-hospital mortality was lower in the CP arm (13%) than in the control arm (25%; HR 0.44; 95% CI, 0.22–0.91; P = 0.034). The treatment difference was not signi cant after adjustment for age, sex, and duration of symptoms at baseline.

• In both arms, mortality at 28 days was the same as in-hospital mortality.

• Time to oxygen discontinuation and time to hospital discharge were similar between the arms.

• 25.5% of patients in the CP arm vs. 36.1% in the control arm experienced SAEs.

difference in mortality between the arms was not signi cant.

• The treatment difference in the primary outcome (clinical status on Day 28) was not statistically signi cant; mortality was a secondary outcome.

• There were no subgroup analyses for mortality.
Interpretation:

• Although the difference between the CP arm and the non-SARS-CoV-2 antibody plasma arm for the primary outcome of clinical status on Day

28 was not statistically signi cant, the lower 28-day mortality in
the CP arm suggests a potential bene t of CP in hospitalized patients with severe COVID-19.

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Study Design

Methods

Results

Limitations and Interpretation

Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults5

Double-blind, placebo- controlled RCT in outpatients with mild COVID-19 in Argentina (n = 160)

Key Inclusion Criteria:

• Aged >75 years or aged
65–74 years with ≥1 coexisting condition

• Outpatient with <72 hours of mild COVID-19 symptoms
Key Exclusion Criteria:
• Severe respiratory disease
Interventions:
• Single 250 mL dose of CP with an IgG titer against SARS- CoV-2 spike protein of >1:1000
• Placebo
Primary Endpoint:
• Severe respiratory disease de ned as a respiratory rate ≥30 breaths/min and/or SpO2 <93% on room air by Day 15

Number of Participants:

• ITT analysis: CP (n = 80) and placebo (n = 80)

Participant Characteristics:

• Mean age was 77 years.
• Most of the patients had comorbidities.

Outcomes:

• 13 of 80 patients (16%) in the CP arm and 25 of 80 (31%) in the placebo arm experienced severe respiratory disease by Day 15 (relative risk 0.52; 95% CI, 0.29–0.94; P = 0.026).

• 2 participants in the CP arm and 5 in the placebo arm died.

• No solicited AEs were reported.

Limitations:

• The trial was terminated early because cases of COVID-19 at the study site decreased.

• The trial included relatively few participants.
Interpretation:

• This trial demonstrated a bene t of CP in elderly outpatients with <72 hours of mild COVID-19 symptoms.

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-Threatening COVID-196

Multicenter, open- label, randomized trial in hospitalized adults with severe or life- threatening COVID-19 in China (n = 103)

Key Inclusion Criteria:

• Aged ≥18 years

• Positive SARS-CoV-2 PCR within 72 hours of randomization

• Met study de nition of severe or life-threatening COVID-19

Number of Participants:

• CP (n = 52) and SOC (n = 51)

Participant Characteristics:

• Median age was 70 years.
• 58.3% of the participants were men.

Outcomes:

• No signi cant difference in time to clinical improvement between the CP arm and the control arm (HR 1.40; 95% CI, 0.79–2.49; P = 0.26).

• No signi cant difference in mortality between the CP arm (16%) and the control arm (24%; P = 0.30).

Limitations:

• The study was not blinded.

• The trial was stopped early because of decreasing numbers of cases of COVID-19 at the study site; therefore, the study lacked suf cient power to detect differences in clinical outcomes.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-Threatening COVID-196, continued

Key Exclusion Criteria:

• Baseline RBD-speci c IgG antibody ≥1:64

• Certain sequalae of severe COVID-19 (e.g., severe septic shock, severe heart failure)
Interventions:

• Single 4–13 mL/kg dose of CP. Only CP units with a SARS- CoV-2 viral spike-RBD-speci c IgG titer of ≥1:640 were transfused.

• SOC
Primary Endpoint:

• Time to clinical improvement (patient discharge or a reduction of 2 points on a 6-point disease severity scale; 6 points = death, 1 point = hospital discharge) within 28 days.

• Only 103 of 200 planned participants were randomized to receive treatment.

• CP was administered late (approximately 1 month) into disease course.

Interpretation:

• This trial did not demonstrate a bene t of CP in hospitalized patients with severe or life- threatening COVID-19.

Early Versus Deferred Anti-SARS-CoV-2 Convalescent Plasma in Hospitalized Patients With COVID-197

Open-label, single- center, Phase 2 randomized trial in hospitalized adults with COVID-19 in Chile (n

= 58)

Key Inclusion Criteria:

• Aged ≥18 years
• ≤7 days of COVID-19

symptoms

• High risk of progression to respiratory failure

Key Exclusion Criteria:

• PaO2/FiO2 <200 mm Hg • Mechanical ventilation

Number of Participants:

• Immediate CP (n = 28) and deferred CP (n = 30)

Participant Characteristics:

• Median age was 66 years.

• 50% of the participants were men.

• Median interval between symptom onset and randomization was 6 days.

• 13 of 28 participants (43%) in the deferred CP arm received CP at a median of 3 days after enrollment.

Limitations:

• The study was not blinded. • Small sample size.

Interpretation:

• This trial did not demonstrate a bene t of immediate vs. deferred administration of CP in hospitalized COVID-19 patients with ≤7 days of COVID-19 symptoms.

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Study Design

Methods

Results

Limitations and Interpretation

Early Versus Deferred Anti-SARS-CoV-2 Convalescent Plasma in Hospitalized Patients With COVID-197, continued

Interventions

Immediate CP:

• Two 400 mL doses of CP with anti-SARS-CoV-2 neutralizing antibody titers ≥1:400, transfused 24 hours apart

Deferred CP:

• CP transfusion only if PaO2/FiO2 <200 mm Hg, or if participant still required hospitalization for COVID-19 symptoms 7 days after enrollment

Primary Endpoint:

• Composite of mechanical ventilation, hospitalization >14 days, or in-hospital death

Outcomes:

• There was no difference between the arms in the percentage of participants who met the primary composite endpoint of death, mechanical ventilation, or >14 days hospitalization (32% in immediate CP arm vs. 33% in deferred CP arm; OR 0.95; 95% CI, 0.32–2.84).

• 18% of participants in the immediate CP arm vs. 7% in the deferred CP arm died within 30 days (OR 3.0; 95% CI, 0.5–17.2; P = 0.25).

Convalescent Plasma for COVID-19 (ConCOVID trial)8

Multicenter, open-label, RCT in hospitalized adults with COVID-19 in the Netherlands (n

= 86)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Aged ≥18 years

• Clinical disease with positive SARS-CoV-2 RT-PCR within 96 hours of enrollment

Key Exclusion Criteria:

• Mechanical ventilation for >96 hours

Interventions:

• One to two 300 mL doses of CP with anti-SARS-CoV-2 neutralizing antibody titers ≥1:80

• SOC

Number of Participants:

• CP (n = 43) and SOC (n = 43)

Participant Characteristics:

• Median age was 63 years.
• Most of the participants were men.

Outcomes:

• No differences in mortality (P = 0.95), length of hospital stay (P = 0.68), or disease severity at Day 15 (P = 0.58) were observed between the study arms.

Limitations:

• The study was not blinded.

• Trial halted early by the investigators when the baseline SARS-CoV-2 neutralizing antibody titers of participant plasma
and CP were found to be comparable, challenging the potential bene t of CP for the study population. Thus, the study lacked suf cient power to detect differences in clinical outcomes between the study arms.

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Study Design

Methods

Results

Limitations and Interpretation

Convalescent Plasma for COVID-19 (ConCOVID trial)8, continued

Primary Endpoint:

• Day-60 mortality

• Only 86 of 426 planned participants were randomized to receive CP or SOC.

Interpretation:

• This trial did not demonstrate a bene t of COVID-19 CP in hospitalized patients.

Convalescent Plasma for COVID-19 (ConPlas-19 Study)9

Multicenter, open-label, RCT in hospitalized adults with COVID-19 in Spain (n = 81)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Aged ≥18 years
Key Exclusion Criteria:

• Receiving IMV, noninvasive ventilation, or high- ow oxygen

Interventions:

• Single dose of 250–300 mL of CP plus SOC.

• All administered units had neutralizing antibodies (VMNT-ID50: all titers >1:80, median titer 1:292, IQR 238– 451; pseudovirus neutralizing ID50 assay: median titer 1:327; IQR 168–882)

• SOC alone

Primary Endpoint:

• Proportion of patients in ordinal scale categories 5, 6, or 7 at Day 15.

Number of Participants:

• CP (n = 38) and SOC (n = 43)

Participant Characteristics:

• Mean age was 59 years.

• At baseline, 49% of the participants were SARS-CoV-2 antibody positive.

Outcomes:

• 0 of 38 participants (0%) in the CP arm progressed to ordinal scale categories 5–7 vs. 6 of 43 participants (14.0%) in the SOC arm (P = 0.57, not statistically signi cant according to the planned analysis; but P = 0.03 using Fisher test as a post hoc sensitivity analysis given small numbers and the by-center heterogenous distribution).

• 0 of 38 participants (0%) in the CP arm died vs. 4 of 43 (9.3%) in the SOC arm (P = 0.06).

Limitations:

• The study was not blinded.

• The trial was stopped early because of decreasing numbers of COVID-19 cases at the study site and, thus, the study lacked suf cient power to detect differences in clinical outcomes.
• Only 81 of planned 278 participants were enrolled.
Interpretation:

• Although the results did not reach statistical signi cance and only a small number
of clinical events related to COVID-19 occurred, these results suggest a potential bene t of CP in hospitalized patients who are not receiving high- ow oxygen, noninvasive ventilation, or invasive ventilation.

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Study Design

Methods

Results

Limitations and Interpretation

Clinical and Immunological Bene ts of Convalescent Plasma Therapy in Severe COVID-1910

Single-center, open-label, RCT in hospitalized adults with COVID-19 and ARDS in India (n = 80)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Evidence of ARDS (de ned as PaO2/FiO2 100–300 mm Hg)

• Not on mechanical ventilation

Key Exclusion Criteria:

• Mechanical ventilation

Intervention:

• 2 consecutive doses of ABO- matched 200 mL CP, 1 day apart

• SOC alone

Primary Endpoint:

• All-cause mortality at Day 30

Number of Participants:

• CP (n = 40) and SOC (n = 40)

Participant Characteristics:

• Mean age was 61 years.

• 71% of the participants were men.

• No difference in mean number of days of hospitalization at enrollment between the CP arm (4.2 days) and the SOC arm (3.9 days).
Outcomes:
• 10 of 40 participants (25%) in the CP arm had died by Day 30 vs.
14 of 40 (35%) in the SOC arm.
• Difference in survival between the arms was not statistically signi cant (HR 0.6731; 95% CI, 0.3010–1.505).

Limitations:

• The study was not blinded.

• The study lacked suf cient power to detect differences in clinical outcomes between the study arms.
Interpretation:

• This trial did not demonstrate a bene t of CP in hospitalized patients with mild to moderate ARDS who are

not receiving mechanical ventilation.

Convalescent Plasma Therapy Versus Standard Therapy in Patients With Severe COVID-1911

Open-label, RCT in hospitalized adults with COVID-19 in Bahrain (n = 40)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

• Aged ≥21 years

• Radiologic evidence of
pneumonia

• Requirement for oxygen therapy for COVID-19
Key Exclusion Criteria:
• Requirement for IMV, noninvasive ventilation, or high- ow oxygen
Interventions:
• Two 200 mL transfusions of CP over 24 hours
• SOC alone
Primary Endpoints:
• Requirement for IMV or noninvasive ventilation

Number of Participants:

• CP (n = 20) and SOC (n = 20)

Participant Characteristics:

• Mean age was 53 years in the CP arm and 51 years in the SOC arm.

• Most of the participants were men (75% in the CP arm and 85% in the SOC arm).

Outcomes:

• 6 patients in the SOC arm and 4 patients in the CP arm required mechanical ventilation (risk ratio 0.67; 95% CI, 0.22–2.0; P = 0.72).

• 2 patients in the SOC arm died vs. 1 in the CP arm.

Limitations:

• The study was not blinded.

• The study lacked suf cient power to detect differences in clinical outcomes between the study arms.
Interpretation:

• This trial did not demonstrate a bene t of CP in hospitalized patients who are not receiving high- ow oxygen, noninvasive ventilation, or invasive ventilation.

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Study Design

Methods

Results

Limitations and Interpretation

Convalescent Plasma Therapy Versus Standard Therapy in Patients With Severe COVID-1911, continued

• In patients who require ventilation, duration of ventilation

Convalescent Plasma Antibody Levels and the Risk of Death from COVID-1912

Retrospective, indirect evaluation of a subset of patients from the Mayo Clinic COVID-19 CP EAP (n = 3,082). More than 100,000 patients hospitalized with COVID-19 in the United States received CP through the Mayo Clinic EAP.

Key Inclusion Criteria:

• Aged ≥18 years

• Severe or life-threatening
(critical) COVID-19

• Analysis limited to patients for whom samples were available for retrospective analysis of CP titer.
Intervention:
• CP transfusion (no titer speci ed in real time; high, medium, and low titer CP determined retrospectively)
Primary Endpoint:
• Mortality 30 days after CP transfusion

Number of Participants:

• High-titer CP (n = 515), medium-titer CP (n = 2,006), and low-titer CP (n = 561)

Participant Characteristics:

• 61% of the participants were men.

• 48% of the participants were White and 37% were Hispanic/Latino.

• 61% of the participants required ICU-level care prior to infusion.

• 33% of the participants were on mechanical ventilation.

• 51% of the participants received corticosteroids; 31% received RDV.
Outcomes:

• The analysis included 3,082 participants who received a single unit of CP. The participants were among 35,322 participants who had received CP through the EAP by July 4, 2020.

• Death within 30 days occurred in 115 of 515 patients (22%) in the high-titer group, 549 of 2,006 patients (27%) in the medium-titer group, and 166 of 561 patients (30%) in the low-titer group.

• Using a relative-risk regression model that assumed all patients who were discharged were alive at Day 30, patients in the high-titer group had a lower relative risk of death within 30 days than patients in the low-titer group (relative risk 0.82; 95% CI, 0.67–1.00).

• Among patients who received mechanical ventilation before transfusion, there was no difference in the risk of death between those who received high-titer CP and those who received low-titer CP (relative risk 1.02; 95% CI, 0.78–1.32).

• Mortality was lower among patients who were not receiving mechanical ventilation before transfusion (relative risk 0.66; 95% CI, 0.48–0.91).

Limitations:

• Lack of untreated control arm limits interpretation of the safety and ef cacy data; the possibility that differences in outcomes are attributable to harm from low- titer plasma rather than bene t from high-titer plasma cannot be excluded.

• Assays to determine the effective antibody titers remain limited, and the antibody titers of currently available CP from COVID-19 survivors are highly variable.

• Ef cacy analysis relied on only
a subset of EAP patients who represent a fraction of the patients who received CP through the EAP.

• Post hoc subgroups were selected by combining several subsetting rules that favored subgroups. This approach tends to overestimate the treatment effect.
Interpretation:

• Given the lack of an untreated control arm and the limitations listed above, this retrospective analysis is not suf cient to establish the ef cacy or safety of CP.

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Key: AE = adverse event; ARDS = acute respiratory distress syndrome; ConCOVID Trial = Convalescent-plasma-for-COVID-9; ConPlas-19 Study = Convalescent Plasma for COVID-19; CP = convalescent plasma; EAP = Expanded Access Program; ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; ID50 = 50% inhibitory dose; IgG = immunoglobulin G; IMV = invasive mechanical ventilation; ITT = intention to treat; the Panel = the COVID-19 Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PCR = polymerase chain reaction; PLACID Trial = Convalescent plasma
in the management of moderate covid-19 in adults in India: open label phase II multicentre randomized controlled trial; PlasmAr Study = A Randomized Trial
of Convalescent Plasma in COVID-19 Severe Pneumonia; RBD = receptor binding domain; RCT = randomized controlled trial; RDV = remdesivir; RECOVERY = Randomised Evaluation of COVID-19 Therapy; RT-PCR = reverse transcriptase polymerase chain reaction; SAE = serious adverse event; SOC = standard of care; SpO2 = saturation of oxygen; VMNT = virus microneutralization test

References

1. The RECOVERY Collaborative Group, Horby PW, Estcourt L, et al. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.09.21252736v1.

2. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate COVID-19 in adults in India: open label Phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939. Available at: https://pubmed.ncbi.nlm.nih.gov/33093056/.

3. Simonovich VA, Pratx LDB, Scibona P, et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med. 2021;384(7):619-629. Available at: https://pubmed.ncbi.nlm.nih.gov/33232588/.

4. O’Donnell MR, Grinsztejn B, Cummings MJ, et al. A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.12.21253373v1?%25253fcollection=.

5. Libster R, Perez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med. 2021;384(7):610-618. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2033700.

6. Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. JAMA. 2020;324(5):460-470. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492084.

7. Balcells ME, Rojas L, Le Corre N, et al. Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: a randomized Phase II clinical trial. PLoS Med. 2021;18(3):e1003415. Available at: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003415.

8. Gharbharan A, Jordans CCE, Geurtsvankessel C, et al. Convalescent plasma for COVID-19: a randomized clinical trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.01.20139857v1.

9. Avendano-Sola C, Ramos-Martinez A, Muñez-Rubio E, et al. Convalescent plasma for COVID-19: a multicenter, randomized clinical trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.full.pdf.

10. Ray Y, Paul SR, Bandopadhyay P, et al. Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.25.20237883v1.

11. AlQahtani M, Abdulkarim A, Almadani A, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.02.20224303v1.full.

12. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med. 2021;384(11):1015-1027. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2031893.

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Immunoglobulins: SARS-CoV-2 Specific

Last Updated: July 17, 2020

Recommendation

• There are insufficient data for the COVID-19 Treatment Guidelines Panel to recommend either for or against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulins for the treatment of COVID-19.

Rationale

Currently, there are no clinical data on the use of SARS-CoV-2 immunoglobulins. Trials evaluating SARS-CoV-2 immunoglobulins are in development but not yet active and enrolling participants.

Proposed Mechanism of Action and Rationale for Use in Patients with COVID-19

Concentrated antibody preparations derived from pooled plasma collected from individuals who
have recovered from COVID-19 can be manufactured as SARS-CoV-2 immunoglobulin, which
could potentially suppress the virus and modify the inflammatory response. The use of virus-specific immunoglobulins for other viral infections (e.g., cytomegalovirus [CMV] immunoglobulin for the prevention of post-transplant CMV infection and varicella zoster immunoglobulin for postexposure prophylaxis of varicella in individuals at high-risk) has proven to be safe and effective; however, there are currently no clinical data on the use of such products for COVID-19. Potential risks may include transfusion reactions. Theoretical risks may include antibody-dependent enhancement of infection.

Clinical Data

There are no clinical data on the use of SARS-CoV-2 immunoglobulins for the treatment of COVID-19. Similarly, there are no clinical data on use of specific immunoglobulin or hyperimmunoglobulin products in patients with severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS).

Considerations in Pregnancy

Pathogen-specific immunoglobulins are used clinically during pregnancy to prevent varicella zoster virus (VZV) and rabies and have also been used in clinical trials of therapies for congenital CMV infection.

Considerations in Children

Hyperimmunoglobulin has been used to treat several viral infections in children, including VZV, respiratory syncytial virus, and CMV; efficacy data on their use for other respiratory viruses is limited.



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Table 3c. Characteristics of SARS-CoV-2 Antibody-Based Products Under Evaluation for the Treatment of COVID-19
Last Updated: April 21, 2021

• The information in this table is derived from data on the use of these products in investigational trials in patients with COVID-19. The table includes dose recommendations from the FDA EUAs for patients with COVID-19 who meet specified criteria.

• There are limited or no data on dose modifications for patients with organ failure or those who require extracorporeal devices. Please refer to product labels, when available.

• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the treatment of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.

• The potential additive, antagonistic, or synergistic effects and the safety of using combination therapies for the treatment of COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.

• For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.

• For the Panel’s recommendations for the drugs listed in this table, please refer to the drug-specific sections of the Guidelines and
Therapeutic Management of Adults With COVID-19.

   

Dosing Regimens

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)

Dose Recommended in EUA:

• BAM 700 mg and ETE 1,400 mg IV administered together as a single dose

• Nausea

• Dizziness

• Rash

• Pruritis

• Pyrexia

• Hypersensitivity, including anaphylaxis and infusion-related reactions

• Unexpected SAEs may occur.

• These AEs were observed in a trial where the doses of BAM and ETE given (BAM 2,800 mg and ETE 2,800 mg) were higher than the EUA doses.

• Only for administration in health care settings by quali ed health care providers who have immediate access to medications to treat a severe infusion reaction and emergency medical services.

• Monitor patient during the infusion and for ≥1 hour after the infusion is completed.

• Drug-drug interactions are unlikely between BAM plus ETE and medications that are renally excreted or that are CYP substrates, inhibitors, or inducers.

Availability:

• BAM plus ETE is available through the FDA EUA
for high-risk outpatients with mild to moderate COVID-19.1 See Anti- SARS-CoV-2 Monoclonal Antibodies for a list of high-risk conditions.

• A list of clinical trials is available: Bamlanivimab plus Etesevimab

    

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Dosing Regimens

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Casirivimab Plus Imdevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)

Dose Recommended in EUA:

• CAS 1,200 mg and IMD 1,200 mg IV administered together as a single dose

• Hypersensitivity, including anaphylaxis and infusion- related reactions

• Unexpected SAEs may occur.

• Only for administration
in health care settings
by quali ed health care providers who have immediate access to medications to treat a
severe infusion reaction and emergency medical services.

• Monitor patient during the infusion and for ≥1 hour after the infusion is completed.

• Drug-drug interactions are unlikely between CAS plus IMD and medications that are renally excreted or that are CYP substrates, inhibitors, or inducers.

Availability:

• CAS plus IMD is available through the FDA EUA for high-risk outpatients with mild to moderate COVID-19.2 See Anti-SARS-CoV-2 Monoclonal Antibodies for a list of high-risk conditions.

• A list of clinical trials is available: Casirivimab plus Imdevimab

  

COVID-19 Convalescent Plasma

Dose Recommended in EUA Authorizing the Use of High-Titer COVID-19 CP for Hospitalized Patients With COVID-19:

• Per the EUA, consider starting clinical dosing
with 1 high-titer COVID-19 CP unit (about 200 mL), with administration of additional CP units based on the prescribing provider’s medical judgment and the patient’s clinical response.

• TRALI

• TACO

• Allergic reactions

• Anaphylactic reactions

• Febrile nonhemolytic reactions

• Hemolytic reactions

• Hypothermia

• Metabolic complications

• Transfusion-transmitted infections3

• Thrombotic events

• Theoretical risk of antibody- mediated enhancement of infection and suppressed long-term immunity

• Before administering CP
to patients with a history
of severe allergic or anaphylactic transfusion reactions, the Panel recommends consulting
a transfusion medicine specialist who is associated with the hospital blood bank.

• Monitor for transfusion- related reactions.

• Monitor patient’s vital signs at baseline and during and after transfusion.

• Drug products should not be added to the IV infusion line for the blood product.

• The decision to treat patients aged <18 years with COVID-19 CP should be based on an individualized assessment of risk and bene t.4

• Patients with impaired cardiac function and heart failure may require a smaller volume of CP or slower transfusion rate.
Availability:

• High-titer COVID-19 CP is available through the FDA EUA for hospitalized patients with COVID-19.5 See Anti- SARS-CoV-2 Monoclonal Antibodies.

• A list of clinical trials is available: COVID-19 Convalescent Plasma

   

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Dosing Regimens

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

SARS-CoV-2-Speci c Immunoglobulin

Dose varies by clinical trial

• TRALI

• TACO

• Allergic reactions

• Antibody-mediated enhancement of infection

• RBC alloimmunization

• Transfusion-transmitted infections3

• Monitor for transfusion- related reactions.

• Monitor patient’s vital signs at baseline and during and after transfusion.

• Drug products should not be added to the IV infusion line for the blood product.

• A list of clinical trials is available: SARS-CoV-2 Immunoglobulin

 

Key: AE = adverse event; BAM = bamlanivimab; CAS = casirivimab; CP = convalescent plasma; CYP = cytochrome P450; ETE = etesevimab; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; IMD = imdevimab; IV = intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; RBC = red blood cell; SAE = serious adverse event; TACO = transfusion-associated circulatory overload; TRALI = transfusion-related acute lung injury

References

1. Food and Drug Administration. Fact sheet for health care providers: emergency use authorization (EUA) of bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download.

2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of casirivimab and imdevimab. 2020. Available at: https://www.fda.gov/media/143892/download.

3. Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus. 2016;14(2):152-157. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26674811.

4. Food and Drug Administration. Fact sheet for health care providers: emergency use authorization (EUA) of COVID-19 convalescent plasma for treatment of hospitalized patients with COVID-19. 2021. Available at: https://www.fda.gov/media/141478/download.

5. Food and Drug Administration. Convalescent Plasma Letter of Authorization. 2020. Available at: https://www.fda.gov/media/141477/download.

    

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Cell-Based Therapy Under Evaluation for the Treatment of COVID-19
Last Updated: April 21, 2021

Mesenchymal Stem Cells

Mesenchymal stem cells are investigational products that have been studied extensively for broad clinical applications in regenerative medicine1 and for their immunomodulatory properties.2 It is hypothesized that mesenchymal stem cells could reduce the acute lung injury and inhibit the cell- mediated inflammatory response induced by SARS-CoV-2.

Recommendation

• The COVID-19 Treatment Guidelines Panel recommends against the use of mesenchymal stem cells for the treatment of COVID-19, except in a clinical trial (AIIb).

Rationale for Recommendation

No mesenchymal stem cells products are approved by the Food and Drug Administration (FDA) for the treatment of COVID-19. There are limited data to date to assess the role of mesenchymal stem cells for the treatment of COVID-19.

The FDA has recently issued several warnings about patients being vulnerable to stem cell treatments that are illegal and potentially harmful.3 Several umbilical cord blood-derived products are currently licensed by the FDA for indications such as the treatment of cancer (e.g., stem cell transplant) or rare genetic diseases, and as scaffolding for cartilage defects and wound beds. None of these products are approved for the treatment of COVID-19 or any other viral disease.4 In the United States, mesenchymal stem cells should not be used for the treatment of COVID-19 outside of an FDA-approved clinical trial, expanded access program, or an Emergency Investigational New Drug application (AII).

Rationale for Use in COVID-19

Mesenchymal stem cells are multipotent adult stem cells that are present in most human tissues, including the umbilical cord. Mesenchymal stem cells can self-renew by dividing and can differentiate into multiple types of tissues (including osteoblasts, chondroblasts, adipocytes, hepatocytes, and others), which has led to a robust clinical research agenda in regenerative medicine. It is hypothesized that mesenchymal stem cells could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by SARS-CoV-2. Furthermore, because they lack the angiotensin-converting enzyme 2 (ACE2) receptor that SARS-CoV-2 uses for viral entry into cells, mesenchymal stem cells are resistant to infection.5,6

Clinical Data

Data supporting the use of mesenchymal stem cells in patients who have viral infections, including SARS-CoV-2 infection, are limited to case reports and small, open-label studies.

