An overview of the MATH+, I-MASK+ and I-RECOVER Protocols. In covid


A Guide to the Management of COVID-19

Developed and Updated by Paul Marik, MD, FCP (SA), FRCP (C), FCCP, FCCM for the COVID-19 Critical Care Alliance (FLCCC Alliance).

This is our recommended approach to COVID-19 based on the best (and most recent) literature. This is a highly dynamic topic; therefore, we will be updating the guideline as new information emerges. Please check on the FLCCC Alliance website for updated versions of this protocol.


Disclaimer: The information in this document is provided as guidance to physicians World-Wide on the prevention and treatment of COVID-19. Our guidance should only be used by medical professionals in formulating their approach to COVID-19. Patients should always consult with their physician before starting any medical treatment.

The FLCCC AllianceTM is registered as a 501(c)(3) non-profit organization.

Page 1 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 1. The course of COVID-19 and General Approach to treatment

Not too early Not too late.

Page 2 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Table 1. Pharmacological therapy for COVID by stage of illness: What has worked and what has failed*

*based on randomized controlled trials (see supporting information below)

Page 3 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 2. Timing of the initiation of anti-inflammatory therapy

Page 4 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 3. Time course of laboratory tests for COVID-19

Figure 4. SARS-Co-V-2 RNA genome

Page 5 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

While there is no cure or “Magic-bullet” for COVID-19, recently, a number of therapeutic agents have shown great promise for both the prevention and treatment of this disease including Ivermectin, Vitamin D, quercetin, melatonin, Vitamin C, fluvoxamine and corticosteroids. It is likely that no single drug will be effective in treating this complex disease and that multiple drugs with different mechanisms of action used in specific phases of the disease will be required. Furthermore, a growing body of evidence suggests that many of these agents may act synergistically in various phases of the disease. [1- 3]

As the pandemic has played out over the last year over three million patients have died world-wide and the pandemic shows no signs of abating. Most countries across the globe have limited resources to manage this humanitarian crisis. We developed the MATH+ protocol to provide guidance for the treatment of the pulmonary phase of this disease with the goal of reducing the hospital mortality from this devastating disease. However, it soon became obvious that our emphasis needed to shift to the prevention and early (home) treatment of this catastrophic disease to prevent patients progressing to the pulmonary phase and requiring hospitalization (see Figure 5). Hence, we developed the I-MASK+ protocol. While we strongly believe that such an approach can mitigate the development and progression of this disease, limit deaths, and allow the economy to re-open, “Health-Care authorities” across the globe have been silent in this regard, including the WHO, CDC, NIH, etc (see NIH Guidance, Figure 6a and 6b). While vaccination is part of the solution, it will take many months if not years to vaccinate 70-85% of the world’s population of 7.8 billion people required for “herd immunity” (it is questionable whether this goal will ever be achieved). We believe that the I-MASK+ protocol provides a bridge to universal vaccination. Furthermore, mutant strains of SARS-CoV-2 have recently appeared, these stains have demonstrated increased transmissibility.[4,5] Many of these mutations involve the spike protein (against which almost all of the vaccines have targeted), raising the real possibility that the vaccines may become less effective against the mutating strains of SARS-CoV-2.[5-7] And, finally the Post-COVID syndrome or “long-hauler syndrome” has emerged as a common and disabling disorder its pathophysiology of which is poorly understood. We offer the I-RECOVER protocol to help treat this disabling disorder.

Figure 5. Treatment Phases of COVID-19

Page 6 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 6a. NIH Recommendations for the Treatment of COVID-19 across the stages of the disease.


Page 7 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 6b. NIH Recommendations for the prevention and prophylaxis of COVID-19.

Page 8 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Pre and Postexposure Prophylaxis (The I-MASK+ protocol)

The components of the I-MASK Prophylaxis and Early Treatment protocol are illustrated in Figures 7 and 9. Recent data suggests that ivermectin, melatonin as well as the combination of quercetin (or mixed flavanoids) and vitamin C may play an important role in both pre-exposure and postexposure prophylaxis. [2,8] The evidence supporting the use of Ivermectin for the prophylaxis of COVID-19 is provided by the comprehensive review by Kory et al and the meta-analysis below (Figure 8). [9] It is important to emphasize that ALL of the medications included in our prophylactic regimen are inexpensive, safe, and widely available. The I-MASK + protocol MUST be part of an overall strategy which includes common sense public health measures, i.e., masks, social distancing, and avoidance of large groups of people.[10]

Figure 7. The I-MASK prophylactic and Early Treatment Protocol.


Page 9 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 8. Ivermectin for Pre-and postexposure prophylaxis.

Components of the I-MASK Prophylactic Protocol

• Ivermectin for postexposure prophylaxis (see NCT04422561). 0.2 mg/kg immediately then repeat 2nd dose in 48 hours. Ivermectin is best taken with a meal or just following a meal (greater absorption). [11] Oropharyngeal sanitation also suggested (see section on home treatment below).

• Ivermectin for pre-exposure prophylaxis (in HCW) and for prophylaxis in high-risk individuals
(> 60 years with co-morbidities, morbid obesity, long term care facilities, etc). 0.2 mg/kg per dose – start treatment with one dose, 2nd dose 48 hours later, then 1 dose every 7 days (i.e. weekly). [12-18] (also see NCT04425850). We believe that bi-weekly dosing is likely the most practical, cost effective and safest prophylactic regimen. See dosing Table below and Figures 8 and 9. NB. Ivermectin has a number of potentially serious drug-drug interactions; please check for potential drug interactions at Ivermectin Drug Interactions – (also see below) . The most important drug-drug interactions occur with cyclosporin, tacrolimus, anti- retroviral drugs, and certain anti-fungal drugs. While ivermectin has a remarkable safety record, [19] fixed drug eruptions (diffuse rash) and Stevens Johnson Syndrome have rarely been reported. [20,21] While hepatitis is commonly quoted as a side effect, we are aware of a single case report of reversible hepatitis.[22] The safety of ivermectin in pregnancy has not been determined. [23] Ivermectin may increase the risk of congenital malformations particularly when used in the first trimester. [23] US Food and Drug Administration (FDA) has classified ivermectin as pregnancy category C—i.e, “Animal reproduction studies have shown an adverse effect on the foetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks”. In pregnant patients with symptomatic COVID-19 infections the risk and benefits of ivermectin should be discussed with the patient, and informed consent obtained from the patient should the drug be prescribed. Additionally, women should be counselled that low concentrations of ivermectin are present in breast milk; the implications of this finding are unclear. [24]

Page 10 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

• Vitamin D3 1000–3000 IU/day. An alternative strategy is 40 000 IU weekly. Note RDA (Recommended Daily Allowance) is 800–1000 IU/day. The safe upper-dose daily limit is likely < 4000 IU/day. Vitamin D insufficiency has been associated with an increased risk of acquiring COVID-19 and from dying from the disease. [13,25-47] Vitamin D supplementation may therefore prove to be an effective and cheap intervention to lessen the impact of this disease, particularly in vulnerable populations, i.e., the elderly, those of color, obese and those living > 45o latitude. [30-45] It is likely that the greatest benefit from vitamin D supplementation will occur in vitamin D insufficient individuals who take vitamin D prophylactically; once vitamin D insufficient individuals develop COVID-19 the benefits will likely be significantly less. [48] This concept is supported by a recent study which demonstrated that residents of a long-term care facility who took vitamin D supplementation had a much lower risk of dying from COVID-19. [46]

It should be noted that Former CDC Chief Dr. Tom Frieden has stated ”Coronavirus infection risk may be reduced by Vitamin D”. dr-tom-frieden-coronavirus-infection-risk-may-be-reduced-by-vitamin-d/

• Vitamin C 500 – 1000 mg BID (twice daily) and Quercetin 250 mg daily. [49-61] Due to the possible drug interaction between quercetin and ivermectin (see below) these drugs should not be taken simultaneously (i.e. should be staggered morning and night). Vitamin C has important anti-inflammatory, antioxidant, and immune enhancing properties, including increased synthesis of type I interferons.[52,62,63] Quercetin has direct viricidal properties against a range of viruses, including SARS-CoV-2, and is a potent antioxidant and anti-inflammatory agent. [50,55,60,60,64-72] Quercetin is a potent inhibitor of inflammasome activation, which believed to play a major role in the pathophysiology of the COVID-19 immune dysfunction.[72] In addition, quercetin acts as a zinc ionophore. [73] It is likely that vitamin C and quercetin have synergistic prophylactic benefit. [2] A mixed flavanoid supplement containing quercetin, green tea catechins and anthrocyanins (from berries) may be preferable to a quercetin supplement alone; [74-78] this may further minimize the risk of quercetin related side-effects. It should be noted that in vitro studies have demonstrated that quercetin and other flavonoids interfere with thyroid hormone synthesis at multiple steps in the synthetic pathway. [79-82] The use of quercetin has rarely been associated with hypothyroidism. The clinical impact of this association may be limited to those individuals with pre-existent thyroid disease or those with sub-clinical thyroidism.[83] In women high consumption of soya was associated with elevated TSH concentrations.[84] The effect on thyroid function may be dose dependent, hence for chronic prophylactic use we suggest that the lowest dose be taken. Quercetin should be used with caution in patients with hypothyroidism and TSH levels should be monitored. It should also be noted quercetin may have important drug-drug interactions; the most important drug-drug interaction is with cyclosporin and tacrolimus. [85] In patients taking these drugs it is best to avoid quercetin; if quercetin is taken cyclosporin and tacrolimus levels must be closely monitored.

• Melatonin (slow release): Begin with 0.3 mg and increase as tolerated to 6 mg at night. [1,8,86- 92]. Melatonin has anti-inflammatory, antioxidant, immunomodulating and metabolic effects that are likely important in the mitigation of COVID-19 disease.[93-95] A recent large retrospective study demonstrated that the use of melatonin in intubated patients with COVID- 19 significantly reduced the risk of death (HR 0.1; p=0.0000000715).[94] It is intriguing to recognize that bats, the natural reservoir of coronavirus, have exceptionally high levels of melatonin, which may protect these animals from developing symptomatic disease. [96] The slow release (extended release) formulation of melatonin is preferred as it more closely replicates the normal circadian rhythm. [86]

• Zinc 30–40 mg/day (elemental zinc). [56,58,59,97-101] Zinc is essential for innate and adaptive immunity.[99] In addition, Zinc inhibits RNA dependent RNA polymerase in vitro against SARS-

Page 11 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

CoV-2 virus.[98] Due to competitive binding with the same gut transporter, prolonged high dose

zinc (> 50mg day) should be avoided as this is associated with copper deficiency. [102] • B complex vitamins [103-107]

• Optional: Famotidine 20–40 mg/day [108-114]. Low level evidence suggests that famotidine may reduce disease severity and mortality. However, the findings of some studies are contradictory. While it was postulated that famotidine inhibits the SARS-CoV-2 papain- like protease (PLpro) as well as the main protease (3CLpro) this mechanism has been disputed. [111] Furthermore, a number of studies have demonstrated an association between the use of proton pump inhibitors (PPI’s) with an increased risk of contracting COVID-19 and with worse outcomes. [115,116] This data suggest that famotidine may be the drug of choice when acid suppressive therapy is required.

• Optional/Experimental: Interferon-α nasal spray for health care workers [117].

Ivermectin dosing: 200 ug/kg or fixed dose of 12 mg (≤ 80kg) or 18 mg (≥ 80kg).[118] Depending on the manufacturer ivermectin is supplied as 3mg, 6 mg or 12 mg tablets.

50-64.9 kg
65-79.9 kg
80-94.9 kg 95-109.9 kg – 21mg

– 12mg – 15mg – 18mg

≥ 110 kg – 24mg

Figure 9. I-MASK prophylaxis protocol.


Page 12 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Drug Interactions with Ivermectin

Drug Interactions. (From Medscape).

Patents taking any of these medications should discuss with their treating physicians.

Serious – Use Alternative (4) erdafitinib

lasmiditan quinidine tepotinib

Monitor closely (possible) (49) (esp. those bolded)

• amiodarone

• atorvastatin

• berotralstat

• bosutinib

• clarithromycin

• clotrimazole

• dronedarone

• elagolix

• eliglustat

• erythromycin base

• erythromycin ethylsuccinate

• erythromycin lactobionate

• erythromycin stearate

• felodipine

• fosphenytoin

• fostamatinib

• glecaprevir/pibrentasvir

• indinavir

• istradefylline

• sarecycline

• simvastatin

• sirolimus

• St John’s Wort

• stiripentol

• tacrolimus

• tolvaptan

• trazodone

• tucatinib

• verapamil

• warfarin

itraconazole • ivacaftor
ketoconazole • lapatinib

• lomitapide • lonafarnib • loratadine • lovastatin
• nefazodone • nicardipine • nifedipine

• nilotinib
• phenobarbital
• phenytoin
• ponatinib
• quercetin (unclear: may increase

ivermectin levels). • ranolazine

rifampin ritonavir

Page 13 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Symptomatic patients at home (I-MASK+ EARLY Treatment Protocol)

• Ivermectin 0.2- 0.4 mg/kg – one dose daily for 5 days or until recovered. [13,15,19,25-28,119- 131] . Higher doses (0.4 mg/kg) often required in a) regions with more aggressive variants, b) treatment started on or after 5 days of symptoms or c) in patients in pulmonary phase, d) extensive CT involvement or e) extensive comorbidities/risk factors (older age, obesity, diabetes). Ivermectin is best taken with a meal or just following a meal (greater absorption). See Table 1, Figure 9 and NCT04523831. See drug-drug interactions above. It should be noted that multiday treatment has been shown to be more clinically effective than single-day dosing.

• Vitamin C 500 – 1000 mg BID and Quercetin 250 mg BID (or mixed flavanoid supplement). Due to the possible drug interaction between quercetin and ivermectin (see above) these drugs should not be taken simultaneously (i.e. should be staggered morning and night).

• Zinc 75–100 mg/day (elemental zinc)

• Melatonin 10 mg at night (the optimal dose is unknown) [92-95]

• Calcifediol 0.2 mg day 1, day 3 and day 7 then weekly. Vitamin D3 2000–4000 IU/day is an
alternative. [132] In the acute setting calcifediol appears to be more effective than vitamin D3.[133] Calcifediol is more efficiently absorbed, achieves 25-OH vitamin D levels quicker and is three times more potent than vitamin D3. [134,135] However, it is important to note that the optimal dose of vitamin D in the acute setting is unknown.[136,137] Very high doses may paradoxically block the vitamin D receptor.

• ASA 81–325 mg/day (unless contraindicated). ASA has antiinflammatory, antithrombotic, immunomodulatory and antiviral effects.[138-140] Platelet activation plays a major role in propagating the prothrombotic state associated with COVID-19. [141-143]

• B complex vitamins

• Oropharyngeal sanitization. [144] Inhaled steam supplemented with antimicrobial essential oils
(e.g VapoRub inhalations) [145] and/or antiseptic mouthwashes/throat rinses (chlorhexidine, povidone-iodine) and/or povidone-iodine (Betadine) nasal spray/antiseptic applied 2-3 times per day. [146-148] Oropharyngeal sanitization likely reduce the viral load in the upper airways and thereby reducing the risk of symptomatic disease and likely reducing disease severity.

• Fluvoxamine 50 – 100 mg BID. [149-153] Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that activates sigma-1 receptors decreasing cytokine production. [150,151] In addition, fluvoxamine reduces serotonin uptake by platelets, reduces histamine release from mast cells, interferes with lysosomal trafficking of virus and inhibits melatonin degradation.[154] Furthermore, it should be recognized that antidepressant medications (SSRI) deplete platelet serotonin content, thereby diminishing the release of serotonin following platelet aggregation.[155-157]

Optional: Famotidine 40 mg BID (reduce dose in patients with renal dysfunction) [108-114].

• Optional: Vascepa (Ethyl eicosapentaenoic acid) 4g daily or Lovaza (EPA/DHA) 4g daily; alternative DHA/EPA 4g daily. Vascepa and Lovaza tablets must be swallowed and cannot be crushed, dissolved, or chewed. Omega-3 fatty acids have anti-inflammatory properties and play an important role in the resolution of inflammation. In addition, omega-3 fatty acids may have antiviral properties. [58,158-161]

• Optional: Interferon-α/β nasal spray, inhalation or s/c injection. [117,162-165] It should be noted that Zinc potentiates the effects of interferon.[166,167]

• Optional (In MEN ONLY): Men who develop COVID-19 have a significantly worse outcome than women (independent of other risk factors). [168] This effect may be mediated in part by testosterone. Testosterone increases the expression of the transmembrane protease, serine 2

Page 14 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

(TMPRSS2) which is required for priming of the spike protein for cell fusion. [169] The anti- androgens dutasteride 0.5 mg/day [170] and proxalutamide 200 mg /day (NCT 04446429) have been demonstrated to reduce time to viral clearance, improve time to recovery and reduce hospitalization in men with COVID-19 in the outpatient setting. It should be noted that proxalutamide in not available in the USA.

• In symptomatic patients, monitoring with home pulse oximetry is recommended (due to asymptomatic hypoxia). The limitations of home pulse oximeters should be recognized, and validated devices are preferred.[171] Multiple readings should be taken over the course of the day, and a downward trend should be regarded as ominous.[171] Baseline or ambulatory desaturation < 94% should prompt hospital admission. [172] The following guidance is suggested: [171]

o Usetheindexormiddlefinger;avoidthetoesorearlobe
o Onlyacceptvaluesassociatedwithastrongpulsesignal
o Observereadingsfor30–60secondstoidentifythemostcommonvalue o Removenailpolishfromthefingeronwhichmeasurementsaremade
o Warmcoldextremitiespriortomeasurement

• Unclear benefit: Inhaled corticosteroids (budesonide). Two recent RCTs have demonstrated more rapid symptomatic improvement in ambulatory patients with COVID-19 treated with inhaled budesonide, however, there with no difference in the rate of hospitalization.[173,174] It should be noted that both these studies were open label (no placebo in the control arm) and that the primary end-point was subjective (time to symptom resolution). Corticosteroids downregulate the expression of interferons (hosts primary antiviral defenses) and downregulated ACE-2 expression (harmful). Furthermore, two population level studies suggest that inhaled corticosteroids may increase the risk of death in patients with COVID-19. [175,176] Based on these data the role of inhaled corticosteroids in the early phase of COVID-19 is unclear.

• Unclear benefit (best avoided). Colchicine 0.6mg BID for 3 days then reduce to 0.6mg daily for total of 30 days. In the COLCORONA study colchicine reduced the need for hospitalization (4.5 vs 5.7%) in high risk patients. [177] Colchicine was associated with an increased risk of side effects most notably diarrhea and pulmonary embolism. It should be noted that in the RECOVERY trial colchicine failed to demonstrate a survival benefit in hospitalized patients. Due to potentially serious drug interactions with ivermectin (and other CYP 3A4 and p-glycoprotein inhibitors) as well as with statins, [178] together with its marginal benefit colchicine is best avoided.

