Chinese Guideline of Diagnosis and treatment of COVID-19

(7th Version)

Severe Acute Respiratory Syndrome Coronavirus-2

◼ Belong to the β genus; Have envelopes; Round or oval; diameter being 60 to 140 nm

◼ showed 79.0% nucleotide identity with the sequence of SARS-CoV and 51.8% identity with the sequence of MERS-CoV.

◼ Sensitive to ultraviolet and heat. 75% ethanol, chlorine-containing disinfectant, peracetic acid, and chloroform can effectively inactivate the virus.

◼ Chlorhexidine was not effective

2

Epidemiology of COVID-19 globally
◼ COVID-19 has spread to the world rapidly. —— A threat of the word

  

https://www.who.i nt/doc s/de faul t-sou rc e /c oronavi ruse/si tua ti on-re por ts/20 200317-si t re p-57-c ovi d-19.pdf?sfv rsn=a 26922f2_4

3

Pathogenic changes of severe COVID-19 in lung

◼ The pathological features in lungs greatly resemble those seen in SARS and MERS infection

◼ bilateral diffuse alveolar damage with cellular fibromyxoid exudates

Hyaline membrane Interstitial mononuclear Thrombus in pulmonary formation(blue arrow) inflammatory infiltrates arterioles (black arrow)

Xiaohong Yao et al. Chinese Journal of Pathology.2020,49 (2020-03-15).

  

4

Severe Acute Respiratory Syndrome Coronavirus-2

◼ Viral particle in Alveolar type II cells (Electron microscopy)

Zhe Xu et al. Lancet Respir Med.2020. DOI: 10.1016/S2213-2600(20)30076-X
5

  

Pathogenic changes of severe COVID-19 in other organs

◼ Degeneration and necrosis of parenchymal cells, formation of hyaline thrombus in small vessels, and pathological changes of chronic diseases were observed in other organs and tissues

◼ Decreased numbers of lymphocyte, cell degeneration and necrosis were observed in spleen

Zhe Xu et al. Lancet Respir Med.2020. DOI: 10.1016/S2213-2600(20)30076-X
6

   

Diagnostic criteria of COVID-19——Suspected cases

Suspected cases

Epidemiological history (≤14 days)

Clinical symptoms

➢ travel /residence in Wuhan and its surrounding areas,or other communities where COVID-19 has been found

➢ fever and/or respiratory symptoms

➢ contact with COVID-19 patients

➢ imaging characteristics of COVID-19

➢ Contact with patients with fever or respiratory symptoms and from Wuhan and its surrounding areas, or from communities where COVID-19 has been found

➢ Normal or decreased of WBC ;Normal or decreased of Lymphocytes

➢ Clustered cases

Any one criteria of Epidemiological history + Any two Clinical symptoms All three clinical symptoms

7

Diagnostic criteria of COVID-19——Confirmed cases

Confirmed cases

Etiological or serological evidences

Nucleic acid testing

◼ SARS-CoV-2 RNA was positive detected by real time RT-PCR

◼ Viral gene sequence is highly homologous to known new coronaviruses

Serum antibody testing

◼ SARS-CoV-2 specific IgM and IgG are positive in serum

◼ SARS-CoV-2 specific IgG is detectable from negative to positive

◼ SARS-CoV-2 specific IgG antibody titer shows a 4-fold or higher change between the two sets of serum samples from acute and recovery phase

Suspect cases + one of etiological or serological evidences

8

IgG/IgM Dynamic changes of Adults with COVID-19

 

Zhong Liu et al. unpublished data

9

Transmission and incubation of COVID-19

    

Basic reproductive Median incubation period 4-5.2 days The 95th number R0=2.2-2.95 percentile of the distribution was 12.5 days

COVID-19 patients including the asymptomatic infected people are the main source of infection

◼ Route of transmission
◼ Respiratorydropletsandclosecontact
◼ Long-timeexposuretotheenvironmentwithahighconcentrationsofaerosol ◼ Environmentcontaminatedbyfeces/urine→aerosolorcontacttransmission