Clinical Data for COVID-19

A pilot study of intravenous mesenchymal stem cell transplantation in China enrolled 10 patients with confirmed COVID-19 categorized according to the National Health Commission of China criteria as critical, severe, or common type. Seven patients (one with critical illness, four with severe illness, and two with common-type illness) received mesenchymal stem cells; three patients with severe illness

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received placebo. All seven patients who received mesenchymal stem cells recovered. Among the three severely ill placebo-treated patients, one died, one developed acute respiratory distress syndrome (ARDS), and one remained stable with severe disease.7

A small clinical trial evaluated human umbilical cord mesenchymal stem cell (hUC-MSC) infusion in patients with severe COVID-19 who had not responded to standard of care therapies after 7 to 10 days of treatment. The standard of care therapies included supplemental oxygen, umifenovir/oseltamivir, antibiotics if indicated, and glucocorticoids. The study was intended as a randomized controlled trial; however, due to the lack of sufficient hUC-MSCs, it was not possible to randomize the participants as originally planned. Among the 41 patients eligible to participate in the study, 12 received hUC-MSC infusion and 29 received standard of care therapies only. The study arms were well balanced with regard to demographic characteristics, laboratory test results, and disease severity. All 12 participants who received hUC-MSC infusion recovered without requiring mechanical ventilation and were discharged to home. Four patients who received only standard of care therapies progressed to critical illness requiring mechanical ventilation; three of these patients died. These results are not statistically significant, and interpretation of the findings is limited by the study’s lack of randomization and small sample size.8

A double-blind randomized controlled trial investigated the safety and efficacy of hUC-MSC infusions in patients with COVID-19 ARDS. Twenty-four patients were randomized to receive either two infusions of hUC-MSC (prepared at a single site) or placebo on Day 0 and Day 3. The primary endpoints were occurrence of prespecified infusion-associated adverse events within 6 hours of each hUC-MSC infusion; cardiac arrest or death within 24 hours after an infusion; and the incidence of adverse events. Secondary endpoints included survival at 31 days after hUC-MSC infusion and time to recovery.9

There were no differences between the arms in the primary safety analysis; however, more deaths occurred in the placebo arm (7 deaths) than in the hUC-MSC arm (2 deaths) by Day 31. Data for
one participant in the hUC-MSC arm who died due to a failed intubation was censored from the analysis. Time to recovery was shorter in the hUC-MSC arm than in the placebo arm (HR 0.29; 95%
CI, 0.09–0.95). Interpretation of these results is limited by the small sample size and a change in an eligibility criterion from enrolling only individuals on invasive mechanical ventilation to including those receiving high-flow oxygen or on noninvasive ventilation.

Clinical Data for Other Viral Infections

In an open-label study of mesenchymal stem cells for the treatment of H7N9 influenza in China, 17 patients received mesenchymal stem cell treatment plus standard of care, and 44 patients received standard of care only. Three patients (17.6%) in the mesenchymal stem cell arm died versus 24 patients (54.5%) in the standard of care arm. The 5-year follow-up was limited to five patients in the mesenchymal stem cell arm. No safety concerns were identified.10

Clinical Trials

See ClinicalTrials.gov for a list of clinical trials evaluating mesenchymal stem cells for the treatment of COVID-19, COVID-19-related ARDS, and COVID-19-associated multisystem inflammatory syndrome in children (MIS-C).

Adverse Effects

Risks associated with mesenchymal stem cell transfusion appear to be uncommon. The potential risks include the potential for mesenchymal stem cells to multiply or change into inappropriate cell types, product contamination, growth of tumors, infections, thrombus formation, and administration site reactions.11

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Considerations in Pregnancy

There are insufficient data to assess the risk of using mesenchymal stem cell therapy during pregnancy.

Considerations in Children

There are insufficient data to assess the efficacy and safety of using mesenchymal stem cell therapy in children.

References

1. Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med. 2017;6(12):2173-2185. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29076267.

2. Li N,Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74(13):2345-2360. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28214990.

3. Food and Drug Administration. FDA warns about stem cell therapies. 2019. Available at: https://www.fda.gov/ consumers/consumer-updates/fda-warns-about-stem-cell-therapies. Accessed January 26, 2021.

4. Food and Drug Administration. Approved cellular and gene therapy products. 2019. Available at: https:// http://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy- products. Accessed January 26, 2021.

5. Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S,Drela K. Challenges and controversies in human mesenchymal stem cell therapy. Stem Cells Int. 2019;2019:9628536. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31093291.

6. Shetty AK. Mesenchymal stem cell infusion shows promise for combating coronavirus (COVID-19)-induced pneumonia. Aging Dis. 2020;11(2):462-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32257554.

7. Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020;11(2):216-228. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32257537.

8. Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020;11(1):361. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32811531.

9. Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, Phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33400390.

10. Chen J, Hu C, Chen L, et al. Clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic Influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering (Beijing). 2020;6(10):1153-1161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32292627.

11. Centers for Disease Control and Prevention. Stem cell and exosome products. 2019. Available at: https://www.cdc.gov/hai/outbreaks/stem-cell-products.html. Accessed January 26, 2021.

             

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Immunomodulators Under Evaluation for the Treatment of COVID-19
Last Updated: April 21, 2021



Summary Recommendations

See Therapeutic Management of Adults with COVID-19 for the COVID-19 Treatment Guidelines Panel’s (the Panel’s) recommendations on the use of the following:

• Baricitinib in combination with remdesivir when corticosteroids cannot be used, • Dexamethasone (or other corticosteroids) with or without remdesivir, and
• Tocilizumab with dexamethasone (with or without remdesivir).

See additional recommendations on the use of baricitinib and tocilizumab below.

Other Immunomodulators

There are insuf cient data for the Panel to recommend either for or against the use of the following immunomodulators for the treatment of COVID-19:

• Baricitinib in combination with a corticosteroid; because both agents are potent immunosuppressants, there is a potential additive risk of infection.

• Baricitinib in combination with remdesivir for hospitalized patients with COVID-19 when corticosteroids can be used

• Colchicine for nonhospitalized patients with COVID-19

• Fluvoxamine

• Interleukin (IL)-1 inhibitors (e.g., anakinra)

• Interferon beta for the treatment of early (i.e., <7 days from symptom onset) mild to moderate COVID-19

• Sarilumab for patients who are within 24 hours of admission to the intensive care unit (ICU) and who require invasive
mechanical ventilation, noninvasive ventilation, or high- ow oxygen (>0.4 FiO2/30 L/min of oxygen ow)

• Tocilizumab for most hospitalized patients with hypoxemia who require conventional oxygen therapy (see Therapeutic
Management of Adults With COVID-19 for more detailed information)
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a
clinical trial:

• Baricitinib without remdesivir (AIII)

• Colchicine for hospitalized patients with COVID-19 (AIII)

• Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19 (AIII)

• Kinase inhibitors:
• Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) (AIII)
• Janus kinase inhibitors other than baricitinib (e.g., ruxolitinib, tofacitinib) (AIII)

• Non-SARS-CoV-2-speci c intravenous immunoglobulin (IVIG) (AIII). This recommendation should not preclude the use of IVIG when it is otherwise indicated for the treatment of complications that arise during the course of COVID-19.

• Sarilumab for patients who do not require ICU-level care or who are admitted to the ICU for >24 hours but do not require invasive mechanical ventilation, noninvasive ventilation, or supplemental oxygen administered through a high- ow device (BIIa)

• The anti-IL-6 monoclonal antibody siltuximab (AIII).

  

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

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Colchicine

Last Updated: April 21, 2021

Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout, recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been studied for the prevention of major cardiovascular events in those with coronary artery disease.2 Colchicine has several potential mechanisms of action, including mechanisms that reduce the chemotaxis of neutrophils, inhibit inflammasome signaling, and decrease the production of cytokines such as interleukin-1 beta.3 When colchicine is administered early in the course of COVID-19, these mechanisms may potentially mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory properties (as well as the drug’s limited immunosuppressive potential, widespread availability, and favorable safety profile) have prompted investigation of colchicine for the treatment of COVID-19.

Recommendations

• There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of colchicine for the treatment of nonhospitalized patients with COVID-19.

• A large, randomized trial in outpatients, the Colchicine Coronavirus SARS-CoV-2 Trial (COLCORONA), did not reach its primary efficacy endpoint of reducing hospitalizations and death. However, a slight reduction in hospitalizations was observed in the subset of patients whose diagnosis was confirmed by a positive nasopharyngeal swab on a SARS-CoV-2 polymerase chain reaction (PCR) test.

• The Panel recommends against the use of colchicine in hospitalized patients for the treatment of COVID-19, except in a clinical trial (AIII).

Clinical Data for COVID-19

Colchicine in Nonhospitalized Patients With COVID-19: The COLCORONA Trial

COLCORONA was a contactless, double-blind, placebo-controlled randomized trial in outpatients who were diagnosed with COVID-19 within 24 hours of enrollment.4 Participants had to have at least one risk factor for COVID-19 complications, including age ≥70 years, body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease,
fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were randomized 1:1
to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by Day 30. Given the contactless design of the study, outcomes were ascertained by patient self-report via telephone at 15 and 30 days after randomization; in some cases, clinical data was confirmed by medical chart review.

Results

• The study enrolled a total of 4,488 participants.

• The primary endpoint was reached in 104 of 2,235 participants (4.7%) in the colchicine arm versus in 131 of 2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).

• There were no statistically significant differences in the secondary outcomes between the arms.
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• In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by a nasopharyngeal PCR test (93% of those enrolled), those in the colchicine arm were significantly less likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup of patients who were SARS-CoV-2 positive, there were fewer hospitalizations (a secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of patients; OR 0.75; 95% CI, 0.57–0.99).

• More gastrointestinal adverse events occurred in the colchicine arm, including diarrhea (occurred in 13.7% of patients vs. in 7.3% of patients in the placebo arm; P <0.001). Unexpectedly, more pulmonary emboli were reported among patients in the colchicine arm (11 events [0.5% of patients] vs. 2 [0.1% of patients] in the placebo arm; P = 0.01).
Limitations

• Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target enrollment, which may have limited the study’s power to detect differences for the primary outcome.

• There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.

• Patient-reported clinical outcomes were potentially misclassified.
Colchicine in Hospitalized Patients With COVID-19: The RECOVERY Trial
This study has not been published.
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial randomized hospitalized patients with COVID-19 to receive colchicine (1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 9 days or until discharge) or usual care.5
Results

• In a preliminary, unpublished report of results for 11,162 patients randomized to colchicine or usual care, there was no significant difference in the primary endpoint of 28-day mortality between the arms.

• Of the 2,178 patients who died, 20% were in the colchicine arm versus 19% in the usual care arm (risk ratio 1.02; 95% CI, 0.94–1.11; P = 0.63).

• Among the patients who died, 94% had received concomitant corticosteroids.
Study of the Effects of Colchicine in Hospitalized Patients With COVID-19: The GRECCO-19 Trial
The GReek Study in the Effects of Colchicine in Covid-19 cOmplications Prevention (GRECCO-19) was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until hospital discharge or up to 3 weeks) or standard of care alone.6
Results

• Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50 patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by two points on a seven-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).

• Participants in the colchicine group were significantly more likely to experience diarrhea
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(occurred in 45.5% vs. 18.0% of participants in the colchicine and standard of care arms, respectively; P = 0.003).

Limitations

• The number of clinical events reported for the trial was small.

• The study design was open-label treatment assignment.
The results of several small randomized trials and retrospective cohort studies that have evaluated various doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer- reviewed journals or made available as preliminary, non-peer-reviewed reports.7-10 Some have shown benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies have reported higher discharge rates or fewer deaths among patients who received colchicine than among those who received comparator drugs or placebo. However, these studies also had significant design or methodological limitations, including small sample sizes, open-label designs, and differences between the treatment arms in participants’ clinical and demographic characteristics and the permitted use of various cotreatments (e.g., remdesivir, corticosteroids), that limit interpretability of the studies.
Adverse Effects, Monitoring, and Drug-Drug Interactions
Common side effects of colchicine include diarrhea, nausea, vomiting, cramping, abdominal pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors, such as atorvastatin, lovastatin, and simvastatin, due to potential competitive interactions mediated by CYP3A4 and P-gp pathways.11,12 Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.
Considerations in Pregnancy
There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on
data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent systematic review of the literature did not find higher rates of miscarriage or major fetal malformations in pregnant women who were exposed to colchicine than in pregnant women who were not exposed to the drug. There are no data for colchicine use in pregnant women with acute COVID-19. Risks of use should be balanced against potential benefits.11,13
Considerations in Children
Colchicine use in children is limited to the treatment of periodic fever syndromes, primarily familial Mediterranean fever. There are no data on the use of colchicine to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C).
References

1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.

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2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.

3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293273.

4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.01.26.21250494v1.

5. Randomised Evaluation of COVID-19 Therapy (RECOVERY). RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19. 2021. https://www.recoverytrial.net/news/ recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19. Accessed March 9, 2021.

6. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32579195.

7. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med. 2020;9(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.

8. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.

9. Lopes MIF, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a randomized, double-blinded, placebo controlled clinical trial. medRxiv. 2020;preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.08.06.20169573v2.

10. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.

11. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf.

12. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at:

https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for- management-of-clinically-significant-drug. Accessed February 24, 2021.

13. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta- analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29029311.

             

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Corticosteroids

Last Updated: November 3, 2020

Patients with severe COVID-19 can develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these deleterious effects. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, a multicenter, randomized, open-label trial in hospitalized patients with COVID-19, showed that the mortality from COVID-19 was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care.1 Details of the RECOVERY trial are discussed in Table 4a.1

The safety and efficacy of combination therapy of corticosteroids and an antiviral agent targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the treatment of COVID-19 have not
been rigorously studied in clinical trials. However, there are theoretical reasons that such combination therapy may be beneficial in patients with severe disease. See Therapeutic Management of Patients with COVID-19 for the Panel’s recommendations on use of dexamethasone with or without remdesivir in certain hospitalized patients.

Rationale for Use of Corticosteroids in Patients With COVID-19

Both beneficial and deleterious clinical outcomes have been reported with use of corticosteroids (mostly prednisone or methylprednisolone) in patients with other pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxia, prednisone therapy reduced the risk of death;2 however, in outbreaks of other novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance.3,4 In severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and death.5

Corticosteroids have been studied in critically ill patients with acute respiratory distress syndrome (ARDS) with conflicting results.6-8 Seven randomized controlled trials that included a total of 851 patients evaluated use of corticosteroids in patients with ARDS.7-13 A meta-analysis of these trial results demonstrated that, compared with placebo, corticosteroid therapy reduced the risk of all-cause mortality (risk ratio 0.75; 95% CI, 0.59–0.95) and duration of mechanical ventilation (mean difference, -4.93 days; 95% CI, -7.81 to -2.06 days).14,15

Recommendations on the use of corticosteroids for COVID-19 are largely based on data from the RECOVERY trial, a large, multicenter, randomized, open-label trial performed in the United Kingdom. This trial compared hospitalized patients who received up to 10 days of dexamethasone to those who received the standard of care. Mortality at 28 days was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care.1 This benefit was observed in patients who were mechanically ventilated or required supplemental oxygen at enrollment. No benefit of dexamethasone was seen in patients who did not require supplemental oxygen at enrollment. Details of the RECOVERY trial are discussed in Table 4a.1

Corticosteroids used in various formulations and doses and for varying durations in patients with COVID-19 were also studied in several smaller randomized controlled trials.16-20 Some of these trials were stopped early due to under enrollment following the release of the results from the RECOVERY trial. Given that the sample size of many these trials was insufficient to assess efficacy, evidence to support the use of methylprednisolone and hydrocortisone for the treatment of COVID-19 is not as robust as that demonstrated for dexamethasone in the RECOVERY trial. Data from some of these studies can be found in Table 4a.

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Corticosteroids Other Than Dexamethasone

• If dexamethasone is not available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be used.

• For these drugs, the total daily dose equivalencies to dexamethasone 6 mg (oral or intravenous [IV])21 are:

• Prednisone 40 mg

• Methylprednisolone 32 mg

• Hydrocortisone 160 mg

• Half-life, duration of action, and frequency of administration vary among corticosteroids.

• Long-acting corticosteroid: dexamethasone; half-life: 36 to 72 hours, administer once daily.

• Intermediate-acting corticosteroids: prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.

• Short-acting corticosteroid: hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.

• Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; see Care of Critically Ill Patients With COVID-19 for more information. Unlike other corticosteroids previously studied in patients with ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on sodium balance and fluid volume.10
Monitoring, Adverse Effects, and Drug-Drug Interactions

• Clinicians should closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, avascular necrosis).

• Prolonged use of systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus [HBV], herpesvirus infections, strongyloidiasis, tuberculosis).

• The risk of reactivation of latent infections for a 10-day course of dexamethasone (6 mg once daily) is not well-defined. When initiating dexamethasone, appropriate screening and treatment to reduce the risk of Strongyloides hyperinfection in patients at high risk of strongyloidiasis (e.g., patients from tropical, subtropical, or warm, temperate regions or those engaged in agricultural activities)22-24 or fulminant reactivations of HBV25 should be considered.

• Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer. As such, it may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates. Clinicians should review a patient’s medication regimen to assess potential interactions.

• Coadministration of remdesivir and dexamethasone has not been formally studied, but a clinically significant pharmacokinetic interaction is not predicted.

• Dexamethasone should be continued for up to 10 days or until hospital discharge, whichever comes first.
Considerations in Pregnancy
A short course of betamethasone and dexamethasone, which are known to cross the placenta, is routinely used to decrease neonatal complications of prematurity in women with threatened preterm delivery.26,27
Given the potential benefit of decreased maternal mortality and the low risk of fetal adverse effects for a short course of dexamethasone therapy, the Panel recommends using dexamethasone in hospitalized
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pregnant women with COVID-19 who are mechanically ventilated (AIII) or who require supplemental oxygen but who are not mechanically ventilated (BIII).

Considerations in Children

The safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have not been sufficiently evaluated in pediatric patients. Importantly, the RECOVERY trial did not include a significant number of pediatric patients, and mortality from COVID-19 is significantly lower among pediatric patients than among adult patients. Thus, caution is warranted when extrapolating the results of the RECOVERY trial to patients aged <18 years. Dexamethasone may be beneficial in pediatric patients with COVID-19 respiratory disease who require mechanical ventilation. Use of dexamethasone in patients who require other forms of supplemental oxygen support should be considered on a case- by-case basis and is generally not recommended for pediatric patients who require only low levels of oxygen support (i.e., nasal cannula only). Additional studies are needed to evaluate the use of steroids for the treatment of COVID-19 in pediatric patients, including for multisystem inflammatory syndrome in children (MIS-C).

Clinical Trials

Several clinical trials to evaluate corticosteroids for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.

References

1. Recovery Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19 – preliminary report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.

2. Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323(21):1451-1457. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2233917.

3. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29161116.

4. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16968120.

5. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26950335.

6. Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RAC, Kocak M. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 2016;42(5):829-840. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26508525.

7. Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17426195.

8. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16625008.

9. Liu L, Li J, Huang YZ, et al. [The effect of stress dose glucocorticoid on patients with acute respiratory distress syndrome combined with critical illness-related corticosteroid insufficiency]. Zhonghua Nei Ke Za

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Zhi. 2012;51(8):599-603. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23158856.

10. Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32043986.

11. Rezk NA, Ibrahim AM. Effects of methyl prednisolone in early ARDS. Egypt J Chest Dis Tuberc. 2013;62(1):167-172. Available at: https://www.sciencedirect.com/science/article/pii/S0422763813000265.

12. Tongyoo S, Permpikul C, Mongkolpun W, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care. 2016;20(1):329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27741949.

13. Zhao WB, Wan SX, Gu DF, Shi B. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients. Med J Chinese PLA. 2014;39(9):741-745. Available at: http://www.plamj.org/index.php/plamj/article/view/1009.

14. Mammen MJ, Aryal K, Alhazzani W, Alexander PE. Corticosteroids for patients with acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials. Pol Arch Intern Med. 2020;130(4):276- 286. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32186831.

15. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32224769.

16. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32785710.

17. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876695.

18. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.

19. Writing Committee for the R-CAPI, Angus DC, Derde L, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876697.

20. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876694.

21. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61-98. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15634032.

22. Centers for Disease Control and Prevention. Parasites – strongyloides: resources for health professionals. 2020; https://www.cdc.gov/parasites/strongyloides/health_professionals/index.html. Accessed October 30, 2020.

23. Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020. Available at: http://www.ajtmh.org/docserver/fulltext/14761645/103/4/tpmd200699. pdf?expires=1606941469&id=id&accname=guest&checksum=9728AC8BEDF3E8369A7D3E6C2AFEB27E.

24. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid- related strongyloides hyperinfection. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.

25. Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic HBV infection. Hepatol Res. 2020. Available at:

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https://www.ncbi.nlm.nih.gov/pubmed/32761993.

26. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515-525. Available at: https://www.ncbi.nlm.nih.gov/pubmed/4561295.

27. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med. 2016;374(14):1311-1320. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26842679.

  

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Table 4a. Corticosteroids: Selected Clinical Data

Last Updated: February 11, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.



Study Design

Methods

Results

Limitations and Interpretation

Dexamethasone in Hospitalized Patients With COVID-19—Preliminary Report (RECOVERY Trial)1

Multi-center, randomized open-label adaptive trial in hospitalized patients with suspected or con rmed COVID-19 (n = 6,425)

Country: United Kingdom

Key Inclusion Criteria:

• Hospitalization with clinically suspected or laboratory-con rmed SARS-CoV-2 infection

Key Exclusion Criteria:

• Physician determination that risks of participation too great based
on patient’s medical history or an indication for corticosteroid therapy outside of the study

Interventions:

• Patients randomized 2:1 to receive:

• Dexamethasone 6 mg PO or IV once daily plus SOC for up to 10 days or until hospital discharge, whichever came rst, or

• SOC alone
Primary Endpoint:
• All-cause mortality at 28 days after randomization

Number of Participants:

• Dexamethasone plus SOC (n = 4,321) and SOC (n = 2,104)

Participant Characteristics:

• Mean age was 66 years.

• 64% of participants were men.

• 56% of participants had ≥1 comorbidity; 24% had diabetes.

• 89% of participants had laboratory- con rmed SARS-CoV-2 infection.

• At randomization, 16% of participants received invasive mechanical ventilation or ECMO, 60% required supplemental oxygen but not invasive ventilation, and 24% required no oxygen supplementation.

• 0% to 3% of the participants in both arms received RDV, HCQ, LPV/RTV, or tocilizumab; approximately 8% of participants in SOC alone arm received dexamethasone after randomization.
Outcomes:
• 28-day mortality was 22.9% in dexamethasone arm and 25.7% in SOC arm (age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P < 0.001).

Limitations:

• Open label study

• This preliminary study analysis
did not include the results for key secondary endpoints (e.g., cause- speci c mortality, need for renal replacement), AEs, and the ef cacy of dexamethasone in key subgroups (e.g., patients with comorbidities).

• Study participants with COVID-19 who required oxygen (but not mechanical ventilation) had variable disease severity; it is unclear whether all patients in this heterogeneous group derived bene t from dexamethasone, or whether bene t is restricted to those requiring higher levels of supplemental oxygen or oxygen delivered through a high- ow device.

• The age distribution of participants differed by respiratory status at randomization.

• The survival bene t of dexamethasone for mechanically ventilated patients aged >80 years is unknown because only 1% of the participants in this group were ventilated.

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Study Design

Methods

Results

Limitations and Interpretation

Dexamethasone in Hospitalized Patients With COVID-19—Preliminary Report (RECOVERY Trial)1, continued

• The treatment effect of dexamethasone varied by baseline severity of COVID-19. Survival bene t appeared greatest among participants who required invasive mechanical ventilation at randomization. Among these participants, 28-day mortality was 29.3% in dexamethasone arm vs. 41.4% in SOC arm (rate ratio 0.64; 95% CI, 0.51–0.81).

• Among patients who required supplemental oxygen but not mechanical ventilation at randomization, 28-day mortality was 23.3% in dexamethasone arm vs. 26.2% in SOC arm (rate ratio 0.82; 95% CI, 0.72–0.94).

• No survival bene t in participants who did not require oxygen therapy at enrollment. Among these participants, 28-day mortality was 17.8% in dexamethasone arm vs. 14.0% in SOC arm (rate ratio 1.19; 95% CI, 0.91–1.55).

• It is unclear whether younger patients were more likely to receive mechanical ventilation than patients aged >80 years, given similar disease severity
at baseline, with older patients preferentially assigned to oxygen therapy.

• The high baseline mortality of
this patient population may limit generalizability of the study results to populations with a lower baseline mortality.
Interpretation:

• In hospitalized patients with severe COVID-19 who required oxygen support, using dexamethasone 6
mg daily for up to 10 days reduced mortality at 28 days, with the greatest bene t seen in those who were mechanically ventilated at baseline.

• There was no observed survival bene t of dexamethasone in patients who did not require oxygen support at baseline.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-Analysis (REACT Working Group)2

Meta-analysis of 7 RCTs of corticosteroids in critically ill patients with COVID-19 (n = 1,703)

Countries: Multinational

Key Inclusion Criteria:

• RCTs evaluating corticosteroids in critically ill patients with COVID-19 (identi ed via comprehensive search of ClinicalTrials.gov, Chinese Clinical Trial Registry, and EU Clinical Trials Register)



Number of Participants:

• Corticosteroids (n = 678) and usual care or placebo (n = 1,025)

Participant Characteristics:

• Median age was 60 years.

• 29% of patients were women.

• 1,559 patients (91.5%) were on mechanical ventilation.

Limitations:

• The design of the trials included in the meta-analysis differed in several ways, including the following:

• De nition of critical illness
• Speci c corticosteroid used
• Dose of corticosteroid
• Duration of corticosteroid treatment

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Study Design

Methods

Results

Limitations and Interpretation

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-Analysis (REACT Working Group)2, continued

Interventions:

• Corticosteroids (i.e., dexamethasone, hydrocortisone, methylprednisolone)

• Usual care or placebo

Primary Endpoint:

• All-cause mortality up to 30 days after randomization

• 47% of patients were on vasoactive agents at randomization across the 6 trials that reported this information.

Outcomes:

• Mortality was assessed at 28 days in 5 trials, 21 days in 1 trial, and 30 days in 1 trial.

• Reported all-cause mortality at 28 days: Death occurred in 222 of 678 patients (32.7%) in corticosteroids group vs. 425 of 1,025 patients (41.5%) in usual care or placebo group; summary OR 0.66 (95% CI, 0.53–0.82; P < 0.001).

• The xed-effect summary ORs for the association with all-cause mortality were:

• Dexamethasone: OR 0.64 (95% CI, 0.50–0.82; P < 0.001) in 3 trials with 1,282 patients

• Hydrocortisone: OR 0.69 (95% CI, 0.43–1.12; P = 0.13) in 3 trials with 374 patients.

• Methylprednisolone: OR 0.91 (95% CI, 0.29– 2.87; P = 0.87) in 1 trial with 47 patients

• For patients on mechanical ventilation (n = 1,559): OR 0.69 (95% CI, 0.55–0.86), with mortality of 30% for corticosteroids vs. 38% for usual care or placebo

• For patients not on mechanical ventilation (n
= 144): OR 0.41 (95% CI, 0.19–0.88) with mortality of 23% for corticosteroids vs. 42% for usual care or placebo

• Across the 6 trials that reported SAEs, 18.1% of patients randomized to corticosteroids and 23.4% randomized to usual care or placebo experienced SAEs.

• Type of control group (i.e., usual care or placebo)

• Reporting of SAEs

• The RECOVERY trial accounted for 59% of the participants, and 3 trials enrolled <50 patients each.

• Some studies con rmed SARS- CoV-2 infection for participant inclusion while others enrolled participants with either probable or con rmed infection.

• Although the risk of bias was low in 6 of the 7 trials, it was assessed as “some concerns” for 1 trial (which contributed only 47 patients).
Interpretation:

• Systemic corticosteroids decrease 28-day mortality in critically ill patients with COVID-19 without safety concerns.

• Most of the participants were from the RECOVERY trial, thus
the evidence of bene t in the meta-analysis is strongest for dexamethasone, the corticosteroid used in the RECOVERY trial.