• Not recommended: Systemic corticosteroids. In the early symptomatic (viral replicative phase), corticosteroids may increase viral replication and disease severity.[179]

• Not recommended: Hydroxychloroquine (HCQ). The use of HCQ is highly controversial.[180] The best scientific evidence from randomized controlled trials suggests that HCQ has limited/no proven benefit for post exposure prophylaxis, for the early symptomatic phase and in hospitalized patients. [181-202] Considering, the unique pharmacokinetics of HCQ it is unlikely that HCQ would be of benefit in patients with COVID-19 infection (it takes 5–10 days to achieve adequate plasma and lung concentrations).[191,203-205] Finally, it should be recognized that those studies which are widely promoted to support the use of HCQ are severely methodologically flawed.[206-209]

• Not recommended: Azithromycin, doxycycline, or quinolone antibiotics. [210,211]

Page 15 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Mildly Symptomatic patients (on floor/ward in hospital).

• Ivermectin 0.4 – 0.6 mg/kg daily for 5 days or until recovered. A higher dose may be required in patins with more severe disease and in those in whom treatment is delayed. [13,15,19,25- 28,119-128,130]. Ivermectin is best taken with a meal or just following a meal (greater absorption). It should be noted that ivermectin has potent anti-inflammatory properties apart from its antiviral properties.[212-215] See Table 1 and Figure 10. See drug-drug interactions above.

• Methylprednisolone 80 mg bolus then 40 mg q 12 hourly (alternative: 80 mg bolus followed by 80 mg/240 ml normal saline IV infusion at 10 ml/hr); increase to 80 mg and then 125 mg q 12 hourly in patients with progressive symptoms and increasing CRP. There is now overwhelming and irrefutable evidence that corticosteroids reduce the risk of death in patients with the pulmonary phase of COVID-19 i.e., those requiring supplemental oxygen or higher levels of support. [216-228] We believe that the use of low-fixed dose dexamethasone is inappropriate for the treatment of the pulmonary phase of COVID-19 (see section on MATH+ below). The role of inhaled corticosteroids (budesonide) is unclear and appears to be rather limited.

• Enoxaparin 1mg/kg 12 hourly (see dosage adjustments and Xa monitoring below). An interim analysis of the ATTACC, ACTIV-4a & REMAP-CAP trials demonstrated a mortality reduction with full anticoagulation (regardless of D-dimer level) in hospitalized patients with COVID-19.

• Vitamin C 500–1000 mg q 6 hourly and Quercetin 250–500 mg BID (if available)

• Zinc 75–100 mg/day

• Melatonin 10 mg at night (the optimal dose is unknown) [92]

• Calcifediol 0.2 mg day 1, day 3 and day 7 then weekly. [132] Vitamin D3 20,000–60,000 IU single
oral dose is an alternative; this should be followed by 20,000 IU D3 weekly until discharged from
hospital. In the acute setting calcifediol appears to be more effective than vitamin D3. [133]

• ASA 81-325 mg (if not contraindicated). Moderate-severe COVID infection results in profound
platelet activation contributing to the pro-thrombotic state and increasing the inflammatory

• B complex vitamins

• Famotidine 40 mg BID (20–40 mg/day in renal impairment). [108-114] Famotidine may be useful for its protective effect on gastric mucosa, its anti-viral properties and histamine blocking properties.

• Fluvoxamine 50 -100 mg BID.

• Optional (In MEN ONLY): The anti-androgen agents dutasteride 0.5 mg/day, proxalutamide 200
mg daily or finasteride 5 mg daily. It should be noted that proxalutamide in not available in the

• Optional: The anti-serotonin agent, cyproheptadine 4–8 mg PO q 6 hour should be considered in
patients with more severe disease. [231,232] Patients with COVID-19 have increased circulating levels of serotonin likely the result of increased platelet activation and decreased removal by the pulmonary circulation due to an extensive microcirculatory vasculopathy. [231,233-235] Increased circulating serotonin is associated with pulmonary, renal and cerebral vasoconstriction, and may partly explain the V/Q mismatch and reduced renal blood flow noted in patients with severe COVID-19 infection. [236-239] Furthermore, serotonin itself enhances platelet aggregation creating a propagating immuno-thrombotic cycle.[240] In addition, serotonin receptor blockade may reduce progression to pulmonary fibrosis. [241]

• Optional: Vascepa (Ethyl eicosapentaenoic acid) 4g daily or Lovaza (EPA/DHA) 4g daily; alternative DHA/EPA 4g daily. [242]

Optional: Remdesivir 200 mg IV loading dose D1, followed by 100mg day IV for 9 days. [243,244] This agent has been reported to reduce time to recovery (based on an ordinal scale) in patients

Page 16 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

requiring low levels of supplemental oxygen. [244,245] The recently published SOLIDARITY trial demonstrated no mortality benefit of this agent in the entire treatment cohort or any subgroup.[246] Considering the high cost of this agent and the lack of benefit on patient centered outcomes the role of this drug seems very limited. A recent in vitro study demonstrated marked synergy between Remdesivir and Ivermectin. [247] Considering the broad antiviral and anti-inflammatory effects of ivermectin, together with its remarkable safety record, this finding suggest that ivermectin should be prescribed in all patients receiving Remdesivir.

• Not recommended: Hydroxychloroquine, azithromycin, doxycycline, or quinolone antibiotics. [172,173]

• Not recommended: Colchicine. Recruitment to the colchicine arm of the RECOVERY trial has been closed as no mortality benefit was noted with colchicine (Mortality 20% colchicine, 19% standard of care). In addition, potentially serious drug-drug interactions exist with the use of colchicine and CYP 3A4 and p-glycoprotein inhibitors (ivermectin, macrolide antibiotics, cyclosporin, etc) as well as with the use of statins. [178]

• N/C 2L/min if required (max 4 L/min; consider early t/f to ICU for escalation of care).

• Avoid Nebulization and Respiratory treatments. Use “Spinhaler” or MDI and spacer if required.

• T/f EARLY to the ICU for increasing respiratory signs/symptoms, increasing oxygen requirements
and arterial desaturation.

Figure 10. Metaanalysis of Ivermectin clinical studies (in hospital mortality)

Page 17 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

MATH + PROTOCOL (for patients admitted to the ICU) [248,249]

1. Methylprednisolone 80 mg loading dose then 40 mg q 12 hourly for at least 7 days and until transferred out of ICU (alternative: 80 mg bolus followed by 80 mg/240 ml normal saline IV infusion at 10 ml/hr). In patients with an increasing CRP or worsening clinical status increase the dose to 80 mg q 12 hourly (then 125mg q 12 hourly), then titrate down as appropriate. [216-228] Pulse methylprednisolone 250–500 mg mg/day for 3 days (followed by taper) may be required.[226] We suggest that all patients admitted to the ICU have a chest CT scan on admission to allow risk stratification based on the extent of the disease; those with extensive disease should be initiated on high dose corticosteroids (see section below on severe COVID). As depicted in Table 1, methylprednisolone is the corticosteroid of choice. Observational and randomized studies have clearly demonstrated the superiority of methylprednisolone over low dose dexamethasone.[250,251] These clinical findings are supported by a genomic study.[140] Methylprednisolone should be weaned slowly over two weeks once oxygen is discontinued to prevent relapse/recurrence (20mg twice daily once of oxygen, then 20 mg/day for 5 days, then 10 mg/day for 5 days). The effect of corticosteroids on the profile of dysregulated immune markers is clearly illustrated in Figure 12. [252]

2. Ascorbic acid (Vitamin C) 50 mg/kg (or 3000 mg) IV q 6 hourly for at least 7 days and/or until transferred out of ICU.[53,62,63,253-263]. Mega-dose vitamin C should be considered in severely ill patients, those with progressive respiratory failure and as salvage therapy: 25 g vitamin C in 200-500 cc saline over 4-6 hours every 12 hourly for 3-5 days, then 3g IV q 6 hourly for total of 7- 10 days of treatment [264] (also see ). Mega- dose Vitamin C appears safe in patients with ARF and ESRD. In patients with CRF a dose of 12.5 g q 12 hourly may be an adequate compromise.[265] In the study by Lankadeva et al, mega-dose vitamin C increased renal cortical blood flow and renal cortical pO2; oxalate crystals were not detected.[264] Note caution with POC glucose testing (see below). Oral absorption is limited by saturable transport and it is difficult to achieve adequate levels with PO administration. However, should IV Vitamin C not be available, it would be acceptable to administer PO vitamin C at a dose of 1g every 4–6 hours.

3. Anticoagulation: An interim analysis of the ATTACC, ACTIV-4a & REMAP-CAP trials demonstrated a marginally increased mortality in ICU patients treated with full anti-coagulation (35.3% vs. 32.6)%. Critically ill COVID-19 patients frequently have impaired renal and it is likely that in the absence of Xa monitoring patients were over-anticoagulated. However, full anti-coagulation should be continued on floor patients transitioned to the ICU who have normal renal function. In all other patients we would suggest intermediate dose enoxaparin i.e 60 mg/day (enhanced thromboprophylaxis).[266] Full anticoagulation (enoxaparin or heparin) may be required in patients with increasing D-dimer or with thrombolic complications. Due to augmented renal clearance some patients may have reduced anti-Xa activity despite standard dosages of LMWH.[236] We therefore recommend monitoring anti-Xa activity aiming for an anti-Xa activity of 0.5 – 0.9 IU/ml. Heparin is suggested with CrCl < 15 ml/min. It should also be appreciated that vitamin C is a prerequisite for the synthesis of collagen and vitamin C deficiency is classically associated with vascular bleeding.[62,63] This is relevant to COVID-19, as vitamin C levels are undetectable in severely ill COVID-19 patients and this may partly explain the increased risks of anticoagulation in ICU patients (not treated with vitamin C). [267-269]

Note: A falling SaO2 and the requirement for supplemental oxygen should be a trigger to start anti- inflammatory treatment (see Figure 2).

Note: Early termination of ascorbic acid and corticosteroids will likely result in a rebound effect with clinical deterioration.

Page 18 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Additional Treatment Components

4. Highly recommended: Ivermectin 0.4 – 0.6 mg/kg day orally for 5 days or until recovered [19,25- 27,119,122-129,212-214,270-276]. A higher dose (0.6mg/kg) is suggested in patients with severe disease and/or those with delayed initiation of therapy. Note that ivermectin has potent antiviral and ant-inflammatory effects. See Table 1 and Figure 10. As noted above clinical outcomes are superior with multiday as opposed to single day dosing.

5. Melatonin 10 mg at night (the optimal dose is unknown).[93-95]

6. Calcifediol 0.2–0.5 mg (25-OH Vitamin D). [132] This should be followed by 0.2 mg calcifediol weekly
until discharged from hospital. Should calcifediol not be available, supplement with vitamin D3 (cholecalciferol) 20,000–60,000 IU single oral dose, followed by 20,000 IU D3 weekly until discharged from hospital. In the acute setting calcifediol appears to be more effective than vitamin D3. [133] Vitamin D3 takes many days to be converted to 25OH vitamin D; [277] this may explain the lack of benefit of D3 in patients hospitalized with severe COVID-19. [48]

7. Thiamine 200 mg IV q 12 hourly for 3-5 days then 200mg daily [278-283] Thiamine may play a role in dampening the cytokine storm. [279,284]

8. ASA 325 mg. COVID infection results in profound platelet activation contributing to the severe pro- thrombotic state and increasing the inflammatory response.[142,143,229,230] As the risk of significant bleeding is increased in patients receiving both ASA and heparin, ASA should therefore not be used in patients at high risk of bleeding. In addition (as noted below) patients should receive famotidine concurrently.

9. The anti-serotonin agent, cyproheptadine. Platelet activation results in the release of serotonin, which may contribute to the immune and vascular dysfunction associated with COVID-19. [215-219] Therefore, the serotonin receptor blocker cyproheptadine 4–8 mg PO q 6 hours should be considered.

10. B complex vitamins.

11. Fluvoxamine 50 -100 mg BID.

12. Magnesium: 2 g stat IV. Keep Mg between 2.0 and 2.2 mmol/l. [106] Prevent hypomagnesemia
(which increases the cytokine storm and prolongs Qtc). [285-287]

13. Famotidine 40 mg BID (20–40 mg/day in renal impairment). [108-114].

14. Optional. Atorvastatin 80 mg/day (reduce dose to 40mg if taken with ivermectin due to possible
drug-drug interaction). Statins have pleotropic anti-inflammatory, immunomodulatory, antibacterial, and antiviral effects. In addition, statins decrease expression of PAI-1. Simvastatin has been demonstrated to reduce mortality in the hyper-inflammatory ARDS phenotype. [288] Preliminary data suggests atorvastatin may improve outcome in patients with COVID-19.[289-293] Due to numerous drug-drug interactions simvastatin should be avoided.

15. Optional: Vascepa, Lovaza or DHA/EPA 4g day (see above). [242]

16. Optional (In MEN ONLY): The anti-androgen agent’s dutasteride 0.5 mg/day, proxalutamide 200 mg
daily or finasteride 5 mg daily. It should be noted that proxalutamide in not available in the USA.

17. Unclear benefit. The role of the IL-1 receptor blocker ANAKINRA is unclear. Anakinra together with
corticosteroids may have a role in patients with evidence of the macrophage activation syndrome/hemophagocytotic lymphohistiocytosis. While observational studies suggest a dramatic improvement in outcome (OR 0.258 95% CI 0.162 – 0.410), [294-300] a single RCT was stopped prematurely due to futility.[301]

18. Not recommended: The best information to date suggests that prophylactic azithromycin as well as doxycycline and quinolone antibiotics are of little benefit in patients with COVID-19.[210,302,303] Patients with COVID-19 are at an increased risk of developing bacterial superinfections and prophylactic antibiotics may increase the risk of infection with multiresistant organisms.

19. Not recommended: Remdesivir. This drug has no benefit at this stage of the disease.

Page 19 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

20. Not recommended. Convalescent serum [304-309] nor monoclonal antibodies. [310] However, convalescent serum/ monoclonal antibodies may have a role in patients with hematologic malignancies.[311]

21. Not recommended. Colchicine (see above).

22. Not recommended. Tocilizumab. Five RCTS have now failed to demonstrate a clinical benefit from
tocilizumab. [312-316] Considering the effect of IL-6 inhibitors on the profile of dysregulated inflammatory mediators this finding is not surprising (see Figure 12). [247] Tocilizumab may have of benefit in patients receiving an inadequate dose of corticosteroids.[317] In patients who receive an adequate therapeutic dose of corticosteroid the role of this drug appears limited.

23. Broad-spectrum antibiotics if superadded bacterial pneumonia is suspected based on procalcitonin levels and resp. culture (no bronchoscopy). Due to the paradox of hyper-inflammation and immune suppression (a major decrease of HLA-DR on CD14 monocytes, T cell dysfunction and decreased CD4 and CD8 counts) secondary bacterial and fungal infections (Candida and Aspergillus species) and viral reactivation is not uncommon. [318-320] Patients with non-resolving fever, increasing WBC count and progressive pulmonary infiltrates should be screened for COVID-19-associated pulmonary aspergillosis (CAPA). [321] Recommended first-line therapy for CAPA is either voriconazole or isavuconazole (beware drug-drug interactions). While low CD4 counts are typical of severe COVID-19 infection, PJP infections have not been reported; therefore PJP prophylaxis is not required.

24. Maintain EUVOLEMIA (this is not non-cardiogenic pulmonary edema). Due to the prolonged “symptomatic phase” with flu-like symptoms (6–8 days) patients may be volume depleted. Cautious rehydration with 500 ml boluses of Lactate Ringers may be warranted, ideally guided by non- invasive hemodynamic monitoring. Diuretics should be avoided unless the patient has obvious intravascular volume overload. Avoid hypovolemia.

25. Early norepinephrine for hypotension. It should however be appreciated that despite the cytokine storm, vasodilatory shock is distinctly uncommon in uncomplicated COVID-19 (when not complicated by bacterial sepsis). This appears to be due to the fact that TNF-α which is “necessary” for vasodilatory shock is only minimally elevated.

26. Escalation of respiratory support (steps); Try to avoid intubation if at all possible, (see Figure 13)

a. Accept “permissive hypoxemia” (keep O2 Saturation > 84%); follow venous lactate and
Central Venous O2 saturations (ScvO2) in patents with low arterial O2 saturations

b. N/C 1–6 L/min

c. High Flow Nasal canula (HFNC) up to 60–80 L/min

d. Trial of inhaled Flolan (epoprostenol)

e. Attempt proning (cooperative repositioning-proning) [322-325]

f. Intubation … by Expert intubator; Rapid sequence. No Bagging; Full PPE.
Crash/emergency intubations should be avoided.

g. Volume protective ventilation; Lowest driving pressure and lowest PEEP as possible.
Keep driving pressures < 15 cm H2O.

h. Moderate sedation to prevent self-extubation

i. Trial of inhaled Flolan (epoprostenol)

j. Prone positioning.

There is widespread concern that using HFNC could increase the risk of viral transmission. There is however, no evidence to support this fear.[326] HFNC is a better option for the patient and the health care system than intubation and mechanical ventilation. CPAP/BiPAP may be used in select patients, notably those with COPD exacerbation or heart failure.

A sub-group of patients with COVID-19 deteriorates very rapidly. Intubation and mechanical ventilation may be required in these patients.

Page 20 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Table 2: Comparison of Methylprednisolone, Dexamethasone and Hydrocortisone- Number Need to Treat (NNT)

Page 21 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

An Approach to the patient with SEVERE Life threatening COVID-19 Organizing Pneumonia

The first task of the clinician is to determine the reversibility of the pulmonary disease…. This is a critical assessment. Aggressive anti-inflammatory treatment is futile in patients with advanced fibrotic lung disease…. The horse has already bolted and allowing the patient a “peaceful death” is the most compassionate and humane approach. The reversibility of the pulmonary is dependent on a number of factors superseded by a good deal of clinical judgement; these include:

. a)  The length of time that has elapsed since the onset of symptoms. Early aggressive treatment is critical to prevent disease progression. With each day the disease becomes more difficult to reverse. The ‘traditional’ approach of supportive care alone is simply unacceptable.

. b)  The level of inflammatory biomarkers particularly the CRP. In general the CRP tracks the level of pulmonary inflammation.[327] A very high CRP may indicate reversible pulmonary inflammation.

