FLCCC Management Protocols: MATH+, I-MASK+ and I-RECOVER (2022)

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.

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 we have developed the I-MASS protocol for a MASS Distribution campaign to lessen the impact of COVID-19 in resource-poor countries. 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.

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 flavonoids) 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]

Components of the I-MASK Prophylactic Protocol 
  • Ivermectin for post-exposure prophylaxis (see ClinTrials.gov 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 ClinTrials.gov 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 - Drugs.com. (also see below) . The most important drug-drug interactions occur with cyclosporin, tacrolimus, antiretroviral 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]
  • Vitamin D3 1000–3000 IU/day (25-75 mcg). 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”. https://preventepidemics.org/covid19/press/former-cdc-chiefdr-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 COVID19 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 30–50 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 SARSCoV-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] Commercial zinc supplements contain 7 to 80 mg of elemental zinc, and are commonly formulated as zinc oxide or salts with acetate, gluconate, and sulfate. 220 mg zinc sulfate contains 50 mg elemental zinc. 
  • B complex vitamins [103-107]. 
  • Oropharyngeal hygiene with twice daily anti-viral mouth mouth/gargle (see below). 
  • 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 papainlike 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 - 12mg 
  • 65-79.9 kg - 15mg 
  • 80-94.9 kg - 18mg 
  • 95-109.9 kg - 21mg 
  • ≥ 110 kg - 24mg 
I-MASS: Mass distribution protocol for the Prophylaxis and Early Outpatient treatment for COVID-19

The I-MASS protocol has been developed for MASS Distribution in resource poor countries to lessen the impact of COVID-19. 

PREVENTION PROTOCOL (for adults > 18 years and > 40 kg/90 lbs.) 
  • IVERMECTIN: 18 mg. [118] Start treatment with one dose on day 1, and then repeat weekly (every 7 days) 
  • VITAMIN D3: 2000 IU (50 mcg) daily 
  • Multivitamin: Take 1 daily 
  • Digital thermometer (optional) 
EARLY AT HOME TREATMENT PROTOCOL (for adults > 18 years and > 40 kg/90 lbs.) 
  • IVERMECTIN: 18 mg daily for 5 days 
  • Melatonin: 6 mg at night for 5 days 
  • Aspirin 81 mg daily for 5 days (unless contraindicated) 
  • Antiseptic mouth wash: Three times daily (gargle do not swallow); if available 
Post-Exposure Prevention for household/close contacts (for adults > 18 years and > 40 kg/90 lbs.) 
  • IVERMECTIN 18mg day 1 and day 3 
Disclaimer/Caution: The safety of ivermectin in pregnancy has not been established.

Drug Interactions with Ivermectin 

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

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 ClinTrials.gov 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 (50-100 mcg) 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. 

• Optional: Fluvoxamine 50 – 100 mg BID. [149-153] This SSRI is recommended in those patients with more severe symptoms/more advanced disease. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that activates sigma-1 receptors decreasing cytokine production. [149,150] 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] Antidepressant medications (SSRI) deplete platelet serotonin content, thereby diminishing the release of serotonin following platelet aggregation.[155-157] The use of antidepressants has be associated with a lower risk of intubation and death in patients hospitalized with COVID-19. [152,153] 

• 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 (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] 
  • Use the index or middle finger; avoid the toes or ear lobe 
  • Only accept values associated with a strong pulse signal 
  • Observe readings for 30–60 seconds to identify the most common value 
  • Remove nail polish from the finger on which measurements are made 
  • Warm cold extremities prior to measurement 
• 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 was 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]

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 (as reviewed above). While 1) methylprednisolone is the corticosteroid of choice (see below) in those regions/counties where it is not available the following (in order of preference) may be substituted for methylprednisolone (dose adjusted according to methylprednisolone dosages), 2) prednisolone, 3) prednisone, 4) hydrocortisone, and 5) LASTLY dexamethasone. 
• 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 response.[142,143,229,230] 
• 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 USA. 
• 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 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.

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] While 1) methylprednisolone is the corticosteroid of choice (see below) in those regions/counties where it is not available the following (in order of preference) may be substituted for methylprednisolone (dose adjusted according to methylprednisolone dosages), 2) prednisolone, 3) prednisone, 4) hydrocortisone, and 5) LASTLY dexamethasone. 

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 https://www.youtube.com/watch?v=Au-mp6RZjCQ ). Megadose 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 antiinflammatory treatment (see Figure 2). Note: Early termination of ascorbic acid and corticosteroids will likely result in a rebound effect with clinical deterioration. 

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 prothrombotic 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. 

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 noninvasive 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. 

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, [388-398] 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.[410] 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,[407,411- 414] and have been demonstrated to reduce neuroinflammation. [415] 

• Famotidine 20-40mg day (histamine-2 blocker for Mast Cell Activation syndrome). [406] 

• 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.[399] 

• Behavioral modification and psychological support may help improve survivors’ overall well-being and mental health. [399] 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: https://covidlonghaulers.com/

For details of supporting reference links mentioned above, check out REFERENCES (page 43 onwards).



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