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Study Design

Methods

Results

Limitations and Interpretation

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial3

Randomized, double-blind, placebo-controlled, single- center study of short-course methylprednisolone in hospitalized patients with con rmed or suspected COVID-19 pneumonia (n = 416)

Country: Brazil

Key Inclusion Criteria:

• Aged ≥18 years

• Suspected or con rmed COVID-19

• SpO2 ≤94% on room air or while using supplementary oxygen or under invasive mechanical ventilation
Key Exclusion Criteria:

• Hypersensitivity to methylprednisolone

• Chronic use of corticosteroids or immunosuppressive agents

• HIV, decompensated cirrhosis, chronic renal failure
Interventions:
• Methylprednisolone IV 0.5 mg/kg twice daily for 5 days
• Placebo (saline) IV
Primary Endpoint:
• Mortality by Day 28
Secondary Endpoints:

• Early mortality at Days 7 and 14

• Need for mechanical ventilation by Day 7

• Need for insulin by Day 28

• Positive blood culture at Day 7, sepsis by Day 28

• Mortality by Day 28 in speci ed subgroups

Number of Participants:

• mITT analysis (n = 393): Methylprednisolone (n = 194) and placebo (n = 199)

Participant Characteristics:

• Mean age was 55 years.

• 65% of patients were men.

• 29% of patients had diabetes.

• At enrollment, 34% of participants in each group required invasive mechanical ventilation; 51% in methylprednisolone group and 45% in placebo group required supplemental oxygen.

• Median time from illness onset to randomization was 13 days (IQR 9–16).

• None of the participants received anti-IL-6, anti- IL-1, RDV, or convalescent plasma.

• Hydrocortisone use for shock among patients was 8.7% in methylprednisolone group and 7.0% in placebo group.
Primary Outcomes:
• No difference in 28-day mortality: 37.1% in methylprednisolone arm vs. 38.2% in placebo arm (HR 0.92; 95% CI, 0.67–1.28; P = 0.63).
Secondary Outcomes:

• No difference between groups in early mortality at Day 7 (HR 0.68; 95% CI, 0.43–1.06) or Day 14 (HR 0.82; 95% CI, 0.57–1.18)

• No difference in need for mechanical ventilation by Day 7: 19.4% of methylprednisolone recipients vs. 16.8% of placebo recipients (P = 0.65)

Limitations:

• The median days from illness onset to randomization was longer than in other corticosteroid studies.

• The high baseline mortality of
this patient population may limit generalizability of the study results to populations with a lower baseline mortality.
Interpretation:

• Use of weight-based methylprednisolone for 5 days did not reduce overall 28-day mortality.

• In a post hoc subgroup analysis, mortality among those aged
>60 years was lower in the methylprednisolone group than in the placebo group.

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Study Design

Methods

Results

Limitations and Interpretation

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial3, continued

• No signi cant difference between the methylprednisolone and placebo groups in need
for insulin (59.5% vs. 49.4% of patients), positive blood cultures at Day 7 (8.3% vs. 8.0% of patients), or sepsis by Day 28 (38.1% vs. 38.7% of patients)

• In post hoc analysis, 28-day mortality in participants aged >60 years was lower in methylprednisolone group than in placebo group (46.6% vs. 61.9%; HR 0.63; 95% CI, 0.41–0.98).

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial4

Multicenter, randomized, clinical trial in patients with COVID-19 and moderate to severe ARDS (n = 299)

Country: Brazil

Key Inclusion Criteria:

• Aged ≥18 years

• Con rmed or suspected COVID-19

• On mechanical ventilation within 48 hours of meeting criteria for moderate to severe ARDS with PaO2/FiO2 ≤200 mm Hg
Key Exclusion Criteria:
• Recent corticosteroid use
• Use of immunosuppressive drugs in the past 21 days
• Expected death in next 24 hours
Interventions:

• Dexamethasone 20 mg IV daily for 5 days, then 10 mg IV daily for 5 days or until ICU discharge plus SOC

• SOC alone

Number of Participants:

• ITT analysis (n = 299): Dexamethasone plus SOC (n = 151) and SOC alone (n = 148)

Participant Characteristics:

• Dexamethasone group included more women than the SOC group (40% vs. 35%), more patients with obesity (31% vs. 24%), and fewer patients with diabetes (38% vs. 47%).

• Other baseline characteristics were similar for the dexamethasone and SOC groups:

• Mean age was 60 vs. 63 years; vasopressor use by 66% vs. 68% of patients; mean PaO2/FiO2 of 131 mm Hg vs. 133 mm Hg.

• Median time from symptom onset to randomization was 9–10 days.

• Median time from mechanical ventilation to randomization was 1 day.

• No patients received RDV; anti-IL-6 and convalescent plasma were not widely available.

• Median duration of dexamethasone therapy was 10 days (IQR 6–10 days).

Limitations:

• Open-label study

• The study was underpowered to assess some outcomes because it stopped enrollment after data from the RECOVERY trial were released.

• During the study, 35% of the patients in the SOC group received corticosteroids for shock, bronchospasm, or other reasons.

• Patients who were discharged from the hospital before 28 days were not followed for rehospitalization or mortality.

• The high baseline mortality of the patient population may limit generalizability of the study results to populations with a lower baseline mortality.
Interpretation:
• Compared with SOC alone, dexamethasone at a higher dose than used in the RECOVERY trial plus SOC

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial4, continued

Primary Endpoint:

• Mean number of days alive and free from mechanical ventilation by Day 28

Secondary Endpoints:

• All-cause mortality at Day 28

• ICU-free days by Day 28

• Duration of mechanical ventilation by Day 28

• Score on 6-point WHO ordinal scale at Day 15

• SOFA score at 7 days

• Components of the primary outcome or in the outcome of discharged alive within 28 days

• 35% of patients in SOC alone group also received corticosteroids.

Primary Outcomes:

• The mean number of days alive and free from mechanical ventilation by Day 28 was higher in the dexamethasone group than in the SOC group (6.6 vs. 4.0 days, estimated difference of 2.3 days; 95% CI, 0.2–4.4; P = 0.04).

Secondary Outcomes:

• There were no differences between the dexamethasone and SOC groups for the following outcomes:
• All-cause mortality at Day 28 (56.3% vs. 61.5%: HR 0.97; 95% CI, 0.72–1.31; P = 0.85)
• ICU-free days by Day 28 (mean of 2.1 vs. 2.0 days; P = 0.50)

• Duration of mechanical ventilation by Day 28 (mean of 12.5 vs.13.9 days; P = 0.11)

• Score on 6-point WHO ordinal scale at Day 15 (median score of 5 for both groups)

• The mean SOFA score at 7 days was lower in the dexamethasone group than in the SOC group (6.1 vs. 7.5, difference -1.16; 95% CI, -1.94 to -0.38; P = 0.004).

• The following safety outcomes were comparable for dexamethasone and SOC groups: need for insulin (31.1% vs. 28.4%), new infections (21.9% vs. 29.1%), bacteremia (7.9% vs. 9.5%), and other SAEs (3.3% vs. 6.1%).

• In post hoc analysis, the dexamethasone group had a lower cumulative probability of death or mechanical ventilation at Day 15 than the SOC group (67.5% vs. 80.4%; OR 0.46; 95% CI, 0.26–0.81; P = 0.01).

increased the number of days alive and free of mechanical ventilation over 28 days of follow-up in patients with COVID-19 and moderate to severe ARDS.

• Dexamethasone was not associated with an increased risk of AEs in this population.

• More than one-third of those randomized to the standard care alone group also received corticosteroids; it is impossible to determine the effect of corticosteroid use in these patients on the overall study outcomes.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial5

Multicenter, randomized, double-blind, sequential trial in patients with con rmed or suspected COVID-19 and acute respiratory failure (n = 149)

Country: France

Key Inclusion Criteria:

• Aged ≥18 years

• Con rmed SARS-CoV-2 infection or radiographically suspected COVID-19, with at least 1 of 4 severity criteria:

• Need for mechanical ventilation with PEEP ≥5 cm H2O

• High- ow oxygen with PaO2/ FiO2 <300 mm Hg and FiO2 ≥50%

• Reservoir mask oxygen with PaO2/FiO2 <300 mm Hg (estimated)

• Pneumonia severity index >130 (scoring table)
Key Exclusion Criteria:
• Septic shock
• Do-not-intubate orders
Interventions:

• Continuous infusion hydrocortisone 200 mg/day until Day 7, then hydrocortisone 100 mg/day for 4 days, and then hydrocortisone 50 mg/day for
3 days, for a total treatment duration of 14 days

• Patients who showed clinical improvement by Day 4 were switched to a shorter 8-day regimen.

Number of Participants:

• ITT analysis (n = 149 participants): Hydrocortisone (n = 76) and placebo (n = 73)

Participant Characteristics:

• Mean age of participants was 62 years; 70% were men; median BMI was 28.

• 96% of participants had con rmed SARS-CoV-2 infection.

• Median symptom duration before randomization was 9 days in hydrocortisone group vs. 10 days in placebo group.

• 81% of the patients overall were mechanically ventilated, and 24% in hydrocortisone group and 18% in placebo group were receiving vasopressors.

• Among the patients receiving concomitant COVID-19 treatment, 3% received RDV, 14% LPV/RTV, 13% HCQ, and 34% HCQ plus AZM.

• Median treatment duration was 10.5 days in hydrocortisone group vs. 12.8 days in placebo group (P = 0.25).
Primary Outcome:

• There was no difference in the proportion of patients with treatment failure by Day 21, which occurred in 32 of 76 patients (42.1%) in hydrocortisone group and 37 of 73 patients (50.7%) in placebo group (difference -8.6%; 95% CI, -24.9% to 7.7%; P = 0.29).

Secondary Outcomes:

• There was no difference between the groups in the need for intubation, rescue strategies, or oxygenation (i.e., change in PaO2/FiO2).

• Among the patients who did not require mechanical ventilation at baseline, 8 of 16 patients (50%) in hydrocortisone group required subsequent

Limitations:

• Small sample size. Planned sample size of 290, but 149 enrolled because study was terminated early after the release of results from the RECOVERY trial.

• Limited information about comorbidities (e.g., hypertension)

• Participants’ race and/or ethnicity were not reported.

• Nosocomial infections were recorded but not adjudicated.
Interpretation:

• Compared to placebo, hydrocortisone did not reduce treatment failure (de ned as death or persistent respiratory support) at Day 21 in ICU patients with COVID-19 and acute respiratory failure.

• Because this study was terminated early, it is dif cult to make conclusions about the ef cacy and safety of hydrocortisone therapy.

• The starting dose of hydrocortisone used in this study were slightly higher than the 6 mg dose of dexamethasone used in the RECOVERY study. The hydrocortisone dose was adjusted according to clinical response.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial5, continued

Primary Endpoint:

• Treatment failure (de ned as death or persistent dependency on mechanical ventilation or high- ow oxygen) by Day 21

Secondary Endpoints:

• Need for intubation, rescue strategies, or oxygenation (i.e., change in PaO2/FiO2)

• Nosocomial infections on Day 28

• Clinical status on Day 21

intubation vs. 12 of 16 (75%) in placebo group.

• 3 SAEs were reported (cerebral vasculitis, cardiac arrest due to PE, and intra-abdominal hemorrhage from anticoagulation for PE); all occurred in the hydrocortisone group, but none were attributed to the intervention.
• There was no difference between the groups in proportion of patients with nosocomial infections on Day 28.

• In post hoc analysis, clinical status on Day 21 did not signi cantly differ between the groups except for fewer deaths in the hydrocortisone group (14.7% of patients died vs. 27.4% in placebo group; P = 0.06):

• By Day 21, 57.3% of patients in hydrocortisone group vs. 43.8% in placebo group were discharged from the ICU and 22.7% in hydrocortisone group vs. 23.3% in placebo group were still mechanically ventilated.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial (CAPE COD)6

Randomized, embedded, multifactorial, adaptive platform trial of patients with severe COVID-19 (n = 403)

Countries: Multinational

Key Inclusion Criteria:

• Aged ≥18 years

• Presumed or con rmed SARS-
CoV-2 infection

• ICU admission for respiratory or cardiovascular organ support
Key Exclusion Criteria:
• Presumed imminent death
• Systemic corticosteroid use
• >36 hours since ICU admission

Number of Participants:

• mITT analysis (n = 384): Fixed-dose hydrocortisone (n=137), shock-based hydrocortisone (n = 146), and no hydrocortisone (n = 101)

Participant Characteristics:

• Mean age was 60 years.

• 71% of patients were men.

• Mean BMI was 29.7–30.9.

• 50% to 64% of patients received mechanical ventilation.

Limitations:

• Early termination following release of RECOVERY study results

• Randomized study, but open label

Interpretation:

• Corticosteroids did not signi cantly increase support-free days in either
the xed-dose hydrocortisone or the shock-dependent hydrocortisone group, although the early termination of the trial led to limited power to detect difference between the study arms.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial (CAPE COD)6, continued

Interventions:

• Hydrocortisone 50 mg 4 times daily for 7 days

• Septic shock-based hydrocortisone 50 mg 4 times daily for the duration of shock

• No hydrocortisone
Primary Endpoint:

• Days free of respiratory and cardiovascular organ support
up to Day 21. (For this ordinal outcome, patients who died were assigned -1 day.)

Secondary Endpoints:

• In-hospital mortality • SAEs

Primary Outcome:

• No difference between the groups in organ-support free-days at Day 21 (median of 0 days in each group).

• Compared to the no hydrocortisone group, median adjusted OR for the primary outcome:

• OR 1.43 (95% credible interval, 0.91–2.27) with 93% Bayesian probability of superiority for the xed-dose hydrocortisone group

• OR 1.22 (95% credible interval, 0.76–1.94) with 80% Bayesian probability of superiority for the shock-based hydrocortisone group
Secondary Outcomes:

• No difference between the groups in mortality; 30%, 26%, and 33% of patients died in the xed- dose, shock-based, and no hydrocortisone groups, respectively.

• SAEs reported in 3%, 3%, and 1% of patients in the xed-dose, shock-based, and no hydrocortisone groups, respectively.

Ef cacy Evaluation of Early, Low-Dose, Short-Term Corticosteroids in Adults Hospitalized with Non-Severe COVID-19 Pneumonia: A Retrospective Cohort Study7

Retrospective cohort study in patients with nonsevere COVID-19 pneumonia and propensity score- matched controls (n = 55 matched case-control pairs)

Country: China

Key Inclusion Criteria:

• Con rmed COVID-19
• Pneumonia on chest CT scan • Aged ≥16 years

Key Exclusion Criteria:

• Severe pneumonia de ned as having any of the following: respiratory distress, respiratory rates >30 breaths/min, SpO2 <93%, oxygenation index <300 mm Hg, mechanical ventilation, or shock

Number of Participants:

• Corticosteroids (n = 55): IV methylprednisolone (n=50) and prednisone (n = 5)

• No corticosteroids (n = 55 matched controls chosen from 420 patients who did not receive corticosteroids)

Participant Characteristics:

• Median age was 58–59 years.

• Median oxygen saturation was 95%.

• 42% of patients in corticosteroids group and 46% in no corticosteroids group had comorbidities, including 35% to 36% with hypertension and 11% to 13% with diabetes.

Limitations:

• Retrospective, case-control study

• Small sample size (55 case-control pairs)

• Corticosteroid therapy was selected preferentially for patients who had more risk factors for severe progression
of COVID-19; the propensity score matching may not have adjusted for some of the unmeasured confounders.

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Study Design

Methods

Results

Limitations and Interpretation

Ef cacy Evaluation of Early, Low-Dose, Short-Term Corticosteroids in Adults Hospitalized with Non-Severe COVID-19 Pneumonia: A Retrospective Cohort Study7, continued

• Immediate ICU admission upon hospitalization

• Use of corticosteroids after progression to severe disease

Interventions:

• Early, low-dose corticosteroids:

• IV methylprednisolone 20 mg/ day or 40 mg/day for 3–5 days

• PO prednisone 20 mg/day for 3 days

• No corticosteroids

Primary Endpoint:

• Rates of severe disease and death

Secondary Endpoints:

• Duration of fever
• Virus clearance time
• Length of hospital stay • Use of antibiotics

Primary Outcomes:

• 7 patients (12.7%) in the corticosteroids group developed severe disease vs. 1 (1.8%) in the no corticosteroids group (P = 0.03); time to severe disease: HR 2.2 (95% CI, 2.0–2.3; P < 0.001).

• There was 1 death in the methylprednisolone group vs. none in the no corticosteroids group.
Secondary Outcomes:

• Each of the following outcomes was longer in the corticosteroids group than in the no corticosteroids group (P < 0.001 for each outcome): duration of fever (5 vs. 3 days), virus clearance time (18 vs. 11 days), and length of hospital stay (23 vs. 15 days).

• More patients in the corticosteroids group than in the no corticosteroids group were prescribed antibiotics (89% vs. 24%) and antifungal therapy (7% vs. 0%).

• Selection bias in favor of the no corticosteroids group may have been introduced by excluding patients who used corticosteroids after progression to severe disease from the study.

Interpretation:

• In this nonrandomized, case-control study, methylprednisolone therapy
in patients with nonsevere COVID-19 pneumonia was associated with worse outcomes, but this nding is dif cult to interpret because of potential confounding factors.

• It is unclear whether the results for methylprednisolone therapy can be generalized to therapy with other corticosteroids.

Key: AE = adverse event; ARDS = acute respiratory distress syndrome; AZM = azithromycin; BMI = body mass index; CT = computerized tomography; ECMO = extracorporeal membrane oxygenation; EU = European Union; HCQ = hydroxychloroquine; ICU = intensive care unit; IL = interleukin; ITT = intention-to-treat; IV = intravenous; LPV/RTV = lopinavir/ritonavir; mITT = modi ed intention-to-treat; the Panel = the COVID-19 Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PE = pulmonary embolism; PEEP = positive end-expiratory pressure; PO = oral; RCT = randomized controlled trial; RDV = remdesivir; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SOC = standard of care; SOFA = sequential organ failure assessment; SpO2 = saturation of oxygen; WHO = World Health Organization

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References

1. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.

2. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group, Sterne JAC, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876694.

3. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, Phase IIb, placebo-controlled trial. Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32785710.

4. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-1316.. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876695.

5. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.

6. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: The REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-1329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876697.

7. Li Q, Li W, Jin Y, et al. Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32880102.

      

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Fluvoxamine

Last Updated: April 23, 2021

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the Food and
Drug Administration (FDA) for the treatment of obsessive-compulsive disorder and is used for other conditions, including depression. Fluvoxamine is not FDA-approved for the treatment of any infection.

Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines.1 In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.2 Further studies are needed to establish whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans beings and are clinically relevant in the setting of COVID-19.

Recommendation

There are insufficient data for the COVID-19 Treatment Guidelines Panel to recommend either for
or against the use of fluvoxamine for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of fluvoxamine for the treatment of COVID-19.

Clinical Trial Data

Placebo-Controlled Randomized Trial in Nonhospitalized Adults With Mild COVID-19

In this contactless, double-blind, placebo-controlled randomized trial, nonhospitalized adults with
mild COVID-19 confirmed by SARS-CoV-2 polymerase chain reaction (PCR) assay within 7 days of symptom onset were randomized to receive fluvoxamine up to 100 mg three times daily or matching placebo for 15 days. The primary endpoint was clinical deterioration (defined as having dyspnea or hospitalization for dyspnea or pneumonia and oxygen saturation [SpO2] <92% on room air or requiring supplemental oxygen to attain SpO2 ≥92%) within 15 days of randomization. Participants self-assessed their blood pressure, temperature, oxygen saturation, and COVID-19 symptoms and reported the information by email twice daily.3

Participant Characteristics

• A total of 152 participants were randomized to receive fluvoxamine (n = 80) or placebo (n = 72).

• The mean age of the participants was 46 years; 72% were women, 25% were Black, and 56% had obesity.
Results

• None of 80 participants (0%) who received fluvoxamine and six of 72 participants (8.3%) who received placebo reached the primary endpoint (absolute difference 8.7%; 95% CI, 1.8% to 16.5%; P = 0.009).

• Five participants in the placebo arm and one in the fluvoxamine arm required hospitalization.

• Only 76% of the participants completed the study, and 20% of the participants stopped responding to the electronic survey during the study period but were included in the final analysis.
Limitations

• The study had a small sample size.

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• A limited number of events occurred.

• Ascertaining clinical deterioration was challenging because all assessments were done remotely.
Interpretation
In this small placebo-controlled trial, none of the participants who received fluvoxamine and six (8.3%) of those who received placebo reached the primary endpoint. However, due to the study’s reliance on participant self-reports and missing data, it is difficult to draw definitive conclusions about the efficacy of fluvoxamine for the treatment of COVID-19.3
Prospective Observational Study During an Outbreak of SARS-CoV-2 Infections
A prospective, nonrandomized observational cohort study evaluated fluvoxamine for the treatment of COVID-19 in 113 outpatients who tested positive for SARS-CoV-2 antigen with the result confirmed by a PCR test. The trial was conducted in an occupational setting during an outbreak of COVID-19. Patients were offered the option of receiving fluvoxamine 50 mg twice daily for 14 days or no therapy.4
Patient Characteristics

• Of the 113 participants with positive SARS-CoV-2 antigen, 65 opted to take fluvoxamine and 48 did not.

• More of the patients who did not take fluvoxamine had hypertension. In addition, more of those who were Latinx and more of those who were initially symptomatic opted to take fluvoxamine.
Results

• At Day 14, none of the patients who received fluvoxamine versus 60% of those who did not had persistent symptoms (e.g., anxiety, difficulty concentrating, fatigue) (P < 0.001).

• By Day 14, none of the fluvoxamine-treated patients were hospitalized; six patients who did not receive fluvoxamine were hospitalized, including two patients who required care in the intensive care unit.

• No serious adverse events were reported following receipt of fluvoxamine.
Limitations

• The study was a nonrandomized trial.

• The study had a small sample size.

• Limited data were collected during the study.
Limitations (e.g., small sample size) and differences in study populations and fluvoxamine doses make it difficult to interpret and generalize the findings of these trials.
Additional studies, including a Phase 3 randomized controlled trial (ClinicalTrials.gov Identifier: NCT04668950), are ongoing to provide more specific evidence-based guidance on the role of fluvoxamine for the treatment of COVID-19.
Adverse Effects, Monitoring, and Drug-Drug Interactions
When fluvoxamine is used to treat psychiatric conditions, the most common adverse effect is nausea, but adverse effects can include other gastrointestinal effects (e.g., diarrhea, indigestion), neurologic effects (e.g., asthenia, insomnia, somnolence), dermatologic reactions (sweating), and rarely suicidal ideation.
Fluvoxamine is a cytochrome P450 (CYP) D6 substrate and a potent inhibitor of CYP1A2 and 2C19 and a moderate inhibitor of CYP2C9, 2D6, and 3A4.5 Fluvoxamine may enhance the anticoagulant effects
of antiplatelets and anticoagulants. In addition, it can enhance the serotonergic effects of other SSRIs
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or monoamine oxidase inhibitors (MAOIs) resulting in serotonin syndrome. Fluvoxamine should not be used within 2 weeks of receipt of other SSRIs or MAOIs and should be used with caution with other QT-interval prolonging medications.

Considerations in Pregnancy

Fluvoxamine is not thought to increase the risk of congenital abnormalities; however, the data on its use in pregnancy are limited.6,7 A small, increased risk of primary persistent pulmonary hypertension in the newborn associated with SSRI use in the late third trimester has not been excluded, although the absolute risk is likely low.8 The risk of fluvoxamine use in pregnancy for the treatment of COVID-19 should be balanced with the potential benefit.

Considerations in Children

Fluvoxamine is approved by the FDA for the treatment of obsessive compulsive disorder in children aged ≥8 years.9 Adverse effects due to SSRI use seen in children are similar to those seen in adults, although children and adolescents appear to have higher rates of behavioral activation and vomiting than adults.10 There are no data on the use of fluvoxamine for the prevention or treatment of COVID-19 in children.

References

1. Rosen DA, Seki SM, Fernández-Castañeda A, et al. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Science Translation Medicine. 2019. Available at: https://stm.sciencemag.org/content/11/478/eaau5266.editor-summary.

2. Rafiee L, Hajhashemi V, Javanmard SH. Fluvoxamine inhibits some inflammatory genes expression in LPS/ stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat. Iran J Basic Med Sci. 2016;19(9):977-984. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27803785.

3. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292-2300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33180097.

4. Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect Dis. 2021;8(2):ofab050. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33623808.

5. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11876575.

6. Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry. 2009;54(4):242-246. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19321030.

7. Furu K, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. BMJ. 2015;350:h1798. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25888213.

8. Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-51. Available at: https://pubmed.ncbi.nlm.nih.gov/26034955/.

9. Fluvoxamine maleate [package insert ]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021519s012lbl.pdf.

10. Safer DJ, Zito JM. Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents. J Child Adolesc Psychopharmacol. 2006;16(1-2):159-169. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16553536.

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Immunoglobulins: Non-SARS-CoV-2 Specific

Last Updated: July 17, 2020

Recommendation

• The COVID-19 Treatment Guidelines Panel recommends against the use of non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific intravenous immunoglobulin (IVIG) for the treatment of COVID-19, except in a clinical trial (AIII). This recommendation should not preclude the use of IVIG when otherwise indicated for the treatment of complications that arise during the course of COVID-19.

Rationale for Recommendation

It is unknown whether products derived from the plasma of donors without confirmed SARS-CoV-2 infection contain high titer of SARS-CoV-2 neutralizing antibodies. Furthermore, although other blood components in IVIG may have general immunomodulatory effects, it is unclear whether these theoretical effects will benefit patients with COVID-19.

Clinical Data for COVID-19

This study has not been peer reviewed.

A retrospective, non-randomized cohort study of IVIG for the treatment of COVID-19 was conducted across eight treatment centers in China between December 2019 and March 2020. The study showed no difference in 28-day or 60-day mortality between 174 patients who received IVIG and 151 patients who did not receive IVIG.1 More patients in the IVIG group had severe disease at study entry (71 patients [41%] with critical status in the IVIG group vs. 32 patients [21%] in the non-IVIG group). The median hospital stay was longer in the IVIG group (24 days) than in the non-IVIG group (16 days), and the median duration of disease was also longer (31 days in the IVIG group vs. 23 days in the non-IVIG group). A subgroup analysis that was limited to the critically ill patients suggested a mortality benefit at 28 days, which was no longer significant at 60 days.

The results of this study are difficult to interpret because of important limitations in the study design.
In particular, patients were not randomized to receive either IVIG or no IVIG, and the patients in the IVIG group were older and more likely to have coronary heart disease than those in the non-IVG group. In addition, the IVIG group had a higher proportion of patients with severe COVID-19 disease at study entry. Patients in both groups also received many concomitant therapies for COVID-19.

Considerations in Pregnancy

IVIG is commonly used in pregnancy for other indications such as immune thrombocytopenia with an acceptable safety profile.2,3

Considerations in Children

IVIG has been widely used in children for the treatment of a number of conditions. including Kawasaki disease, and is generally safe.4 IVIG has been used in pediatric patients with COVID-19 and multiorgan inflammatory syndrome in children (MIS-C), especially those with a Kawasaki disease-like presentation, but the efficacy of IVIG in the management of MIS-C is still under investigation.

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References

1. Shao Z, Feng Y, Zhong L, et al. Clinical efficacy of intravenous immunoglobulin therapy in critical patients with COVID-19: A multicenter retrospective cohort study. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.04.11.20061739v2.

2. Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 207: thrombocytopenia in pregnancy. Obstet Gynecol. 2019;133(3):e181-e193. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30801473.

3. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21325604.

4. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol. 2017;13(3):247-258. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27590181.

   

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Interferons (Alfa, Beta)

Last Updated: August 27, 2020

Interferons are a family of cytokines with antiviral properties. They have been suggested as a potential treatment for COVID-19 because of their in vitro and in vivo antiviral properties.

Recommendation

The COVID-19 Treatment Guidelines Panel recommends against the use of interferons for the treatment of patients with severe or critical COVID-19, except in a clinical trial (AIII). There are insufficient data to recommend either for or against the use of interferon beta for the treatment of early (i.e., <7 days from symptom onset) mild and moderate COVID-19.