. c)  It is likely that advanced age is a moderating factor making the pulmonary disease less reversible.

. d)  A chest CT is extremely helpful in determining the reversibility of disease. BEWARE this is not ARDS but organizing pneumonia.[328] The extent of the pulmonary involvement may be determined qualitatively or preferably quantitatively.[327,329-335] The Ichikado is a useful quantitative score to evaluate the extent of lung involvement with COVID-19.[336,337] The changes in the CT follow a stereotypic progressive pattern:

I. Peripheral, patchy, predominantly basal ground glass opacification (GGO). GGO is defined an increase in density of lung with visualization of bronchial and vascular structures through it

II. Progressive widespread bilateral GGO

I. Crazy paving (CGO with interlobular and intralobular septal thickening)

II. Air space consolidation (air bronchograms)

III. Dense airspace consolidation

IV. Coalescent consolidation

V. Segmental/subsegmental pulmonary vessel dilatation

VI. Bronchial wall thickening

VII. Linear opacities

VIII. Traction bronchiectasis

IX. Cavitation

X. Fibrotic changes with bullae and reticulation

GGO pattern is significantly more prevalent in early-phase disease compared with late-phase disease while crazy-paving and consolidation patterns are significantly more common in late-phase.[327] Therefore widespread GGO suggests reversibility while widespread consolidation with other features of more advanced disease suggest irreversible lung disease. However, when in doubt (borderline cases) a time limited therapeutic trial of the aggressive full “Monty” approach may be warranted.

Page 22 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 11. “Typical” progression of Chest CT findings.

The FULL “MONTY” for SEVERE COVID Pulmonary disease

I. Methylprednisolone 250-500 mg q 12 hourly for at least 3 days then titrate guided by clinical status and CRP.

II. Ivermectin 0.4 mg kg for 5 days

III. Vitamin C 3 g 6 hourly to 25g q 12 hourly

IV. Cyproheptadine 4–8 mg PO q 6 hourly

V. Melatonin 10mg PO at night

VI. Enoxaparin 60 mg daily; critically ill patients usually have some degree of renal impairment and
will require a renally adjusted lower dose. Patients with very high D-dimer and or thrombotic complications may require full anti-coagulant doses of Lovenox. It may be prudent to monitor Xa levels aiming for 0.4-0.8 IU/ml (a somewhat lower anti-Xa).

VII. Fluvoxamine 50- 100 mg BID

VIII. Atorvastatin 80 mg/day (reduce dose to 40mg if taken with ivermectin due to possible drug-drug

IX. Famotidine 40 mg BID

X. Thiamine 200 mg q 12 hourly

XI. MEN only: Finasteride 5 mg daily or dutasteride 0.5 mg daily

Page 23 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

While it is unclear which of the above medications included in the “Severe Covid-19” cocktail contributes to improved outcomes, all of these drugs have been shown to be safe and independently to improve the ocutome of patients with COVID-19. Ultimately it is irrelevant as to the contribution of each element as long as the patient improves and survives his/her ICU stay. We are in the midst of a pandemic caused by a virus causing devastating lung disease, and there is no place for “ivory tower medicine”.

Figure 12. Comparison of circulating COVID-19 related biomarkers in response to immunomodulatory therapy.[252]

Page 24 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Figure 13.

Page 25 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Salvage Treatments

• High dose bolus corticosteroids; 500–1000 mg/day methylprednisolone for 3 days then taper. [224,226]

• Plasma exchange [338-344]. Should be considered in patients with progressive oxygenation failure despite corticosteroid therapy as well as in patients with severe MAS. Patients may require up to 5 exchanges. FFP is required for the exchange; giving back “good humors” appears to be more important than taking out “bad humors”.

• Mega-dose vitamin C should be considered in severely ill patients and as salvage therapy: 25g vitamin C in 200-500 cc saline over 4-6 hours, 12 hourly for 3-5 days, then 3g IV q 6 hourly for total of 7-10 days of treatment.[264,265] (also see mp6RZjCQ)

• In patients with a large dead-space ventilation i.e. high PaCO2 despite adequate minute ventilation consider “Half-dose rTPA” to improve pulmonary microvascular blood flow; 25mg of tPA over 2 hours followed by a 25mg tPA infusion administered over the subsequent 22 hours, with a dose not to exceed 0.9 mg/kg followed by full anticoagulation.[345,346]

• Etoposide IV once per week at 50 mg/m2 until improved. [347,348] Severe-COVID pneumonia/organizing pneumonia is in essence caused by the “pulmonary macrophage activation syndrome”. [349,350] Similar to the treatment of macrophage activation syndrome and HLH, etoposide may reduce macrophage numbers and improve outcome.[351- 353] Etoposide is a chemotherapeutic agent and the risk/benefits should be considered in consultation with a hematologist. Furthermore, the changes in the hematological profile should be closely monitored.

• Combination inhaled nitric oxide (or epoprostenol) and intravenous almitrine (10 – 16 ug/kg/min). The combination of inhaled nitric oxide, a selective pulmonary vasodilator, and almitrine, a specific pulmonary vasoconstrictor, may improve the severe V/Q mismatch in patients with severe COVID-19 “pneumonia”. [354-357]

• ECMO [358-360]. Unlike “typical ARDS”, COVID-19 patients may not progress into a resolution phase. Rather, patients with COVID-19 with unresolved inflammation may progress to a severe fibro-proliferative phase and ventilator dependency. ECMO in these patients would likely serve little purpose. ECMO however may improve survival in patients with severe single organ failure (lung) if initiated within 7 days of intubation. [361]
Salvage treatments of unproven/no benefit.

• Convalescent serum/monoclonal antibodies: Four RCT’s failed to demonstrate a clinical benefit with the use of convalescent serum. [304-306,308,309] Eli Lilly suspended the ACTIV- 33 clinical trial as their monoclonal antibody failed to demonstrate a clinical benefit in hospitalized patients.[362] It is noteworthy that the only RCT demonstrating efficacy of convalescent plasma for an infectious disease was conducted more than 40 years ago, for treating Argentine hemorrhagic fever. [211] Furthermore, giving antibodies directed against SARS-CoV-2 appears pointless when the virus is already DEAD (pulmonary phase). In addition, IgG is a large protein which penetrates tissues poorly, and is unlikely to achieve submucosal concentrations required for mucosal immunity.[363] And lastly, COVID-19 pulmonary disease is immune mediated, and it would therefore appear paradoxical to enhance the antibody response with convalescent serum. [364]

• Janus Kinase inhibitors downregulate cytokine expression and may have a role in this disease. [365-367] The role of the combination of Baricitinib and Remdesivir is unclear.[368]

• In patients with progressive fibrosis the combination of anti-fibrotic therapy with corticosteroids should be considered. [369-372] It should however be recognized that unlike all the medications in the MATH+ protocol, pirfenidone and nintedanib have complex side-


Page 26 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

effects and drug interactions and should be prescribed by pulmonary physicians who have

experience with these drugs.
• CVVH/D with cytokine absorbing/filtering filters [373,374] This treatment strategy appears to

have an extremely limited role.

Treatment of Macrophage Activation Syndrome (MAS)

• Severe-COVID pneumonia/organizing pneumonia is in essence caused by the “pulmonary macrophage activation syndrome” and the distinction between severe COVID and MAS is unclear. [349,350]

• A ferritin > 4400 ng/ml is considered diagnostic of MAS. Other diagnostic features include increasing AST/ALT and CRP and progressive multi-system organ failure.[351]

• “High dose corticosteroids.” Methylprednisolone 500-1000 mg daily for three days and then then wean according to Ferritin, CRP, AST/ALT. Ferritin should decrease by at least 15% before weaning corticosteroids.

• Similar to the treatment of macrophage activation syndrome and HLH, etoposide may reduce macrophage numbers and improve outcome (see above).[351-353] The combination of high dose corticosteroids and “low-dose” etoposide is an effective treatment for MAS.

• Consider plasma exchange.

• On admission: Procalcitonin (PCT), CRP, BNP, Troponins, Ferritin, Neutrophil-Lymphocyte ratio, D-dimer and Mg. CRP and D-dimer are important prognostic markers.[375] A PCT is essential to rule out coexisting bacterial pneumonia.[376]

• As indicated above (corticosteroid section), a chest CT scan on admission to the ICU is very useful for risk stratification and for the initial corticosteroid dosing strategy. The Ichikado Score is a quantitative method to assess the extent of lung involvement on the CT scan.[336,377] Follow-up CXR, CT scan (if indicated) and chest ultrasound as clinically indicated.

• Daily: CRP, Ferritin, D-Dimer and PCT. CRP and Ferritin track disease severity closely (although ferritin tends to lag behind CRP). Early high CRP levels are closely associated with the degree of pulmonary involvement and the CT score. [378]

• In patients receiving IV vitamin C, the Accu-ChekTM POC glucose monitor will result in spuriously high blood glucose values. Therefore, a laboratory glucose is recommended to confirm the blood glucose levels. [379,380]

• ECHO as clinically indicated; Patients may develop a severe “septic” cardiomyopathy and/or COVID-19 myocarditis. [381,382]
Post ICU management

• Enoxaparin 40–60 mg s/c daily

• Methylprednisolone 40 mg day, then wean slowly, follow CRP and oxygen requirements –
wean off over two weeks once oxygen is discontinued to prevent relapse/recurrence

• Vitamin C 500 mg PO BID

• Melatonin 3–6 mg at night

• Vascepa, Lovaza or DHA/EPA 4g day (important for resolution of inflammation)

Page 27 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Post Hospital Discharge management

a. Patients have an increased risk of thromboembolic events post-discharge. [383,384] Extended thromboprophylaxis (? with a DOAC) should be considered in high-risk patients. Risk factors include:[385]
i. Increased D dimer (> 3 times ULN) ii. Increased CRP (> 2 times ULN) [386]
iii. Age > 60
iv. Prolonged immobilization

b. Patients with unresolved pulmonary infiltrates and/or those who remain dyspneic and/or
oxygen dependent should be discharged on a tapering course of corticosteroids (prednisone).

c. Patients should continue to receive vitamin C, melatonin, omega-3 fatty acids and ? famotidine.
These agents may reduce this risk of developing the post-COVID syndrome.

The post-COVID-19 syndrome (Long-haul syndrome)

The post-COVID syndrome is characterized by prolonged malaise, headaches, generalized fatigue, sleep difficulties, hair loss, smell disorder, decreased appetite, painful joints, dyspnea, chest pain and cognitive dysfunction.[387-398] Up to 80% of patients experience prolonged illness after Covid-19. The post-COVID-19 syndrome may persistent for months after the acute infection and almost half of patients report reduced quality of life. Patients may suffer prolonged neuropsychological symptoms, including multiple domains of cognition.[396,399] A puzzling feature of the long-haul syndrome is that it is not predicted by initial disease severity; post-COVID-19 frequently affects mild-to-moderate cases and younger adults that do not require respiratory support or intensive care. [398]

The post-COVID syndrome in highly heterogenous and likely results from a variety of pathogenetic mechanisms. Ongoing respiratory symptoms (SOB, cough, reduced effort tolerance) may be related to unresolved organizing pneumonia. The neurological symptoms may be related micro- and/or macrovascular thrombotic disease which appears to be common in severe COVID-19 disease.[400] Brain MRIs’ 3 months post-infection demonstrated micro-structural changes in 55% of patients. [401] In addition, features of encephalopathy may be related to encephalitis and auto-reactive brain antibodies [402] as well as severe cerebral vasoconstriction. [403] The brain microvasculature expresses ACE-2 receptors and SARS-CoV-2 “pseudovirons” may bind to the microvascular endothelium causing cerebral microvascular inflammation and clotting.[404] The features of the post-COVID syndrome overlap with those of the myalgic encephalomyelitis/chronic fatigue syndrome.[398] Furthermore, the similarity between the mast cell activation syndrome and post-COVID syndrome has been observed, and many consider post-COVID to be a variant of the mast cell activation syndrome.[405] Mast cells are present in the brain, especially in the median eminence of the hypothalamus, where they are located perivascularly close to nerve endings positive for corticotrophin releasing hormone.[406] Following stimulation, mast cells release proinflammatory mediators such as histamine, tryptase, chemokines and cytokines which may result in neurovascular inflammation.[406] The “brain-fog”, cognitive impairment and general fatigue reported in log-COVID may be due to neurovascular inflammation. Auto-reactive antibodies have been reported in patients with post-COVID syndrome and COVID-19 autoimmunity may play a role in this syndrome. [398]

It is likely that patients who received inadequate anti-inflammatory treatment (corticosteroids, fluvoxamine, ivermectin, etc) during the acute phase of COVID are much more likely to develop the post-COVID syndrome. In patients with ongoing respiratory symptoms chest imaging is suggested (preferably a chest CT scan). Those with unresolved pulmonary inflammation (organizing pneumonia)

Page 28 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

should be treated with a course of corticosteroids (prednisone) and closely followed. Similar to patients who have recovered from septic shock, [407] a prolonged (many months) immune disturbance with elevated pro- and anti-inflammatory cytokines may contribute to the post-COVID-19 syndrome. Consequently, a CRP should be measured and extended corticosteroids (titrated to the CRP) offered to these patients. It should be noted that much like omega-3 fatty acids (see below) corticosteroids have been demonstrated to increase expression of pro-resolving lipids including Protectin D1 and Resolvin D4.[408]

An unknown number of patients who have recovered from COVID-19 organizing pneumonia will develop pulmonary fibrosis with associated limitation of activity. Pulmonary function testing demonstrates a restrictive type pattern with decreased residual volume and DLCO.[393] These patients should be referred to a pulmonologist with expertise in pulmonary fibrosis. Anti-fibrotic therapy may have a role in these patients, [369-372] however additional data is required before this therapy can be more generally recommended. As discussed above, the serotonin receptor blocker cyproheptadine may reduce the risk of pulmonary fibrosis. [241]

I-RECOVER: The I-RECOVER Protocol for the treatment of the “Long-haul Syndrome”.

Although numerous reports describe the epidemiology and clinical features of post-COVID syndrome, [387-397] studies evaluating treatment options are glaringly sparse.[312] Indeed, the NICE guideline for managing the long-term effects of COVID-19 provide no specific treatment recommendations.[409] In general, while the treatment of ‘Long COVID” should be individualized, the following treatments may have a role in the treatment of this disorder.

First-line treatment.

• Prednisone 60 mg daily then taper, based on clinical response (in patients with ongoing organizing pneumonia and those with ongoing inflammation; see above)

• Ivermectin has been reported to have a role in the treatment of post-COVID-19 syndrome. [312] A dose of 0.2mg/kg day for 5 days is suggested. A repeat course is suggested in those who respond poorly or relapse once the treatment is stopped. The anti-inflammatory properties of ivermectin may mediate this benefit.

• Omega-3 fatty acids: Vascepa, Lovaza or DHA/EPA 4 g day. Omega-3 fatty acids play an important role in the resolution of inflammation by inducing resolvin production. [160,161]

• Luteolin 100-200 mg day or quercetin 250 mg day (or mixed flavanoids). Luteolin and quercetin have broad spectrum anti-inflammatory properties. These natural flavonoids inhibit mast cells,[406,410- 413] and have been demonstrated to reduce neuroinflammation. [414]

• Famotidine 20-40mg day (histamine-2 blocker for Mast Cell Activation syndrome). [405]

• Melatonin 2- 5mg at night (slow release/extended release) with attention to sleep hygiene.

• Vitamin D3 1000-3000 u/day and Vitamin C 500 mg BID (vitamin C inhibits histamine).[62]

• Functional rehabilitation with light aerobic exercise paced according to individual capacity.[398]

• Behavioral modification and psychological support may help improve survivors’ overall well-being
and mental health. [398]

Page 29 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Second-line approach (after poor response to first-line protocol)

• Repeat first-line therapy including corticosteroids and ivermectin. Increase dose of ivermectin to 0.4mg/kg day for 5-10 days.

• Atorvastatin 40 mg daily (increase resolvin synthesis) [408]

• Fluvoxamine, especially in those with neurocognitive issues. Start at 25 mg daily, Increase slowly to
50 -100 mg day. Monitor response closely. Teens and young adults who are prescribed fluvoxamine can experience acute anxiety which needs to be monitored for and treated by the prescribing clinician to prevent rare escalation to suicidal or violent behavior

• Optional: H1 receptor blocker (for mast cell activation syndrome).

• Optional: montelukast 10mg/day (for mast cell activation syndrome)
Patients and health care providers are referred to the following Website:



Page 30 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Maintaining mental health and the avoiding the misinformation pandemic

Misinformation on the Coronavirus might be the most contagious thing about it”
Dr. Tedros, WHO Director General

• The Panic and misinformation spread by Social Media travels faster than the pandemic itself. What you can do?

o Avoidsocialmediaasmuchaspossible;excesssocialmediaexposureincreasesthe likelihood of anxiety and depression[415]

o Readthenews/informationfromreliablesources(ifyoucanfindone)
o Haveadesignatedtimeforcheckinginformation
o PeoplesharefalseclaimsaboutCOVID-19partlybecausetheysimplyfailtothinksufficiently

about whether or not the content is accurate when deciding what to share. [416] o Stayconnectedtopositivepeople!Remotely!
o Haveaplanforstayingintouchwithfamilyandfriends
o Identifypositiveinfluencers…limitcontactwithother“worriers”
o Isolationcancauserumination/anxiousthinkingtoescalate
o Maintainasenseofhope,humanityandkindnesstowardothers
o Seekprofessionalhelpifanxietyisoverwhelming

• Recognize the things you can control
o WEARAMASKwhenincontactwithothers
o Establishsocialdistancing;stand/sitabout6feetawayfromothers o Limitattendanceatlargegatherings
o Eliminateyourcontactwiththosewhoareill
o DON’Tgotoworkorschoolifyouaresick
o Practiceself-care

 Good sleep, balanced diet, exercise
 Mindfulness/Meditation/Relaxation activities

Page 31 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Key Concepts of the I-MASK and MATH+ Treatment Protocols

This is an extraordinarily complex disease; many of the mysteries are still unravelling. However, a number of concepts are key to the management of this “treatable disease; they include.

1. Patients transition through a number of different phases (clinical stages). The treatment of each phase is distinct … this is critically important (see Figures 1 & 2).

2. Antiviral therapy is likely to be effective only during the viral replicative phase whereas anti- inflammatory therapy is expected to be effective during the pulmonary phase and possibly the post-COVID-19 phase. While Remdesivir is a non-specific antiviral agent that targets RNA viruses, it is likely that agents specifically designed to target SARS-CoV-2 will be developed.

3. The SARS-CoV-2 PCR remains positive for at least 2 weeks following detection of whole virus (by culture, See figure 3). Patients who progress to the pulmonary phase are usually PCR positive despite cessation of viral replication (and are therefore less likely to be infectious).