◼ All the population are generally susceptible

Y Wang et al. Zhonghua Liu Xing Bing Xue Za Zhi.41 (4), 476-479; Qun Li et al. N Engl J Med. DOI: 10.1056/NEJMoa2001316
Guan WJ et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa2002032
10

Disease spectrum of COVID-19

81% were mild status
◼ No pneumonia or mild pneumonia

14% were severe status

◼  Dyspnea or Respiratory Rate ≥ 30/min or
SpO2 < 93% or PaO2/FiO2 <300 mmHg

◼  Lung infiltrates >50% within 24 to 48
hours
5% were critical ill status

◼  Needs mechanical ventilation

◼  Shock

◼  Complicated with other organ failure
required ICU admission

mild severe 5%

14%

critical

        

Zunyou Wu et al.JAMA.2020. DOI: 10.1001/jama.2020.2648

11

81%

Clinical features of COVID-19 patients

Symptoms and complications N%

Fever 98%

Cough 76%

Myalgia or fatigue 44%

Sputum production 28%

Diarrhea 3%

WBC ≤ 10 × 109/L 70% Lymphocytopnia 63%

  

ALT> 40U/L

Cr > 133 mmol/L

LDH > 243 U/L

HypersensitivetroponinI >28pg/ml

Procalcitonin < 0.1 ng/ml

37% Symptoms and complications N% 10% Acute cardiac injury 12% 73% Acute kidney injury 7% 12% Septic shock 7% 69% Secondary infection 10%

Acute respiratory distress syndrome 29%

Huang C et al. Lancet. 2020;395(10223):497-506. 12

Clinical course of COVID-19——Severe and critical illness

    

◼ Duration of dyspnea was 13 days in survivors
◼ 45% survivors still had cough on discharge
◼ Median duration of viral shedding was 20 days, could prolong as 37 days
◼ lymphocyte count was lowest on day 7 after illness onset and improved during hospitalisation in

survivors but whereas severe lymphopenia was observed until death in non-survivors.

Fei Zhou et al. Lancet.2020. DOI: 10.1016/S0140-6736(20)30566-3

13

Inflammation of COVID-19——Severe and critical illness

25 20 15 10

5 0

IL-2

p = 0·26 p=0·02 p=0·04

                                                

Healthy control

ICU No ICU care care

                                                                                                                                  

                                                                                                        

 

◼  IL-1β, IL-6, G-SCF, IP-10, and MCP1 were significantly elevated

◼  Peripheral lymphocyte counts, mainly T cells were substantially reduced in severe COVID-19 patients
Host-directed therapies might be an option

Huang C, et al. Lancet 2020; 395(10223): 497-506; Liu J, et al. BMJ 2020;published online Feb 19.

14

pg/ml

SARS-CoV-2 Viral sepsis——From Bedside to Bench

Multi-organ dysfunction

◼  Pneumonia, Respiratory failure, Acute respiratory distress syndrome

◼  Metabolic acidosis and internal environment disorders

◼  Acute kidney injury

◼  Acute cardiac injury

◼  ………

——Viral Sepsis

Ren L, et al. Chin Med J 2020; DOI: 10.1097/CM9.0000000000000722;Huang C, et al. Lancet 2020; 395(10223): 497-506 HuiLi,etal.2020;unpublished, underrevision 15

Abnormal coagulation is common in severe COVID-19

D-Dimer > 1ug/ml was independent risk factor of in-hospital death

◼ Significantly increased D-dimer and FDP were associated with poor prognosis

◼ Vascular endothelium inflammation Extensive intravascular microthrombosis on autopsy

◼ Vascular endothelial cells express high levels of ACE2

                                                                                                  

Anticoagulation therapy should be initiated for severe COVID-19 patients if otherwise contraindicated.

                                                                  

Zhou F, et al. Lancet 2020; DOI:10.1016/S0140-6736(20)30566-3; Hamming I, et al. J Pathol 2004; 203(2): 631-7.