Rationale

Studies have shown no benefit of interferons in patients with other coronavirus infections (i.e., Middle East respiratory syndrome [MERS], severe acute respiratory syndrome [SARS]) who have severe or critical disease. In addition, interferons have significant toxicities that outweigh the potential for benefit. Interferons may have antiviral activity early in the course of infection. However, there is insufficient data to assess the potential benefit of interferon use during early disease versus the toxicity risks.

Clinical Data for COVID-19

Interferon Beta-1a

Press release, July 20, 2020: A double-blind, placebo-controlled trial conducted in the United Kingdom evaluated inhaled interferon beta-1a (once daily for up to 14 days) in nonventilated patients hospitalized with COVID-19. Compared to the patients receiving placebo (n = 50), the patients receiving inhaled interferon beta-1a (n = 48) were more likely to recover to ambulation without restrictions (HR 2.19; 95% CI, 1.03–4.69; P = 0.04), had decreased odds of developing severe disease (OR 0.21; 95% CI, 0.04–0.97; P = 0.046), and had less breathlessness. Additional detail is required to fully evaluate

these findings and their implications. Of note, inhaled interferon beta-1a as used in this study is not commercially available in the United States.1

Preprint manuscript posted online, July 13, 2020: An open-label, randomized trial at a single center in Iran evaluated subcutaneous interferon beta-1a (three times weekly for 2 weeks) in patients with severe COVID-19. There was no difference in the primary outcome of time to clinical response between the interferon beta-1a group (n = 42) and the control group (n = 39), and there was no difference between the groups in overall length of hospital stay, length of intensive care unit stay, or duration of mechanical ventilation. The reported 28-day overall mortality was lower in the interferon beta-1a group; however, four patients in the interferon beta-1a group who died before receiving the fourth dose of interferon beta-1a were excluded from the analysis, which makes it difficult to interpret these results.2

Combination of Interferon Beta-1b, Lopinavir/Ritonavir, and Ribavirin in the Treatment of Hospitalized Patients With COVID-19

An open-label, Phase 2 clinical trial randomized 127 participants (median age of 52 years) 2:1 to combination antiviral therapy or lopinavir/ritonavir. In the combination antiviral therapy group, the treatment regimen differed by time from symptom onset to hospital admission. Participants hospitalized within 7 days of symptom onset (n = 76) were randomized to triple drug therapy (interferon beta-1b 8 million units administered subcutaneously every other day for up to 7 days total, lopinavir/ritonavir,

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and ribavirin); those hospitalized ≥7 days after symptom onset (n = 51) were randomized to double therapy (lopinavir/ritonavir and ribavirin) because of concerns regarding potential inflammatory effects of interferon. Patients in the control group received lopinavir/ritonavir alone regardless of the time from symptom onset to hospitalization. The study participants were patients in Hong Kong with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were hospitalized, regardless of disease severity, until they had two negative nasopharyngeal (NP) swab tests.

The time to a negative result on a polymerase chain reaction SARS-CoV-2 test on an NP swab (the primary endpoint) was shorter in the combination therapy group than in the control group (median of 7 days vs. 12 days; P = 0.001). The combination group had more rapid clinical improvement as assessed by the National Early Warning Score (NEWS) 2 and Sequential Organ Failure Assessment (SOFA) score and a shorter hospital stay (median of 9 days for the combination group vs. 14.5 days for the control group; P = 0.016). There was no difference in oxygen use between the groups. The antiviral and clinical effect was more pronounced in the patients hospitalized within 7 days of symptom onset, suggesting

that interferon beta-1b with or without ribavirin was the critical component of the combination antiviral therapy. The study provides no information about the effect of interferon beta-1b when administered ≥7 days after symptom onset.3

Interferon Alfa-2b

In a retrospective cohort study of 77 adults with moderate COVID-19 in China, participants were treated with nebulized interferon alfa-2b, nebulized interferon alfa-2b with umifenovir, or umifenovir only. The time to viral clearance in the upper respiratory tract and reduction in systemic inflammation was faster in the interferon alfa-2b groups than in the umifenovir only group. However, the results
of this study are difficult to interpret because participants in the interferon alfa-2b with umifenovir group were substantially younger than those in the umifenovir only group (mean age of 40 years in the interferon alfa-2b with umifenovir group vs. 65 years in the umifenovir only group) and had fewer comorbidities (15% in the interferon alfa-2b with umifenovir group vs. 54% in the umifenovir only group) at study entry. The nebulized interferon alfa-2b formulation is not approved by the Food and Drug Administration for use in the United States.4

Clinical Data for SARS and MERS

Interferon beta used alone and in combination with ribavirin in patients with SARS and MERS has failed to show a significant positive effect on clinical outcomes.5-9

In a retrospective observational analysis of 350 critically ill patients with MERS6 from 14 hospitals in Saudi Arabia, the mortality rate was higher among patients who received ribavirin and interferon (beta-1a, alfa-2a, or alfa-2b) than among those who did not receive either drug.

A randomized clinical trial that included 301 patients with acute respiratory distress syndrome10 found that intravenous interferon beta-1a had no benefit over placebo as measured by ventilator-free days over a 28-day period (median of 10.0 days in the interferon beta-1a group vs. 8.5 days in the placebo group) or mortality (26.4% in the interferon beta-1a group vs. 23.0% in the placebo group).

Clinical Trials

See ClinicalTrials.gov for a list of ongoing clinical trials for interferon and COVID-19. Adverse Effects

The most frequent adverse effects of interferon alfa include flu-like symptoms, nausea, fatigue, weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (e.g., depression and

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suicidal ideation). Interferon beta is better tolerated than interferon alfa.11,12

Drug-Drug Interactions

The most serious drug-drug interactions with interferons are the potential for added toxicity with concomitant use of other immunomodulators and chemotherapeutic agents.11,12

Considerations in Pregnancy

Analysis of data from several large pregnancy registries did not demonstrate an association between exposure to interferon beta-1b preconception or during pregnancy and an increased risk of adverse birth outcomes (e.g., spontaneous abortion, congenital anomaly),13,14 and exposure did not influence birth weight, height, or head circumference.15

Considerations in Children

There are limited data on the use of interferons for the treatment of respiratory viral infections in children.

References

1. Synairgen announces positive results from trial of SNG001 in hospitalised COVID-19 patients [press release]. July 20, 2020. Available at: https://www.synairgen.com/wp-content/uploads/2020/07/200720-Synairgen- announces-positive-results-from-trial-of-SNG001-in-hospitalised-COVID-19-patients.pdf. Accessed August 24, 2020.

2. Davoudi-Monfared E, Rahmani H, Khalili H, et al. A randomized clinical trial of the efficacy and safety of interferon beta-1a in treatment of severe COVID-19. Antimicrob Agents Chemother. 2020;64(9):e01061-20. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32661006.

3. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial. Lancet. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.

4. Zhou Q, Chen V, Shannon CP, et al. Interferon-alpha2b treatment for COVID-19. Front Immunol. 2020;11:1061. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32574262.

5. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis. 2014;20:42-46. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24406736.

6. Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study. Clin Infect Dis. 2020;70(9):1837-1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31925415.

7. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14985565.

8. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25278221.

9. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015;70(7):2129-2132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25900158.

10. Ranieri VM, Pettila V, Karvonen MK, et al. Effect of intravenous interferon beta-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32065831.

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11. Interferon alpha-2b (Intron A) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103132Orig1s5199lbl.pdf.

12. Interferon beta-1a (Rebif) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103780s5204lbl.pdf.

13. Sandberg-Wollheim M, Alteri E, Moraga MS, Kornmann G. Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler. 2011;17(4):423-430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21220368.

14. Hellwig K, Duarte Caron F, Wicklein EM, Bhatti A, Adamo A. Pregnancy outcomes from the global pharmacovigilance database on interferon beta-1b exposure. Ther Adv Neurol Disord. 2020;13:1756286420910310. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32201504.

15. Burkill S, Vattulainen P, Geissbuehler Y, et al. The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis. PLoS One. 2019;14(12):e0227120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31887199.

    

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Interleukin-1 Inhibitors

Last Updated: July 17, 2020

Recommendation

• There are insufficient data to recommend for or against the use of interleukin (IL)-1 inhibitors, such as anakinra, for the treatment of COVID-19.

Rationale

There are case series data but no clinical trial data on the use of IL-1 inhibitors in patients with COVID-19.

Anakinra is a recombinant human IL-1 receptor antagonist. It is approved by the Food and Drug Administration (FDA) to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes, specifically neonatal-onset multisystem inflammatory disease.1 It is also used off-label for severe chimeric antigen receptor T cell (CAR T-cell)-mediated cytokine release syndrome (CRS) and macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis.

Rationale for Use in Patients with COVID-19

Endogenous IL-1 is elevated in patients with COVID-19 and other conditions, such as severe CAR T-cell-mediated CRS. Case reports and case series have described favorable responses to anakinra in patients with these syndromes, including a survival benefit in patients with sepsis and reversal of cytokine storm after tocilizumab failure in adults with MAS.2,3

Clinical Data for COVID-19

• A case-control study compared outcomes in 52 consecutive patients with COVID-19 treated with anakinra and 44 historical controls. The patients in both groups were all admitted to the same hospital in Paris, France. Case patients were consecutive admissions from March 24 to April 6, 2020, with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or lung infiltrates on chest imaging typical of COVID-19, and either significant hypoxia (SpO2 ≤93% with ≥6L/min O2) or worsening hypoxia (SpO2 ≤93% with >3L/min O2 and a loss

of ≥3% of O2 saturation on room air in the previous 24 hours). The historic controls were patients who fulfilled the same eligibility criteria and admitted to the hospital during the same period.
As standard of care for both groups, some patients received hydroxychloroquine, azithromycin, or parenteral beta-lactam antibiotics. Anakinra was dosed as 100 mg subcutaneous (SQ) twice daily for 72 hours, followed by anakinra 100 mg SQ daily for 7 days. Clinical characteristics were similar between the groups, except that the cases had a lower mean body mass index than the controls (25.5 kg/m2 vs. 29.0 kg/m2, respectively), longer duration of symptoms (mean of

8.4 days for cases vs. 6.2 days for controls), and a higher frequency of hydroxychloroquine use (90% for cases vs. 61% for controls) and azithromycin use (49% for cases vs. 34% for controls). The primary outcome of admission to the intensive care unit for mechanical ventilation or death occurred among 13 case patients (25%) and 32 control patients (73%) (hazard ratio 0.22; 95% confidence interval, 0.11 to 0.41). However, within the first 2 days of follow up, in the control group, six patients (14%) had died and 19 patients (43%) had reached the composite primary outcome, which further limited intragroup comparisons and specifically analyses of time to event. C-reactive protein (CRP) levels decreased by Day 4 among those receiving anakinra. Thromboembolic events occurred in 10 patients (19%) who received anakinra and in five control patients (11%). The clinical implications of these findings are uncertain due to limitations in the

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study design related to unmeasured confounding combined with the very high early event rate among the retrospective controls.4

• A single-center, retrospective cohort study compared outcomes in 29 patients following open-label use of anakinra to outcomes in 16 historical controls enrolled at the same medical center in Italy. All patients had COVID-19 with moderate to severe acute respiratory distress syndrome (ARDS) that required non-invasive ventilation and evidence of hyperinflammation (CRP ≥100 mg/L and/ or ferritin ≥900 ng/mL). High-dose intravenous anakinra 5 mg/kg twice daily was administered for a median of 9 days, followed by SQ administration of anakinra 100 mg twice daily for 3
days to avoid inflammatory relapses. Patients in both the anakinra and control groups received hydroxychloroquine and lopinavir/ritonavir. In the anakinra group, reductions in CRP levels were noted over several days following anakinra initiation, and the 21-day survival rate was higher than in the control group (90% vs. 56%, respectively; P = 0.009). However, the patients in the anakinra group were younger than those in the control group (median age 62 years vs. 70 years, respectively), and fewer patients in the anakinra group had chronic kidney disease. High-dose anakinra was discontinued in seven patients (24%) because of adverse events (four patients developed bacteremia and three patients had elevated liver enzymes); however, retrospective assessment showed that these events occurred with similar frequency in the control group. An additional group of seven patients received low-dose SQ anakinra 100 mg twice daily; however, treatment in this group was stopped after 7 days because of lack of clinical or anti-inflammatory effects.5

• Other small case series have reported anakinra use for the treatment of COVID-19 and anecdotal evidence of improvement in outcomes.6
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials evaluating anakinra for the treatment of COVID-19. Adverse Effects
Anakinra was not associated with any significant safety concerns when used in clinical trials for the treatment of sepsis.7-9 Increased rates of infection were reported with prolonged anakinra use in combination with tumor necrosis factor-alpha blockade, but not with short-term use.10
Considerations in Pregnancy
There is limited evidence on which to base a recommendation in pregnancy, but unintentional first trimester exposure is unlikely to be harmful.11
Considerations in Children
Anakinra has been used extensively in the treatment of severely ill children with complications of rheumatologic conditions, including MAS. Pediatric data on the use of anakinra in ARDS/sepsis are limited.
Drug Availability
Procuring anakinra may be a challenge at some hospitals in the United States. Anakinra is FDA- approved only for SQ injection.
References

1. Anakinra (kineret) [package insert]. Food and Drug Administration. 2012. Available at:

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https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf. Accessed April 8, 2020.

2. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior Phase III trial. Crit Care Med. 2016;44(2):275-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26584195.

3. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome. ACR Open Rheumatol. 2020;2(5):276-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32267081.

4. Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatology. 2020;2(7):e393-e400. Available at: https://www.theLancet.com/pdfs/journals/lanrhe/PIIS2665-9913(20)30164-8.pdf.

5. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatology. 2020;2(6): e325-e331. Available at: https://www.theLancet.com/journals/lanrhe/article/PIIS2665-9913(20)30127-2/fulltext.

6. Aouba A, Baldolli A, Geffray L, et al. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Ann Rheum Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32376597.

7. Fisher CJ, Jr., Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836-1843. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8196140.

8. Fisher CJ, Jr., Slotman GJ, Opal SM, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med. 1994;22(1):12-21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8124953.

9. Opal SM, Fisher CJ, Jr., Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a Phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115-1124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9233735.

10. Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective (soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect. 2018;24 Suppl 2:S21-S40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29447987.

11. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford). 2016;55(9):1698-1702. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26750125.

          

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Interleukin-6 Inhibitors

Last Updated: April 21, 2021

Interleukin (IL)-6 is a pleiotropic, proinflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts. Infection by the severe acute respiratory syndrome- associated coronavirus (SARS-CoV) induces a dose-dependent production of IL-6 from bronchial epithelial cells.1 COVID-19-associated systemic inflammation and hypoxic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin.2-4 It is hypothesized that modulating the levels of IL-6 or its effects may reduce the duration and/or severity of COVID-19 illness.

There are two classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) and anti-IL-6 monoclonal antibodies (i.e., siltuximab). These drugs have been evaluated for the management of patients with COVID-19 who have systemic inflammation. The COVID-19 Treatment Guidelines Panel’s (the Panel’s) recommendations on the use IL-6 inhibitors in patients with COVID-19 and related clinical data to date are described below.

Recommendations

• The Panel recommends using tocilizumab (single intravenous [IV] dose of tocilizumab 8 mg/kg actual body weight up to 800 mg) in combination with dexamethasone (6 mg daily for up to 10 days) in certain hospitalized patients who are exhibiting rapid respiratory decompensation due to COVID-19. These patients are:

• Recently hospitalized patients (i.e., within first 3 days of admission) who have been admitted to the intensive care unit (ICU) within the prior 24 hours and who require invasive mechanical ventilation, noninvasive ventilation, or high-flow nasal canula (HFNC) oxygen (>0.4 FiO2/30 L/min of oxygen flow) (BIIa); or

• Recently hospitalized patients (i.e., within first 3 days of admission) not admitted to the ICU who have rapidly increasing oxygen needs and require noninvasive ventilation or HFNC oxygen and who have significantly increased markers of inflammation (CRP ≥75 mg/L) (BIIa).

• For hospitalized patients with hypoxemia who require conventional oxygen therapy, there is insufficient evidence to specify which of these patients would benefit from the addition of tocilizumab. Some Panel members would also give tocilizumab to patients who are exhibiting rapidly increasing oxygen needs while on dexamethasone and have a CRP ≥75 mg/L, but who do not yet require noninvasive ventilation or HFNC oxygen as described above.

• There are insufficient data for the Panel to recommend either for or against the use of sarilumab for hospitalized patients with COVID-19 who are within 24 hours of admission to the ICU and who require invasive mechanical ventilation, noninvasive ventilation, or high-flow oxygen (>0.4 FiO2/30 L/min of oxygen flow).

• The Panel recommends against the use of anti-IL-6 monoclonal antibody therapy (i.e., siltuximab) for the treatment of COVID-19, except in a clinical trial (BI).
Additional Considerations

• Tocilizumab should be avoided in patients who are significantly immunosuppressed, particularly in those with recent use of other biologic immunomodulating drugs, and in
patients who have alanine aminotransferase >5 times the upper limit of normal; high risk for gastrointestinal perforation; an uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral

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infection; absolute neutrophil count <500 cells/μL; platelet count <50,000 cells/μL; or known hypersensitivity to tocilizumab.

• Tocilizumab should only be given in combination with a course of dexamethasone (or an alternative corticosteroid at a dose equivalency to dexamethasone 6 mg) therapy.

• Some clinicians may assess the patient’s clinical response to dexamethasone before deciding whether tocilizumab is needed.

• Although some patients in the Randomised, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) and the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial received a second dose of tocilizumab at the discretion of treating physicians, there are insufficient data to indicate which patients, if any, would benefit from an additional dose of tocilizumab.

• Cases of severe and disseminated strongyloidiasis have been reported with use of tocilizumab and corticosteroids in patients with COVID-19.5,6 Prophylactic treatment with ivermectin should be considered for patients who are from strongyloidiasis endemic areas.7
Rationale
The results of the RECOVERY trial and REMAP-CAP provide consistent evidence that tocilizumab, when administered with corticosteroids, offers a modest mortality benefit in certain patients with COVID-19 who are severely ill, rapidly deteriorating with increasing oxygen needs, and have a significant inflammatory response. However, the Panel found it challenging to define the specific patient population(s) that would benefit from this intervention. See an overview of the clinical trial data on the use of tocilizumab in patients with COVID-19 below.
Sarilumab and tocilizumab have a similar mechanism of action. However, in REMAP-CAP, the number of participants who received sarilumab was relatively small. Moreover, the trial evaluated sarilumab for IV administration, which is not the approved formulation in the United States. The results of randomized controlled trials of sarilumab that are underway will further define the role sarilumab plays in the treatment of COVID-19.
There are only limited data describing the potential for efficacy of siltuximab in patients with COVID-19.11
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Tocilizumab
Tocilizumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that is approved by the FDA for use in patients with rheumatologic disorders and cytokine release syndrome (CRS) induced by chimeric antigen receptor T cell (CAR T-cell) therapy. Tocilizumab can be dosed for IV or subcutaneous (SQ) injection. The IV formulation should be used to treat CRS.8
Clinical Data for COVID-19
Clinical data on the use of tocilizumab (and other IL-6 inhibitors) for the treatment of COVID-19, including data from several randomized trials and large observational studies, are summarized in Table 4b.
Initial studies that evaluated the use of tocilizumab for the treatment of COVID-19 produced conflicting results. Many of these trials were limited by low power, heterogenous populations, and/or a low frequency of concomitant use of corticosteroids (now the standard of care for patients with severe COVID-19).9-11 For example, trials that reported a treatment benefit of tocilizumab enrolled patients who
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were receiving higher levels of oxygen support (e.g., HFNC oxygen, noninvasive ventilation, invasive mechanical ventilation) and/or included more patients who used corticosteroids.12,13 Subsequently, REMAP-CAP and the RECOVERY trial—the two largest randomized controlled tocilizumab trials— reported a mortality benefit of tocilizumab in certain patients, including patients exhibiting rapid respiratory decompensation associated with an inflammatory response. REMAP-CAP enrolled a narrowly defined population of critically ill patients who were enrolled within 24 hours of starting respiratory support in an ICU and randomized to receive open-label tocilizumab or usual care.14 The RECOVERY trial enrolled hospitalized patients with COVID-19 into an open label, platform trial of several treatment options;15 a subset of participants with hypoxemia and CRP ≥75 mg/L were offered enrollment into a second randomization to tocilizumab versus usual care. Additional findings from REMAP-CAP and the RECOVERY trial and the rationale for using tocilizumab in certain hospitalized patients who are exhibiting rapid respiratory decompensations due to COVID-19 can be found in Therapeutic Management of Adults With COVID-19.

The Panel’s recommendations for using tocilizumab are based on the collective evidence from clinical trials reported to date (see Table 4b).

Clinical Trials

Ongoing trials are evaluating the use of tocilizumab for the treatment of COVID-19. See ClinicalTrials. gov for the latest information.

Adverse Effects

The primary laboratory abnormalities reported with tocilizumab treatment are elevated liver enzyme levels that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. Additional adverse effects, such as risk for serious infections (e.g., tuberculosis [TB], bacterial or fungal infections) and bowel perforation, have been reported only in the context of tocilizumab use for the treatment of chronic disease.

Considerations in Pregnancy

There are insufficient data to determine whether there is a tocilizumab-associated risk for major birth defects or miscarriage. Monoclonal antibodies are actively transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in
utero in the exposed fetus. Given the paucity of data, current recommendations advise against the

use of tocilizumab during pregnancy.16 Decisions about tocilizumab administration during pregnancy must include shared decision-making between the pregnant individual and their health care provider, considering potential maternal benefit and fetal risks.

Considerations in Children

There are no systematic observational or randomized controlled trial data available on the effectiveness of tocilizumab for the treatment of COVID-19 or multisystem inflammatory syndrome in children (MIS-C) in children. Tocilizumab has been used for children with CRS associated with CAR T-cell therapy and systemic and polyarticular juvenile idiopathic arthritis.17 There are insufficient data for the Panel to recommend either for or against the use of tocilizumab in hospitalized children with COVID-19 or MIS-C.

Sarilumab

Sarilumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that is approved by the FDA for use in patients with rheumatoid arthritis. It is available as an SQ formulation and is not approved for the treatment of CRS.

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Clinical Data for COVID-19

Clinical data for sarilumab (and other IL-6 inhibitors) as treatment for COVID-19, including data from several randomized trials and large observational studies, are summarized in Table 4b.

An adaptive Phase 2 and 3 double-blind, placebo-controlled randomized (2:2:1) trial compared the efficacy and safety of sarilumab 400 mg IV and sarilumab 200 mg IV versus placebo in patients hospitalized with COVID-19 (ClinicalTrials.gov Identifier NCT04315298). Results from this trial did not support a clinical benefit of sarilumab in hospitalized patients receiving supplemental oxygen.18 Preliminary efficacy results from REMAP-CAP for sarilumab were similar to those for tocilizumab. Compared to placebo, sarilumab reduced both mortality and time to ICU discharge, and increased the number of organ support-free days; however, the number of participants who received sarilumab in this trial was relatively small, limiting the conclusions and implications of these findings.19

Clinical Trials

Ongoing trials are evaluating the use of sarilumab for the treatment of COVID-19. See ClinicalTrials. gov for the latest information.

Adverse Effects

The primary lab abnormalities that have been reported with sarilumab treatment are transient and/
or reversible elevations in liver enzymes that appear to be dose dependent and rare occurrences of neutropenia and thrombocytopenia. Risk for serious infections (e.g., TB, bacterial or fungal infections) and bowel perforation have been reported only with long-term use of sarilumab.

Considerations in Pregnancy

There are insufficient data to determine whether there is a sarilumab-associated risk for major birth defects or miscarriage. Monoclonal antibodies are actively transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in utero in the exposed fetus.

Considerations in Children

There are no data on the use of sarilumab in children other than data from ongoing trials assessing the drug’s safety in children with juvenile idiopathic arthritis. There are no systematic observational or randomized controlled trial data available on the efficacy of sarilumab for the treatment of COVID-19 or MIS-C in children.

Drug Availability

The SQ formulation of sarilumab is not approved for the treatment of CRS. The IV formulation is not approved by the FDA, but it is being studied in a clinical trial of hospitalized patients with COVID-19.

Anti-Interleukin-6 Monoclonal Antibody

Siltuximab

Siltuximab is a recombinant human-mouse chimeric monoclonal antibody that binds IL-6 and is approved by the FDA for use in patients with multicentric Castleman disease. Siltuximab prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling. Siltuximab is dosed as an IV infusion.

Clinical Data for COVID-19

There are limited data describing the efficacy of siltuximab in patients with COVID-19.20 There are no data describing clinical experiences using siltuximab for patients with other novel coronavirus infections

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(i.e., severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]).

Clinical Trials

See ClinicalTrials.gov for a list of current clinical trials for siltuximab and COVID-19. Adverse Effects

The primary adverse effects reported for siltuximab have been related to rash. Additional adverse effects (e.g., serious bacterial infections) have been reported only with long-term dosing of siltuximab once every 3 weeks.

Considerations in Pregnancy

There are insufficient data to determine whether there is a siltuximab-associated risk for major birth defects or miscarriage. Monoclonal antibodies are transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in the exposed fetus.

Considerations in Children

The safety and efficacy of siltuximab have not been established in pediatric patients.

References

1. Yoshikawa T, Hill T, Li K, Peters CJ,Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus- induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19004938.

2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32171076.

3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.

4. Wang Z, Yang B, Li Q, Wen L,Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176772.

5. Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32830642/.

6. Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32910321.

7. Stauffer WM, Alpern JD,Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid- related strongyloides hyperinfection. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.

8. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29622697.

9. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333-2344. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33085857.

10. Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41-51. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080002.

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11. Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32-40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080017.

12. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332779.

13. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/33676590/.

14. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.

15. RECOVERY Collaborative Group, Horby PW, Pessoa-Amorim G, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021;preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.

16. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529-556. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32090480.

17. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125276s131lbl.pdf.

18. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676590.

19. The REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19–Preliminary report. medRxiv. 2021. Available at: https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1.

20. Gritti G, Raimondi F, Ripamonti D, et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v1.

         

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Table 4b. Interleukin-6 Inhibitors: Selected Clinical Data

Last Updated April 21, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for IL-6 inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.



Study Design

Methods

Results

Limitations and Interpretation

Tocilizumab in Hospitalized Patients With COVID-19 (RECOVERY Trial)1

Second randomization of the RECOVERY trial, an open-label, randomized controlled-platform

trial assessing several treatments in hospitalized patients with COVID-19 in the United Kingdom

(n = 4,116; 19% of
all RECOVERY trial participants [n = 21,550])

Key Inclusion Criteria:

• Suspected or laboratory-con rmed COVID-19

• Participant within 21 days of enrollment into the initial randomization of the RECOVERY trial

• Hypoxia evidenced by SpO2 <92% on room air or receipt of supplemental oxygen

• CRP ≥75 mg/L
Key Exclusion Criteria:

• Tocilizumab unavailable at participating hospital

• Evidence of active non-SARS-CoV-2 infection, including TB or other bacterial, fungal, or viral infection
Interventions
1: 1 Randomization:
• Single dose of tocilizumab 8 mg/kg, and possible second dose, or
• Usual care
Primary Endpoint:
• All-cause mortality through 28 days
Secondary Endpoints:
• Time to discharge alive
• Among those not on mechanical ventilation at enrollment, receipt of mechanical ventilation or death

Number of Participants:

• Tocilizumab (n = 2,022) and usual care (n = 2,094)

• Recruitment period: April 14, 2020, through January 24, 2021

Participant Characteristics:

• Mean age was 63.6 years.

• 67% of participants were men.

• 68% of participants were white.

• 94% of participants had PCR-con rmed SARS- CoV-2 infection.