4. Due to the imperfect sensitivity of the PCR test as many as 20% of patients who progress to the pulmonary phase will be PCR negative (even on repeat testing). At symptom onset PCR will be positive in approximately 60% of patients; maximal positivity rate is on day 8 (post infection) when 80% of patients will be positive (see Figure3). [417]

5. Symptomatic patients are likely to be infectious during a narrow window starting 2–3 days before the onset of symptoms and to up to 6 days after the onset of symptoms (see Figure 3).[418]

6. It is important to recognize that COVID-19 patients present with a variety of phenotypes, likely dependent on inoculum size and viral load, genetic heterogeneity mutations and polymorphisms, biotypes, blood type, sex and androgen status, age, race, BMI (obesity), immunological and nutritional status, and co-morbidities.[219,419-429] The phenotype at presentation determines the prognosis and impacts the optimal approach to treatment. It is noteworthy that obesity and increasing BMI are critical prognostic factors. This may be related to the fact that there are more ACE-2 receptors in visceral fat than in the lung. [430]

7. The pulmonary phase is characterized by immune dysregulation, [365,367,400,422,431-442] a pulmonary microvascular injury (vasculopathy),[400,442-445] with activation of clotting and a pro-coagulant state together with the characteristics of an organizing pneumonia. [328,446]

8. Endothelial damage and an imbalance of both innate and adaptive immune responses, with aberrant macrophage activation, plays a central role in the pathogenesis of the severe COVID-19 Disease. [400]

9. As patients, progress down the pulmonary cascade the disease becomes more difficult to reverse. The implications of this are twofold.
a. Early treatment (of the pulmonary phase) is ESSENTIAL to a good outcome. b. Treatment in the late pulmonary phase may require escalation of the dose of
corticosteroids as well as the use of salvage methods (i.e., plasma exchange). However, patients who present in the late pulmonary phase may have progressed to the irreversible pulmonary fibroproliferative phase.

10. The pulmonary phase of COVID-19 is a treatable disease; it is inappropriate to limit therapy to “supportive care” alone. Furthermore, it is unlikely that there will be a single “silver bullet” to treat severe COVID-19 disease. Rather, patients will require treatment with multiple drugs/interventions that have synergistic and overlapping biological effects. Repurposed FDA approved drugs that are safe, inexpensive, and “readily” available are likely to have a major therapeutic effect on this disease. The impact of COVID-19 on middle- and low-income countries is enormous; these countries are not able to afford expensive propriety “designer” molecules.

11. The radiographic and pathological finding of COVID-19 lung disease are characteristic of a Secondary Organizing Pneumonia (and not ARDS). [328,447,448]

Page 32 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

12. THIS is NOT ARDS (at least initially), but rather an organizing pneumonia. The initial pulmonary phase neither looks like, smells like nor is ARDS.[449-451] The ground glass infiltrates are peripheral and patchy, [447] and do not resemble the dependent air space consolidation (sponge/baby lung) seen with “typical ARDS”.[452] Extravascular lung water index (EVLWI) is normal or only slightly increased; this by definition excludes non-cardiogenic pulmonary edema (ARDS). Lung compliance is normal (this excludes ARDS). Patients are PEEP unresponsive. Treating patients as if they ARDS is an extremely dangerous approach. The hypoxia is due to a organizing pneumonia with severe ventilation/perfusion mismatch likely due to the microvascular narrowing, thrombosis and vasoplegia.

13. The core principles of the pulmonary phase (MATH+) is the use of anti-inflammatory agents to dampen the “cytokine storms” together with anticoagulation to limit the microvascular and macrovascular clotting and supplemental oxygen to help overcome the hypoxia.

15. The pulmonary phase of COVID-19 is characterized by PROLONGED immune dysregulation that may last weeks or even months. The early and abrupt termination of anti-inflammatory agents will likely result in rebound inflammation. [454]

16. SARS-CoV-2 as compared to all other respiratory viruses, upregulates cytokines and chemokines while at the same time down regulating the expression of Interferon alpha (the hosts primary antiviral defence mechanism). [131,155] Low innate antiviral defenses and high pro- inflammatory mediators contribute to ongoing and progressive lung injury.

17. Patients in whom the cytokine storm is not “dampened” will progress into the “H phenotype” characterized by poor lung compliance, severe oxygenation failure and PEEP recruitability. Progression to this phase is exacerbated by ventilator induced lung injury (VILI). The histologic pattern of the “H Phenotype” is characterized by an acute fibrinous and organizing pneumonia (AFOP), with extensive intra-alveolar fibrin deposition called fibrin “balls” with absent or minimal hyaline membranes.[424,448,455-457] Corticosteroids seem to be of little benefit in established AFOP. High dose methylprednisolone and Mega-dose vitamin C should be attempted in the “early phase” of AFOP, however many patients will progress to irreversible pulmonary fibrosis with prolonged ventilator dependency and ultimately death.

18. An unknown percentage of patients with COVID-19 present with “silent hypoxia” with a blunted respiratory response. This phenomenon may be related to involvement of chemoreceptors of the carotid bodies and/or brain stem dysfunction,[458,459] and necessitates pulse oximetry in symptomatic patients managed at home (as discussed above).

19. It should be recognized that LWMH has non-anticoagulant properties that are likely beneficial in patients with COVID-19, these include anti-inflammatory effects and inhibition of histones.[460] in addition, in vitro studies demonstrate that heparin inhibits SARS-CoV-2 interaction with the ACE-2 receptor and viral entry,[461,462] as well as viral replication [127,463]. Most importantly LWWH inhibits heparanase (HPSE).[464] HSE destroys the endothelial glycocalyx increasing endothelial leakiness, activating clotting and potentiating endothelialitis.[464] HPSE levels have been reported to be increased in patients with severe COVID-19 infection. [465] Due to the ease of administration, greater anti-Xa activity and better safety profile we prefer low molecular weight heparin (LMWH) to unfractionated heparin (UFH).

14. Ivermectin has emerged as a highly effective drug for the prophylaxis and treatment COVID-19. Ivermectin inhibits viral replication and has potent anti-inflammatory properties. Emerging clinical data (including RCT’s) suggest that ivermectin may have an important clinical benefit across the spectrum of phases of the disease, i.e pre-exposure prophylaxis, postexposure prophylaxis, during the symptomatic phase and during the pulmonary phase. [19,25-27,119,122- 128,212-214,270-276,453] In the recommended dosages, Ivermectin is remarkably safe and effective against SARS-CoV-2 (see Table 1 and Figures 8 and 10). However, as noted above there is the potential for serious drug-drug interaction.

Page 33 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

20. The combination of steroids and ascorbic acid (vitamin C) is essential. Both have powerful synergistic anti-inflammatory actions. [255,260] Vitamin C protects the endothelium from oxidative injury.[62,466-468] Furthermore, vitamin C Increases the expression of interferon- alpha [52] while corticosteroids (alone) decease expression of this important protein. [469- 472] It should be noted that when corticosteroids are used in the pulmonary phase (and not in the viral replicative phase) they do not appear to increase viral shedding or decrease the production of type specific antibodies. [221,473] It is likely that heparin (LMWH) acts synergistically with corticosteroids and vitamin C to protect the endothelium and treat the endothelialitis of severe COVID-19 disease.

21. Notwithstanding the particularly important and impressive results of the Recovery- Dexamethasone study, methylprednisolone is the corticosteroid of choice for the pulmonary phase of COVID-19. This is based on pharmacokinetic data (better lung penetration),[474] genomic data specific for SARS-CoV-2,[140] and a long track record of successful use in inflammatory lung diseases. (see Table 1)

Page 34 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Scientific Rationale for MATH+ Treatment Protocol (pulmonary phase)

Three core pathologic processes lead to multi-organ failure and death in COVID-19:

. 1)  Hyper-inflammation (“Cytokine storm”) – a dysregulated immune system whose cells infiltrate and damage the lungs as well as other organs including the heart and bone marrow. It is now widely accepted that SARS-CoV-2 causes aberrant T lymphocyte and macrophage activation resulting in a “cytokine storm.” [365,367,422,431,433-441] In addition, post-mortem examination has demonstrated features of the “macrophage activation syndrome”, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder.[400] These autopsy studies have shown minimal viral cytopathic effects providing further validation that it is the hosts immune response to the virus rather than the virus itself which is killing the host.[400,475-477]

. 2)  Hyper-coagulability (increased clotting) – the dysregulated immune system damages the endothelium and activates blood clotting, causing the formation of micro and macro blood clots. Clotting activation may occur directly due to increased expression of Factor Xa as well as endothelial injury with the release of large aggregates of van Willebrand factor.[141] Furthermore, ACE-2 receptors are present on platelets and this may contribute to the massive platelet aggregation characteristic of severe COVID-19 disease.[143,230,478] These blood clots impair blood flow. [444,445,479-491] It should be noted that the thrombotic microangiopathy appears to target predominantly the pulmonary and cerebral circulation. [400]

. 3)  Severe Hypoxemia (low blood oxygen levels) –lung inflammation caused by the cytokine storm, together with microthrombosis in the pulmonary circulation severely impairs oxygen absorption resulting in oxygenation failure with a sever V//Q mismatch.

The above pathologies are not novel, although the combined severity in COVID-19 disease is considerable. Our long-standing and more recent experiences show consistently successful treatment if traditional therapeutic principles of early and aggressive intervention is achieved, before the onset of advanced organ failure. It is our collective opinion that the historically high levels of morbidity and mortality from COVID-19 is due to a single factor: the widespread and inappropriate reluctance amongst hospitalists and intensivists to employ anti-inflammatory and anticoagulant treatments, including corticosteroid therapy early in the course of a patient’s hospitalization. It is essential to recognize that it is not the virus that is killing the patient, rather it is the patient’s overactive immune system. [364,367,400,459] The flames of the “cytokine fire” are out of control and need to be extinguished. Providing supportive care (with ventilators that themselves stoke the fire) and waiting for the cytokine fire to burn itself out simply does not work… this approach has FAILED and has led to the death of tens of thousands of patients.

“If what you are doing ain’t working, change what you are doing” – PEM

The systematic failure of critical care systems to adopt corticosteroid therapy (early in this pandemic) resulted from the published recommendations against corticosteroids use by the World Health Organization (as recent as May 27th 2020) [492,493]. This recommendation was then perpetuated by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society (ATS), Infectious Diseases Association of America (IDSA) amongst others. A publication authored one of the members of the Front Line COVID-19 Critical Care (FLCCC) Alliance (UM), identified the errors made by these organizations in their analyses of corticosteroid studies based on the findings of the SARS and H1N1 pandemics.[216,494] Their erroneous recommendation to avoid corticosteroids in the treatment of COVID-19 has led to the development of myriad organ failures which have overwhelmed critical care

Page 35 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

systems across the world and led to excess deaths. The recently published results of the RECOVERY- DEXAMETHASONE study provide definitive and unambiguous evidence of the lifesaving benefits of corticosteroids and strong validation of the MATH + protocol. It should be recognized that corticosteroids are the only therapy proven to reduce the mortality in patients with COVID-19.[495] The RECOVERY-DEXAMETHASONE study, randomized 2104 patients to receive dexamethasone 6 mg (equivalent to 32 mg methylprednisolone) once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomized to usual care alone.[179] Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75; p=0.14). The results of this study STRONGLY support the EVMS/MATH+ protocol which recommends the use of corticosteroids for the “pulmonary phase” of COVID-19. It should be noted that we would consider the non-titratable ‘fixed” dose of dexamethasone used in the RECOVERY- DEXAMETHASONE study to be very low. Furthermore, as indicated above we consider methylprednisolone to be the corticosteroid of choice for the treatment of COVID-19 pulmonary disease. The benefit of methylprednisolone in improving respiratory function, ventilator dependency and mortality has been confirmed in a number of observational studies, [217,218,224,473,496-498] as well as a randomized controlled study.[226] A recent study from the COVID-19 SPANISH ICU Network strongly supports our approach. [499] These authors demonstrated that pre-ICU corticosteroids and corticosteroids administered within 48 hours of admission to the ICU reduced mortality. However, patients who received late corticosteroids (> 48 hours after ICU admission) did not demonstrate a mortality benefit and these patients had a significantly higher risk of secondary infections. Furthermore (and most importantly) early high-dose corticosteroids (> 1 mg/kg methylprednisolone eq/day) was associated with a significantly reduced mortality compared to early low-dose corticosteroids. It should be recognized that the mortality benefit with methylprednisolone was not replicated in a Brazilian RCT.[454] In this study, methylprednisolone was started late (day 13 after symptom onset) and 3 days after intubation (???), and was stopped prematurely on day 5. This failed study reinforces the concept of early and prolonged treatment with methylprednisolone titrated to the patient’s clinical response. In patients at high risk of Strongyloides infection, screening and/or treatment of this parasite with ivermectin is suggested prior to treatment with corticosteroids.[500] This will likely be a non-issue when all patients are treated with ivermectin.

Our treatment protocol targeting the key pathologic processes has been highly successful,
if begun within 6 hours of a COVID19 patient presenting with shortness of breath and/or arterial

desaturation and requiring supplemental oxygen.[249] If such early initiation of treatment could be systematically achieved, the need for mechanical ventilators and ICU beds will decrease dramatically.

Further resources:

The scientific rationale for the MATH + protocol is reviewed in this paper.[248,249] please visit our website for further information as well as for common questions (Q & A section). or

In this U-tube video, Professor Britt Glaunsinger, PhD provides an outstanding review on the molecular virology of SARS-CoV-2:



Page 36 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021


1. Fatima S, Zaidi SS, Alsharidah AS et al. Possible prophylactic approach for SARS-CoV-2 infection by combination of melatonin, Vitamin C and Zinc in animals. Fronteirs in Veterinary Science 2020; 7:585789.

2. Arslan B, Ergun NU, Topuz S et al. Synergistic effect of quercetin and vitamin C against COVID-19: Is a possible guard for front liners? ssrn 2020.

3. Ahmed AK, Albalawi YS, Shora HA et al. Effects of quadruple therapy: Zinc, Quercetin, Bromelain and Vitamin C on clinical outcomes of patients infected with COVID-19. Rea Int Jou of End and Dia 2020; 1:1005.

4. Leung K, Shum MMH, Leung GM et al. Early empirical assessment of the N501Y mutant strains of SARS- CoV-2 in the United Kingdom, October to November 2020. medRxiv 2020.

5. Tegally H, Wilkinson E, Giovanetti M et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spke mutations in South Africa. medRxiv 2020.

6. Fratev F. The SARS-CoV-2 S1 spike mutation N501Y alters the protein interactions with both hACE2 and human derived antibody: A free energy of perturbation study. bioRxiv 2020.

7. Nonaka CK, Franco MM, Graf T et al. Genomic evidence of a SARS-C0V-2 reinfection case with E484K spike mutation in Brazil. Preprints 2021.

8. Jehi L, Ji X, Milinovich A et al. Individualizing risk prediction for positive COVID-19 testing. Results from 11,672 patients. Chest 2020; 158:1364-75.

9. Kory P, Meduri GU, Iglesias J et al. Review of the emerging evidence demonstrating the efficacy of ivermectin in the propphylaxis and treatment of COVID-19. ssrn 2020.

10. Guy GP, Lee FC, sunshine G et al. Association of State-Issued mask mandates and allowing on premises restaurant dining with County-levels COVID-19 case and death growth rates-United States, March 1 – December 31, 2020. MMWR 2021; 70.

11. 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; 42:1122-33.

12. 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. medRxiv 2020.

13. Elgazzar A, Hany B, Youssef SA et al. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square 2020.

14. Carvallo H, Hirsch RR, Alkis P et al. Study of the efficacy and safety of topical ivermectin + Iota- carrageenan in the prophylaxis against COVID-19 in health personnel. Journal of Biomedical Research and Clinical Investigation 2020; 2.

15. Kory P, Meduri GU, Iglesias J et al. Review of the emerging evidencce supporting the use of Ivermectin in the prophylaxis and treatment of COVID-19. Front Line Covid-19 Critical Care Alliance. osf io 2020.

16. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administraion of ivermectin. Int J Antimicrob Agents 2020.

17. Morgenstern J, Redondo JN, Olavarria A et al. Retrospective cohort study of Ivermectin as a SARS-CoV-2 pre-exposure prophylaxis method in Healthcare Workers. medRxiv 2021.

18. Chahla RE, Medina Ruiz L, Mena T et al. Ivermectin reproposing for COVID-19 treatment outpatients in mild stage in primary health centers. medRxiv 2021.

19. Kircik LH, Del Rosso JQ, Layton AM et al. Over 25 years of clinical experience with Ivermectin: An overview of safety for an increasing number of indications. J Drugs Dermatol 2016; 15:325-32.

20. Aroke D, Tchouakam DN, Awungia AT et al. Ivermectin induced Steven-Johnsons syndrome: case report. BMC Research Notes 2017; 10:179.

21. Ngwasiri CA, Abanda MH, Aminde LN. Ivermectin-induced fixed drug eruption in an elderly Cameroonian: a case report. Journal of Medical Case Reports 2018; 12:254.

22. Veit O, Beck B, Steuerwald M et al. First case of ivermectin-induced severe hepatitis. Trans R Soc Trop Med Hyg 2021; 100:795-97.

23. Nicolas P, Maia MF, Bassat Q et al. Safety of oral ivermectin during pregnancy: a systematic review and meta-analysis. Lancet Glob Health 2020; 8:e92-e100.

24. Canga AG, Sahagun Prieto AM, Diez Liebana MJ et al. The pharmacokinetics and interactions of Ivermectin in humans-A mini-review. The AAPS Journal 2007; 10:42-46.

Page 37 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

25. Gorial FI, Mashhadani S, Sayaly HM et al. Effectiveness of Ivermectin as add-on therapy in COVID-19 management (Pilot Trial). medRxiv 2020.

26. Khan MS, Khan MS, Debnath Cr et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Archivos de Bronconeumologia 2020.

27. Rajter JC, Sherman MS, Fatteh N et al. ICON (Ivermectin in COvid Ninteen) study: Use of ivermectin is associated with lower mortality in hospitalized patients with COVID-19. Chest 2020.

28. Niaee MS, Gheibl 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.

29. Hashim HA, Maulood MF, rasheed AM et al. Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Bagdad, Iraq. medRxiv 2020.

30. Maghbooli Z, Sahraian MA, Ebrahimi M et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/ml reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS ONE 2020; 15:e0239799.

31. Grant WB, Lahore H, McDonnell SL et al. Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020; 12:988.

32. Kaufman HW, Niles JK, Kroll MH et al. SARS-CoV-2 positivity rates associated with circulating 25- hydroxyvitamin D level. PloS ONE 2020; 15:e0239252.