16

SARS-CoV-2 RNA detection in COVID-19 patients

◼ SARS-CoV-2 RNA could be detected in nasopharyngeal swabs, sputum, lower respiratory tract secretions, blood, feces using RT-PCR and/or NGS methods

◼ Positive rate was higher in lower respiratory tract specimen
◼ The specimens should be submitted for testing as soon as possible after collection

  

1.0 0.8 0.6 0.4 0.2 0.0

mild disease

severe disease 72.10%

 

88.90%
82.20%

Sputum sample

73.30%

                   

Wei Zhang et al.Emerg Microbes Infect, 9 (1), 386-389; Yang Y et al. medRxiv 2020.

17

Nasal swabs

60.00% 61.30%

Throat swabs

Features of CT scan of COVID-19

56-year-old man
Day 3 after symptom onset Focal ground-glass opacity

74-year-old woman
Day 10 after illness onset Bilateral, peripheral ground- glass opacity

61-year-old woman
Day 20 after symptom onset Bilateral and peripheral predominant consolidation

63-year-old woman
Day 17 after symptom onset Bilateral, peripheral mixed pattern;Air bronchogram; Pleural effusion

◼ Common:bilateral lung involvement(79%); peripheral distribution (54%); diffuse distribution (44%) ground glass opacity (65%); without septal thickening(65%).

◼ Less common: nodules (6%), cystic changes (10%), bronchiolectasis (11%), pleural effusion (5%). ◼ Not observed: Tree in bud signs, masses, cavitation, and calcifications

Heshui Shi et al. Lancet Infect Dis.2020. DOI: 10.1016/S1473-3099(20)30086-4 18

Features of imagine change over time

     

Ct scan before illness onset

Heshui Shi et al. Lancet Infect Dis.2020. DOI: 10.1016/S1473-3099(20)30086-4 19

>2 weeks to 3 weeks after symptom onset

 

≤ 1 week after symptom onset

>1 week to 2 weeks after symptom onset

Rapid deterioration on CT scan-case 1

Male, 70 years old

2020-1-28 Day 9 after illness onset

     

2020-2-1 Day 13 after illness onset. Died 2 weeks later.

20

Rapid deterioration on CT scan-case 2

Male, 62 years old

2020-2-7 Day 12 after illness onset

2020-2-7 Day 19 after illness onset. Died 15 days later

       

21

Isolation and Support treatment of COVID-19

◼ All confirmed patients should be isolation.
◼ Suspected case should be treated in isolation in a single room
◼ Hospital and ICU admission decision was according to disease severity
◼ Strengthening support treatment (most patients complicated with hypoproteinemia)

◼ sufficientcaloric

◼ waterandelectrolytebalance ◼ Oxygen therapy

◼ Closely monitoring vital sign and laboratory (progress rapidly in severe patients)
◼ WBC;Lymphocyte
◼ Biochemicalindicators(liverenzyme,myocardialenzyme,renalfunction.etc) ◼ Markerofinflammation(serumferritin,IL-6,cytokine)

◼ Chestimaging

22

Treatment options for severe or critical COVID-19

Respiratory support

    

Other therapeutic measures

Circulatory support

   

Immunotherapy

Renal replacement therapy

   

Blood purification treatment

Convalescent plasma treatment

23

Antiviral interventions

◼ So far, no specific antiviral against SARS-CoV-2 has been proved ◼Clinically evaluated drugs:

◼ Lopinavir/ritonavir monotherapy (LOTUS China, ChiCTR2000029308): completed, manuscript accepted, online tomorrow

◼ Promising results
◼ CAP China Remdesivir 1 (mild-moderate pneumonia, NCT04252664):

ongoing

◼ CAP China Remdesivir 2 (severe-critical pneumonia, NCT04257656): ongoing

Emmie de Wit et al. Nature Reviews Microbiology 2016; 14, 523–534 Timothy P Sheahan; Nat Commun 2020; 11 (1), 222
Yeming wang, et al. Trial, 2020, under peer review