• Median time from hospitalization until enrollment was 2 days (IQR 1–5 days).

• Median CRP 143 mg/L (IQR 107–204 mg/L).

• At baseline, 45% of participants were on conventional oxygen, 41% on HFNC/noninvasive ventilation, and 14% on mechanical ventilation.

• At enrollment, 82% of participants were taking corticosteroids.
Primary Outcomes:

• Mortality by Day 28 was lower in the tocilizumab arm than in the usual care arm (29% vs. 33%; rate ratio 0.86; 95% CI, 0.77–0.96).

• Subgroup analysis: Among those who required mechanical ventilation at baseline, mortality by Day 28 was similar in the tocilizumab and usual care arms (47% vs. 48%).

Limitations:

• Open-label study

• Limited collection of AEs

• Only a small proportion of the participants were from ethnic or racial minority groups.

• Dif cult to de ne exact subset of hospitalized patients in
full RECOVERY cohort who were subsequently selected for secondary randomization/ tocilizumab trial.

• Arbitrary cut off of CRP ≥75 mg/L Interpretation:

• Among hospitalized patients with severe or critical COVID-19 with hypoxia and elevated CRP levels (≥75 mg/L), tocilizumab was associated with reduced all-cause mortality and shorter time to discharge.

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Study Design

Methods

Results

Limitations and Interpretation

Tocilizumab in Hospitalized Patients With COVID-19 (RECOVERY Trial)1, continued

Secondary Outcomes:

• The proportion of patients who were discharged alive within 28 days was greater in tocilizumab arm than usual care arm (54% vs. 47%; rate ratio 1.22; 95% CI, 1.12–1.34).

• Among those not on mechanical ventilation at baseline, the percentage of participants who met the secondary outcome of mechanical ventilation or death was lower in the tocilizumab arm than in the usual care arm (33% vs. 38%; risk ratio 0.85; 95% CI, 0.78–0.93).

Interleukin-6 Receptor Antagonists in Critically Ill Patients With COVID-19–Preliminary Report (REMAP-CAP)2

Multinational RCT in critically ill, hospitalized patients with COVID-19 (n = 865)

Key Inclusion Criteria:

• Suspected or laboratory-con rmed COVID-19

• Admitted to ICU and receiving respiratory or cardiovascular organ support
Key Exclusion Criteria:

• >24 hours since admission to ICU

• Presumption of imminent death with lack of commitment to full support

• Immunosuppression

• ALT >5 times ULN
Interventions
1:1 Randomization:
• Single dose of tocilizumab 8 mg/ kg, and possible second dose, plus SOC, or
• SOC

Number of Participants:

• Tocilizumab plus SOC (n = 353), sarilumab plus SOC (n = 48), and SOC (n = 402)

• Recruitment period: April 19 through October 28, 2020

Participant Characteristics:

• Mean age was 61.4 years.

• 73% of participants were men.

• 72% of participants were White.

• 84.4% of participants had a positive SARS-CoV-2 PCR test.

• Median time from hospitalization until enrollment: 1.2 days (IQR 0.8–2.8 days).

• Median time from ICU admission until enrollment: 13.6 hours (IQR 6.6–19.4 hours).

• Baseline level of oxygen support: 28.8% of participants on HFNC, 41.5% on noninvasive ventilation, 29.4% on mechanical ventilation.

• In mITT analysis, majority of patients (719 of 792 [90%]) received corticosteroids.

Limitations:

• Open-label study

• Very few patients randomized to receive sarilumab.

• Limited collection of AEs

• Low proportion of participants from ethnic/racial minority populations
Interpretation:

• Among the patients with severe/critical COVID-19 who were on high- ow oxygen or noninvasive ventilation or who were mechanically ventilated and within 24 hours of ICU admission, the tocilizumab arm had lower mortality and shorter duration

of organ support. This bene t of tocilizumab may be in conjunction with concomitant corticosteroids given the high rate of corticosteroid use among trial participants.

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Study Design

Methods

Results

Limitations and Interpretation

Interleukin-6 Receptor Antagonists in Critically Ill Patients With Covid-19–Preliminary Report (REMAP-CAP)2, continued

Alternative 1:1:1 Randomization:

• Single dose of tocilizumab 8 mg/ kg, and possible second dose, plus SOC, or

• Single dose of sarilumab 400 mg IV plus SOC, or

• SOC
Primary Endpoint:

• Composite endpoint measured on an ordinal scale combining in- hospital mortality (assigned value: -1) and days free of respiratory or cardiovascular organ support up to Day 21

Primary Outcomes:

• Median number of organ support-free days was 10 (IQR -1 to 16 days), 11 (IQR 0–16 days), and 0 (IQR -1 to 15 days) for the tocilizumab, sarilumab, and SOC arms, respectively.

• Adjusted OR 1.64 (95% CrI, 1.25–2.14) for tocilizumab arm vs. SOC arm

• In-hospital mortality: 28.0% for patients receiving tocilizumab and 35.8% for patients receiving SOC (aOR 1.64; 95% CrI, 1.14–2.35).

• Percentage of patients who were not mechanically ventilated who progressed to intubation or death: 41.3% in tocilizumab arm vs. 52.7% in SOC arm.

• REMAP-CAP enrolled patients within 24 hours of ICU level care who were undergoing rapid progression of respiratory dysfunction, a key difference to other tocilizumab trials.

Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia (COVACTA)3

Multinational, double- blind, placebo-controlled randomized trial in hospitalized patients with COVID-19 (n = 452)

Key Inclusion Criteria:

• COVID-19 con rmed by positive PCR test

• Severe COVID-19 pneumonia evidenced by hypoxemia and bilateral chest in ltrates
Key Exclusion Criteria:
• Death imminent within 24 hours
• Active TB or bacterial, fungal, or viral infection (other than SARS- CoV-2)
Interventions
2:1 Randomization:
• Single dose of tocilizumab 8 mg/ kg, and possible second dose, plus SOC
• Placebo plus SOC

Number of Participants:

• mITT analysis: tocilizumab (n = 294) and placebo (n = 144)

Participant Characteristics:

• Mean age was 61 years.

• 70% of participants were men.

• 58% of participants were White.

• Median time from symptom onset to randomization: 11 days

• Clinical status at baseline by ordinal scale category: 28% of participants on supplemental oxygen (category 3); 30% on HFNC/noninvasive ventilation (category 4); 14% on mechanical ventilation (category 5); and 25% with multiorgan failure (category 6).

• Percentage of participants who received corticosteroids at entry or during follow-up: 36% in tocilizumab arm vs. 55% in placebo arm.

Limitations:

• Modest power to detect differences in clinical status on Day 28 (the primary outcome) between the study arms

• Corticosteroids only used by a subset of patients, which included more patients from the placebo arm; RDV use was rare.

• Results mostly generalizable to the sickest patients with COVID-19.

Interpretation:

• There was no difference between tocilizumab and placebo for clinical status (including death) at Day 28 (the primary outcome), but tocilizumab did demonstrate a shorter time to recovery

and shorter length of ICU stay (secondary outcomes).

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Study Design

Methods

Results

Limitations and Interpretation

Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia (COVACTA)3, continued

Primary Endpoint:

• Clinical status at Day 28 (as measured on a 7-category ordinal scale)

Secondary Endpoints:

• Time to discharge • Length of ICU stay • Mortality at Day 28

Ordinal Scale Categories:

1. Discharged or ready for discharge

2. Hospitalized on medical ward, not on supplemental oxygen

3. Hospitalized on medical ward, on supplemental oxygen

4. On oxygen by HFNC or noninvasive ventilation

5. On mechanical ventilation

6. Multiorgan failure (with ECMO or mechanical ventilation plus other support)

7. Death

Primary Outcome:

• There was no signi cant difference in clinical status on 7-category ordinal scale on Day 28 between the arms: median of category 1 for the tocilizumab arm vs. category 2 for the placebo arm (difference -1.0; 95% CI, -2.5 to 0.0; P = 0.31).

Secondary Outcomes:

• The time to discharge was shorter in the tocilizumab arm than in the placebo arm (median of 20 days vs. 28 days; HR 1.35; 95% CI, 1.02– 1.79).

• ICU stays were shorter in the tocilizumab arm than in the placebo arm (median of 9.8 days vs. 15.5 days; difference of 5.8 days; 95% CI, -15.0 to -2.9).

• There was no difference in mortality by Day 28 between the arms (19.7% in tocilizumab arm vs. 19.4% in placebo arm; 95% CI, -7.6 to 8.2; P = 0.94).

• SAEs occurred in 34.9% of patients in the tocilizumab arm vs. 38.5% in the placebo arm.

Effect of Tocilizumab on Clinical Outcomes at 15 Days in Patients With Severe or Critical COVID-2019 (TOCIBRAS)4

RCT in severe or critically ill hospitalized patients with COVID-19 in Brazil (n = 129)

Key Inclusion Criteria:

• COVID-19 con rmed by PCR test and radiographic imaging

• Receiving oxygen to maintain SpO2 >93% or mechanical ventilation for <24 hours

Key Exclusion Criteria:

• Active, uncontrolled infection

• Elevated AST or ALT >5 times ULN

• Reduced renal function with eGFR <30 mL/min/1.72 m2

Number of Participants:

• Tocilizumab (n = 65) and SOC (n = 64)

Participant Characteristics:

• Mean age was 57 years.

• 68% of participants were men.

• Mean time from symptom onset to randomization: 10 days

• Baseline level of oxygen support: 52% of participants on conventional oxygen, 32% on HFNC or noninvasive ventilation, and 16% on mechanical ventilation.

Limitations:

• Open-label study

• Relatively small sample size

• Study was stopped early during the rst interim review because of increased risk of death at Day 15.
Interpretation:

• In this study population, tocilizumab demonstrated no bene t with respect to mechanical ventilation or death at Day 15 or key secondary outcomes.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Tocilizumab on Clinical Outcomes at 15 Days in Patients With Severe or Critical COVID-2019 (TOCIBRAS)4, continued

Interventions:

• Single dose of tocilizumab 8 mg/kg plus SOC

• SOC

Primary Endpoints:

• Clinical status at 15 days by ordinal scale category.

• Following the statistical analysis plan, the primary outcome for the nal analysis was changed to mechanical ventilation or death at Day 15 (categories 6 and 7), because the assumption of proportional odds was not met for the original 7-category ordinal outcome.
Key Secondary Endpoint:
• All-cause mortality to Day 28
Ordinal Scale:

1. Not hospitalized, no limitation in activities

2. Not hospitalized, limitation in activities

3. Hospitalized, not receiving supplemental oxygen

4. Hospitalized, receiving supplemental oxygen

5. Hospitalized, receiving NIPPV or high- ow oxygen through a nasal cannula

6. Hospitalized, receiving mechanical ventilation

7. Death

• 86% of participants received corticosteroids.

• No patient received RDV, which was unavailable in Brazil during the study period.

Primary Outcomes:

• There was no evidence for a treatment difference in the primary outcome: 28% of participants in the tocilizumab arm vs. 20% in the SOC arm had died or received mechanical ventilation at Day 15 (OR 1.54; 95% CI, 0.66–3.66; P = 0.32).

• The study was stopped early by recommendation of the Data Monitoring Committee because of increased risk of death in the tocilizumab group: by Day 15, 16.9% of participants in the tocilizumab arm vs. 3.1% in SOC arm had died (OR 6.42; 95% CI, 1.59–43.2).
Key Secondary Outcomes:

• Tocilizumab was associated with a trend towards increased mortality at Day 28 (21% in tocilizumab arm vs. 9% in SOC arm; OR 2.70; 95% CI, 0.97– 8.35).

• AEs were reported in 43% of patients in the tocilizumab arm and 34% in the SOC arm.

• There were more deaths at Day 15 in the tocilizumab arm than in the SOC arm.

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Study Design

Methods

Results

Limitations and Interpretation

Tocilizumab in Nonventilated Patients Hospitalized With COVID-19 Pneumonia (EMPACTA)5

Multinational, double- blind, placebo- controlled, Phase 3 randomized trial in hospitalized patients with COVID-19 (n = 389)

Key Inclusion Criteria:

• COVID-19 con rmed by PCR test and radiographic imaging

• Severe COVID-19 pneumonia

Key Exclusion Criteria:

• Receipt of noninvasive ventilation or mechanical ventilation

Interventions

2:1 Randomization:

• Single dose of tocilizumab 8 mg/kg plus SOC, possible second dose if not improving, or

• Placebo plus SOC

Primary Endpoint:

• Mechanical ventilation or death by Day 28

Key Secondary Endpoints:

• Time to hospital discharge or readiness for discharge

• All-cause mortality by Day 28

Number of Participants:

• mITT analysis: Tocilizumab (n = 249) and placebo (n = 128)

Participant Characteristics:

• Mean age was 55.9 years.

• 59.2% of participants were men.

• 56.0% of participants were Hispanic/Latinx, 14.9% were Black/African American, and 12.7% were American Indian/ Alaska Native.

• 81% of participants were enrolled at sites in the United States.

• Median time from symptom onset to randomization was 8 days.

• Percentage of participants who received concomitant medications:
• Tocilizumab arm: 80.3% received corticosteroids (55.4% received dexamethasone) and 52.6% received RDV
• Placebo arm: 87.5% received corticosteroids (67.2% received dexamethasone) and 58.6% received RDV
Primary Outcome:
• By mITT analysis, the cumulative proportion of patients who required mechanical ventilation or who had died by Day 28 was 12.0% in the tocilizumab arm and 19.3% in the placebo arm (HR 0.56; 95% CI, 0.33–0.97; P = 0.04)
Key Secondary Outcomes:

• The median time to hospital discharge or readiness for discharge was 6.0 days in the tocilizumab arm and 7.5 days in placebo arm (HR 1.16; 95% CI, 0.91–1.48).

• All-cause mortality by Day 28 was 10.4% (95% CI, 7.2% to 14.9%) in the tocilizumab arm and 8.6% (95% CI, 4.9% to 14.7%) in the placebo arm.

• SAEs were reported in 15.2% of patients in the tocilizumab arm and 19.7% in the placebo arm.

Limitation:

• Interaction with steroids not explored

Interpretation:

• Among patients with severe COVID-19, tocilizumab lowered rates of mechanical ventilation or death by Day 28 but provided no bene t in 28-day mortality.

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Study Design

Methods

Results

Limitations and Interpretation

Ef cacy of Tocilizumab in Patients Hospitalized With COVID-19 (BACC Bay Tocilizumab Trial)6

Double-blind, placebo- controlled randomized trial in hospitalized patients with COVID-19 in the United States (n = 243)

Key Inclusion Criteria:

• Hospitalized with COVID-19 con rmed by a positive PCR or serum IgM test

• Moderate and severe COVID-19 with >2 of the following symptoms: fever >38°C, pulmonary in ltrates, need for oxygen to maintain saturation >92% and also 1 of the following: CRP ≥50 mg/L, D-dimer >1,000 ng/ mL, LDH ≥250 U/L, ferritin >500 ng/ mL
Interventions
2:1 Randomization:
• Tocilizumab 8 mg/kg once plus usual care; or
• Placebo plus usual care
Primary Endpoint:
• Time to intubation or death (if the patient died without intubation)
Key Secondary Endpoints:
• Clinical worsening
• Discontinuation of supplemental oxygen among patients receiving it at baseline

Number of Participants:

• mITT analysis: Tocilizumab (n = 161) and placebo (n = 81)

Participant Characteristics:

• Median age was 59.8 years (range 21.7–85.4 years).

• 58% of participants were men.

• 45% of participants were Hispanic or Latinx.

• 50% of participants had BMI ≥30; 49% had HTN, and 31% had diabetes.

• 80% of participants were hospitalized in non-ICU wards and receiving supplemental oxygen ≤6 L/min; 4% received high- ow oxygen; 16% required no supplemental oxygen.

• Median time from symptom onset to randomization was 9 days.

• Percentage of participants receiving concomitant medications:
• Glucocorticoids: 11% in tocilizumab arm vs. 6% in placebo arm
• RDV: 33% in tocilizumab arm vs. 29% in placebo arm.
Primary Outcomes:

• There was no evidence of a treatment difference (i.e., time to intubation or death) between tocilizumab and placebo (HR 0.83; 95% CI, 0.38–1.81; P = 0.64).

• By Day 28, 11% of the patients in the tocilizumab arm vs. 13% in the placebo arm had been intubated or had died.
Key Secondary Outcomes:

• By Day 28, 19% of patients in the tocilizumab arm vs. 17% in the placebo arm had experienced worsening of disease (HR 1.11; 95% CI, 0.59–2.10).

• The median time to discontinuation of oxygen was 5.0 days in the tocilizumab arm vs. 4.9 days in placebo arm (P = 0.69).

• Fewer serious infections occurred among participants in the tocilizumab arm than in the placebo arm (8.1% vs. 17.3%; P = 0.03).

Limitations:

• The relatively small sample size and low event rates resulted
in wide con dence intervals
for primary and secondary outcomes.

• Some patients received RDV, and a few patients received steroids.
Interpretation:

• In this study population, tocilizumab provided no bene t in preventing intubation or death (the primary outcome) or reducing the

risk of clinical worsening or time to discontinuation of supplemental oxygen (secondary outcomes).

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Tocilizumab Versus Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia (CORIMUNO-TOCI-1)7

Open-label, randomized clinical trial in hospitalized patients with COVID-19 in France (n = 131)

Key Inclusion Criteria:

• COVID-19 con rmed by positive PCR test and/or ndings/ abnormalities typical of COVID-19 on chest CT

• Severe disease/pneumonia, requiring ≥3 L oxygen
Key Exclusion Criteria:
• Receipt of high- ow oxygen or mechanical ventilation
Interventions
1:1 Randomization:

• Single dose of tocilizumab 8 mg/
kg on Day 1, possible second, xed dose of tocilizumab 400 mg on Day 3 per provider if oxygen requirement not decreased by >50%, plus usual care, or

• Usual care
Primary Endpoint:

• Scores >5 on the 10-point WHO Clinical Progression Scale on Day 4

• Survival without need of ventilation (including noninvasive ventilation) at Day 14
Key Secondary Endpoint:
• Overall survival by Day 28

Number of Participants:

• ITT analysis (n = 130): Tocilizumab (n = 63) and placebo (n = 67)

Participant Characteristics:

• Median age was 64 years.

• 68% of the participants were men.

• Diagnosis of COVID-19 was con rmed by PCR test in 90% of participants.

• Median time from symptom onset to randomization: 10 days

• Baseline corticosteroids use was balanced (received
by approximately 17% of participants in each arm) at randomization, but post randomization, more participants received corticosteroids in the control group (55%) than in the tocilizumab group (30%).
Primary Outcome:

• In the Bayesian analyses, evidence for the superiority of tocilizumab vs. usual care did not reach the prespeci ed threshold for the proportion of patients who died or needed high- ow oxygen, noninvasive ventilation, or IMV by Day 4 (19% of patients in tocilizumab arm vs. 28% in usual care arm), but did reach the threshold by Day 14 (24% of patients in tocilizumab arm vs. 36% in usual care arm (HR 0.58; 90% CrI, 0.33–1.00).

Secondary Outcomes:

• There was no difference in overall survival by Day 28 between tocilizumab arm and usual care arm (89% vs. 88%; adjusted HR 0.92; 95% CI, 0.33–2.53).

• SAEs occurred in 20 patients (32%) in the tocilizumab arm and 29 patients (43%) in the usual care arm (P = 0.21).

• There were fewer serious bacterial infections in the tocilizumab arm (2) than in the usual care arm (11).

Limitations:

• Not blinded

• Underpowered

• More patients received dexamethasone/corticosteroids in the usual care arm.
Interpretation:

• Among patients with severe COVID-19, tocilizumab led
to improved ventilator-free survival at Day 14 suggesting possible bene t, but the clinical implications are unclear as there was no difference in survival

for tocilizumab vs. usual care through Day 28.

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Study Design

Methods

Results

Limitations and Interpretation

Effect of Tocilizumab Versus Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia (RCT-TCZ-C19)8

Open-label RCT in hospitalized patients with COVID-19 in Italy (n = 126)

Key Inclusion Criteria:

• COVID-19 pneumonia con rmed by positive PCR test

• Acute respiratory failure (i.e., PaO2/ FiO2 200–300 mm Hg), fever, and/or a CRP ≥10 mg/dL and/or CRP level increased to at least twice admission value
Key Exclusion Criteria:
• Advanced age, multiple comorbidities, or any other condition precluding ICU-level care
Interventions
1:1 Randomization:
• 2 doses of tocilizumab 8 mg/kg (maximum of 800 mg, second dose after 12 hours), or
• Usual care
Primary Endpoint:

• Composite outcome de ned as entry into ICU with IMV, death from all-causes, or clinical aggravation (PaO2/FiO2 <150 mm Hg) within 14 days

Key Secondary Endpoint:

• Mortality at 30 days

Number of Participants:

• ITT analysis (n = 123): Tocilizumab (n = 60) and usual care (n = 63)

Participant Characteristics:

• Median age was 60 years.

• 61% of participants were men.

• Participants in usual care arm had lower CRP, IL-6, ferritin, and D-dimer levels and received more antivirals than participants in tocilizumab arm.
Primary Outcome:

• No difference in the composite primary outcome of entry into ICU with mechanical ventilation, all-cause death, or clinical deterioration (PaO2/FiO2 <150 mm Hg) within 14 days: Met by 17 participants (28.3%) in tocilizumab arm vs. 17 (27.0%) in usual care arm (rate ratio 1.05; 95% CI, 0.59–1.86; P = 0.87)

• ICU admissions: 10.0% of participants in tocilizumab arm vs. 7.9% in usual care arm (rate ratio 1.26; 95% CI, 0.41–3.91)

• Mortality at 14 days: 1.7% in tocilizumab arm vs. 1.6% in usual care arm (rate ratio 1.05; 95% CI, 0.07–16.4)
Key Secondary Outcomes:

• There was no difference in mortality at 30 days between tocilizumab arm (3.3%) and usual care arm (1.6%; rate ratio 2.10; 95% CI, 0.20–22.6).

• There were more AEs among the participants in tocilizumab arm (23.3%) than among those in usual care arm (11.1%). The reported AEs were mostly elevated ALT levels and reduced neutrophil counts.

Limitations:

• Not blinded

• Small sample size

• Mortality rate in the study population was signi cantly lower (2.4%) than in the general population in Italy (13.2%).9

• Because 14 patients in the control group (22%) received tocilizumab after they reached the primary endpoint, mortality outcomes are dif cult to interpret.

• There were some differences between the arms in baseline participant characteristics, including higher in ammatory markers in the tocilizumab arm.
Interpretation:

• This study demonstrated no evidence for a bene t
of tocilizumab in patients hospitalized with COVID-19 pneumonia.

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Study Design

Methods

Results

Limitations and Interpretation

Sarilumab in Hospitalized Patients With Severe or Critical COVID-1910

Multinational, double- blind, placebo- controlled, Phase 3 randomized trial in patients hospitalized with COVID-19 (n = 420)

Key Inclusion Criteria:

• Aged ≥18 years

• Laboratory-con rmed COVID-19 and clinical or radiographic evidence of pneumonia

• Severe or critical disease (i.e., receiving supplemental oxygen, including delivery by nasal cannula or high- ow device, noninvasive ventilation or invasive ventilation, or treatment in ICU)
Key Exclusion Criteria:

• Low probability of surviving or remaining at investigational site beyond 48 hours

• Dysfunction of ≥2 organ systems, or need for ECMO or renal replacement therapy at screening
Interventions
2:2:1 Randomization:
• Sarilumab IV 400 mg, or • Sarilumab IV 200 mg, or • Placebo
Primary Endpoint:
• Time from baseline to ≥2-point improvement in clinical status on a 7-point ordinal scale
Key Secondary Endpoint:
• Proportion of patients alive at Day 29

Number of Participants:

• mITT analysis (n = 416): Sarilumab 400 mg (n = 173), sarilumab 200 mg (n = 159), and placebo (n = 84)

Participant Characteristics:

• Median age was 59 years.

• 63% of participants were men.

• 77% of participants were White and 36% were Hispanic or Latino.

• 42% of participants had BMI ≥30.

• 43% of participants had HTN and 26% had type 2
diabetes.

• 61% of participants had severe disease and 39% had critical disease.

• 20% of participants received systemic corticosteroids before receiving their assigned intervention.
Primary Outcome:
• There was no difference in the median time to ≥2-point improvement in clinical status from baseline on the 7-point ordinal scale for either dose of sarilumab compared to placebo:
• 12 days for placebo vs. 10 days for sarilumab 200 mg (HR 1.03; 95% CI, 0.75–1.40) and 10 days for sarilumab 400 mg (HR 1.14; 95% CI, 0.84–1.54).
Key Secondary Outcome:
• There was no difference among the arms in proportion of patients who were alive at Day 29 (92% in placebo arm, 90% in sarilumab 200 mg arm, 92% in sarilumab 400 mg arm).

Limitations:

• Low rate of baseline corticosteroid use and varying rate of overall corticosteroid use during the study

• Moderate sample size with few participants in placebo arm
Interpretation:

• In hospitalized adults with severe or critical COVID-19, there
was no bene t of sarilumab
with respect to time to clinical improvement or mortality.

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Study Design

Methods

Results

Limitations and Interpretation

Tocilizumab Plus Standard Care Versus Standard Care in Patients With Moderate to Severe COVID-19-Associated Cytokine Release Syndrome (COVINTOC)11

Open-label, Phase
3 RCT in patients hospitalized with moderate to severe COVID-19 cytokine release syndrome in India

Key Inclusion Criteria:

• Aged ≥18 years

• SARS-CoV-2 infection con rmed by PCR test

• Moderate disease (de ned by respiratory rate 15–30 breaths/min, SpO2 90% to 94%) to severe disease (de ned by respiratory rate ≥30 breaths/min, SpO2 <90% on ambient air, ARDS, or septic shock)
Key Exclusion Criteria:

• Low probability of surviving beyond 24 hours

• Receipt of immunomodulatory drugs within previous 6 months

• Serious medical conditions per judgment of investigators
Interventions
1:1 Randomization:
• Tocilizumab 6 mg/kg (maximum dose 480 mg), second dose allowable if no improvement or worsening of clinical symptoms in next 7 days, or
• Usual care
Primary Endpoint:
• Proportion of patients with progression from moderate to severe disease or from severe disease to death by Day 14
Key Secondary Endpoints:
• Incidence of mechanical ventilation • Ventilator-free days

Number of Participants:

• mITT analysis (n = 179): Tocilizumab (n = 91) and usual care (n = 88)

Participant Characteristics:

• Median age was 55 years.

• 85% of participants were men.

• The mean BMI was 27.

• Approximately 40% of participants had HTN and 41% had type 2 diabetes.

• In the tocilizumab arm, 45% of participants had moderate disease and 55% had severe disease. In the usual care arm, 53% of participants had moderate disease and 47% had severe disease.

• 91% of participants received systemic corticosteroids during the study.
Primary Outcome:
• Overall, the percentage of patients with disease progression was 12.1% in tocilizumab arm and 18.2% in usual care arm.
Key Secondary Outcomes:

• There was no observed difference between the arms in incidence of mechanical ventilation or number of ventilator-free days.

• In post hoc analysis, the percentage of patients who had progressed from severe COVID-19 to death was 16% in tocilizumab arm and 34% in usual care arm (P = 0.04).

Limitations:

• Open-label study

• Underpowered

• Lower dose of tocilizumab than in other trials

Interpretation:

• There was no demonstrated bene t of tocilizumab in hospitalized adults with moderate to severe COVID-19.