33. Lau FH, Majumder R, Torabi R et al. Vitamin D insufficiency is prevalent in severe COVID-19. medRxiv 2020.

34. Marik PE, Kory P, Varon J. Does vitamin D status impact mortlality from SARS-CoV-2 infection? Medicine in Drug Discovery 2020.

35. Rhodes JM, Subramanian S, Laird E et al. Editorial: Low population mortality from COVID-19 in countries south of 35 degrees North – supports vitamin D as a factor determining severity. Alimentary Pharmacology & Therapeutics 2020; (in press).

36. Dancer RC, Parekh D, Lax S et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax 2015; 70:617-24.

37. LLie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res 2020.

38. Daneshkhah A, Eshein A, Subramanian H. The role of vitamin D in suppressing cytokine storm of COVID-19 patients and associated mortality. medRxiv 2020.

39. Bergman P, Lindh AU, Bjorkhem-Bergman L et al. Vitamin D and respiartory tract infections: A systematic review and meta-analysis of randomized controlled trials. PloS ONE 2013; 8:e65835.

40. Carpagnano GE, Lecce V, Quaranta VN et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory fialure due to COVID-19. J Endocrinol Invest 2020.

41. Israel A, Cicurel A, Feldhamer I et al. The link between vitamin D deficiency and Covid-19 in a large population. medRxiv 2020.

42. Radujkovic A, Hippchen T, Tiwari-Heckler S et al. Vitamin D deficiency and outcome of COVID-19 patients. Nutrients 2020; 12:2757.

43. Rizzoli R. Vitamin D supplementation: upper limit for safety revisited. Aging Clin Exp Res 2020.

44. Annweiler C, Hanotte B, de L’Eprevier CG et al. Vitamin D and survival in COVID-19 patients: A quasi-
experimental study. Journal of Steroid Biochemistry & Molecular Biology 2020.

45. Moozhipurath RK, Kraft L, Skiera B. Evidence of protective role of Ultraviolet-B (UVB) radiation in reducing
COVID-19 deaths. Nature Research 2020; 10:17705.

46. Cangiano B, Fatti LM, Danesi L et al. Mortality in an Italian nursing home during COVID-19 pandemic:
correlation with gender, age, ADL, vitamin D supplementaion, and limitations of the diagnostic tests.
Aging 2020; 12.

47. De Smet D, De Smet K, Herroelen P et al. Serum 25(OH)D level on hospital admission assocaited with
COVID-19 stage and mortality. Am J Clin Pathol 2020.

48. Murai IH, Fernandes AL, Sales LP et al. Effect of vitamin D3 supplementaion vs placebo on hospital length
of stay in patients with severe COVID-19: A multicenter, double-blind, randomized controlled trial. JAMA

49. Maggini S, Beveridge S, suter M. A combination of high-dose vitamin C plus zinc for the common cold.
Journal of International Medical Research 2012; 40:28-42.

50. Colunga Biancatelli RM, Berrill M, Catravas JD et al. Quercetin and Vitamin C: experimental therapy for the
prevention and treatment of SARS-CoV-2 via synergistic action. Front Immunol 2020.

Page 38 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

51. Kyung Kim T, Lim HR, Byun JS. Vitamin C supplementaion reduces the odds of developing a common cold in Republic of Korea Army recruits: a randomised controlled trial. BMJ Mil Health 2020.

52. Colunga Biancatelli RM, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert Rev Anti Infect Ther 2020; 18:99-101.

53. Hiedra R, Lo KB, Elbashabsheh M et al. The use of IV vitamin C for patients with COVID-19: a case series. Exp Rev Anti Infect Ther 2020.

54. Khaerunnisa S. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compuns by molecular docking study. medRxiv 2020.

55. Chen L, Li J, Luo C et al. Binding interaction of quercetin-3-B-galactoside and its synthetic derivatives with SARS-CoV 3CL: structure-activity relationship reveal salient pharmacophore features. Bioorganic & Medicinal Chemistry Letters 2006; 14:8295-306.

56. Nain Z, Rana HK, Lio P et al. Pathogenic profiling of COVID-19 and SARS-like viruses. Briefings in Bioinformatics 2020.

57. Yi L, Li Z, Yuan K et al. Small molecules blocking the entry of severe respiratory syndrome coronavirus into host cells. J Virol 2020; 78:11334-39.

58. Shakoor H, Feehan J, Dhaheri AS et al. Immune-boosting role of vitamins D,C,E, zinc, selenium and omega- 3 fatty acids: could they help against COVID-19. Maturitas 2020.

59. Calder PC. Nutrition, immunity and COVID-19. BMJ Nutrition, Prevenion & Health 2020; 3.

60. Abian O, Ortega-Alarcon D, Jimenez-Alesanco A et al. Structural stability of SARS-CoV-2 3CLpro and
identification of quercetin as an inhibitor by experimental screening. International Journal of Biological
Macromolecules 2020; 164:1693-703.

61. Hemila H, Carr A, Chalker E. Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2
infection by 70%: reanalysis of the COVID A to Z randomized clinical trial. Research Square 2021.

62. Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) for the treatment of sepsis. Focus on
ascorbic acid. Nutrients 2018; 10:1762.

63. Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Therapeut 2018;

64. Chen L, Li J, Luo C et al. Binding interaction of quercetin-3-B-galactoside and its synthetic derivatives with
SARS-CoV 3CLpro: Structure-activity relationship studies revela salient pharmacophore features.
Bioorganic & Medicinal Chemistry 2020; 14:8295-306.

65. Ono K, Nakane H. Mechanisms of inhibition of various cellular DNA and RNA polymerases by several
flavonoids. J Biochem 1990; 108:609-13.

66. Kaul TN, Middleton E, Pgra PL. Antiviral effects of flavonoids on human viruses. J Med Virol 1985; 15:71-

67. Shinozka K, Kikuchi Y, Nishino C et al. Inhibitory effect of flavonoids on DNA-dependent DNA and RNA
polymerases. Experientia 1988; 44:882-85.

68. Martin JH, Crotty S, Warren P. Does an apple a day keep the doctor away because a phytoestrogen a day
keeps the virus at bay? A review of the anti-viral properties of phytoestrogens. Phytochemistry 2007;

69. Smith M, Smith JC. Repurposing therapeutics for COVID-19: Supercomputer-based docking to the SARS-
CoV-2 viral spike protein and viral spike protein-human ACE2 interface. ChemRxiv 2020.

70. Leyva-Lopez N, Gutierrez-Grijalva EP, Ambriz-Perez D. Flavonoids as cytokine modulators: A possible
therapy for inflammation-related diseases. Int J Mol Sci 2016; 17:921.

71. Nair MP, Kandaswami C, Mahajan S et al. The flavonoid, quercetin, differentially regulates Th-1 (INF) and
Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochimica et
Biophysica Acta 2020; 1593:29-36.

72. Saeedi-Boroujeni A, Mahmoudian-Sani MR. Anti-inflammatory potential of Quercetin in COVID-19
treatment. J Inflamm 2021; 18:3.

73. Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM et al. Zinc ionophore activity of Quercetin and
Epigallocatechin-gallate:From Hepa 1-6 cells to a liposome model. J Agric Food Chem 2014; 62:8085-93.

74. Nieman DC, Simonson A, Sakaguchi CA et al. Acute Ingestion of a Mixed Flavonoid and Caffeine
Supplement Increases Energy Expenditure and Fat Oxidation in Adult Women: A Randomized, Crossover
Clinical Trial. Nutrients 2019; 11.

75. Nieman DC, Kay CD, Rathore AS et al. Increased Plasma Levels of Gut-Derived Phenolics Linked to Walking
and Running Following Two Weeks of Flavonoid Supplementation. Nutrients 2018; 10.

Page 39 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

76. Nieman DC, Ramamoorthy S, Kay CD et al. Influence of Ingesting a Flavonoid-Rich Supplement on the Metabolome and Concentration of Urine Phenolics in Overweight/Obese Women. Journal of Proteome Research 2017; 16:2924-35.

77. Cialdella-Kam L, Ghosh S, Meaney MP et al. Quercetin and Green Tea Extract Supplementation Downregulates Genes Related to Tissue Inflammatory Responses to a 12-Week High Fat-Diet in Mice. Nutrients 2017; 9.

78. Ohgitani E, Shin-Ya M, Ichitani M et al. Rapid inactivation in vitro of SARS-CoV-2 in saliva by black tea and green tea. bioRxiv 2021.

79. Giuliani C, Bucci I, Di Santo S et al. The flavonoid quercetin in hibits thyroid-restricted genes expression and thyroid function. Food and Chemical Toxicology 2014; 66:23-29.

80. de Souza dos Santos MC, Goncalves CF, Vaisman M et al. Impact of flavonoids on thyroid function. Food and Chemical Toxicology 2011; 49:2495-502.

81. Chandra AK, De N. Catechin induced modulation in the activities of thyroid hormone synthesizing enzymes leading to hypothyroidism. Mol Cell Biochem 2013; 374:37-48.

82. Pistollato F, Masias M, Agudo P et al. Effects of phytochemicals on thyroid function and their possible role in thyroid disease. Ann N Y Acad Sci 2019; 1433:3-9.

83. Sathyapalan T, Manuchehri AM, Thatcher NJ et al. The effect of soy phytoestrogen supplementation on thyroid status and cardiovascular risk markers in patients with subclinical hypothyroidism: A randomized, double-blind, crossover study. J Clin Endocrinol Metab 2020; 96:1422-49.

84. Tonstad S, Jaceldo-Siegl K, Messina M et al. The association between soya consumption and serum thyroid-stimulating hormone in the Adventist Health Study-2. Public Health Nutr 2016; 19:1464-70.

85. Colombo D, Lunardon L, Bellia G. Cyclosporine and herbal supplement interactions. Journal of Toxicology 2014; 2014:145325.

86. Colunga Biancatelli RM, Berrill M, Mohammed YH et al. Melatonin for the treatment of sepsis: the scientific rationale. J Thorac Dis 2020; 12 (Suppl 1):S54-S65.

87. Reiter RJ, Abreu-Gonzalez P, Marik PE et al. Therapeutic algorithm for use of melatonin in patients with COVID-19. Front Med 2020; 7:226.

88. Reiter RJ, Sharma R, Ma Q et al. Melatonin inhibits COVID-19-induced cytokine storm by reversing aerobic glycolysis in immune cells: A mechanistic analysis. Medicine in Drug Discovery 2020; 6:100044.

89. Zhang R, Wang X, Ni L et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci 2020; 250:117583.

90. Kleszczynski K, Slominski AT, Steinbrink K et al. Clinical trials for use of melatonin to fight COVID-19 are urgently needed. Nutrients 2020; 12.

91. Coto-Montes A, Boga JA. ER stress and autophagy induced by SARS-CoV-2: The targer for melatonin treatment. Melatonin Res 2020; 3:346-61.

92. Gandolfi JV, Di Bernardo AP, Chanes DA et al. The effects of melatonin supplementation on sleep quality and assessment of the serum melatonin in ICU patients: A randomized controlled trial. Crit Care Med 2020.

93. Castillo RR, Quizon GR, Juco MJ et al. Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series. Melatonin Res 2021; 3:297- 310.

94. Ramiall V, Zucker J, Tatonetti N. Melatonin is significantly associated with survival of intubated COVID-19 patients. medRxiv 2021.

95. Farnoosh G, Akbaariqomi M, Badri T et al. Efficacy of a low dose of melatonin as an adjunctive therapy in hospitalized patients with COVID-19: A randomized, double-blind clinical trial. medRxiv 2021.

96. Shneider A, Kudriavtsev A, Vakhusheva A. Can melatonin reduce the severity of COVID-19 pandemic. medRxiv 2020.

97. Vogel-Gonzalez M, Tallo-Parra M, Herrera-Fernandez V et al. Low zinc levels at admission associates with poor clinical outcomes in SARS-CoV-2 infection. Nutrients 2021; 13:562.

98. te Velthuis AJ, van den Worm SH, Sims AC et al. Zn2+ 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:e1001176.

99. Gammoh NZ, Rink L. Zinc in Infection and Inflammation. Nutrients 2017; 9.

100. Hemila H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate,
and the role of zinc dosage. J Royal Soc Med Open 2017; 8:1-7.

Page 40 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

101. Hoeger J, Simon TP, Beeker T et al. Persistent low serum zinc is associated with recurrent sepsis in critically ill patients – A pilot study. PloS ONE 2017; 12:e0176069.

102. Willis MS, Monaghan SA, Miller ML et al. Zinc-induced copper deficiency. A report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 2005; 123:125-31.

103. Shakoor H, Freehan J, Mikkelsen K et al. Be well: A potential role for vitamin B in COVID-19. Maturitas 2020.

104. dos Santos LM. Can vitamin B12 be an adjuvant to COVID-19 treatment? GSC Biological and Pharmaceutical Sciences 2020; 11.

105. Kandeel M, Al-Nazawi M. Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease. Life Sci 2020; 251:117627.

106. Tan CW, Ho LP, Kalimuddin S et al. Cohort study to evaluate effect of vitamin D, magnesium, and vitamin b12 in combination on severe outcome progression in older patients with coronavirus (COVID-19). Nutrition 2020; 80:111017.

107. Zhang P, Tsuchiya K, Kinoshita T et al. Vitamin B6 prevents IL-1B protein production by inhibiting NLRP3 inflammasome activation. J Biol Chem 2020; 291:24517-27.

108. Freedberg DE, Conigliaro J, Sobieszczyk ME et al. Famotidine use is associated with impoved clinical outcomes in hospitalized COVID-19 patients: A propensity score matched retrospective cohort study. medRxiv 2020.

109. Janowitz T, Baglenz E, Pattinson D et al. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalized patients: a case series. Gut 2020; 69:1592-97.

110. Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of hospitalized COVID-19 patients. Am J Gastroenterol 2020.

111. Malone RW, Tisdall P, Fremont-Smith P et al. COVID-19: Famotidine, Histamine, Mast Cells, and mechanisms. Research Square 2020.

112. Sethia R, Prasad M, Mahapatra SJ et al. Efficacy of famotidine for COVID-19: A systematic review and meta-analysis. medRxiv 2020.

113. Shoaibi A, Fortin S, Weinstein R et al. Comparative effectiveness of famotidine in hospitalized COVID-19 patients. medRxiv 2020.

114. Yeramaneni S, Doshi P, Sands K et al. Famotidine use is not associated with 30-day mortality: A coarsened exact match study in 7158 hospitalized COVID-19 patients from a large healthcare system. medRxiv 2020.

115. Almario CV, Chey WD, Spiegel BM. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol 2020.

116. Lee SW, Ha EK, Moon SY et al. Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching. Gut 2021; 70:76-84.

117. Meng Z, Wang T, Chen L et al. An experimental trial of recombinant human interferon alpha nasal drops to prevent COVID-19 in medical staff in an epidemic area. medRxiv 2020.

118. Munoz J, Ballester MR, Antonijoan RM et al. Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers. PLoS Neglected Tropical Diseases 2018; 12:e0006020.

119. Hashim HA, Maulood MF, rasheed AM et al. Controlled randomized clinical triaal on using Ivermectin with Doxycycline for treating COVID-19 patients in Bagdad, Iraq. medRxiv 2020.

120. Alam MT, Murshed R, Bhiuyan E et al. A case series of 100 COVID-19 positive patients treated with combination of Ivermectin and Doxycycline. Bangladesh Coll Phys Surg 2020; 38:10-15.

121. Chowdhury AT, Shahabz M, Karim MR et al. A randomized trial of ivermectin-doxycycline and hydrochloroquine-azithromycin therapy on COVID-19 patients. Research Square 2020.

122. Chamie J. Real-World evidence: The case of Peru, casuality between Ivermectin and COVID-19 infection fatality rate. ResearchGate 2020.

123. Caly L, Druce JD, Catton MG et al. The FDA-approved drug Ivermectin inhibits the replication of SARS-CoV- 2 in vitro. Antiviral Res 2020.

124. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In Vivo 2020; 34:3023-26.

125. Maurya DK. A combination of Ivermectin and Doxycycline possibly blocks the viral entry and modulate the innate immune response in COVID-19 patients. ChemRxiv 2020.

126. Yang SN, Atkinson SC, Wang C et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res 2020; 177:104760.

Page 41 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

127. Dayer MR. Coronavirus (2019-nCoV) deactivation via spike glycoprotein shielding by old drugs, bioinformatic study. Preprints 2020.

128. Swargiary A. Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from silico studies. Research Square 2020.

129. Kalfas S, Visvanathan K, Chan K et al. The therapeutic potential of ivermectin for COVID-19: A systematic review of mechanisms and evidence. medRxiv 2020.

130. Chamie-Quintero JJ, Hibberd JA, Scheim DE. Ivermectin for COVID-19 in Peru: 14-fold reduction in nationwide excess deaths, p=0.002 for effect by state, then 13-fold increase after ivermectin use restricted. medRxiv 2021.

131. Wehbe Z, Wehbe M, Iratni R et al. Repurposing Ivermectin for COVID-19: Molecular aspects and therapeutic possibilities. Front Immunol 2021; 12:663586.

132. Castillo ME, Costa LM, Barrios JM et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol 2020; 203:105751.

133. Loucera C, Pena-Chilet M, Esteban-Medina M et al. Real world evidence of calcifediol use and mortality rate of COVID-19 hospitalized in a large cohort of 16,401 Adalusian patients. medRxiv 2021.

134. Quesada-Gomez JJ, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporosis International 2018; 29:1697-711.

135. Cesareo R, Falchetti A, Attanasio R et al. Hypovitaminosis D: Is it time to consider the use of calcifediol? Nutrients 2019; 11:1016.

136. Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med 2019; 381:2529-40.

137. Amrein K, Martucci G, McNAlly JD. When not to use meta-analysis: Analysing the meta-analysis on vitamin
D in critical care. Clin Nutr 2017; 36:1729-30.

138. Bianconi V, Violi F, Fallarino F et al. Is acetylsalicylic acid a safe and potentially useful choice for adult
patients with COVID-19? Drugs 2020.

139. Muller C, Karl N, Ziebuhr J et al. D,L-lysine acetylsalicylate + glycine impairs coronavirus replication. J
Antivir Antiretovir 2020.

140. Draghici S, Nguyen TM, Sonna LA et al. COVID-19: disease pathways and gene expression chnages predict
methylprednisolone can improve outcome in severe cases. Bioinformatics 2020.

141. Varatharajah N. COVID-19 CLOT: What is it? Why in the lungs? Extracellular histone, “auto-activation” of
prothrombin, emperipolesis, megakaryocytes, “self-association” of Von Willebrand factor and beyond.
Preprints 2020.