CAP-China Remdesivir trials on going for COVID-19

Standard care + Remdesivir

Standard care + Placebo

Remdesivir:
First dosage:200mg iv qd×1days; Continuous 100mg qd×9days

2:1 randomization

 

Placebo:50ml qd×10days

Illness

onset
hospitalization

Total course of treatment: 10 days

≤ 12 days

Screen

enroll

Follow up

                    

24h

Day 0

Day1 Day3 Day5 Day7 Day10 Day14 Day21

Day28

 

Primary outcome:Clinical improvement on day 28
Secondary outcome:The time from randomization to clinical improvement

◼ The clinical trail of Remdesivir treatment for severe COVID-19 is on going
25

Antiviral for COVID-19: other potential choices

◼  Alpha-interferon:5MU,atomizationinhalationtwicedaily

◼  Ribavirin: used together with interferon or lopinavir/ritonavir, 500 mg twice or
three times of intravenous injection daily, no longer than 10 days

◼  Chloroquine phosphate: 500 mg bid for 7 days for adults aged 18-65 with body weight over 50 kg; 500 mg bid for Days 1&2, and 500 mg daily for Days 3-7 for
adults with body weight below 50 kg

◼  Arbidol: 200 mg three time daily for adults, no longer than 10 days

◼  Convalescent plasma treatment: infusion dose 200-500ml (4-5 ml/kg)×2

◼  Favipiravir

26

Use of corticosteroid is still controversial

◼ Only for patients with rapid progressive deterioration oxygenation, radiology imaging and excessive inflammation

◼  Contraindications: allergy; un-controlled diabetes; uncontrolled hypertension; glaucoma; GI bleeding; immunodepression; lymphocyte less than 300/ul; severe bacterial and/or fungal infections

◼  Short term, 3-5 days ◼ Low-moderate dosage
◼ nomorethanmethylprednisolone1-2mg/kg/day
Lianghan Shang et al. Lancet.2020. https://doi.org/10.1016/PII
Zhao JP, et al. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43: E007 (in Chinese).

27

Dilemma of ARB/ACEi

◼ Letter from Prof. Giovanni de Simone, Chair, Council on Hypertension, European Society of Cardiology

◼  Anti-RAS meds of course reduce angio-II activity, which is good for lung inflammatory response.

◼  However, too much inhibition of angio-II might increase ACE2 activity, because angio-II increase ACE2 cleavage through AT1R-activated TNF-alfa-ACE, and this might not be good for the COVID-19 action.
◼ Bin Cao’ response to Prof. Giovanni de Simone

◼  In our cohort, 48% (26/48) non-survivors had hypertension, whereas the
percentage of hypertension was only 23% (32/137) in survivors. The OR for
hypertension in ANOVA is 3.05 (1.57-5.92).

◼  No definite answer to the question of ARB/ACEi

Zhou F, et al. Lancet 2020; DOI:10.1016/S0140-6736(20)30566-3 28

Discharge criteria of COVID-19

◼ Body temperature is back to normal for more than three days ◼ Respiratory symptoms improved obviously
◼ Pulmonary imaging shows obvious absorption
◼ Two consecutive negative nucleic acid tests for respiratory

specimens (sampling interval being at least 24 hours)

29

China-Japan Friendship Hospital

Chen Wang; Yeming Wang; Fei Zhou; Guohui Fan; Hui Li; Zhibo Liu; Yi Zhang

Cooperators:

Wuhan Jinyintan Hospital

Wuhan Lung Hospital

Zhongnan Hospital of Wuhan University

Union Hospital

Wuhan Third hospital

University of Virginia

Frederick G Hayden

Oxford University

Peter W Horby

HuaZhong University

Liang Liu

Acknowledgements

Wuhan Tongji Hospital

The Central Hospital of Wuhan

Renmin Hospital of Wuhan University

Wuhan First hospital

Wuhan Fourth hospital

All health-care workers involved in the diagnosis and treatment of patients in Wuhan

  

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