Key: AE = adverse event; ALT = alanine transaminase; ARDS = acute respiratory distress syndrome; AST = aspartate aminotransferase; BMI = body mass index; BACC
= Boston Area COVID-19 Consortium; CRP = C-reactive protein; CT = computed tomography; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular ltration rate; EMPACTA = Evaluating Minority Patients With Actemra; HFNC = high- ow nasal cannula; HTN = hypertension; ICU = intensive care unit; IgM = immunoglobulin M; IL-6 = interleukin 6; IMV = invasive mechanical ventilation; ITT = intention to treat; IV = intravenous; LDH = lactate dehydrogenase; mITT = modi ed intention to treat; NIPPV = noninvasive positive-pressure ventilation; the Panel = the COVID-19 Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PCR = polymerase chain reaction; RCT = randomized controlled trial; RDV = remdesivir; RECOVERY = Randomized Evaluation of COVID-19 Therapy; REMAP-CAP = Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; SAE = serious adverse event; SOC = standard of care; SpO2 = saturation of oxygen; TB = tuberculosis; ULN = upper limit of normal; WHO = World Health Organization

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References

1. RECOVERY Collaborative Group, Horby PW, Pessoa-Amorim G, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021;preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.

2. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.

3. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631066.

4. Veiga VC, Prats J, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33472855.

5. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332779.

6. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333- 2344. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33085857.

7. Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32-40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080017.

8. Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24-31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080005.

9. Parr JB. Time to reassess tocilizumab’s role in COVID-19 pneumonia. JAMA Intern Med. 2021;181(1):12-15. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33079980.

10. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676590.

11. Soin AS, Kumar K, Choudhary NS, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID- 19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, Phase 3 trial. Lancet Respir Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676589.

          

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Kinase Inhibitors: Baricitinib and Other Janus Kinase Inhibitors, and Bruton’s Tyrosine Kinase Inhibitors
Last Updated: February 11, 2021

Janus Kinase Inhibitors

The kinase inhibitors are proposed as treatments for COVID-19 because they can prevent phosphorylation of key proteins involved in the signal transduction that leads to immune activation
and inflammation (e.g., the cellular response to proinflammatory cytokines such as interleukin [IL]-6).1 Janus kinase (JAK) inhibitors interfere with phosphorylation of signal transducer and activator of transcription (STAT) proteins2,3 that are involved in vital cellular functions, including signaling, growth, and survival.

Immunosuppression induced by this class of drugs could potentially reduce the inflammation and associated immunopathologies observed in patients with COVID-19. Additionally, JAK inhibitors, particularly baricitinib, have theoretical direct antiviral activity through interference with viral endocytosis, potentially preventing entry into and infection of susceptible cells.4

Recommendations

• There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized patients, when corticosteroids can be used.

• In the rare circumstance when corticosteroids cannot be used, the Panel recommends baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized, non-intubated patients who require oxygen supplementation (BIIa).

• The Panel recommends against the use of baricitinib without remdesivir, except in a clinical trial (AIII).

• There are insufficient data for the Panel to recommend either for or against the use of baricitinib in combination with corticosteroids for the treatment of COVID-19. Because both baricitinib and corticosteroids are potent immunosuppressants, there is potential for an additive risk of infection.

• The Panel recommends against the use of JAK inhibitors other than baricitinib for the treatment of COVID-19, except in a clinical trial (AIII).
Rationale
The Panel’s recommendations for the use of baricitinib are based on data from the Adaptive COVID-19 Treatment Trial 2 (ACTT-2), a multinational, randomized, placebo-controlled trial of baricitinib use in hospitalized patients with COVID-19 pneumonia (see below for a full description of the ACTT-2 data for baricitinib). Participants (n = 1,033) were randomized 1:1 to oral baricitinib 4 mg or placebo, for
up to 14 days, in combination with intravenous (IV) remdesivir, for up to 10 days. Participants who received baricitinib had a shorter time to clinical recovery than those who received placebo (median recovery time of 7 vs. 8 days, respectively). This treatment effect was most pronounced among those who required high-flow oxygen or non-invasive ventilation but were not on invasive mechanical ventilation. The difference in mortality between the treatment groups was not statistically significant.5
Corticosteroids have established efficacy in the treatment of severe and critical COVID-19 pneumonia (see the Therapeutic Management and Corticosteroids sections). The Panel’s recommendations for the use of baricitinib are based on data for the benefit of corticosteroids and the uncertain clinical impact of
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the modest difference in time to recovery between the placebo-treated and baricitinib-treated patients in the ACTT-2 trial. The Panel also considered the infrequent use of corticosteroids in the ACTT-2 trial, given that patients receiving corticosteroids for the treatment of COVID-19 at study entry were excluded.

On November 19, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).6

The issuance of an EUA does not constitute FDA approval. An EUA indicates that a product may be effective in treating a serious or life-threatening disease or condition. FDA approval occurs when a product has been determined to provide benefits that outweigh its known and potential risks for the intended population.

Monitoring, Adverse Effects, and Drug-Drug Interactions

Most of the data on adverse effects of JAK inhibitors refer to chronic use of the agents. Adverse effects include infections (typically respiratory and urinary tract infections) and the reactivation of herpes viruses. Additional toxicities include myelosuppression and transaminase elevations. In addition, there may be a slightly higher risk of thrombotic events and gastrointestinal perforation in patients who receive JAK inhibitors.

Complete blood count with differential, liver function tests, and kidney function tests should be obtained in all patients before baricitinib is administered and during treatment as clinically indicated. Screening for viral hepatitis and tuberculosis should be considered. Considering its immunosuppressive effects, all patients receiving baricitinib should also be monitored for new infections.

The ACTT-2 study evaluated oral baricitinib 4 mg once daily;5 however, the standard dosage of baricitinib for FDA-approved indications is 2 mg once daily. Baricitinib use is not recommended in patients with impaired hepatic or renal function (estimated GFR <60 mL/min/1.73 m2).7 There are limited clinical data on the use of baricitinib in combination with strong organic anion transporter 3 inhibitors, and, in general, coadministration is not advised.7,8

Considerations in Pregnancy

There is a paucity of data on the use of JAK inhibitors in pregnancy. As small molecule-drugs, JAK inhibitors are likely to pass through the placenta, and therefore fetal risk cannot be ruled out.9 Decisions about the administration of JAK inhibitors must include shared decision-making with the pregnant individual, considering potential maternal benefit and fetal risks. Factors that may weigh into the decision-making process include maternal COVID-19 severity, comorbidities, and gestational age. When the benefits outweigh the risks, use of JAK inhibitors may be considered.

Considerations in Children

An EUA has been issued for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or ECMO. The safety and efficacy of baricitinib or other JAK inhibitors has not been evaluated in pediatric patients with COVID-19, and data on the use of the drugs in children with other conditions are extremely limited. Thus, there are insufficient data to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized children when corticosteroids cannot be used. Use of JAK inhibitors other than baricitinib for the treatment of COVID-19 in pediatric patients is not recommended, except in a clinical trial.

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Baricitinib

Baricitinib is an oral JAK inhibitor that is selective for JAK1 and JAK2 and FDA approved for the treatment of rheumatoid arthritis.7 Baricitinib can modulate downstream inflammatory responses
via JAK1/JAK2 inhibition and has exhibited dose-dependent inhibition of IL-6-induced STAT3 phosphorylation.10 Baricitinib has postulated antiviral effects by blocking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from entering and infecting lung cells.11 Baricitinib reduced inflammation and lung pathology in macaques infected with SARS-CoV-2 but an antiviral effect was not confirmed.12

Clinical Data for COVID-19

The multicenter, randomized, double-blind ACTT-2 trial compared (1:1 allocation) oral baricitinib 4
mg daily (for up to 14 days or until hospital discharge) versus placebo, both given in combination with
IV remdesivir (for 10 days or until hospital discharge). The trial included 1,033 patients hospitalized
with moderate to severe COVID-19. The primary endpoint was time to recovery, which was defined as reaching Category 1 (not hospitalized, no limitations), Category 2 (not hospitalized, with limitations),
or Category 3 (hospitalized, no active medical problems) on an eight-category ordinal scale within
28 days of treatment initiation. Patients who were using a medication off-label as a specific treatment
for COVID-19, including corticosteroids, at study entry were excluded from the trial. In the overall cohort, the median time to recovery was shorter in the baricitinib plus remdesivir arm (7 days) than in
the placebo plus remdesivir arm (8 days) (rate ratio for recovery 1.16; 95% CI, 1.01–1.32; P = 0.03).
In subgroup analyses according to disease severity, the difference in time to recovery was greatest
among the participants who required high-flow oxygen or non-invasive ventilation (10 vs. 18 days for
the baricitinib and placebo recipients, respectively; rate ratio for recovery 1.51; 95% CI, 1.10–2.08). However, the treatment effect within this subgroup should be interpreted with caution given the relatively small sample size. Within the subgroup of patients on invasive mechanical ventilation or ECMO at study entry, it was not possible to estimate the median time to recovery within the first 28 days following treatment initiation, and there was no evidence of benefit with baricitinib use (rate ratio for recovery 1.08; 95% CI, 0.59–1.97). Improvement across ordinal categories at Day 15 was a key secondary endpoint, and again baricitinib demonstrated a significant benefit only in the subgroup of patients requiring high-flow oxygen or non-invasive ventilation (OR 2.3; 95% CI, 1.4–3.7). Mortality by 28 days was lower in the baricitinib arm than in the placebo arm, but the difference was not statistically significant (OR 0.65;
95% CI, 0.39–1.09). There was no evidence that the risk of serious adverse events or new infections was higher in the baricitinib arm than in the placebo arm (16% vs. 20% for adverse events and 6% vs. 11% for new infections in the baricitinib and placebo arms, respectively).5

Even though the use of corticosteroids for the treatment of COVID-19 was prohibited at study entry, the protocol allowed for the adjunctive use of corticosteroids at the discretion of the treating provider for the treatment of standard medical indications (e.g., asthma exacerbation, acute respiratory distress syndrome, chronic obstructive pulmonary disease). During the study, 10.9% of the patients in the baricitinib group and 12.9% in the placebo group were prescribed corticosteroids. Overall, the incidence of serious or non-serious infections was lower in the baricitinib group (30 patients [6%]) than in the placebo group (57 patients [11%]) (RD -5; 95% CI, -9 to -2). There were no statistically significant differences between the baricitinib and placebo arms in the frequency of pulmonary embolism (5 vs. 2 patients, respectively) or deep vein thrombosis (11 vs. 9 patients, respectively).

Preliminary results of this study suggest that baricitinib improves time to recovery in patients who require supplemental oxygen but not invasive mechanical ventilation. However, a key limitation of the study is the inability to evaluate the treatment effect of baricitinib in addition to, or in comparison to, corticosteroids used as standard treatment for severe or critical COVID-19 pneumonia.

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Clinical Trials

Please check ClinicalTrials.gov for the latest information on studies of baricitinib and COVID-19. Ruxolitinib

Ruxolitinib is an oral JAK inhibitor selective for JAK1 and JAK2 that is currently approved for myelofibrosis, polycythemia vera, and acute graft-versus-host disease.13 Like baricitinib, it can modulate downstream inflammatory responses via JAK1/JAK2 inhibition and has exhibited dose-dependent inhibition of IL-6-induced STAT3 phosphorylation.10 Ruxolitinib also has postulated antiviral effects by blocking SARS-CoV-2 from entering and infecting lung cells.11

Clinical Data for COVID-19

A small, single-blind, randomized, controlled Phase 2 trial in patients with COVID-19 in China compared ruxolitinib 5 mg orally twice daily (n = 20) with placebo (administered as vitamin C 100 mg; n = 21), both given in combination with SOC therapy. The median age of the patients was 63 years. There were no significant demographic differences between the two arms. Treatment with ruxolitinib was associated with a nonsignificant reduction in the median time to clinical improvement (12 days for ruxolitinib vs. 15 days for placebo; P = 0.15), defined as a two-point improvement on a seven-category ordinal scale or as hospital discharge. There was no difference between the groups in the median time
to discharge (17 days for ruxolitinib vs. 16 days for placebo; P = 0.94). More patients in the ruxolitinib group than in the placebo group had radiographic improvement on computed tomography scans of the chest at Day 14 (90% for ruxolitinib vs. 61.9% for placebo; P = 0.05) and a shorter time to recovery from initial lymphopenia (5 days for ruxolitinib vs. 8 days for placebo; P = 0.03), when it was present. The use of ruxolitinib was not associated with an increased risk of adverse events or mortality (no deaths in the ruxolitinib arm vs. three deaths [14% of patients] in the control arm). Despite the theoretical antiviral properties of JAK inhibitors, there was no significant difference in the time to viral clearance among the patients who had detectable viral loads at the time of randomization to ruxolitinib treatment (n = 8) or placebo (n = 9). Limitations of this study include the small sample size, the exclusion of ventilated patients at study entry, and the concomitant use of antivirals and steroids by 70% of the patients.14

Clinical Trials

Please check ClinicalTrials.gov for the latest information on studies of ruxolitinib and COVID-19. Tofacitinib

Tofacitinib is the prototypical JAK inhibitor, predominantly selective for JAK1 and JAK3, with modest activity against JAK2, and, as such, can block signaling from gamma-chain cytokines (e.g., IL-2, IL-4) and gp 130 proteins (e.g., IL-6, IL-11, interferons). It is an oral agent first approved by the FDA for the treatment of rheumatoid arthritis and has been shown to decrease levels of IL-6 in patients with this disease.15 Tofacitinib is also FDA approved for the treatment of psoriatic arthritis, juvenile idiopathic arthritis, and ulcerative colitis.16

Clinical Data for COVID-19

There are no clinical data on the use of tofacitinib to treat COVID-19.

Considerations in Pregnancy

Pregnancy registries provide some outcome data on tofacitinib used during pregnancy for other conditions (e.g., ulcerative colitis, rheumatoid arthritis, psoriasis). Among the 33 cases reported, pregnancy outcomes were similar to those among the general pregnant population.17-19

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Clinical Trials

Please check ClinicalTrials.gov for the latest information on studies of tofacitinib and COVID-19. Bruton’s Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.

Recommendation

• The Panel recommends against the use of BTK inhibitors for the treatment of COVID-19, except in a clinical trial (AIII).

Acalabrutinib

Acalabrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat B-cell malignancies (i.e., chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma). It has a better toxicity profile than first-generation BTK inhibitors (e.g., ibrutinib) because of less off-target activity for other kinases.20 Acalabrutinib is proposed for use in patients with COVID-19 because it can modulate signaling that promotes inflammation.

Clinical Data for COVID-19

Data regarding acalabrutinib are limited to the results from a retrospective case series of 19 patients with severe COVID-19.21 Evaluation of the data to discern any clinical benefit is limited by the study’s small sample size and lack of a control group.

Clinical Trials

Please check ClinicalTrials.gov for the latest information on studies of acalabrutinib and COVID-19. Ibrutinib

Ibrutinib is a first-generation BTK inhibitor that is FDA approved to treat various B-cell malignancies22 and to prevent chronic graft-versus-host disease in stem cell transplant recipients.23 Based on results from a small case series, ibrutinib has been theorized to reduce inflammation and protect against ensuing lung injury in patients with COVID-19.24

Clinical Data for COVID-19

Data regarding ibrutinib are limited to those from an uncontrolled, retrospective case series of six patients with COVID-19 who were receiving the drug for a condition other than COVID-19.24 Evaluation of the data for any clinical benefit is limited by the series’ small sample size and lack of a control group.

Clinical Trials

Please check ClinicalTrials.gov for the latest information on studies of ibrutinib and COVID-19. Zanubrutinib

Zanubrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat mantle cell lymphoma.25 It has been shown to have fewer toxicities than first-generation BTK inhibitors (e.g., ibrutinib) because of less off-target activity for other kinases.26 Zanubrutinib is proposed to benefit patients with COVID-19 by modulating signaling that promotes inflammation.

Clinical Data for COVID-19

There are no clinical data on the use of zanubrutinib to treat COVID-19.

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Clinical Trials

Please check ClinicalTrials.gov for the latest information on studies of zanubrutinib and COVID-19. Adverse Effects and Monitoring

Hemorrhage and cardiac arrhythmia have occurred in patients who received BTK inhibitors.

Considerations in Pregnancy

There is a paucity of data on human pregnancy and BTK inhibitor use. In animal studies, acalabrutinib and ibrutinib in doses exceeding the therapeutic human dose were associated with interference
with embryofetal development.22,27 Based on these data, use of BTK inhibitors that occurs during organogenesis may be associated with fetal malformations. The impact of use later in pregnancy is unknown. Risks of use should be balanced against potential benefits.

Considerations in Children

The safety and efficacy of BTK inhibitors have not been evaluated in pediatric patients with COVID-19, and data on the use of the drugs in children with other conditions are extremely limited. Use of BTK inhibitors for the treatment of COVID-19 in pediatric patients is not recommended, except in a clinical trial.

References

1. Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32222466.

2. Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK) activation. Biochem J. 2014;462(1):1-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25057888.

3. Bousoik E, Montazeri Aliabadi H. “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol. 2018;8:287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30109213.

4. Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400-402. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32113509.

5. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2020;Published online ahead of print. Available at: https://pubmed.ncbi.nlm.nih.gov/33306283/.

6. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of baricitinib. 2020. Available at: https://www.fda.gov/media/143823/download. Accessed December 11, 2020.

7. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207924s001lbl.pdf.

8. Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter-mediated drug-drug interactions for baricitinib. Clin Transl Sci. 2017;10(6):509-519. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28749581.

9. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529-556. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32090480.

10. McInnes IB, Byers NL, Higgs RE, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31375130.

11. Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32032529.

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12. Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278358.

13. Ruxolitinib (JAKAFI) [package insert]. 2020. Available at: https://www.jakafi.com/pdf/prescribing-information.pdf. Accessed: May 28, 2020.

14. Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.

15. Migita K, Izumi Y, Jiuchi Y, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208-214. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24665995.

16. Tofacitinib (Xeljanz) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203214s024,208246s010lbl.pdf.

17. Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016;39(8):755-762. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27282428.

18. Mahadevan U, Dubinsky MC, Su C, et al. Outcomes of pregnancies with maternal/paternal exposure in the tofacitinib safety databases for ulcerative colitis. Inflamm Bowel Dis. 2018;24(12):2494-2500. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29982686.

19. Wieringa JW, van der Woude CJ. Effect of biologicals and JAK inhibitors during pregnancy on health- related outcomes in children of women with inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 2020;44-45:101665. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32359679.

20. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31043832.

21. Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol. 2020;5(48). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32503877.

22. Ibrutinib (Imbruvica) [package insert]. Food and Drug Administration. 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf.

23. Food and Drug Administration. FDA expands ibrutinib indications to chronic GVHD. 2017. Available at:

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ibrutinib-indications-chronic- gvhd. Accessed February 1, 2021.

24. Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients. Blood. 2020;135(21):1912-1915. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32302379.

25. Zanubrutinib (Brukinsa) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213217s000lbl.pdf.

26. Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in
patients with relapsed/refractory B-cell malignancies: initial report of a Phase 1 first-in-human trial. Blood. 2015;126(23):832. Available at: https://ashpublications.org/blood/article/126/23/832/136525/The-BTK-Inhibitor-Bgb-3111-Is-Safe-Tolerable- and.

27. Acalabrutinib (Calquence) [package insert]. Food and Drug Administration. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf.

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Table 4c. Characteristics of Immunomodulators Under Evaluation for the

Treatment of COVID-19

Last Updated: April 21, 2021

• The information in this table is derived from data on the use of these drugs for FDA-approved indications or in investigational trials, and it is supplemented with data on their use in patients with COVID-19, when available.

• For dose modifications for patients with organ failure or those who require extracorporeal devices, please refer to product labels, when available.

• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the treatment of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.

• The potential additive, antagonistic, or synergistic effects and the safety of using certain combination therapies for the treatment of COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.

• For the Panel’s recommendations for the drugs listed in this table, please refer to the drug-specific sections of the Guidelines and to Therapeutic Management of Adults With COVID-19.

  

Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Colchicine

Colchicine

Dose for COVID-19 in Clinical Trial

COLCORONA:

• Colchicine 0.5 mg twice daily for 3 days then once daily for 27 days

• Diarrhea

• Nausea

• Vomiting

• Cramping

• Abdominal pain

• Bloating

• Loss of appetite

• Neuromyotoxicity (rare)1

• Blood dyscrasias (rare)

• CBC

• Renal function

• Hepatic function

• P-gp and CYP3A4 substrate

• The risk of myopathy may be increased with the concomitant
use of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by P-gp and CYP3A4 pathways.

• Fatal colchicine toxicity has been reported in individuals with renal
or hepatic impairment who used colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.

• Colchicine should be avoided in patients with severe renal insuf ciency, and those with moderate renal insuf ciency should be monitored for AEs.

• A list of clinical trials is available: Colchicine

Availability:

• COLCORONA used 0.5 mg tablets for dosing; in the United States, colchicine is available as 0.6 mg tablets.



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Corticosteroids

Dexamethasone

Dose for COVID-19:

• Dexamethasone 6 mg IV or PO once daily, for up to 10 days or until hospital discharge, whichever comes rst2

• Hyperglycemia

• Secondary infections

• Reactivation of latent infections (e.g., HBV, HSV, strongyloidiasis, TB)

• Psychiatric disturbances

• Avascular necrosis

• Adrenal insuf ciency

• Increased blood pressure

• Peripheral edema
• Myopathy (particularly if used with neuromuscular blocking agents)

• Blood glucose

• Blood pressure

• Signs and symptoms of new infection

• When initiating dexamethasone, consider appropriate screening and treatment to
reduce the risk
of Strongyloides hyperinfection in patients at high risk of strongyloidiasis or fulminant reactivations of HBV.3-5

• Moderate CYP3A4 inducer

• CYP3A4 substrate

• Although coadministration
of RDV and dexamethasone has not been formally studied, a clinically signi cant PK interaction is not predicted (Gilead, written communication, August 2020).

• If dexamethasone
is not available, an alternative corticosteroid (e.g., prednisone, methylprednisolone, hydrocortisone) can be used.

• The approximate total daily dose equivalencies for these glucocorticoids to dexamethasone 6
mg (PO or IV) are: prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg.

• A list of clinical trials is available: Dexamethasone

Fluvoxamine

Fluvoxamine

Dose for COVID-19 in Clinical Trials:

• Various dosing regimens used

• Nausea
• Diarrhea
• Dyspepsia
• Asthenia
• Insomnia
• Somnolence
• Sweating
• Suicidal ideation (rare)

• Assess for drug interactions.

• Hepatic function

• Monitor for withdrawal symptoms when tapering dose.

• Fluvoxamine is a CYP2D6 substrate.

• Fluvoxamine inhibits
several CYP450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, CYP2C19, CYP2D6).

• Coadministration of tizanidine, thioridazine, alosetron, or pimozide with uvoxamine is contraindicated.

• Fluvoxamine may enhance anticoagulant effects of antiplatelets and anticoagulants; consider additional monitoring when these drugs are used concomitantly with uvoxamine.

• The use of MAOIs concomitantly with uvoxamine or within 14 days of treatment with uvoxamine is contraindicated.

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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Fluvoxamine, continued

• A list of clinical trials is available: Fluvoxamine

Interferons

Interferon Alfa

Peg-IFN Alfa-2a

Dose for MERS:

• Peg-IFN alfa-2a 180 μg SQ once weekly for 2 weeks6,7

IFN Alfa-2b

Dose for COVID-19 in Clinical Trials:

• Nebulized IFN alfa-2b 5 million international units twice daily (no duration listed in the study methods)8

• Flu-like symptoms (e.g., fever, fatigue, myalgia)9

• Injection site reactions

• Liver function abnormalities

• Decreased blood counts

• Worsening depression

• Insomnia

• Irritability

• Nausea

• Vomiting

• HTN

• Induction of autoimmunity

• CBC with differential

• Liver enzymes; avoid if Child-Pugh Score >6

• Depression, psychiatric symptoms

• Reduce dose in patients with CrCl <30 mL/min.

• Low potential for drug-drug interactions

• Inhibition of CYP1A2

• For COVID-19, IFN
alfa has primarily been used as nebulization and usually as part of a combination regimen.

• Use with caution with other hepatotoxic agents.

• Reduce dose if ALT >5 times ULN; discontinue if bilirubin level also increases.

• Reduce dose or discontinue if neutropenia or thrombocytopenia occur.

• A list of clinical trials is available: Interferon
Availability:
• Neither nebulized IFN alfa-2b nor IFN alfa-1b are FDA-approved for use in the United States.



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Interferons, continued

Interferon Beta

IFN Beta-1a

Dose for MERS:

• IFN beta-1a 44 mcg SQ 3 times weekly7

Dose for COVID-19:

• Dose and duration unknown

IFN Beta-1b

Dose for COVID-19:

• IFN beta-1b 8 million international units SQ every other day, up to 7 days total10

• Flu-like symptoms (e.g., fever, fatigue, myalgia)11

• Leukopenia, neutropenia, thrombocytopenia, lymphopenia

• Liver function abnormalities (ALT > AST)

• Injection site reactions

• Headache

• Hypertonia

• Pain

• Rash

• Worsening depression

• Induction of autoimmunity

• Liver enzymes

• CBC with differential

• Worsening CHF

• Depression, suicidal ideation

• Low potential for drug-drug interactions

• Use with caution with other hepatotoxic agents.

• Reduce dose if ALT >5 times ULN.

• A list of clinical trials is available: Interferon
Availability:
• Several products are available in the United States; product doses differ.
IFN Beta-1a Products:
• Avonex, Rebif
IFN Beta-1b Products:
• Betaseron, Extavia



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Interleukin-1 Inhibitor

Anakinra

Dose for Rheumatoid Arthritis:

• Anakinra 100 mg SQ once daily

Dose for COVID-19:

• Dose and duration vary by study

• Has also been used as IV infusion

• Neutropenia (particularly with concomitant use
of other agents that can cause neutropenia)

• Anaphylaxis

• Headache

• Nausea

• Diarrhea

• Sinusitis

• Arthralgia

• Flu-like symptoms

• Abdominal pain

• Injection site reactions

• Liver enzyme elevations

• CBC with differential

• Renal function (reduce dose in patients with CrCl <30 mL/min)

• Liver enzymes

• Use with TNF-blocking agents is not recommended due to increased risk of infection.

• A list of clinical trials is available: Anakinra



Interleukin-6 Inhibitors

Anti-Interleukin-6 Receptor Monoclonal Antibodies

Sarilumab12

Dose for COVID-19 in Clinical Trial (See ClinicalTrials.gov Identi er NCT04315298):

• Sarilumab 400 mg IV (single dose)13



• Neutropenia, thrombocytopenia

• GI perforation

• HSR

• Increased liver enzymes

• HBV reactivation

• Infusion-related reaction

• Monitor for HSR.

• Monitor for infusion reactions.

• Neutrophils

• Platelets

• Liver enzymes

• Elevated IL-6 may downregulate CYP enzymes; use of sarilumab may lead to increased metabolism
of drugs that are CYP450 substrates.

• Effects on CYP450 may persist for weeks after therapy.

• Treatment with sarilumab may
mask signs of acute in ammation or infection (i.e., by suppressing fever and CRP levels).

• A list of clinical trials is available: Sarilumab
Availability:
• Sarilumab for IV administration is not an approved formulation in the United States.



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Interleukin-6 Inhibitors, continued

Anti-Interleukin-6 Receptor Monoclonal Antibodies, continued

Tocilizumab14

Dose for COVID-19 in Clinical Trial:

• Single dose of tocilizumab 8 mg/kg actual body weight IV

• Dose should not exceed tocilizumab 800 mg.

• Administer in combination with dexamethasone.

• In clinical trials, some patients received a second dose of tocilizumab at the discretion of treating physicians; however, there are insuf cient data to determine which patients, if any, would bene t from an additional dose of the drug.

• Infusion-related reaction

• HSR

• GI perforation

• Hepatotoxicity

• Treatment-related changes on laboratory tests for neutrophils, platelets, lipids, and liver enzymes

• HBV reactivation

• Monitor for HSR.

• Monitor for infusion reactions.