142. Cloutier N, Allaeys I, Marcoux G et al. Platelets release pathogenic serotonin and return to circulation
after immune complex-mediated sequestration. PNAS 2018;E1550-E1559.

143. Hottz ED, Azevedo-Quintanilha Ig, Palhinha L et al. Platelet activation and platelet-monocyte aggregate
formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136:1330-1341.

144. Merchant HA. CoViD-19: An early intervention therapeutic strategy to prevent developing a severe
disease as an alternative approach to control the pandemic. medRxiv 2021.

145. da Silva JK, Figueirdo PL, Byler KG et al. Essential oils as antiviral agents, potential of essential oils to treat
SARS-CoV-2 infection: an In-Silico investigation. Int J Mol Sci 2020; 21:3426.

146. Seet RC, Quek AM, Ooi DS et al. Positive impact of oral hydroxychloroquine and povidone-iodine throat
spray for COVID-19 prophylaxis: an open-label randomized trial. Int J Infect DIs 2021.

147. Seneviratne CJ, Balan P, Ki KK et al. Efficacy of commercial mouth-rinses on SARS-CoV-2 viral load in saliva:
Randomized controlled trial in Singapore. medRxiv 2020.

148. Frank S, Brown SM, Capriotti JA et al. In vitro efficacy of a providone-iodine nasal antiseptic for rapid
inactivation of SARS-CoV-2. JAMA Otolaryngol Head Neck Surg 2020; 146:1054-58.

149. Hoertel N, Sanchez-Rico M, Vernet R et al. Association between antidepressant use and reduced risk of
intubation or death in hospitalized patients with COVId-19: results from an observational study. Molecular
Psychiatry 2021.

150. Lenze EJ, Mattar C, Zorumski CF et al. Fluvoxamine vs placebo and clinical deterioration in outpatietns
with symptomatic COVID-19. A randomized clinical trial. JAMA 2020.

151. Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of COVID-19. Open Forum
Infectious Diseases 2021.

152. Hamed MG, Hagaga RS. The possible immunoreulatory and anti-inflammatory effects of selective
serotonin reuptake inhibitors in coronavirus disease patients. Medical Hypotheses 2020; 144:110140.

Page 42 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

153. Zimering MB, razzaki T, Tsang T et al. Inverse association between serotonin 2A receptor antagonist medication use and mortality in severe COVID-19 infection. Endocrinol Diabetes Metab J 2020; 4:1-5.

154. Sukhatme VP, Reiersen AM, Vayttaden SJ et al. Fluvoxamine: A review of its mechanism of action and its role in COVID-19. Fronteirs in Pharmacology 2021; 12:652688.

155. Maurer-Spurej E, Pittendreigh C, Solomons K. The influence of selective serotonin reuptake inhibitors on human platelet serotonin. Thromb Haemost 2004; 91:119-28.

156. Bismuth-Evenzal Y, Gonopolsky Y, gurwitz D et al. Decreased serotonin content and reduced agonist- induced aggregation in platelets of chronically medicated with SSRI drugs. Journal of Affective Disorders 2012; 136:99-103.

157. Javors MA, Houston JP, Tekell JL et al. Reduction of platelet serotonin content in depressed patients treated with either paroxetine or desipramine. International Journal of Neuropsychopharmacology 2000; 3:229-35.

158. Hammock BD, Wang W, Gilligan MM et al. Eicosanoids. The overlooked storm in Coronavirus Disease 2019 (COVID-19)? Am J Pathol 2020.

159. Das UN. Can bioactive lipids inactivate coronavirus (COVID-19)? Arch Med Res 2020; 51:282-86.

160. Lee CR, Zeldin DC. Resolvin infectious inflammation by targeting the host response. N Engl J Med 2015;

161. Serhan CN. Novel pro-resolving lipid mediators in inflammation are leads for resolution physiology.
Nature 2014; 510:92-101.

162. Idelsis Esquivel-Moynelo I, Perez-Escribano J, Duncan-Roberts Y et al. Effect of combination of interferon
alpha-2b and interferon-gamma or interferon alpha 2b alone for elimination of SARS-CoV-2 viral RNA.
Preliminary results of a randomized controlled clinical trial. medRxiv 2020.

163. Davoudi-Monfarad E, Rahmani H, Khalili H et al. Efficacy and safety of interferon B-1a in treatment of
severe COVID-19: A randomized clinical trial. medRxiv 2020.

164. Wang N, Zhan Y, Zhu L et al. Retrospective multicenter cohort study shows early interferon therapy is
associated with favorable clinical responses in COVID-19 patients. Cell Host & Microbe 2020;ePub.

165. Feld JJ, Kandel C, Biondi MJ et al. Peginterferon lamda for the treatment of outpatients with COVID-19: a
phase 2, placebo-controlled randomised trial. Lancet Resp Med 2021.

166. Berg K, Bolt G, Andersen H et al. Zinc potentiates the antiviral action of human IFN-alpha tenfold. J
Interferon Cytokine Res 2001; 21:471-74.

167. Cakman I, Kirchner H, Rink L. Zinc supplementation reconstitutes the production of interferon-alpha by
leukocytes from elderly persons. J Interferon Cytokine Res 1997; 17:469-72.

168. Marik PE, DePerrior SE, Ahmad Q et al. Gender-based disparities in COVID-19 patient outcomes. Journal of
Investigative Medicine 2021; ePub.

169. Lucas JM, Heinlein C, Kim T et al. The androgen-regulated protease TMPRSS2 activates a proteolytic
cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.
Cancer Discov 2020; 4:1310-1325.

170. Cadegiani FA, McCoy J, Wambier CG et al. Early antiandrogen therapy with dutasteride reduces viral
shedding, inflammatory responses, and time-to remission in males with COVID-19: A randomized, double-
blind, placebo-controlled interventional trial (EAT-DUTA AndroCoV Trial- Biochemical). Cureus 2021.

171. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home: Potential pitfalls
and practical guidance. Ann Thorac Med 2020.

172. Jouffroy R, Jost D, Prunet B. Prehospital pulse oximetry: a red flag for early detection of silent hypoxemia
in COVID-19 patients. Crit Care 2020; 24:313.

173. Yu LM, Bafadhel M, Doeward J et al. Inhaled budesonide for COVID-19 in people at higher risk of adverse
outcomes in the community: interim analyes from the PRINCIPLE trial. medRxiv 2021.

174. Ramakrishnan S, Nicolau DV, Langford B et al. Inhaled budesonide in the treatment of early COVID-19
(STOIC): a phase 2, open-label, randomised controlled trial. Lancet Resp Med 2021.

175. Schultze A, Walker AJ, MacKenna B et al. Inhaled corticosteroids use and the risk of COVID-19 related
death among 966,461 patients with COPD or asthma: An OpenSAFELY analysis. medRxiv 2020.

176. Aveyard P, Gao M, Lindson N et al. Association between pre-existing respiratory disease and its
treatment, and severe COVID-19: a population cohort study. Lancet Resp Med 2021.

177. Tardif JC, Bouabdallaoui N, L’Allier PL et al. Efficacy of colchicine in non-hospitalized patients with COVID-
19. medRxiv 2021.

Page 43 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

178. Finkelstein Y, Aks SE, Hutson JR et al. Colchicine poisoning: the dark side of an acient drug. Clinical Toxicology 2010; 48:407-14.

179. Effect of Dexamethasone in hospitalized patients with COVID-19-Preliminary report. N Engl J Med 2020.

180. Risch HA. Early outpatient treatment of symptomatic, High-Risk Covid-19 patients that should be ramped-
up immediately as key to the pandemic crisis. Am J Epidemiol 2020.

181. Borba MG, Val FF, Sampaio S. Effect of High vs Low Doses of chloroquine diphosphate as adjunctive
therapy for patietns hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection. A randomized clinical trial. JAMA Network Open 2020.

182. Boulware DR, Pullen MF, Bangdiwala AS et al. A randomized trial of hydroxychloroquine as postexposure
prophylaxis for Covid-19. N Engl J Med 2020.

183. Barnabas RV, Brown ER, Bershteyn A et al. Hydroxychloroquine as postexposure prophylaxis to prevent
severe acute respiratory syndrome coronavirus 2 infection. Ann Intern Med 2020.

184. 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.

185. Mitja O, Ubals M, Corbach-Monne M et al. A cluster-randomized trial of hydroxychloroquine as
prevention of Covid-19 transmission and disease. N Engl J Med 2020.

186. Cavalcanti AB, Zampieri FG, Rosa RG et al. Hydroxychloroquine with or without azithromycin in mild-to-
moderate Covid-19. N Engl J Med 2020; 383:2041-52.

187. Skipper CP, Pastick KA, Engen NW. Hydroxychlooquine in nonhospitalized adults with early COVID-19. Ann
Intern Med 2020; 173:623-31.

188. 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; 323:2493-502.

189. Geleris J, Sun Y, Platt J et al. Observational study of hydroxychloroquine in hospitalized patients with
Covid-19. N Engl J Med 2020.

190. Magagnoli J, Narendran S, Pereira F. Outcomes of hydroxychloroquine usage in United states veterans
hospitalized with COVID-19. medRxiv 2020.

191. Lopez A, Duclos G, Pastene B et al. Effects of hydroxychloroquine on Covid-19 in Intensive Care Unit
Patients: Preliminary Results. Int J Antimicrob Agents 2020.

192. Mahevas M, Tran VT, Roumier M et al. No evidence of clinical efficacy of hydroxychloroquine in patients
hospitalized for COVID-19 infection and requiring oxygen: results of a study using routinely collected data
to emulate a target trial. medRxiv 2020.

193. Elsawah HK, Elsokary MA, Elrazzaz MG et al. Hydroxychloroquine for treatment of non-severe COVID-19
patients: systematic review and meta-analysis of controlled clinical trials. medRxiv 2020.

194. Axfors C, Schmitt AM, Janiaud P et al. Mortality outcomes with hydroxychloroquine and chloroquine in
COVID-19: an international collaborative meta-analysis of randomized trials. medRxiv 2020.

195. Sbidian E, Josse J, Lemaitre G et al. Hydroxychloroquine with or without azithromycin and in-hospital
mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients
in France. medrx 2020.

196. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020; 383:2030-2040.

197. Abd-Elsalam S, Esmail ES, Khalaf M et al. Hydroxychloroquine in the Treatment of COVID-19: A
Multicenter Randomized Controlled Study. Am J Trop Med Hyg 2020; 103:1635-39.

198. Rajasingham R, Bangdiwala AS, Nicol MR et al. Hydroxychloroquine as pre-exposure prophylaxis for
COVID-19 in healthcare workers: a randomized trial. medRxiv 2020.

199. Self WE, Semler MW, Leither Lm et al. Effect of hydroxychloroquine on clinical status at 14 days in
hospitalized patients with COVID-19. a randomized clinical trial. JAMA 2020.

200. Johnston C, Brown ER, Stewart J et al. Hydroxychloroquine with or without azithromycin for treatment of
early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.
EClinicalMedicine 2021.

201. Reis G, Silva EA, Silva DC et al. Effect of early treatment with hydroxychloroquine or Lopinavir and
Ritonavir on risk of hospitalization among patients with COVID-19. The TOGETHER randomized clinical
trial. JAMA Network Open 2021; 4:e216468.

202. Dubee V, Roy PM, Vielle B et al. Hydroxychloroquine in mild-to moderate COVID-19: a placebo-controlled
double blind trial. Clinical Microbiology and Infection 2021.

203. Tett SE, Cutler DJ, Day RO et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J
Clin Pharmac 1989; 27:771-79.

Page 44 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

204. MacGowan A, Hamilton F, Bayliss M et al. Hydroxychloroquine serum concentrations in non-critical care patients infected with SARS-CoV-2. medRxiv 2020.

205. Nicol MR, Joshi A, Rizk ML et al. Pharmacokinetic and pharmacological properties of chloroquine and hydroxychloroquine in the context of COVID-19 infection. medRxiv 2020.

206. 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.

207. Lagier JC, Million M, Gautret P et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis. Travel Medicine and Infectious Disease 2020.

208. Million M, Gautret P, Colson P et al. Clinical efficacy of chloroquine derivatives in COVID-19 infection: Comparative meta-analysis between big data and the real world. New Microbes and New Infections 2020.

209. Morgan A, Stevens J. Does Bacopa monnieri improve memoy performance in older persons? Results of a randomized, placebo-controlled, double-blind trial. J Altern Complement Med 2010; 16:753-59.

210. Azithromycin in hospitalized patients with COVID-19 (RECOVERY) a randomised, controlled, open-label, platform trial. medRxiv 2020.

211. Rosenthal N, Zhun Cao Z, Gundrum J et al. Risk factors associated with in-hospital mortality in a US National Sample of patients with COVID-19. JAMA Network Open 2020; 3:e2029058.

212. 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; 57:524-29.

213. 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 pathway. Fundamental & Clinical Pharmacology 2009; 23:449-55.

214. DiNicolantonio JJ, Barroso-Arranda J, McCarty M. Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. Open Heart 2020; 7:e001350.

215. DiNicolantonio JJ, Barroso-Aranda J, McCarty MF. Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors. Open Heart 2021; 8:e001655.

216. Villar J, Confalonieri M, Pastores SM et al. Rationale for prolonged corticosteroid tratment in the acute respiratory distress syndrome (ARDS) caused by COVID-19. Crit Care Expl 2020; 2:e0111.

217. Fadel R, Morrison AR, Vahia A et al. Early course corticosteroids in hospitalized patients with COVID-19. Clin Infect Dis 2020; 71:2114-20.

218. Chroboczek T, Lacoste M, Wackenheim C et al. Beneficial effect of corticosteroids in severe COVID-19 pneumonia: a propensity score matching analysis. medRxiv 2020.

219. 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.

220. Cruz AF, Ruiz-Antoran B, Gomez AM et al. Impact of glucocorticoid treatment in SARS-CoV-2 infection mortality: A retrospective controlled cohort study. medRxiv 2020.

221. Liu J, Zheng X, Huang Y et al. Successful use of methylprednisolone for treating severe COVID-19. J Allergy Clin Immunol 2020.

222. Meduri GU, Bridges L, Shih MC et al. Prolonged glucocorticoid treatment is associated with improved ARDS outomces: analysis of individual patients’ data from four randomized trials and trial-level meta- analysis of the updated literature. Intensive Care Med 2016; 42:829-40.

223. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19. A meta-analysis. JAMA 2020.

224. Ruiz-Irastorza G, Pijoan JI, Bereciatua E et al. Second week methyl-prednisolone pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: An observational comparative study using routine care data. medRxiv 2020.

225. Tomazini BM, Maia IS, Cavalcanti AB et al. Effect of dexamethasone on days alive and ventilaor-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19. The CoDEX randomized clinical trial. JAMA 2020; 324:1307-16.

226. Edalatifard M, Akhtari M, Salehi M et al. Intravenous methylprednisolone pulse as a treatment for hospitalized severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J 2020.

227. 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.

Page 45 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

228. 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.

229. Barrett TJ, Lee AH, Xia Y et al. Platelet and vascular biomarkers associate with thrombosis and death in coronavirus disease. Circulation Research 2020; 127:945-47.

230. Zhang S, Liu Y, Wang X et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. Journal of hematology & oncology 2020; 13:120.

231. Jalali F, Rezaie S, Rola P et al. COVID-19 pathophysiology: Are platelets and serotonin hiding in plain sight? ssrn 2021.

232. Lin OA, Karim ZA, Vemana HP et al. The antidepressant 5-HT2a receptor antagonists Pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function. PloS ONE 2014; 9:e87026.

233. Zaid Y, Guessous F, Puhm F et al. Platelet reactivity to thrombin differs between patients with COVID-19 and those with ARDS unrelated to COVID-19. Blood Advances 2021; 5:635-39.

234. Zaid Y, Puhm F, Allaeys I et al. Platelets can associate with SARS-CoV-2 RNA and are hyperactivated in COVID-19. Circ Res 2020; 127:1404-18.

235. Dawson C, Christensen CW, Rickaby DA et al. Lung damage and pulmonary uptake of serotonin in intact dogs. J Appl Physiol 1985; 58:1761-66.

236. MacLean MR, Herve P, Eddahibi S et al. 5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and the relevance to pulmonary arterial hypertension. Br J Pharmacol 2000; 131:161-68.

237. Blackshear JL, Orlandi C, Hollenberg NK. Constrictive effect of serotonin on visible renal arteries: a pharmacoangiographic study in anesthetized dogs. J Cardiovasc Pharmacol 1991; 17:68-73.

238. Watchorn J, Hang DY, Joslin J et al. Critically ill COVID-19 patients with acute kidney injury have reduced renal blood flow and perfusion despite preserved cardiac function: A case-control study using contrast enhanced ultrasound. Lancet Resp Med 2021.

239. McGoon MD, Vanhoutte PM. Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. J Clin Invest 1984; 74:823-33.

240. Almqvist P, Skudder P, Kuenzig M et al. Effect of cyproheptadine on endotoxin-induced pulmonary platelet trapping. Am Surg 1984; 50:503-5.

241. Skurikhin EG, Andreeva TV, Khnelevskaya ES et al. Effect of antiserotonin drug on the development of lung fibrosis and blood system reactions after intratracheal administration of bleomycin. Bull Exp Biol Med 2012; 152:519-23.

242. Doaei S, Gholami S, Rastgoo S et al. The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. J Transl Med 2021; 19:128.

243. Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicenter trial. Lancet 2020; 395:1569-78.

244. Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the treatment of Covid-19-Preliminary report. N Engl J Med 2020;ePub.

245. 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.

246. Pan H, Peto R, Karim QA et al. Repurposed antiviral drugs for COVID-19 – interim WHO SOLIDARITY trial. medrx 2020.

247. Jeffreys L, Pennington SH, Duggan J et al. Remdesivir-Ivermectin combination displays synergistic interactions with improved in vitro antiviral activity against SARS-CoV-2. bioRxiv 2020.

248. Marik PE, Kory P, Varon J et al. MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale. Exp Rev Anti Infect Ther 2020.

249. Kory P, Meduri GU, Iglesias J et al. Clinical and scientific rationale for the “MATH+” hospital treatment protocol for COVID-19. J Intensive Care Med 2020.

250. Ranjbar K, Shahriarad R, erfani A et al. Methylprednisolone or dexamethasone, which one is the superior corticosteroid in the treatment of hospitalized COVID-19 patients: A triple-blinded randomized controlled trial. Research Square 2021.

251. Ko JJ, Wu C, Mehta N et al. A comparison of methylprednisolone and dexamethasone in intensive care patients with COVID-19. medRxiv 2021.

252. Wang SY, Chang CH, Meizlish ML et al. Changes in inflammatory and immune drivers in response to immunmodulatory therapies in COVID-19. medRxiv 2020.

Page 46 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

253. Fowler AA, Truwit JD, Hite D et al. Vitamin C Infusion for TReatment In Sepsis-Induced Acute Lung Injury- CITRIS-ALI: A Randomized, Placebo Controlled Clinical Trial. JAMA 2018; 322:1261-70.

254. Marik PE, Khangoora V, Rivera R et al. Hydrocortisone, Vitamin C and Thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest 2017; 151:1229-38.

255. Barabutis N, Khangoora V, Marik PE et al. Hydrocortisone and Ascorbic Acid synergistically protect and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Chest 2017; 152:954-62.

256. Cheng RZ. Can early and high-dose vitamin C prevent and treat coronavirus disease 2019 (COVID-19). Medicine in Drug Discovery 2020.

257. Wang Y, Lin H, Lin BW et al. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care 2019; 9:58.

258. Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition 2020; 12:100190.

259. Iglesias J, Vassallo AV, Patel V et al. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis. Chest 2020; 158:164-73.

260. de Melo AF, Homem-de-Mello M. High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection. Crit Care 2020; 24:500.

261. Zhang J, Rao X, Li Y et al. High-dose vitamin C infusion for the treatment of critically ill COVID-19. Research Square 2020.

262. Kumari P, Dembra S, Dembra P et al. The role of vitamin C as adjuvant therapy in COVID-19. Cureus 2020; 12:e11779.

263. Al Sulaiman K, Al Juhani O, Badreldin HA et al. Adjunctive therapy with ascorbic in critically ill patients with COVID-19: A multicenter propensity score matched study. Crit Care 2021.

264. Lankadeva YR, Peiris RM, Okazaki N et al. Reversal of the pathophysiological responses to Gram-negative sepsis by megadose Vitamin C. Crit Care Med 2020.

265. Zhang J, Rao X, Li Y et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intenisve Care 2020.

266. Lavinio A, Ercole A, Battaglini D et al. Safety profile of enhanced thromboprophylaxis strategies for critically ill COVID-19 patients during the first wave of the pandemic: observational report from 28 European intensive care units. Crit Care 2021; 25:155.

267. Patterson G, Isales CM, Fulzele S. Low level of vitamin C and dysregulation of vitamin C transporter might be involved in the severity of COVID-19 infection. Aging and Disease 2020; 12.

268. Tomassa-Irriguible TM, Lielsa-Berrocal L. COVID-19: Up to 87% critically ill patients had low vitamin C values. Research Square 2020.

269. Arvinte C, Singh M, Marik PE. Serum levels of vitamin C and vitamin D in a cohort of critically ill COVID-19 patients of a North American Community Hospital Intensive Care Unit in May 2020. A pilot study. Medicine in Drug Discovery 2020; 8:100064.

270. Murshed MR, Bhiuyan E, Saber S et al. A case series of 100 COVID-19 positive patients treated with combination of Ivermectin and Doxycycline. Bangladesh Coll Phys Surg 2020; 38:10-15.

271. Jans DA, Wagstaff KM. Ivermectin as a broad-spectrum host directed anti-viral: The real deal. Cells 2020; 9:2100.

272. Sharun K, Dhama K, Patel SK et al. Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. Ann Clin Microbiol Antimicrob 2020; 19:23.

273. Peralta EG, Fimia-Duarte R, Cardenas JW et al. Ivermectin, a drug to be considered for the prevention and treatment of SARS-CoV-2. Brief literature review. EC Veterinary Science 2020; 5:25-29.

274. Al-Jassim KB, Jawad AA, Al-Masoudi EA et al. Histopathological and biochemical effects of ivermectin on kidney functions, lung and the ameliorative effects of vitamin C in rabbits. Bas J Vet Res 2016; 14:110-124.

275. Mudatsir M, Yufika A, Nainu F et al. Antiviral activity of ivermectin against SARS-CoV-2: an old-fashioned dog with a new trick- Literature review. Sci Pharm 2020; 88:36.

276. Carvallo H, Hirsch R, Farinella ME. Safety and efficacy of the combined use of Ivermectin, dexamethasone, enoxaparin and aspirin against COVID-19. medRxiv 2020.

277. Heaney RP, Armas LA, Shary JR et al. 25-hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr 2008; 87:1738-42.

278. Menezes RR, Godin AM, Rodrigues FF et al. Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund’s adjuvant. Pharmacological Reports 2020; 69:1036-43.

Page 47 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

279. Vatsalya V, Li F, Frimodig J et al. Therapeutic prospects for Th-17 cell immune storm syndrome and neurological symptoms in COVID-19: Thiamine efficacy and safety, In-vitro evidence and pharmacokinetic profile. medRxiv 2020.

280. Mallat J, Lemyze M, Thevenin D. Do not forget to give thiamine to your septic shock patient! J Thorac Dis 2016; 8:1062-66.

281. Moskowitz A, Donnino MW. Thiamine (vitamin B1) in septic shock: a targeted therapy. J Thorac Dis 2020; 12 (suppl 1):S78-S83.

282. Woolum JA, Abner EL, Kelly A et al. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med 2018; 46:1747-52.

283. Marik PE. Thiamine: An essential component of the metabolic resuscitation protocol. Crit Care Med 2018; 46:1869-70.

284. Al Sulaiman K, Aljuhani O, Al Dossari M et al. Evaluation of thiamine as adjunctive therapy in COVID-19 critically ill patients: A multicenter propensity score matched study. Research Square 2021.

285. Lee CY, Jan WC, Tsai PS et al. Magnesium sulfate mitigates acute lung injury in endotoxemia rats. J Trauma 2011; 70:1177-85.

286. Salem M, Kasinski N, Munoz R et al. Progressive magnesium deficiency inceases mortality from endotoxin challenge:Protective effects of acute magnesium replacement therapy [abstract]. Crit Care Med 1995;A260.

287. Jiang P. Does hypomagnesemia impact on the outcome of patients admitted to the intensive care unit? A systematic review and meta-analysis. Shock 2019; 47:288-95.

288. Calfee CS, Delucchi KL, Sinha P et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Resp Med 2018; 6:691-98.

289. Zhang XJ, Qin JJ, Cheng X et al. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metabolism 2020.

290. Rodriguez-Nava G, Trelles-Garcia DP, Yanez-Bello MA et al. Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study. Crit Care 2020; 24:429.

291. Gupta A, Madhavan MV, Poterucha TJ et al. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Research Square 2020.

292. Kow CS, Hasan SS. Meta-analysis of effectiveness of statins in patients with severe COVID-19. Am J Cardiol 2020.

293. Tan WY, Young BE, Lye DC et al. Statin use is assocaited with lower disease severity in COVID-19 infection. Nature Research 2020.

294. Bozzi G, Mangioni D, Minoia F et al. Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: an observational cohort study. J Allergy Clin Immunol 2021.

295. Cauchois R, Koubi M, Delarbre D et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19. PNAS 2021; 117:18951-53.

296. Cavalli G, Larcher A, Tomelleri A et al. Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study. Lancet Rheumatol 2021.

297. 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 Rheumatol 2020.

298. Dimopoulos G, de Mast Q, Markou N et al. Favorable anakinra responses in severe Covid-19 patients with
secondary hemophagocytic lymphohistiocytosis. Cell Host & Microbe 2020; 28:117-23.

299. Huet T, Beaussier H, Voisin O et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet
Rheumatol 2020; 2:e393-400.

300. Kooistra EJ, Waalders NJ, Grondman I et al. Anakinra treatment in critically ill COVID-19 patients: a
prospective cohort study. Crit Care 2020; 24:688.

301. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia
(CORIMUNO-ANA-!):a randomised controlled trial. Lancet Resp Med 2021.

302. Oldenburg CE, Doan T. Azithromycin for severe COVID-19. Lancet 2020.

303. Futado RH, 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 trial. Lancet 2020.

Page 48 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

304. 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.

305. Simonovich VA, Pratx LD, Scibona P et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med 2020.

306. Avendano-Sola C, Ramos-Martinez A, Munez-Rubio E et al. Convalescent plasma for COVID-19: A multicenter, randomized clinical trial. medRxiv 2020.

307. 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:e1003415.

308. Janiaud P, Axfors C, Schmitt AM et al. Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19. A systematic review and meta-analysis. JAMA 2021.

309. 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; 324:460-470.

310. Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria Jurnal 2003; 3 (Suppl I):S8.

311. Thompson MA, Henderson JP, Shah PK et al. Convalescent plasma and improved survival in patients with
hematologic malignancies and COVID-19. medRxiv 2021.

312. Rosas IO, Brau N, Waters M et al. Tocilizumab in hospitalized patients with COVID-19 pneumonia. medRxiv

313. 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 2020.

314. Stone JH, Frigault MJ, Sterling-Boyd NJ et al. Efficacy of tocilizumab in patients hospitalized with Covid-19.
N Engl J Med 2020.

315. 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 2020.

316. Salama C, Han J, Yau L et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med

317. Gordon AC, Mouncey PR, Rowan KM et al. Interleukin-6 receptor antagonists in critically ill patients with
COVID-19 – Preliminary report. medRxiv 2021.

318. Bassetti M, Kollef MH, Timsit JF. Bacterial and fungal superinfections in critically ill patients with COVID-
19. Intensive Care Med 2020.

319. Rawson TM, Wilson RC, Holmes A. Understanding the role of bacterial and fungal infection in COVID-19.
Clinical Microbiology & Infection 2021; 27:9-11.

320. Le Balc’h P, Pinceaux K, Pronier C et al. Herpes simplex virus and cytomegalovirus reactivations among
severe COVID-19 patients. Crit Care 2020; 24:530.

321. Koehler P, Bassetti M, Chen SC et al. Defining and managing COVID-19-associated pulmonary aspergillosis:
the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis 2021.

322. Xu Q, Wang T, Quin X et al. Early awake prone position combined with high-flow nasal oxygen therapy in
severe COVID-19; a case series. Crit Care 2020; 24:250.

323. Elharrar X, Trigui Y, Dois AM et al. Use of prone positioning in nonintubated patients with COVID-19 and
hypoxemic acute respiratory failure. JAMA 2020.

324. Reddy MP, Subramaniam A, Afroz A et al. Prone positioning of nonintubated patients with Coronavirus
Disease 2019- A systematic review and meta-analysis. Crit Care Med 2021.

325. Xin Y, Martin K, Morais CC et al. Diminishing efficacy of prone positioning with late application in evolving
lung injury. Crit Care Med 2021.

326. Haymet A, Bassi GL, Fraser JF. Airborne spread of SARS-CoV-2 while using high-flow nasal cannula oxygen
therapy: myth or reality. Intensive Care Med 2020; 46:2248-51.

327. Francone M, Lafrate F, Masci GM et al. Chest CT score in COVID-19 patients: correlation with disease
severity and short-term prognosis. European Radiology 2020; 30:6808-17.

328. Kory P, Kanne JP. SARS-CoV-2 organizing pneumonia:”Has there been a widespread failure to identify and
treat this prevalent condition in COVID-19?’. BMJ Open Resp Res 2020; 7:e000724.

329. Parry AH, Wani AH, Shah NN et al. Chest CT features of coronavirus disease-19 (COVID-19) pnemonia: which findings on initial CT can predict an adverse short-term outcome? BJR Open 2020; 2:20200016.

330. Zhang J, Meng G, Li W et al. Relationship of chest CT score with clinical characteristics of 108 patients hospitalized with COVID-19 in Wuhan, China. Respiratory Research 2020; 21:180.

Page 49 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

331. Yang R, Li X, Liu H et al. Chest CT severity score: An imaging tool for assessing severe COVID-19. Radiology: Cardiothoracic Imaging 2020; 2:e2000047.

332. Li K, Wu J, Wu F et al. The clinical and chest CT features associated with severe and critical COVID-19 pneumonia. Investigative Radiology 2020; 55:1-5.

333. Pan F, Ye T, Sun P et al. Time course of lung changes at Chest CT during recovery from Coronavirus Disease 2019 (COVID-19). Radiology 2021; 295:715-21.

334. Ding X, Xu J, Zhou J et al. Chest CT findings of COVID-19 pneumonia by duration of symptoms. European Journal of Radiology 2020; 127:109009.

335. Bernheim A, Mei X, Huang M et al. Chest CT findings in Coronavirus disease 2019 (COVID-19): relationship to duration of infection. Radiology 2020; 295:685-91.

336. Ichikado K, Suga M, Muranka H et al. Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: Validation in 44 cases. Radiology 2006; 238:321-29.

337. Ichikado K, Suga M, Muller NL et al. Acute interstitial pneumonia. Comparison of high-resolution computed tomography findings between survivors and nonsurvivors. Am J Respir Crit Care Med 2002; 165:1551-56.

338. Keith P, Day M, Perkins L et al. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care 2020.

339. Keith P, Wells AH, Hodges J et al. The therapeutic efficacy of adjunct therapeutic plasma exchange for septic shock with multiple organ failure: A single center experience. Crit Care 2020; 24:518.

340. Busund R, Koukline V, Utrobin U et al. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med 2002; 28:1434-39.

341. Morath C, Weigand MA, Zeier M et al. Plasma exchange in critically ill COVID-19 patients. Crit Care 2020; 24:481.

342. Khamis F, Al-Zakwani I, Al Hashmi S et al. Therapeutic plasma exchange in adults with severe COVID-19 infection. Int J Infect DIs 2020.

343. Fernandez J, Gratacos-Gines J, Olivas P et al. Plasma exchange: An effective rescue therapy in critically ill patients with Coronavirus Disease 2019 infection. Crit Care Med 2020.

344. Gucyetmez B, Atalan HK, Sertdemir I et al. Therapeutic plasma exchange in patients with COVID-19 pneumonia in intensive care unit: a retrospective study. Crit Care 2020; 24:492.

345. Poor HD, Ventetuolo CE, Tolbert T et al. COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfuncion responsive to thrombolysis. medRxiv 2020.

346. Wang J, Najizadeh N, Moore EE et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated respiratory distress syndrome (ARDS): A case series. J Thromb Haemost 2020.

347. Patel M, Dominguez E, Sacher D et al. Etoposide as salvage therapy for cytokine storm due to Coronavirus Disease 2019. Chest 2021; 159:e7-e11.

348. Hamizi K, Aouidane S, Belaaloui G. Etoposide-based therapy for severe forms of COVID-19. Medical Hypotheses 2020; 142:109826.

349. Otsuka R, Seino KI. Macrophage activation syndrome and COVID-19. Inflammation Regeneration 2020; 40:19.

350. Opoka-Winiarska V, Grywalska E, Rolinski J. Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases? BMC Medicine 2020; 18:214.

351. Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Medicine 2017; 15:172.

352. Brisse E. Hemophagocytic lymphohistiocytosis (HLH): A heterogenous spectrum of cytokine-driven immune disorders. Cytokine Growth Factors Reviews 2015; 26:263-80.

353. Mehta R. Hemophagocytic lymphohistiocytosis (HLH) : a review of literature. Med Oncol 2013; 30:740.

354. Abou-Arab O, Huette P, Debouvries F et al. Inhaled nitric oxide for critically ill Covid-19 patients: a
prospective study. Crit Care 2020; 24:645.

355. Bagate F, Tuffet S, Masi P et al. Rescue thearpy with inhaled nitric oxide and almitrine in COVID-19
patients with severe acute respiratory distress syndrome. Ann Intensive Care 2020.

356. Caplan M, Goutay J, Bignon A et al. Almitrine infusion in severe acute respiratory syndrome coronavirus-2
indued acute respiratory distress syndrome: A single-center observational study. Crit Care Med 2020.

357. Payen D. Coronavirus disease 2019 acute respiratory failure: Almitrine drug resuscitaion or resuscitating
patients by almitrine? Crit Care Med 2020.

Page 50 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

358. Henry MB, 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.

359. Abrams D, Lorusso R, Vincent JL et al. ECMO during the COVID-19 pandemic: when is it unjustified. Crit Care 2020; 24:507.

360. Supady A, Taccone FS, Lepper PM et al. Survival after extracorporeal membrane oxygenation in severe COVID-19 ARDS: results from an international multicenter registry. Crit Care Med 2021; 25:90.

361. 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.

362. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med 2020.

363. Cerutti A, Chen K, Chorny A. Immunoglobulin responses at the mucosal interface. Annu Rev Immunol
2011; 29:273-93.

364. Jacobs JJ. Neutralizing antibodies mediate virus-immue pathology of COVID-19. Med Hypotheses 2020;

365. Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor
Febratinib. J Microbiol Immunol Infect 2020.

366. Favalli EG, Biggioggero M, Maioli G et al. Baricitinib for COVID-19: a suitable treatment? Lancet Infect Dis

367. Mehta P, McAuley DF, Brown M et al. COVID-19: consider cytokine storm syndromes and
immunosuppression. Lancet 2020; 395:1033-34.

368. Kalil AC, Patterson TF, Mehta AK et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N
Engl J Med 2020; 384:795-807.

369. Seifirad S. Pirfenidone: A novel hypothetical treatment for COVID-19. Medical Hypotheses 2020;

370. Saba A, Vaidya PJ, Chavhan VB et al. Combined pirfenidone, azithromycin and prednisolone in post-H1N1
ARDS pulmonary firbosis. Sarcoidosis Vasc Diffuse Lung Dis 2018; 35:85-90.

371. Spagnolo P, Balestro E, Aliberti S et al. Pulmonary fibrosis secondary to COVID-19: a call to arms? Lancet
Resp Med 2020; 8:750-752.

372. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antibibrotic
therapy. Lancet Resp Med 2020; 8:807-15.

373. Brouwer WP, Duran S, Kuijper M et al. Hemoadsorption with CytoSorb shows a decreased observed
versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted
retrospective study. Crit Care 2019; 23:317.

374. Villa G, Romagnoli S, De Rosa S et al. Blood purification therapy with a hemodiafilter featuring enhanced
adsorptive properties for cytokine removal in patients presenting COVID-19: a pilot study. Crit Care 2020;

375. Ahmad Q, DePerrior SE, Dodani S et al. Role of inflammatory biomarkers in the prediction of ICU
admission and mortality in patients with COVID-19. Medical Research Archives 2020; 8:1-10.

376. Marik PE, Stephenson E. The ability of procalcitonin, lactate, white blood cell count and neutrophil-
lymphocyte count ratio to predict blood stream infection. Analysis of a large database. J Crit Care 2020;

377. Ichikado K, Muranaka H, Gushima Y et al. Fibroproliferative changes on high-resolution CT in the acute
respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational
cohort study. BMJ Open 2012; 2:e000545.

378. 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; 92:856-62.