• Neutrophils

• Platelets

• Liver enzymes

• Cases of severe
and disseminated strongyloidiasis have been reported with the use of tocilizumab and corticosteroids in patients with COVID-19.15,16 Prophylactic treatment with ivermectin should be considered for persons who are from areas where strongyloidiasis is endemic.3

• Elevated IL-6 may downregulate CYP enzymes; use of tocilizumab may lead to increased metabolism of drugs that are CYP450 substrates.

• Effects on CYP450 may persist for weeks after therapy.

• Tocilizumab use should be avoided in patients who are signi cantly immunocompromised. The safety of using tocilizumab plus

a corticosteroid in immunocompromised patients is unknown.

• May mask signs of acute in ammation
or infection (i.e., by suppressing fever and CRP levels).

• The SQ formulation of tocilizumab is not intended for IV administration.

• A list of clinical trials is available: Tocilizumab

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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Interleukin-6 Inhibitors, continued

Anti-Interleukin-6 Monoclonal Antibody

Siltuximab

Dose for Multicentric Castleman Disease:

• Siltuximab 11 mg/kg administered over 1 hour by IV infusion every 3 weeks17

Dose for COVID-19:

• Dose and duration unknown

• Infusion-related reaction

• HSR

• GI perforation

• Neutropenia

• HTN

• Dizziness

• Rash

• Pruritus

• Hyperuricemia

• Monitor for HSR.

• Monitor for infusion reactions.

• Neutrophils

• Elevated IL-6 may downregulate CYP enzymes; use of siltuximab may lead to increased metabolism of drugs that are CYP450 substrates.

• Effects on CYP450 may persist for weeks after therapy.

• May mask signs of acute in ammation
or infection (i.e., by suppressing fever and CRP levels).

• A list of clinical trials is available: Siltuximab



Kinase Inhibitors

Bruton’s Tyrosine Kinase Inhibitors

Acalabrutinib

Dose for FDA-Approved Indications:

• Acalabrutinib 100 mg PO every 12 hours

Dose for COVID-19:

• Dose and duration unknown

• Hemorrhage

• Cytopenias (neutropenia, anemia, thrombocytopenia, lymphopenia)

• Atrial brillation and utter

• Infection

• Headache

• Diarrhea

• Fatigue

• Myalgia

• CBC with differential

• Signs and symptoms of bleeding (particularly when coadministered with anticoagulant or antiplatelet therapy)

• Monitor for cardiac arrhythmias.

• Monitor for new infections.

• Avoid concomitant use with strong CYP3A inhibitors or inducers.

• Dose reduction may be necessary with moderate CYP3A4 inhibitors.

• Avoid concomitant PPI use.

• H2-receptor antagonist should be administered 2 hours after acalabrutinib.

• Avoid use in patients with severe hepatic impairment.

• Patients with underlying cardiac risk factors, hypertension, or acute infections may be predisposed to atrial brillation.

• A list of clinical trials is available: Acalabrutinib



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Kinase Inhibitors, contined

Bruton’s Tyrosine Kinase Inhibitors, continued

Ibrutinib

Dose for FDA-Approved Indications:

• Ibrutinib 420 mg or 560 mg PO once daily

Dose for COVID-19:

• Dose and duration unknown

• Hemorrhage

• Cardiac arrhythmias

• Serious infections

• Cytopenias (thrombocytopenia, neutropenia, anemia)

• HTN

• Diarrhea

• Musculoskeletal pain

• Rash

• CBC with differential

• Blood pressure

• Signs and symptoms of bleeding (particularly when coadministered with anticoagulant or antiplatelet therapy)

• Monitor for cardiac arrhythmias.

• Monitor for new infections.

• Avoid concomitant use with strong CYP3A inhibitors or inducers.

• Dose reduction may be necessary with moderate CYP3A4 inhibitors.

• Avoid use in patients with severe baseline hepatic impairment. Dose modi cations required in patients with mild or moderate hepatic impairment.

• Patients with underlying cardiac risk factors, HTN, or acute infections may be predisposed to cardiac arrhythmias.

• A list of clinical trials is available: Ibrutinib

Zanubrutinib

Dose for FDA-Approved Indications:

• Zanubrutinib 160 mg PO twice daily or 320 mg PO once daily

Dose for COVID-19:

• Dose and duration unknown

• Hemorrhage

• Cytopenias (neutropenia, thrombocytopenia, anemia, leukopenia)

• Atrial brillation and utter

• Infection

• Rash

• Bruising

• Diarrhea

• Cough

• Musculoskeletal pain

• CBC with differential

• Signs and symptoms of bleeding

• Monitor for cardiac arrhythmias.

• Monitor for new infections.

• Avoid concomitant use with moderate or strong CYP3A inducers.

• Dose reduction required with moderate and strong CYP3A4 inhibitors.

• Dose reduction required in patients with severe hepatic impairment.

• A list of clinical trials is available: Zanubrutinib



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Janus Kinase Inhibitors

Baricitinib18

Dose for Rheumatoid Arthritis:

Adults:

• Baricitinib 2 mg PO once daily

Dose for COVID-19:19

Adults:

• Baricitinib 4 mg PO once daily for 14 days or until hospital discharge

Children:

• Limited data are available. Dose per the FDA EUA:

• Aged ≥9 years: Baricitinib 4 mg PO once daily for 14 days or until hospital discharge

• Aged ≥2 years to <9 years: Baricitinib 2 mg PO once daily for 14 days or until hospital discharge

• See full prescribing information for dosing recommendations in patients with renal or hepatic impairment.18

• Lymphoma and other malignancies

• Thrombosis

• GI perforation

• Treatment-
related changes
in lymphocytes, neutrophils, Hgb, liver enzymes

• HSV reactivation

• Herpes zoster

• CBC with differential

• Renal function

• Liver enzymes

• Monitor for new infections.

• Dose modi cation is recommended when concurrently administering a strong OAT3 inhibitor.

• Avoid concomitant administration of live vaccines.

• Baricitinib is not recommended for patients with severe hepatic or renal impairment.

• A list of clinical trials is available: Baricitinib

Availability:

• Baricitinib is available through an FDA EUA. The EUA allows for
the use of baricitinib, in combination with RDV, for the treatment of COVID-19 for hospitalized adults and pediatric patients aged ≥2 years who require supplemental oxygen, IMV, or ECMO.19



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Janus Kinase Inhibitors, continued

Ruxolitinib

Dose for FDA-Approved Indications:

• Ruxolitinib 5 mg–20 mg PO twice daily

Dose for COVID-19 in Clinical Trials:

• Ruxolitinib 5 mg–20 mg PO twice daily, for 14 days

• Thrombocytopenia

• Anemia

• Neutropenia

• Liver enzyme elevations

• Risk of infection

• Dizziness

• Headache

• Diarrhea

• CPK elevation

• Herpes zoster

• CBC with differential

• Liver enzymes

• Monitor for new infections.

• Dose modi cations required when administered with strong CYP3A4 inhibitors.

• Avoid use with doses of uconazole >200 mg.

• Dose modi cation may be required
in patients with hepatic impairment, moderate or severe renal impairment, or thrombocytopenia.

• A list of clinical trials is available: Ruxolitinib



Tofacitinib

Dose for FDA-Approved Indications:

• Tofacitinib 5 mg PO twice daily for rheumatoid and psoriatic arthritis

• Tofacitinib 10 mg PO twice daily for ulcerative colitis
Dose for COVID-19:
• Dose and duration unknown; a
planned COVID-19 clinical trial
will evaluate tofacitinib 10 mg twice daily for 14 days.



• Thrombotic events (pulmonary embolism, DVT, arterial thrombosis)

• Anemia

• Risk of infection

• GI perforation

• Diarrhea

• Headache

• Herpes zoster

• Lipid elevations

• Liver enzyme elevations

• Lymphoma and other malignancies

• CBC with differential

• Liver enzymes

• Monitor for new infections.

• Dose modi cations required when administered with strong CYP3A4 inhibitors or when used with a moderate CYP3A4 inhibitor that is coadministered with a strong CYP2C19 inhibitor.

• Avoid administration of live vaccines.

• Avoid use in patients with ALC <500 cells/ mm3, ANC <1,000 cells/ mm3, or Hgb <9 grams/ dL.

• Dose modi cation may be required in patients with moderate or severe renal impairment or moderate hepatic impairment.

• A list of clinical trials is available: Tofacitinib



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Drug Name

Dosing Regimen

There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.

Adverse Effects

Monitoring Parameters

Drug-Drug Interaction Potential

Comments and Links to Clinical Trials

Non-SARS-CoV-2 Speci c Immunoglobulin

Non-SARS- CoV-2 Speci c Immunoglobulin

• Dose varies based on indication and formulation.

• Allergic reactions, including anaphylaxis

• Renal failure

• Thrombotic events

• Aseptic meningitis syndrome

• Hemolysis

• TRALI

• Transmission of infectious pathogens

• AEs may vary by formulation.

• AEs may be increased with high-dose, rapid infusion, or in patients with underlying conditions.

• Monitor for transfusion- related reactions.

• Monitor vital signs at baseline and during and after infusion.

• Discontinue if renal function deteriorates during treatment.

• IVIG may interfere with immune response to certain vaccines.

• A list of clinical trials is available: Intravenous Immunoglobulin

 

Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CBC
= complete blood count; CHF = congestive heart failure; COLCORONA = Colchicine Coronavirus SARS-CoV2 Trial; CPK = creatine phosphokinase; CrCl = creatinine clearance; CRP = C-reactive protein; CYP = cytochrome P; DVT = deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI = gastrointestinal; HBV = hepatitis B; Hgb = hemoglobin; HSR = hypersensitivity reaction; HSV = herpes simplex virus; HTN = hypertension; IFN = interferon; IL = interleukin; IMV = invasive mechanical ventilation; IV = intravenous; IVIG = intravenous immunoglobulin; MAOI = monoamine oxidase inhibitor; MERS = Middle East respiratory syndrome; OAT = organic anion transporter; the Panel = the COVID-19 Treatment Guidelines Panel; Peg-IFN = pegylated interferon; P-gp= P-glycoprotein; PK = pharmacokinetic; PO = orally; PPI = proton pump inhibitor; RDV = remdesivir; SQ = subcutaneous; TB = tuberculosis; TNF = tumor necrosis factor; TRALI = transfusion-related acute lung injury; ULN = upper limit of normal

References

1. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2009/022351lbl.pdf.

2. Randomised Evaluation of COVID-19 Therapy (RECOVERY). Low-cost dexamethasone reduces death by up to one third in hospitalised patients with

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severe respiratory complications of COVID-19. 2020. Available at: https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up- to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19. Accessed February 9, 2021.

3. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.

4. Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic HBV infection. Hepatol Res. 2020;50(11):1211-1221. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761993.

5. Centers for Disease Control and Prevention. Parasites—strongyloides: resources for health professionals. 2020. Available at: https://www.cdc.gov/ parasites/strongyloides/health_professionals/index.html. Accessed April 8, 2021.

6. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25278221.

7. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015;70(7):2129-2132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25900158.

8. Zhou Q, Chen V, Shannon CP, et al. Interferon-alpha2b treatment for COVID-19. Front Immunol. 2020;11:1061. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32574262.

9. Peginterferon alfa-2a (Pegasys) [package insert]. Food and Drug Administration. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103964s5270lbl.pdf.

10. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial. Lancet. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.

11. Interferon beta-1a (Rebif) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103780s5204lbl.pdf.

12. Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761037s001lbl.pdf.

13. Regeneron and Sanofi provide update on U.S. Phase 2/3 adaptive-designed trial of KEVZARA® (sarilumab) in hospitalized COVID-19 patients. News release. Regeneron. 2020. Available at: https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-us- phase-23-adaptive. Accessed: April 8, 2021.

14. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125276s127,125472s040lbl.pdf.

15. Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020;103(4):1590- 1592. Available at: https://pubmed.ncbi.nlm.nih.gov/32830642/.

16. Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32910321.

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17. Siltuximab (Sylvant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125496s018lbl.pdf.

18. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207924s001lbl.pdf.

19. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of baricitinib. 2020. Available at: https://www.fda.gov/media/143823/download.

  

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Antithrombotic Therapy in Patients with COVID-19

Last Updated: February 11, 2021



Summary Recommendations

Laboratory Testing

• In nonhospitalized patients with COVID-19, there are currently no data to support the measurement of coagulation markers (e.g., D-dimers, prothrombin time, platelet count, brinogen) (AIII).

• In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly measured, although there are currently insuf cient data to recommend either for or against using this data to guide management decisions.
Chronic Anticoagulant and Antiplatelet Therapy
• Patients who are receiving anticoagulant or antiplatelet therapies for underlying conditions should continue these medications if they receive a diagnosis of COVID-19 (AIII).
Venous Thromboembolism Prophylaxis and Screening

• For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the prevention of venous thromboembolism (VTE) or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIII).

• Hospitalized nonpregnant adults with COVID-19 should receive prophylactic dose anticoagulation (AIII) (see the recommendations for pregnant individuals below). Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19 (AIII).

• There are currently insuf cient data to recommend either for or against the use of thrombolytics or higher than the prophylactic dose of anticoagulation for VTE prophylaxis in hospitalized COVID-19 patients outside of a clinical trial.

• Hospitalized patients with COVID-19 should not routinely be discharged from the hospital while on VTE prophylaxis (AIII). Continuing anticoagulation with a Food and Drug Administration-approved regimen for extended VTE prophylaxis after hospital discharge can be considered for patients who are at low risk for bleeding and high risk for VTE, as per the protocols for patients without COVID-19 (see details on de ning at-risk patients below) (BI).

• There are currently insuf cient data to recommend either for or against routine deep vein thrombosis screening in COVID-19 patients without signs or symptoms of VTE, regardless of the status of their coagulation markers.

• For hospitalized COVID-19 patients who experience rapid deterioration of pulmonary, cardiac, or neurological function, or of sudden, localized loss of peripheral perfusion, the possibility of thromboembolic disease should be evaluated (AIII).
Hospitalized Children With COVID-19
• For hospitalized children with COVID-19, indications for VTE prophylaxis should be the same as those for children without COVID-19 (BIII).
Treatment

• When diagnostic imaging is not possible, patients with COVID-19 who experience an incident thromboembolic event or who are highly suspected to have thromboembolic disease should be managed with therapeutic doses of anticoagulant therapy (AIII).

• Patients with COVID-19 who require extracorporeal membrane oxygenation or continuous renal replacement therapy or who have thrombosis of catheters or extracorporeal lters should be treated with antithrombotic therapy as per the standard institutional protocols for those without COVID-19 (AIII).
Special Considerations During Pregnancy and Lactation

• If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, this therapy should be continued (AIII).

• For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is recommended unless contraindicated (see below) (BIII).

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• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not recommended for pregnant patients (AIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be individualized, considering concomitant VTE risk factors.

• Anticoagulation therapy use during labor and delivery requires specialized care and planning. It should be managed in pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions that require anticoagulation in pregnancy (AIII).

• Unfractionated heparin, low molecular weight heparin, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the newborn; therefore, they can be used by breastfeeding individuals with or without COVID-19 who require VTE prophylaxis or treatment (AIII). In contrast, use of direct-acting oral anticoagulants during pregnancy is not routinely recommended due to lack of safety data (AIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion

Association Between COVID-19 and Thromboembolism

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting syndrome, COVID-19, have been associated with inflammation and a prothrombotic state, with increases in fibrin, fibrin degradation products, fibrinogen, and D-dimers.1,2 In some studies, elevations in these markers have been associated with worse clinical outcomes.3,4

A number of studies have reported varying incidences of venous thromboembolism (VTE) in patients with COVID-19. A meta-analysis of studies in hospitalized patients with COVID-19 found an overall VTE prevalence of 14.1% (95% CI, 11.6–16.9).5 The VTE prevalence was higher in studies that used ultrasound screening (40.3%; 95% CI, 27.0–54.3) than in studies that did not (9.5%; 95% CI, 7.5–11.7). In randomized controlled trials conducted prior to the COVID-19 pandemic, the incidence of VTE

in non-COVID-19 hospitalized patients who received VTE prophylaxis ranged from 0.3% to 1% for symptomatic VTE and from 2.8% to 5.6% for VTE overall.6-8 The VTE incidence in randomized trials in critically ill non-COVID-19 patients who received prophylactic dose anticoagulants ranged from 5% to 16%, and a prospective cohort study of critically ill patients with sepsis reported a VTE incidence
of 37%.9-12 VTE guidelines for non-COVID-19 patients have recommended against routine screening ultrasounds in critically ill patients because no study has shown that this strategy reduces the rate of subsequent symptomatic thromboembolic complications.13 Although the incidence of thromboembolic events, especially pulmonary emboli, can be high among hospitalized patients with COVID-19, there are no published data demonstrating the clinical utility of routine surveillance for deep vein thrombosis using lower extremity ultrasound in this population.

A meta-analysis performed by an American Society of Hematology guidelines panel compared the odds of bleeding and thrombotic outcomes in patients with COVID-19 treated with prophylactic dose anticoagulation versus in those treated with intermediate or therapeutic dose anticoagulation.14 Overall, the odds of VTE and mortality were not different between the patients treated with prophylactic
dose anticoagulation and those treated with higher doses of anticoagulation. In critically ill patients, intermediate or therapeutic dose anticoagulation was associated with a lower odds of pulmonary embolism (OR 0.09; 95% CI, 0.02–0.57) but a higher odds of major bleeding (OR 3.84; 95% CI, 1.44– 10.21). In studies in patients with COVID-19, incidences of symptomatic VTE between 0% to 0.6%
at 30 to 42 days after hospital discharge have been reported.15-17 Epidemiologic studies that control for clinical characteristics, underlying comorbidities, prophylactic anticoagulation, and COVID-19-related therapies are needed.

There are limited prospective data demonstrating the safety and efficacy of using therapeutic doses
of anticoagulants to prevent VTE in patients with COVID-19. A retrospective analysis of 2,773
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hospitalized COVID-19 patients from a single center in the United States reported in-hospital mortality in 22.5% of patients who received therapeutic anticoagulation and 22.8% of patients who did not receive anticoagulation. The study further reported that in a subset of 395 mechanically ventilated patients, 29.1% of the patients who received anticoagulation and 62.7% of those who did not receive anticoagulation died. The study had important limitations: it lacked details on patient characteristics, indications for anticoagulant initiation, and descriptions of other therapies that the patients received that may have influenced mortality. In addition, the authors did not discuss the potential impact of survival bias on the study results. For these reasons, the data are not sufficient to influence standard

of care, and this study further emphasizes the need for prospective trials to define the risks and
potential benefits of therapeutic anticoagulation in patients with COVID-19.18 Three international
trials (Antithrombotic Therapy to Ameliorate Complications of COVID-19 [ATTACC], Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 [ACTIV-4], and the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia [REMAP-CAP]) compared the effectiveness of therapeutic dose anticoagulation and prophylactic

dose anticoagulation in reducing the need for organ support over 21 days in moderately ill or critically ill adults hospitalized for COVID-19. The need for organ support was defined as requiring high-flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or extracorporeal membrane oxygenation (ECMO). The trials paused enrollment of patients requiring intensive care unit (ICU)-level care after an interim pooled analysis demonstrated futility of therapeutic anticoagulation in improving organ support, and a concern for safety. The results of the interim analysis are available on the ATTACC website. Unblinded data and additional study outcomes, including the occurrence of thrombosis, are expected to be reported soon.19

A small, single-center randomized trial (n = 20) compared therapeutic and prophylactic anticoagulation in mechanically ventilated patients with D-dimers >1,000 μg/L (as measured by the VIDAS D-dimer Exclusion II assay). Only the patients treated with therapeutic anticoagulation showed improvement
in the ratio of arterial oxygen partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2). The number of ventilator-free days was higher in the therapeutic anticoagulation arm than in the prophylactic anticoagulation arm (15 days [IQR 6–16] vs. 0 days [IQR 0–11]; P = 0.028). There was no difference between the arms in in-hospital or 28-day mortality. Two patients treated with therapeutic anticoagulation had minor bleeding, and two patients in each arm experienced thrombosis.20 Additional evidence from large, multicenter trials is needed, and the trial results are expected soon.

Several randomized controlled trials have been developed to evaluate the risks and benefits of anticoagulation in patients with COVID-19 (visit ClinicalTrials.gov for the current list of trials). Guidelines about coagulopathy and prevention and management of VTE in patients with COVID-19 have been released by multiple organizations, including the Anticoagulation Forum,21 the American College of Chest Physicians,22 the American Society of Hematology,23 the International Society of Thrombosis and Haemostasis (ISTH),24 the Italian Society on Thrombosis and Haemostasis,25 and the Royal College of Physicians.26 In addition, a paper that outlines issues related to thrombotic disease with implications for prevention and therapy has been endorsed by the ISTH, the North American Thrombosis Forum, the European Society of Vascular Medicine, and the International Union of Angiology.27

All of the guidelines referenced above agree that hospitalized patients with COVID-19 should receive prophylactic dose anticoagulation for VTE. Some guidelines note that intermediate dose anticoagulation can be considered for critically ill patients.21,23,26,28 Given the variation in VTE incidence and the unknown risk of bleeding in critically ill patients with COVID-19, the COVID-19 Treatment Guidelines Panel and guideline panels of the American Society of Hematology and the American College of Chest Physician recommend treating all hospitalized patients with COVID-19, including critically ill patients, with prophylactic dose anticoagulation.22,29 Results from clinical trials that assess the safety and efficacy

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of different anticoagulant doses will provide further information on the best prophylactic strategies for patients with COVID-19.

Monitoring Coagulation Markers in Patients With COVID-19

In nonhospitalized patients with COVID-19, markers of coagulopathy, such as D-dimer level, prothrombin time, fibrinogen level, and platelet count, should not routinely be obtained (AIII). Although abnormalities in these coagulation markers have been associated with worse outcomes, prospective data demonstrating that the markers can be used to predict the risk of VTE in those who are asymptomatic or who have mild SARS-CoV-2 infection is lacking.

In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly measured; however, there are currently insufficient data to recommend either for or against using such data to guide management decisions.

Managing Antithrombotic Therapy in Patients With COVID-19

Selection of Anticoagulant or Antiplatelet Drugs for Patients With COVID-19

Whenever anticoagulant or antiplatelet therapy is used, potential drug-drug interactions with other concomitant drugs must be considered (AIII). The University of Liverpool has collated a list of drug interactions. In hospitalized, critically ill patients, low molecular weight heparin or unfractionated heparin is preferred over oral anticoagulants because the two types of heparin have shorter half-lives, can be administered intravenously or subcutaneously, and have fewer drug-drug interactions (AIII).

Chronic Anticoagulant or Antiplatelet Therapy

COVID-19 outpatients receiving warfarin who are in isolation and thus unable to have international normalized ratio monitoring may be candidates for switching to direct oral anticoagulant therapy. Patients receiving warfarin who have a mechanical heart valve, ventricular assist device, valvular atrial fibrillation, or antiphospholipid antibody syndrome or who are lactating should continue treatment with warfarin (AIII). Hospitalized patients with COVID-19 who are taking anticoagulant or antiplatelet therapy for underlying medical conditions should continue this treatment unless significant bleeding develops, or other contraindications are present (AIII).

Patients with COVID-19 Who Are Managed as Outpatients

For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIII).

Hospitalized Patients With COVID-19

For hospitalized patients with COVID-19, prophylactic dose anticoagulation should be prescribed unless contraindicated (e.g., a patient has active hemorrhage or severe thrombocytopenia) (AIII). Although data supporting this recommendation are limited, a retrospective study showed reduced mortality in patients who received prophylactic anticoagulation, particularly if the patient had a sepsis-induced coagulopathy score ≥4.4 For those without COVID-19, anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the standard of care (AIII). Anticoagulation is routinely used to prevent arterial thromboembolism in patients with heart arrhythmias. Although there are reports of strokes and myocardial infarction in patients with COVID-19, the incidence of these events is unknown.

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When imaging is not possible, patients with COVID-19 who experience an incident thromboembolic event or who are highly suspected to have thromboembolic disease should be managed with therapeutic doses of anticoagulant therapy as per the standard of care for patients without COVID-19 (AIII).

There are currently insufficient data to recommend either for or against the use of thrombolytic agents or higher than the prophylactic dose of anticoagulation for VTE prophylaxis for hospitalized patients with COVID-19 outside of a clinical trial. Three international trials (ACTIV-4, REMAP-CAP, and ATTACC) compared the effectiveness of therapeutic dose anticoagulation and prophylactic dose anticoagulation

in reducing the need for organ support over 21 days in moderately ill or critically ill adults hospitalized for COVID-19. The need for organ support was defined as requiring high-flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO. The trials paused enrollment of patients requiring ICU-level care at enrollment after an interim pooled analysis demonstrated futility of therapeutic anticoagulation in reducing the need for organ support and a concern for safety. The results of the interim analysis are available on the ATTACC website. Unblinded data and additional study outcomes, including the occurrence of thrombosis, are expected to be reported soon.19

Although there is evidence that multi-organ failure is more likely in patients with sepsis who develop coagulopathy,30 there is no convincing evidence to show that any specific antithrombotic treatment will influence outcomes in those with or without COVID-19. Participation in randomized trials is encouraged.

Patients with COVID-19 who require ECMO or continuous renal replacement therapy or who have thrombosis of catheters or extracorporeal filters should be treated as per the standard institutional protocols for those without COVID-19 (AIII).

Hospitalized Children With COVID-19

A recent meta-analysis of publications on COVID-19 in children did not discuss VTE.31 Indications for VTE prophylaxis in hospitalized children with COVID-19 should be the same as those for hospitalized children without COVID-19 (BIII).

Patients With COVID-19 Who Are Discharged from the Hospital

VTE prophylaxis after hospital discharge is not recommended for patients with COVID-19 (AIII). For certain high-VTE risk patients without COVID-19, post-discharge prophylaxis has been shown to be beneficial. The Food and Drug Administration approved the use of rivaroxaban 10 mg daily for 31 to 39 days in these patients.32,33 Inclusion criteria for the trials that studied post-discharge VTE prophylaxis included:

• Modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score ≥4; or

• Modified IMPROVE VTE risk score ≥2 and D-dimer level >2 times the upper limit of normal.32
Any decision to use post-discharge VTE prophylaxis for patients with COVID-19 should include consideration of the individual patient’s risk factors for VTE, including reduced mobility, bleeding risks, and feasibility. Participation in clinical trials is encouraged.
Special Considerations During Pregnancy and Lactation
Because pregnancy is a hypercoagulable state, the risk of thromboembolism is greater in pregnant individuals than in nonpregnant individuals.34 It is not yet known whether COVID-19 increases this risk. In several cohort studies of pregnant women with COVID-19 in the United States and Europe,
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VTE was not reported as a complication even among women with severe disease, although the receipt of prophylactic or therapeutic anticoagulation varied across the studies.35-37 The American College
of Obstetricians and Gynecologists (ACOG) advises that, although there are no data for or against thromboprophylaxis in the setting of COVID-19 in pregnancy, VTE prophylaxis can reasonably be considered for pregnant women hospitalized with COVID-19, particularly for those who have severe disease.38 If there are no contraindications to use, the Society of Maternal Fetal Medicine recommends prophylactic heparin or low molecular weight heparin in critically ill or mechanically ventilated pregnant patients.39 Several professional societies, including the American Society of Hematology

and ACOG, have guidelines that specifically address the management of VTE in the context of pregnancy.40,41 If delivery is threatened, or if there are other risks for bleeding, the risk of bleeding may outweigh the potential benefit of VTE prophylaxis in pregnancy.

There are no data on the use of scoring systems to predict VTE risk in pregnant individuals. Additionally, during pregnancy, the D-dimer level may not be a reliable predictor of VTE because there is a physiologic increase of D-dimer levels throughout gestation.42-44

In general, the preferred anticoagulants during pregnancy are heparin compounds. Because of its reliability and ease of administration, low-molecular weight heparin is recommended, rather than unfractionated heparin, for the prevention and treatment of VTE in pregnancy.41

Direct-acting anticoagulants are not routinely used during pregnancy due to the lack of safety data in pregnant individuals.40 The use of warfarin to prevent or treat VTE should be avoided in pregnant individuals, regardless of their COVID-19 status, and especially during the first trimester due to the concern for teratogenicity.

Specific recommendations for pregnant or lactating individuals with COVID-19 include:

• If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, this
therapy should be continued (AIII).

• For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is
recommended unless contraindicated (BIII).

• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not recommended for pregnant patients (AIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient should be individualized, considering concomitant VTE risk factors.

• Anticoagulation therapy use during labor and delivery requires specialized care and planning. It should be managed in pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions that require anticoagulation in pregnancy (AIII).

• Unfractionated heparin, low molecular weight heparin, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the newborn; therefore, they can be used by breastfeeding women with or without COVID-19 who require VTE prophylaxis or treatment (AIII). In contrast, use of direct-acting oral anticoagulants during pregnancy is not routinely recommended due to lack of safety data (AIII).40
References

1. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32172226.

2. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32201335.

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3. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.

4. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32220112.

5. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a systematic review and meta-analysis. Res Pract Thromb Haemost. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33043231.

6. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006;332(7537):325-329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16439370.

7. Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874-879. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15289368.

8. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341(11):793-800. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10477777.

9. Fraisse F, Holzapfel L, Couland JM, et al. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1109-1114. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10764298.

10. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, et al. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364(14):1305-1314. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21417952.

11. Shorr AF, Williams MD. Venous thromboembolism in critically ill patients. Observations from a randomized trial in sepsis. Thromb Haemost. 2009;101(1):139-144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19132200.

12. Kaplan D, Casper TC, Elliott CG, et al. VTE incidence and risk factors in patients with severe sepsis and septic shock. Chest. 2015;148(5):1224-1230. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26111103.

13. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e195S-e226S. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22315261.

14. American Society of Hematology. Should DOACs, LMWH, UFH, Fondaparinux, Argatroban, or Bivalirudin at intermediate-intensity or therapeutic-intensity vs. prophylactic intensity be used for patients with COVID-19 related critical illness who do not have suspected or confirmed VTE? 2020. Available at: https://guidelines.ash.gradepro.org/profile/3CQ7J0SWt58. Accessed December 7, 2020.

15. Roberts LN, Whyte MB, Georgiou L, et al. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood. 2020;136(11):1347-1350. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32746455.

16. Engelen MM, Vanassche T, Balthazar T, et al. Incidence of venous thromboembolism in patients discharged after COVID-19 Hostpialization [abstract]. Res Pract Thromb Haemost. 2020;4 (Suppl 1). Available at: https://abstracts.isth.org/abstract/incidence-of-venous-thromboembolism-in-patients-discharged-after-covid- 19-hospitalisation/.

17. Patell R, Bogue T, Koshy A, et al. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood. 2020;136(11):1342-1346. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32766883.

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18. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. Journal of the American College of Cardiology. 2020;In press. Available at: https://www.sciencedirect.com/science/article/pii/S0735109720352189?via%3Dihub.

19. NIH ACTIV Trial of blood thinners pauses enrollment of critically ill COVID-19 patients [press release]. 2020. Available at: https://www.nih.gov/news-events/news-releases/nih-activ-trial-blood-thinners-pauses- enrollment-critically-ill-covid-19-patients. Accessed February 8, 2021.

20. Lemos ACB, do Espirito Santo DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized Phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359-366. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32977137.

21. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72- 81. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32440883.

22. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020;158(3):1143-1163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32502594.

23. American Society of Hematology. ASH guidelines on use of anticoagulation in patients with COVID-19. 2020. Available at: https://www.hematology.org/education/clinicians/guidelines-and-quality-care/ clinical-practice-guidelines/venous-thromboembolism-guidelines/ash-guidelines-on-use-of-anticoagulation-in- patients-with-covid-19. Accessed November 13, 2020.

24. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32338827.

25. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18(3):167-169. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32281926.

26. Royal College of Physicians. Clinical guide for the prevention, detection and management of thromboembolic disease in patients with COVID-19. 2020. Available at: https://icmanaesthesiacovid-19.org/clinical-guide- prevention-detection-and-management-of-vte-in-patients-with-covid-19. Accessed November 13, 2020.

27. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32311448.

28. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-1865. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459046.

29. American Society of Hematology. COVID-19 and VTE/anticoagulation: frequently asked questions. 2020. Available at: https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation. Accessed February 8, 2021.

30. Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017;7(9):e017046. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28963294.

31. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32202343.

32. Spyropoulos AC, Lipardi C, Xu J, et al. Modified IMPROVE VTE risk score and elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH Open. 2020;4(1):e59-e65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32190813.

33. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill

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medical patients. N Engl J Med. 2016;375(6):534-544. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27232649.

34. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143(10):697-706. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16287790.

35. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. Coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am J Obstet Gynecol MFM. 2020;2(2):100118. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32292903.

36. Knight M, Bunch K, Vousden N, et al. Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study. BMJ. 2020;369:m2107. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32513659.

37. Delahoy MJ, Whitaker M, O’Halloran A, et al. Characteristics and maternal and birth outcomes of hospitalized pregnant women with laboratory-confirmed COVID-19 – COVID-NET, 13 states, March 1–August 22, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(38):1347-1354. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32970655.

38. The American College of Obstetricians and Gynecologists. COVID-19 FAQs for obstetrician-gynecologists, obstetrics. 2020. Available at: https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob- gyns-obstetrics. Accessed February 8, 2021.

39. Society for Maternal Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_ COVID_pos_preg_patients_4-30-20_final.pdf. Accessed February 8, 2021.

40. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317-3359. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30482767.

41. ACOG practice bulletin no. 196 summary: thromboembolism in pregnancy. Obstet Gynecol. 2018;132(1):243- 248. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29939933.

42. Wang M, Lu S, Li S, Shen F. Reference intervals of D-dimer during the pregnancy and puerperium period on the STA-R evolution coagulation analyzer. Clin Chim Acta. 2013;425:176-180. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23954836.

43. Reger B, Peterfalvi A, Litter I, et al. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant women. Thromb Res. 2013;131(4):e183-187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23481480.

44. Hu W, Wang Y, Li J, et al. The predictive value of D-dimer test for venous thromboembolism during puerperium: a prospective cohort study. Clin Appl Thromb Hemost. 2020;26:1076029620901786. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32090610.

             

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Supplements

Last Updated: February 11, 2021



Summary Recommendations

Vitamin C

• There are insuf cient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19.

Vitamin D

• There are insuf cient data for the Panel to recommend either for or against the use of vitamin D for the treatment of COVID-19.

Zinc

• There are insuf cient data for the Panel to recommend either for or against the use of zinc for the treatment of COVID-19.

• The Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or ob-servational cohort studies; III = Expert opinion

In addition to the antiviral medications and the immune-based therapies that are discussed elsewhere in the COVID-19 Treatment Guidelines, adjunctive therapies are frequently used in the prevention and/or treatment of COVID-19 or its complications. Some of these agents are being studied in clinical trials.

Some clinicians advocate for the use of vitamin and mineral supplements to treat respiratory viral infections. Ongoing studies are evaluating the use of vitamin and mineral supplements for both the treatment and prevention of severe acute respiratory syndrome coronavirus 2 infection.

The following sections describe the underlying rationale for using adjunctive therapies and summarize the existing clinical trial data. Other adjunctive therapies will be added as new evidence emerges.

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Vitamin C

Last Updated: April 21, 2021

Vitamin C (ascorbic acid) is a water-soluble vitamin that is thought to have beneficial effects in
patients with severe and critical illnesses. It is an antioxidant and free radical scavenger that has anti- inflammatory properties, influences cellular immunity and vascular integrity, and serves as a cofactor in the generation of endogenous catecholamines.1,2 Because humans may require more vitamin C in states of oxidative stress, vitamin C supplementation has been evaluated in numerous disease states, including serious infections and sepsis. Because SARS-CoV-2 infection may cause sepsis and acute respiratory distress syndrome (ARDS), the potential role of high doses of vitamin C in ameliorating inflammation and vascular injury in patients with COVID-19 is being studied.

Recommendation for Non-Critically Ill Patients With COVID-19

• There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19 in non-critically ill patients.

Rationale

Because patients who are not critically ill with COVID-19 are less likely to experience oxidative stress or severe inflammation, the role of vitamin C in this setting is unknown.

Clinical Data on Vitamin C in Outpatients With COVID-19

Oral Ascorbic Acid Versus Zinc Gluconate Versus Both Agents Versus Standard of Care

In an open-label clinical trial that was conducted at two sites in the United States, outpatients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of oral ascorbic acid 8,000 mg, zinc gluconate 50 mg, both agents, or standard of care.3 The primary end point was the number of days required to reach a 50% reduction in the patient’s symptom severity score. The study was stopped early by an operational and safety monitoring board due to futility after 40% of the planned 520 participants were enrolled (n = 214).

Patients who received standard of care achieved a 50% reduction in their symptom severity scores at
a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic acid arm, 5.9 days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the arm that received both agents (overall P = 0.45). Nonserious adverse effects occurred more frequently in patients who received supplements than in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in the zinc gluconate arm, and 32.1% in the arm that received both agents experienced nonserious adverse effects compared with 0% of patients in the standard of care arm (overall P < 0.001). The most common nonserious adverse effects in this study were gastrointestinal events.

The limitations of this study include the small sample size and the lack of a placebo control. In outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the two supplements did not significantly decrease the number of days required to reach a 50% reduction in a symptom severity score compared with standard of care.

Recommendation for Critically Ill Patients With COVID-19

• There are insufficient data for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in critically ill patients.

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Rationale

There are no controlled trials that have definitively demonstrated a clinical benefit for vitamin C in critically ill patients with COVID-19, and the available observational data are inconclusive. Studies of vitamin C regimens in sepsis patients and ARDS patients have reported variable efficacy and few safety concerns.

Clinical Data on Vitamin C in Critically Ill Patients

Intravenous Vitamin C Alone in Patients With COVID-19

A pilot clinical trial in China randomized 56 adults with COVID-19 in the intensive care unit to receive intravenous (IV) vitamin C 24 g per day or placebo for 7 days. The study was terminated early due to a reduction in the number of cases of COVID-19 in China. Overall, the study found no differences between the arms in mortality, the duration of mechanical ventilation, or the change in median sequential organ failure assessment (SOFA) scores. The study reported improvements in oxygenation (as measured by the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2]) from baseline to Day 7 in the treatment arm that were statistically greater than those observed in the placebo arm (+20.0 vs. -51.9; P = 0.04).4

Intravenous Vitamin C Alone in Patients Without COVID-19

A small, three-arm pilot study compared two regimens of IV vitamin C to placebo in 24 critically ill patients with sepsis. Over the 4-day study period, patients who received vitamin C 200 mg/kg per day and those who received vitamin C 50 mg/kg per day had lower SOFA scores and lower levels of proinflammatory markers than patients who received placebo.5

In a randomized controlled trial in critically ill patients with sepsis-induced ARDS (n = 167), patients who received IV vitamin C 200 mg/kg per day for 4 days had SOFA scores and levels of inflammatory markers that were similar to those observed in patients who received placebo. However, 28-day mortality was lower in the treatment group (29.8% vs. 46.3%; P = 0.03), coinciding with more days alive and free of the hospital and the intensive care unit.6 A post hoc analysis of the study data reported a difference in median SOFA scores between the treatment group and placebo group at 96 hours; however, this difference was not present at baseline or 48 hours.7

Intravenous Vitamin C Plus Thiamine With or Without Hydrocortisone in Critically Ill Patients Without COVID-19

Two small studies that used historic controls reported favorable clinical outcomes (i.e., reduced mortality, reduced risk of progression to organ failure, and improved radiographic findings) in patients with
sepsis or severe pneumonia who received a combination of vitamin C, thiamine, and hydrocortisone.8,9 Subsequently, several randomized trials in which patients received vitamin C and thiamine (with or without hydrocortisone) to treat sepsis and septic shock showed that this combination conferred benefits for certain clinical parameters. However, no survival benefit was reported. Two trials observed reductions in organ dysfunction (as measured by change in SOFA score on Day 3)10,11 or the duration of shock12 without an effect on clinical outcomes. Three other trials, including a large trial of 501 sepsis patients, found no differences in any physiologic or outcome measures between the treatment and placebo groups.13-15

See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of vitamin C in patients with COVID-19.

Other Considerations

It is important to note that high circulating concentrations of vitamin C may affect the accuracy of point- of-care glucometers.16,17

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References

1. Wei XB, Wang ZH, Liao XL, et al. Efficacy of vitamin C in patients with sepsis: an updated meta-analysis. Eur J Pharmacol. 2020;868:172889. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31870831.

2. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med. 2011;39(6):1454-1460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21358394.

3. Thomas S, Patel D, Bittel B, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID A to Z randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33576820.

4. Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intensive Care. 2021;11(1):5. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33420963.

5. Fowler AA, 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24484547.

6. Fowler AA, 3rd, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019;322(13):1261-1270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31573637.

7. Fowler AA, 3rd, Fisher BJ, Kashiouris MG. Vitamin C for sepsis and acute respiratory failure-reply. JAMA. 2020;323(8):792-793. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32096845.

8. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-1238. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27940189.

9. Kim WY, Jo EJ, Eom JS, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after cohort study. J Crit Care. 2018;47:211-218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30029205.

10. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31950979.

11. Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest. 2020;158(1):174-182. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32243943.

12. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest. 2020;158(1):164-173. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194058.

13. Hwang SY, Ryoo SM, Park JE, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi- centre, double-blinded randomized, controlled study. Intensive Care Med. 2020;46(11):2015-2025. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32780166.

14. Moskowitz A, Huang DT, Hou PC, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642-650. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32809003.

15. Sevransky JE, Rothman RE, Hager DN, et al. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA. 2021;325(8):742-750. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33620405.

16. Hager DN, Martin GS, Sevransky JE, Hooper MH. Glucometry when using vitamin C in sepsis: a note of caution. Chest. 2018;154(1):228-229. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30044741.

17. Food and Drug Administration. Blood glucose monitoring devices. 2019. Available at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/blood-glucose-monitoring-devices. Accessed March 26, 2021.

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Vitamin D

Last Updated: April 21, 2021

Recommendation

• There are insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19.

Rationale

Vitamin D is critical for bone and mineral metabolism. Because the vitamin D receptor is expressed on immune cells such as B cells, T cells, and antigen-presenting cells, and because these cells can synthesize the active vitamin D metabolite, vitamin D also has the potential to modulate innate and adaptive immune responses.1

Vitamin D deficiency (defined as a serum concentration of 25-hydroxyvitamin D ≤20 ng/mL) is common in the United States, particularly among persons of Hispanic ethnicity and Black race. These groups are also overrepresented among cases of COVID-19 in the United States.2 Vitamin D deficiency is also more common in older patients and patients with obesity and hypertension; these factors have been associated with worse outcomes in patients with COVID-19. In observational studies, low vitamin D levels have been associated with an increased risk of community-acquired pneumonia in older adults3 and children.4

Vitamin D supplements may increase the levels of T regulatory cells in healthy individuals and patients with autoimmune diseases; vitamin D supplements may also increase T regulatory cell activity.5 In a meta-analysis of randomized clinical trials, vitamin D supplementation was shown to protect against acute respiratory tract infection.6 However, in two double-blind, placebo-controlled, randomized clinical trials, administering high doses of vitamin D to critically ill patients with vitamin D deficiency (but

not COVID-19) did not reduce the length of the hospital stay or the mortality rate when compared to placebo.7,8 High levels of vitamin D may cause hypercalcemia and nephrocalcinosis.9

The rationale for using vitamin D is based largely on immunomodulatory effects that could potentially protect against COVID-19 infection or decrease the severity of illness. Ongoing observational studies are evaluating the role of vitamin D in preventing and treating COVID-19. Some investigational trials on the use of vitamin D in people with COVID-19 are being planned or are already accruing participants. These trials will administer vitamin D alone or in combination with other agents to participants with

and without vitamin D deficiency. The latest information on these clinical trials can be found on ClinicalTrials.gov.

Clinical Data

Randomized Clinical Trial of Vitamin D Versus Placebo in Patients With Moderate to Severe COVID-19

In a double-blind, placebo-controlled randomized trial that was conducted at two sites in Brazil, 240 hospitalized patients with moderate to severe COVID-19 received either a single dose of 200,000 international units of vitamin D3 or placebo.10 Moderate to severe COVID-19 was defined as patients with a positive result on a SARS-CoV-2 polymerase chain reaction test (or compatible computed tomography scan findings) and a respiratory rate >24 breaths/min, oxygen saturation <93% on room air, or risk factors for complications. The primary outcome in this study was the length of the hospital stay.

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The median length of stay was not significantly different between the vitamin D3 arm (7.0 days [IQR 4.0–10.0 days]) and the placebo arm (7.0 days [IQR 5.0–13.0 days]; P = 0.59, log-rank test). No significant differences were observed between the arms in the percentages of patients who were admitted to the intensive care unit, who required mechanical ventilation, or who died during hospitalization.

It should be noted that this study had a small sample size and enrolled participants with a variety of comorbidities and concomitant medications. The time between symptom onset and randomization was relatively long, with patients randomized at a mean of 10.3 days after symptom onset. In this study, a single, high dose of vitamin D3 did not significantly reduce the length of stay for hospitalized patients with COVID-19.

References

1. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881-886. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21527855.

2. Forrest KY,Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31(1):48-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21310306.

3. Lu D, Zhang J, Ma C, et al. Link between community-acquired pneumonia and vitamin D levels in older patients. Z Gerontol Geriatr. 2018;51(4):435-439. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28477055.

4. Science M, Maguire JL, Russell ML, Smieja M, Walter SD,Loeb M. Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013;57(3):392-397. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23677871.

5. Fisher SA, Rahimzadeh M, Brierley C, et al. The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: a systematic review. PLoS One. 2019;14(9):e0222313. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31550254.

6. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28202713.

7. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520- 1530. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25268295.

8. National Heart L, Blood Institute PCTN, Ginde AA, et al. Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med. 2019;381(26):2529-2540. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31826336.

9. Institue of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. The National Academies Press; 2011.

10. Murai IH, Fernandes AL,Sales LP. Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial. 2021; Published online ahead of print. Available at: https://pubmed.ncbi.nlm.nih.gov/33595634/.

        

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Zinc

Last Updated: April 21, 2021

Recommendations

• There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of zinc for the treatment of COVID-19.

• The Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).
Rationale
Increased intracellular zinc concentrations efficiently impair replication in a number of RNA viruses.1 Zinc has been shown to enhance cytotoxicity and induce apoptosis when used in vitro with a zinc ionophore (e.g., chloroquine). Chloroquine has also been shown to enhance intracellular zinc uptake
in vitro.2 The relationship between zinc and COVID-19, including how zinc deficiency affects the severity of COVID-19 and whether zinc supplements can improve clinical outcomes, is currently under investigation.3 Zinc levels are difficult to measure accurately, as zinc is distributed as a component of various proteins and nucleic acids.4
Several clinical trials are currently investigating the use of zinc supplementation alone or in combination with hydroxychloroquine for the prevention and treatment of COVID-19 (see ClinicalTrials.gov for more information about ongoing studies). The recommended dietary allowance for elemental zinc is
11 mg daily for men and 8 mg for nonpregnant women.5 The doses used in registered clinical trials for patients with COVID-19 vary between studies, with a maximum dose of zinc sulfate 220 mg (50 mg of elemental zinc) twice daily. However, there are currently insufficient data to recommend either for or against the use of zinc for the treatment of COVID-19.
Long-term zinc supplementation can cause copper deficiency with subsequent reversible hematologic defects (i.e., anemia, leukopenia) and potentially irreversible neurologic manifestations (i.e., myelopathy, paresthesia, ataxia, spasticity).6,7 The use of zinc supplementation for durations as short as 10 months has been associated with copper deficiency.4 In addition, oral zinc can decrease the absorption of medications that bind with polyvalent cations.5 Because zinc has not been shown to have a clinical benefit and may be harmful, the Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).
Clinical Data
Randomized Clinical Trial of Zinc Plus Hydroxychloroquine Versus Hydroxychloroquine Alone in Hospitalized Patients With COVID-19
In a randomized clinical trial that was conducted at three academic medical centers in Egypt, 191 patients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either zinc 220 mg twice daily plus hydroxychloroquine or hydroxychloroquine alone for a 5-day course. The primary endpoints were recovery within 28 days, the need for mechanical ventilation, and death. The two arms were matched for age and gender.8
Results

• There were no significant differences between the two arms in the percentages of patients who recovered within 28 days (79.2% in the hydroxychloroquine plus zinc arm vs. 77.9% in the hydroxychloroquine only arm; P = 0.969), the need for mechanical ventilation (P = 0.537), or

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overall mortality (P = 0.986).
• The only risk factors for mortality were age and the need for mechanical ventilation.

Limitations

• This study had a relatively small sample size.

Interpretation

A moderately sized randomized clinical trial failed to find a clinical benefit for the combination of zinc and hydroxychloroquine.

Open-Label, Randomized Trial of Zinc Versus Ascorbic Acid Versus Zinc Plus Ascorbic Acid Versus Standard of Care in Outpatients With COVID-19

In an open-label clinical trial that was conducted at two sites in the United States, outpatients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of zinc gluconate 50 mg, ascorbic acid 8,000 mg, both agents, or standard of care. The primary end point was the number of days required to reach a 50% reduction in the patient’s symptom severity score. The study was stopped early by an operational and safety monitoring board due to futility after 40% of the planned 520 participants were enrolled (n = 214).9

Results

• Participants who received standard of care achieved a 50% reduction in their symptom severity scores at a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic acid arm, 5.9 days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the arm that received both agents (overall P = 0.45).

• Nonserious adverse effects occurred more frequently in patients who received supplements than in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in the zinc gluconate arm, and 32.1% in the arm that received both agents experienced nonserious adverse effects compared with 0% of patients in the standard of care arm (overall P < 0.001). The most common nonserious adverse effects in this study were gastrointestinal events.
Limitations

• The study had a small sample size.

• There was no placebo control.
Interpretation
In outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the two supplements did not significantly decrease the number of days required to reach a 50% reduction in a symptom severity score compared with standard of care.
Observational Study of Zinc Supplementation in Hospitalized Patients
A retrospective study enrolled 242 patients with polymerase chain reaction-confirmed SARS-CoV-2 infection who were admitted to Hoboken University Medical Center. One hundred and ninety-six patients (81.0%) received a total daily dose of zinc sulfate 440 mg (100 mg of elemental zinc); of those, 191 patients (97%) also received hydroxychloroquine. Among the 46 patients who did not receive
zinc, 32 patients (70%) received hydroxychloroquine. The primary outcome was days from hospital admission to in-hospital mortality, and the primary analysis explored the causal association between zinc therapy and survival.10
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Results

• There were no significant differences in baseline characteristics between the arms. In the zinc arm, 73 patients (37.2%) died compared with 21 patients (45.7%) in the control arm. In the primary analysis, which used inverse probability weighting (IPW), the effect estimate of zinc therapy was an additional 0.84 days of survival (95% CI, -1.51 days to 3.20 days; P = 0.48).

• In a multivariate Cox regression analysis with IPW, the use of zinc sulfate was not significantly associated with a change in the risk of in-hospital mortality (aHR 0.66; 95% CI, 0.41–1.07; P = 0.09).

• Older age, male sex, and severe or critical COVID-19 were significantly associated with an increased risk of in-hospital mortality.
Limitations

• This is a retrospective study; patients were not randomized to receive zinc supplementation or to receive no zinc.

Interpretation

This single-center, retrospective study failed to find a mortality benefit in patients who received zinc supplementation.

Multicenter, Retrospective Cohort Study That Compared Hospitalized Patients Who Received Zinc Plus Hydroxychloroquine to Those Who Did Not

This study has not been peer reviewed.

This multicenter, retrospective cohort study of hospitalized adults with SARS-CoV-2 infection who were admitted to four New York City hospitals between March 10 and May 20, 2020, compared patients who received zinc plus hydroxychloroquine to those who received treatment that did not include this combination.11

Results

• The records of 3,473 patients were reviewed.

• The median patient age was 64 years; 1,947 patients (56%) were male, and 522 patients (15%) were mechanically ventilated.

• Patients who received an interleukin-6 inhibitor or remdesivir were excluded from the analysis.

• A total of 1,006 patients (29%) received zinc plus hydroxychloroquine, and 2,467 patients (71%) received hydroxychloroquine without zinc.

• During the study, 545 patients (16%) died. In univariate analyses, mortality rates were significantly lower among patients who received zinc plus hydroxychloroquine than among those who did not (12% vs. 17%; P < 0.001). Similarly, hospital discharge rates were significantly higher among patients who received zinc plus hydroxychloroquine than among those who did not (72% vs. 67%; P < 0.001).

• In a Cox regression analysis that adjusted for confounders, treatment with zinc plus hydroxychloroquine was associated with a significantly reduced risk of in-hospital death (aHR 0.76; 95% CI, 0.60–0.96; P = 0.023). Treatment with zinc alone (n = 1,097) did not affect mortality (aHR 1.14; 95% CI, 0.89–1.44; P = 0.296), and treatment with hydroxychloroquine alone (n = 2,299) appeared to be harmful (aHR 1.60; 95% CI, 1.22–2.11; P = 0.001).

• There were no significant interactions between zinc plus hydroxychloroquine and other COVID- 19-specific medications.
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Limitations

• This is a retrospective review; patients were not randomized to receive zinc plus hydroxychloroquine or to receive other treatments.

• The authors do not have data on whether patients were taking zinc and/or hydroxychloroquine prior to study admission.

• The arms were not balanced; recipients of zinc plus hydroxychloroquine were more likely to be male, Black, or to have a higher body mass index and diabetes. Patients who received zinc plus hydroxychloroquine were also treated more often with corticosteroids and azithromycin and less often with lopinavir/ritonavir than those who did not receive this drug combination.
Interpretation
In this preprint, the use of zinc plus hydroxychloroquine was associated with decreased rates of in-hospital mortality, but neither zinc alone nor hydroxychloroquine alone reduced mortality. Treatment with hydroxychloroquine alone appeared to be harmful.
References

1. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ,van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21079686.

2. Xue J, Moyer A, Peng B, Wu J, Hannafon BN,Ding WQ. Chloroquine is a zinc ionophore. PLoS One. 2014;9(10):e109180. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25271834.

3. Calder PC, Carr AC, Gombart AF,Eggersdorfer M. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients. 2020;12(4). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32340216.

4. Hambridge K. The management of lipohypertrophy in diabetes care. Br J Nurs. 2007;16(9):520-524. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17551441.

5. National Institutes of Health. Office of Dietary Supplements. Zinc fact sheet for health professionals. 2020. Available at: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/.

6. Myint ZW, Oo TH, Thein KZ, Tun AM,Saeed H. Copper deficiency anemia: review article. Ann Hematol. 2018;97(9):1527-1534. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29959467.

7. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc. 2006;81(10):1371-1384. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17036563.

8. Abd-Elsalam S, Soliman S, Esmail ES, et al. Do zinc supplements enhance the clinical efficacy of hydroxychloroquine?: a randomized, multicenter trial. Biol Trace Elem Res. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33247380.

9. Thomas S, Patel D,Bittel B. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 Infection: the COVID a to z randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at: https://pubmed.ncbi.nlm.nih.gov/33576820/.

10. Yao JS, Paguio JA, Dee EC, et al. The minimal effect of zinc on the survival of hospitalized patients with COVID-19: an observational study. Chest. 2021;159(1):108-111. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32710890.

11. Frontera JA, Rahimian JO, Yaghi S, et al. Treatment with zinc is associated with reduced in-hospital mortality among COVID-19 patients: a multi-center cohort study. Res Sq. 2020;Preprint. Availab