379. Howell AP, Parrett JL, Malcom DR. Impact of high-dose intravenous vitamin C for treatment of sepsis on
point-of-care blood glucose readings. J Diabetes Sci Technol 2019.

380. Stephenson E, Hooper MH, Marik PE. Vitamin C and Point of Care glucose measurements: A retrospective,
Observational study [Abstract]. Chest 2018; 154 (suppl.):255a.

381. Hekimian G, Kerneis M, Zeitouni M et al. COVID-19 acute myocarditis and multisystem inflanmmatory
syndrome in Adult Intensive and cardiac Care Units. Chest 2020.

382. Ma KL, Liu ZH, Cao CF et al. COVID-19 myocarditis and severity factors: An adult cohort study. medRxiv

Page 51 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

383. Brosnahan SB, Bhatt A, Berger JS et al. COVID-19 pneumonia hospitalizations followed by re-presentation for presumed thrombotic event. Chest 2020.

384. Giannis D, allen SL, Tsang J et al. Post-discharge thromboembolic outcomes and mortality of hospitalized COVID-19 patients: The CORE-19 registry. Blood 2021.

385. 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:e59-e65.

386. Kunutsor SK, Seidu S, Blom AW et al. Serum C-reactive protein increases the risk of venous thromboembolism: a prospective study and meta-analysis of published prospective evidence. Eur J Epidemiol 2017; 32:657-67.

387. Carfi A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA 2020.

388. Prescott HC, Girard TD. Recovery from Severe COVID-19. Leveraging the lessons of survival from sepsis.
JAMA 2020.

389. Greenhalgh T, Knight M, A’Court C et al. Management of post-acute Covid-19 in primary care. BMJ 2020.

390. Chopra V, Flanders SA, O’Malley M. Sixty-day outcomes among patients hospitalized with COVID-19. Ann
Intern Med 2020.

391. Mandal S, Barnett J, Brill SE et al. ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker
and imaging abnormalities following hospitalization for COVID-19. Thorax 2020.

392. Michelen M, Manoharan L, Elkheir N et al. Characterising long-term covid-19: a rapid living systematic
review. medRxiv 2020.

393. Huang C, Huang L, Wang Y et al. 6-month consequences of COVID-19 in patients discharged feom hospital:
a cohort study. Lancet 2021.

394. Logue JK, Franko NM, McCulloch DJ et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA
Network Open 2021; 4:e210830.

395. Janiri D, Carfi A, Kotzalidis GD et al. Posttraumatic stress disorder in patients after severe COVID-19
infection. JAMA Psychiatry 2021.

396. Voruz P, Allali G, Benzakour L et al. Long COVID neuropsychological deficits after severe, moderate or mild
infection. medRxiv 2021.

397. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequalae of COVID-19. Nature

398. Yong SJ. Long-haul COVID-19: Putative pathophysiology, risk factors, and treatments. medRxiv 2020.

399. Taquet M, Geddes JR, Husain M et al. 6-month neurological and psychiatric outcomes in 236 379 survivors
of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry 2021.

400. Bryce C, Grimes Z, Pujadas E et al. Pathopysiology of SARS-CoV-2: targeting of endothelial cells renders a
complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai
COVID-19 autopsy experience. medRxiv 2020.

401. Lu Y, Li X, Geng D et al. Cerebral micro-structutal changes in COVID-19 patients – An MRI-based 3-month
follow-up study. EClinicalMedicine 2020.

402. Franke C, Ferse C, Kreye J et al. High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients
with neurological symptoms. Brain,Behavor, and Immunity 2021.

403. Sirous R, Taghvaei R, Hellinger JC et al. COVID-19-associated encephalopathy with fulminant cerebral
vasoconstriction: CT and MRI findings. Radiology Case Reports 2020; 15:2208-12.

404. Magro CM, Mulvey JJ, Laurence J et al. Docked severe acute respiratory syndrome coronavirus 2 proteins
within the cutaneous and subcutaneous microvasculature and their role in the pathogenesis of severe
coronavirus disease 2019. Human Pathology 2020; 106:106-16.

405. Afrin LB, Weinstock LB, Molderings GJ. COVID-19 hyperinflammation and post-Covid-19 illness may be
rooted in mast cell activation syndrome. Int J Infect DIs 2020.

406. Theoharides TT, Cholevas C, Polyzoidis K et al. Long-COVID syndrome-associated brain fog and chemofog:
Luteolin to the rescue. Biofactors 2021; 47:232-41.

407. Riche F. Protracted immune disorders at one year after ICU discharge in patients with septic shock. Crit
Care 2018; 22:42.

408. Andreakos E, Papadaki M, Serhan CN. Dexamethasone, pro-resolving lipid mediators and resolution of
inflammation in COVID-19. Allergy 2020.

409. COVID-19 rapid guideline: managing the long-term effects of COVID-19.
. 2020. National Institute for Health and Care Excellence. 4-26-2021.

Page 52 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

410. Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors 2020; 46:306-8.

411. Bawazeer MA, Theoharides TC. IL-33 stimulates human mast cell release of CCL5 and CCL2 via MAPK and NF-kB, inhibited by methoxyluteolin. Eur J Pharmacol 2019; 865:172760.

412. Weng Z, Patel AB, Panagiotidou S et al. The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol 2015; 135:1044-52.

413. Patel AB, Theoharides TC. Methoxyluteolin inhibits neuropeptide-stimulated proinflammatory mediator release via mTOR activation from human mast cells. J Pharmacol Exp Ther 2017; 361:462-71.

414. Calis Z, Mogulkoc R, Baltaci AK. The roles of flavonols/flavonoids in neurodegeneration and neuroinflammation. Mini Rev Med Chem 2020; 20:1475-88.

415. Gao J, Zheng P, Jia Y et al. Mental health problems and social media exposure during COVID-19 outbreak. PloS ONE 2020; 15:e0231924.

416. Pennycook G, McPhetres J, Zhang Y et al. Fighting COVID-19 misinformation on Social Media: Experimental Evidence fo a Scalable Accuracy-Nudge Intervention. Psychological Science 2020; 31:770- 780.

417. Kurcicka L, Lauer SA, Laeyendecker O et al. Variation in false-negative rate of reverse transcriptase polmerase chain reacion-based SARS-CoV-2 tests by time since exposure. Ann Intern Med 2020; 173:262- 67.

418. Cheng HY, Jian SW, Liu DP et al. Contact tracing assessment of COVI-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset. JAMA Intern Med 2020; 180:1156- 63.

419. Zhao J, Yang Y, Huang H et al. Relationship between ABO blood group and the COVID-19 susceptibility. medRxiv 2020.

420. Banerjee A, Pasea L, Harris S et al. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study. Lancet 2020; 395:1715-25.

421. Goren A, Vamo-Galvan S, Wambier CG et al. A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain- A potential clue to the role of androgens in COVID-19 severity. J Cosmetic Dermatol 2020.

422. Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan,China. Lancet 2020; 395:497-506.

423. Guan W, Ni Z, Hu Y et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020.

424. von der Thusen J, van der Eerden M. Histopathology and genetic susceptibility in COVID-19 pneumonia.
Eur J Clin Invest 2020.

425. Sweeney TE, Liesenfeld O, Wacker J et al. Validation of inflammopathic, adaptive, and coagulopathic
sepsis endotypes in Coronavirus disease 2019. Crit Care Med 2020.

426. Tartof SY, Qian L, Hong V et al. Obesity and mortality among patients diagnosed with COVID-19: Results
from an integrated health care organization. Ann Intern Med 2020.

427. Pujadas E, Chaudhry F, McBride R et al. SARS-CoV-2 viral load predictes COVID-19 mortality. Lancet Resp
Med 2020.

428. Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science 2020; 369.

429. Zhang Q, Bastard P, Liu Z et al. Inborn errors of type I IFN immunity in patients with life-threatening
COVID-19. Science 2020.

430. Li MY, Li L, Zhang Y et al. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human
tissues. Infectious Diseases of Poverty 2020; 9:45.

431. Zhou Y, Fu B, Zheng X et al. Pathogenic T cellls and inflammatory monocytes incite inflammatory storm in
severe COVID-19 patients. Natl Sci Rev 2020; 7:998-1002.

432. Blanco-Melo D, Nilsson-Payant BE, Liu WC et al. Imbalanced host response to SARS-CoV-2 drives
development of COVID-19. Cell 2020; 181:1036-45.

433. Giamarellos-Bouboulis EJ, Netea MG, Rovina N et al. Complex immune dysregulation in COVID-19 patients
with severe respiratory failure. Cell Host & Microbe 2020.

434. McGonagle D, Sharif K, O’Regan A et al. The role of cytokines including interleukin-6 in COVID-19 induces
pneumonia and macrophage activation syndrome-like disease. Autoimmunity Reviews 2020; 19:102537.

435. Zhou F, Yu T, Du R et al. Clinical course and risk factor for mortality of adult inpatients with COVID-19 in
Wuhan, China: a retrospective cohort study. Lancet 2020.

Page 53 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

436. Giamarellos-Bourboulis EJ, Netea MG, Rovina N et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. medRxiv 2020.

437. Qin C, Zhou L, Hu Z et al. Dysregulation of the immune response in patiens with COID-19 in Wuhan, China. Lancet Infect Dis 2020.

438. Zhang C, Wu Z, Li JW et al. The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonsit Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents 2020.

439. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the “Cytokine Storm” in COVID-19. J Infection 2020.

440. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020.

441. Tay MZ, Poh CM, Renia L et al. The trinity of COVID-19: immunity, inflammation and intervention. Nature
Reviews 2020; 20:363-74.

442. Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis,
and dysregulated inflammation. Intensive Care Med 2020; 46:1105-8.

443. Teuwen LA, Geldhof V, Pasut A et al. COVID-19: the vasculature unleashed. Nature Reviews 2020.

444. Varga Z, Flammer AJ, Steiger P et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020.

445. Ackermann M, Verleden SE, Kuehnel M et al. Pulmonary vascular endothelialitis, Thrombosis, and
Angiogenesis in COVID-19. N Engl J Med 2020; 383:120-128.

446. Torrealba JR, Fisher S, Kanne JP et al. Pathology-radiology correlation of common and uncommon
computed tomographic patterns of organizing pneumonia. Human Pathology 2018; 71:30-40.

447. Kanne JP, Little BP, Chung JH et al. Essentials for radiologists on COVID-19: an Update-Radiology Scientific
Expert Panel. Radiology 2020.

448. Copin MC, Parmentier E, Duburcq T et al. Time to consider histologic pattern of lung injury to treat
critically ill patietns with COVID-19 infection [letter]. Intensive Care Med 2020.

449. Gattinoni L, Chiumello D, Caironi P et al. COVID-19 pneumonia: different respiratory treatment for
different phenotypes? Intensive Care Med 2020; 46:1099-102.

450. Chiumello D, Cressoni M, Gattinoni L. Covid-19 does not lead to a “typical” Acute Respiratory Distress
syndrome. Lancet 2020.

451. Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care 2020; 24:154.

452. Gattinoni L, Pesenti A. The concept of “baby lung”. Intensive Care Med 2005; 31:776-84.

453. Patel AN, Desai SS, Grainger DW et al. Usefulness of ivermectin in COVID-19 illness. medRxiv 2020.

454. Jeronimo CM, Farias ME, Almeida FF et al. Methylprednisolone as adjunctive therapy for patients
hospitalized with COVID-19 (Metcovid): A ramdomised, double-blind, phase IIb, placebo-controlled trial.
Clin Infect Dis 2020.

455. Carsana L, Sonzogni A, Nasr A et al. Pulmonary post-mortem findings in a large series of COVID-19 cases
from Northern Italy. medRxiv 2020.

456. Menter T, Haslbauer JD, Nienhold R et al. Post-mortem examination of COVID19 patients reveals diffuse
alveolar damage with severe capillary congestion and variegated findings of lungs and other organs
suggesting vascular dysfunction. medRxiv 2020.

457. Xu Z, Shi L, Wang Y et al. Pathological findings of COVID-19 associated with acute respiratory distress
syndrome. Lancet Resp Med 2020.

458. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care
Med 2020.

459. Schurink B, Roos E, Radonic T et al. Viral presence and immunopathology in patients with lethal COVID-19:
a prospective autopsy cohort study. Lancet Microbe 2020.

460. Buijsers B, Yanginlar C, Maciej-Hulme ML et al. Beneficial non-anticoagulant mechanisms underlying
heparin treatment of COVID-19 patients. EBioMedicine 2020.

461. Kim SY, Jin W, Sood A et al. Characterization of heparin and severe acute respiratory syndrome-related
coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Antiviral Res 2020; 181:104873.

462. Clausen TM, Sandoval DR, Spliid CB et al. SARS-CoV-2 infection depends on cellular heparan sulphate and
ACE2. bioRxiv 2020.

463. Kwon PS, Oh H, Kwon SJ et al. Sulphated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell
Discovery 2020; 6:50.

464. Huang X, Han S, Liu x et al. Both UFH and NAH alleviate shedding of endothelial glycocalyx and
coagulopathy in LPS-induced sepsis. Exp Thera Med 2020; 19:913-22.

Page 54 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

465. Buijsers B, Yanginlar C, de Nooijer A et al. Increased plasma heparanase activity in COVID-19 patients. medRxiv 2020.

466. May JM, Qu ZC. Ascorbic acid prevents oxidant-induced increases in endothelial permeability. Biofactors 2011; 37:46-50.

467. Utoguchi N, Ikeda K, Saeki K et al. Ascorbic acid stimulates barrier function of cultured endothelial cell monolayer. Journal of Cellular Physiology 1995; 163:393-99.

468. Han M, Pendem S, Teh SL et al. Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A. Free Radic Biol Med 2010; 48:128-35.

469. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 2004; 1024:138-46.

470. Shodell M, Siegal FP. Corticosteroids depress INF-alpha-producing plasmacytoid dentritic cells in human
blood. J Allergy Clin Immunol 2001; 108:446-48.

471. Thomas BJ, Porritt RA, Hertzog PJ et al. Glucocorticosteroids enhance replication of respiratory viruses:
effect of adjuvant interferon. Scientific Reports 2014; 4:7176.

472. Singanayagam A, Glanville N, Girkin JL et al. Corticosteroid suppression of antiviral immunity increases
bacterial loads and mucus production in COPD exacerbations. Nature Communications 2018; 9:2229.

473. Salton F, Confalonieri P, Santus P et al. Prolonged low-dose methylprednisolone in patients with severe
COVID-19 pneumonia. medRxiv 2020.

474. Braude AC, Rebuck AS. Prednisone and methylprednisolone disposition in the lung. Lancet 1983;995-97.

475. Carsana L, Sonzogni A, Nasr A et al. Pulmonary post-mortem findings in a series of COVID-19 ccases from
northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 20:1135-40.

476. Hariri LP, North CM, Shih AR et al. Lung histopathology in COVID-19 as compared to SARS and H1N1
influenza: A systematic review. Chest 2020.

477. Dorward DA, Russell CD, Um IH et al. Tissue-specific immunopathology in fatal COVID-19. Am J Respir Crit
Care Med 2020.

478. Barrett TJ, Lee AH, Xia Y et al. Platelet and vascular biomarkers associated with thrombosis and death in
coronavirus disease. Circulation Research 2020; 127:945-47.

479. Bikdeli B, Madhavan MV, Jimenez et al. COVID-19 and thrombotic or thromboembolic disease:
Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020.

480. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020.

481. Klok FA, Kruip MJ, van der Meer NJ et al. Incidence of thrombotic complications in critically ill ICU patients
with COVID-19. Thrombosis Research 2020.

482. Tang N, Bai H, Chen X et al. Anticoagulant treatment is associated with decreased mortality in severe
coronavirus disease 2019 with coagulopathy. medRxiv 2020.

483. Zhai Z, Li C, Chen Y et al. Prevention and treatment of venous thromboembolism assocaited with
Coronavirus Disease 2019 Infection: A consensus statement before guidelines. Thromb Haemost 2020.

484. Paranjpe I, Fuster V, Lala A et al. Association of treatment dose anticoagulation with in-hospital survival
among hospitalized patietns with COVID-19. J Am Coll Cardiol 2020.

485. Iba T, Levy JH, Levi M et al. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020.

486. Joly BS, Siguret V, Veyradier A. Understanding pathophysiology of hemostasis disorders in critically ill
patients with COVID-19. Intensive Care Med 2020; 46:1603-6.

487. 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; 46:1089-98.

488. Varatharajah N, Rajah S. Microthrombotic complications of COVID-19 are likely due to embolism of
circulating endothelial derived ultralarge Von Willebrand Factor (eULVWF) decorated-platelet strings.
Federal Practitioner 2020.

489. Du L, Kao RY, Zhou Y et al. Cleavage of spike protein of SARS coronavirus by protease factor Xa is
associated with viral infectivity. Biochemical & Biophysical Research Communications 2007; 359:174-79.

490. Sardu C, Gambardella J, Morelli MB et al. Is COVID-19 an endothelial disease? Clinical and basic evidence.
medRxiv 2020.

491. Taccone FS, Gevenois PA, Peluso L et al. Higher intensity thromboprophylaxis regimens and pulmonary
embolism in critically ill coronavirus disease 2019 patients. Crit Care Med 2020.

492. World Health Organization: Coronavirus Disease 2019 (COVID-19): Situation Report -54 (14th March
2020). covid-19.pdf . 2020. 7-9-2020.


Page 55 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

493. Clinical management of COVID-19. Interim guidance. 27th May 2020. WHO/2019- nCoV/clinical/2020.5 . 2020. World Health Organization. 7-10-2020.

494. Yam LY, Lau AC, Lai FY et al. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. J Infection 2007; 54:28-39.

495. Siemieniuk RA, Bortoszko JJ, Ge L et al. Drug treatments for Covid-19: living systematic review and network meta-analysis. BMJ 2020.

496. Saune PM, Bryce-Alberti M, Portmann-Baracco AS et al. Methylprednisolone pulse therapy: An alternative management of severe COVID-19. Respiratory Medicine Case Reports 2020; 31:101221.

497. Fernandez-Cruz A, Ruiz-Antoran B, Gomez AM et al. Impact of glucocorticocoid treatment in SARS-CoV-2 infection mortality: A retrospective controlled cohort study. medRxiv 2020.

498. Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv 2020.

499. Monedero P, Gea A, Castro P et al. Early corticosteroids are associated with lower mortality in critically ill patients with COVID-19: a cohort study. Crit Care 2021; 25:2.

500. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone. A potential strategy to avoid steroid- related Strongyloides hyperinfection. JAMA 2020; 324:623-24.

Page 56 of 56 | FLCCC Alliance – COVID-19 Management Protocol 05-04-2021

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: