Marik Critical Care COVID-19 Protocol

COVID-19 MANAGEMENT PROTOCOL
An overview of the MATH+ and I-MASK+ Protocols

Developed and Updated by Paul Marik, MD, FCP (SA), FRCP (C), FCCP, FCCM.
Professor of Medicine, Chief of Pulmonary and Critical Care Medicine
Eastern Virginia Medical School
December 27th, 2020
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 NOTE: Updates will no longer be posted on the EVMS Website. Please check on the FLCCC
Alliance website for updated versions of this protocol. www.flccc.net
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.
Please Note: The NIH has not approved the use of IVERMECTIN for the treatment or
prophylaxis of COVID-19.
Page 1 of 49 | COVID-19 Management Protocol 12-27-2020

Figure 1. The course of COVID-19 and General Approach to treatment
THIS IS A STEROID RESPONSIVE DISEASE:

HOWEVER, TIMING IS CRITICAL

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)

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

Figure 3. Time course of laboratory tests for COVID-19
Figure 4. SARS-Co-V-2 RNA genome

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 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 nine months almost two million patients have died world-
wide and the pandemic shows no signs of abating. Hospitals in the USA are now overwhelmed, and
many have exceeded their ICU capacity. 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 late pulmonary phase of this disease with the goal of reducing the hospital mortality
from COVID-19. However, it has now become blatantly clear that our emphasis needs to shift to the
prevention and early 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”. 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.[6]
Figure 5. Treatment Phases of COVID-19

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

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

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 and vitamin
C may play an important role in both pre-exposure and postexposure prophylaxis. [2,7] 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). [8] 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.
Figure 7. The I-MASK prophylactic and Early Treatment Protocol.

Figure 8. Ivermectin for Pre-and postexposure prophylaxis.
Components of the I-MASK Prophylactic Protocol
• Ivermectin for postexposure prophylaxis (see ClinTrials.gov NCT04422561). 0.2 mg/kg

immediately then repeat day 3.
• 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 Day 1,
Day 3 and then bi-weekly. [9-13] (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. 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, [14] fixed drug eruptions (diffuse rash) and Stevens Johnson
Syndrome have rarely been reported. [15,16]
• 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. [10,17-37] Vitamin D insufficiency has been associated with an increased risk of
acquiring COVID-19 and from dying from the disease. 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.
[22-37] 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. 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. [38]
Furthermore, 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-chief-dr-tom-frieden-coronavirus-
infection-risk-may-be-reduced-by-vitamin-d/
• Vitamin C 500 mg BID (twice daily) and Quercetin 250 mg daily. [39-50] Vitamin C has important
anti-inflammatory, antioxidant, and immune enhancing properties, including increased synthesis
of type I interferons.[42,51,52] Quercetin has direct viricidal properties against a range of
viruses, including SARS-CoV-2, and is a potent antioxidant and anti-inflammatory agent.
[40,45,50,50,53-60] In addition, quercetin acts as a zinc ionophore. [61] It is likely that vitamin C
and quercetin have synergistic prophylactic benefit. [2] 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. [62-65] 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.[66] In
women high consumption of soya was associated with elevated TSH concentrations.[67] 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. [68] 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 2 mg at night. [1,7,69-
75]. Melatonin has anti-inflammatory, antioxidant, immunomodulating and metabolic effects
that are likely important in the mitigation of COVID-19 disease. 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. [76]
• Zinc 30–50 mg/day (elemental zinc). [46,48,49,77-80] Zinc is essential for innate and adaptive
immunity.[78] In addition, Zinc inhibits RNA dependent RNA polymerase in vitro against SARS-
CoV-2 virus.[77]
• B complex vitamins [81-85]
• Optional: Famotidine 20–40 mg/day [55–61]. 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.[58] Furthermore, a single study suggested that users of
PPI’s had a significantly increased odds for reporting a positive COVID-19 test when
compared with those not taking PPIs, while individuals taking histamine-2 receptor
antagonists were not at elevated risk.[62] 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 [54]
Ivermectin dosing: 200 ug/kg or fixed dose of 12 mg (≤ 80kg) or 18 mg (≥ 80kg).[86] 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

Figure 9. I-MASK prophylaxis protocol.

Symptomatic patients at home (I-MASK+ EARLY Treatment Protocol)
• Ivermectin 0.2 mg/kg on day 1 and day 3 (repeat on day 5 and 7 if poor response). [10,12,14,17-
20,87-97] See Table 1, Figure 9 and ClinTrials.gov NCT04523831. See drug-drug interactions
above.
• Vitamin C 500 mg BID and Quercetin 250–500 mg BID
• Zinc 75–100 mg/day (elemental zinc)
• Melatonin 10 mg at night (the optimal dose is unknown) [75]
• Vitamin D3 2000–4000 IU/day. Calcifediol 0.2 mg is an alternative. [98]
• ASA 81–325 mg/day (unless contraindicated). ASA has antiinflammatory, antithrombotic,
immunomodulatory and antiviral effects.[99-101] Platelet activation plays a major role in
propagating the prothrombotic state associated with COVID-19. [102]
• B complex vitamins
• Optional: Famotidine 40 mg BID (reduce dose in patients with renal dysfunction) [103-109].
• 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. [48,110-113]
• Optional: Interferon-α/β s/c, nasal spray or inhalation. [114-117] It should be noted that Zinc
potentiates the effects of interferon.[118,119]
• 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.[120] Multiple readings should be taken over the course of the
day, and a downward trend should be regarded as ominous.[120] Baseline or ambulatory
desaturation < 94% should prompt hospital admission. [121] The following guidance is
suggested: [120]
o Use the index or middle finger; avoid the toes or ear lobe
o Only accept values associated with a strong pulse signal
o Observe readings for 30–60 seconds to identify the most common value
o Remove nail polish from the finger on which measurements are made
o Warm cold extremities prior to measurement
• Not recommended: Hydroxychloroquine (HCQ). The use of HCQ is highly controversial.[122] The
best scientific evidence to date suggests that HCQ has no proven benefit for post exposure
prophylaxis, for the early symptomatic phase and in hospitalized patients. [123-141] 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).[133,142-144] Finally, it should be recognized that those studies which are
widely promoted to support the use of HCQ are severely methodologically flawed.[145-148]
• Not recommended: Systemic or inhaled corticosteroids (budesonide). In the early symptomatic
(viral replicative phase), corticosteroids may increase viral replication and disease severity.[149]
An OpenSAFELY analysis in patients with COVID-19 demonstrated a higher risk of death in COPD
and asthmatic patients using high dose ICS. [150] The role of ICS in the pulmonary phase is
unclear as patients require systemic corticosteroids to dampen the cytokine storm, with ICS
having little systemic effects.
• Not recommended: Azithromycin. [151,152]

Mildly Symptomatic patients (on floor/ward in hospital).
• Ivermectin 0.2 mg/kg orally on day 1 and day 3 (repeat on day 5 and 7 if poor response)
[10,12,14,17-20,87-96]. It should be noted that ivermectin has potent anti-inflammatory
properties apart from its antiviral properties.[153-155] See Table 1 and Figure 10. See drug-drug
interactions above.
• 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) [75]
• Vitamin D3 20,000–60,000 IU single oral dose. Calcifediol 0.2–0.5 mg is an alternative. [98] This
should be followed by 20,000 IU D3 (or 0.2 mg calcifediol) weekly until discharged from hospital.
Calcifediol is more efficiently absorbed, achieves 25-OH vitamin D levels quicker and is three
times more potent than vitamin D3. [156,157] However, it is important to note that the optimal
dose of vitamin D in the acute setting is unknown.[158,159] Very high doses may paradoxically
block the vitamin D receptor.
• Enoxaparin 60 mg/day [95,160-173] Consider increasing the dose to 1mg/kg q 12 hourly in those
with a high D-Dimer (3-5 x ULN) or an increasing D-Dimer (see Xa monitoring below).
• ASA 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.[174-176]
• Methylprednisolone 40 mg q 12 hourly; 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. [177-
189] The role of inhaled corticosteroids (budesonide) is unclear and appears to be rather
limited.
• B complex vitamins
• Famotidine 40 mg BID (20–40 mg/day in renal impairment). [103-109] Famotidine may be useful
for its protective effect on gastric mucosa, its anti-viral properties and histamine blocking
properties.
• Optional: Vascepa (Ethyl eicosapentaenoic acid) 4g daily or Lovaza (EPA/DHA) 4g daily;
alternative DHA/EPA 4g daily.
• Optional: Remdesivir 200 mg IV loading dose D1, followed by 100mg day IV for 9 days. [190,191]
This agent has been reported to reduce time to recovery (based on an ordinal scale) in patients
requiring low levels of supplemental oxygen. [191,192] The recently published SOLIDARITY trial
demonstrated no mortality benefit of this agent in the entire treatment cohort or any
subgroup.[193] 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. [194] 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.
• 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.
Page 14 of 49 |COVID-19 Management Protocol 12-27-2020

Figure 10. Metaanalysis of Ivermectin clinical studies (in hospital mortality)
MATH + PRTOCOL (for patients admitted to the ICU) [195,196]
1. Methylprednisolone 80 mg loading dose then 40 mg q 12 hourly for at least 7 days and until
transferred out of ICU. 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. [177-189]
Pulse methylprednisolone 250–500 mg mg/day may be required.[187] As depicted in Table 1,
methylprednisolone is the corticosteroid of choice. Methylprednisolone should be weaned slowly
over two weeks once oxygen is discontinued to prevent relapse/recurrence. The effect of
corticosteroids on the profile of dysregulated immune markers is clearly illustrated in Figure 11.
[197]
2. Ascorbic acid (Vitamin C) 50 mg/kg q 6 hourly for at least 7 days and/or until transferred out of
ICU.[43,51,52,198-207]. Mega-dose vitamin C should be considered in severely ill patients, those
with progressive respiratory failure and as salvage therapy: 25g 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 [208] (also see https://www.youtube.com/watch?v=Au-mp6RZjCQ ). 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.[209] 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.[208] 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. Full anticoagulation: Unless contraindicated we suggest FULL anticoagulation (on admission to
the ICU) with enoxaparin, i.e., 1 mg kg s/c q 12 hourly (dose adjust with Cr Cl < 30mls/min) in
those patients with a D-dimer > 3-5 X ULN and those with a rising D-dimer. Heparin is suggested
with CrCl < 15 ml/min. In all other ICU patients, we would suggest medium dose anticoagulation;
enoxaparin 0.5 mg/kg q 12 hourly. While observational studies have suggested that full
anticoagulation reduces mortality of hospitalized patients with COVID-19 [160,162,163,165-
173,210], the NIH ACTIV anticoagulation trial recently paused enrollment of critically ill COVID-19
patients (Press Release) for? lack of benefit. While the details and results of this study are
pending, we still recommend FULL anticoagulation in those patients at highest risk of severe
micro- and macro-vascular thrombosis. In our experience we have not observed increased
bleeding in patients treated with the full MATH+ protocol. It should be noted that COVID-19
causes a vasculitis (with increased risk of bleeding) and that both corticosteroids and vitamin C are
required to limit the vascular injury. Furthermore, vitamin C is a prerequisite for the synthesis of
collagen and vitamin C deficiency is classically associated with vascular bleeding.[51,52] This is
relevant to COVID-19 as vitamin C levels are undetectable in most COVID-19 patients.[211-213]
Due to augmented renal clearance patients may have reduced anti-Xa activity despite standard
dosages of LMWH.[214] We therefore recommend monitoring anti-Xa activity aiming for an anti-
Xa activity of 0.6–1.1 IU.ml to reduce the risk of both under-dosing and excessive anticoagulation.
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.
Additional Treatment Components (the Full Monty)
4. Highly recommended: Ivermectin 0.2 mg/kg on day 1 and day 3; repeat on day 5 and day 7 if poor
response (see doing above). [14,17-19,87,90-97,153-155,215-221] Note that ivermectin has
potent antiviral and ant-inflammatory effects. See Table 1 and Figure 10.
5. Melatonin 10 mg at night (the optimal dose is unknown).
6. Calcifediol 0.2–0.5 mg (25OH Vitamin D). [98] This should be followed by 0.2 mg calcifediol weekly
until discharged from hospital. If calcifediol s not 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. Vitamin D3 takes many days to be converted to 25OH vitamin D; [222]
this may explain the lack of benefit of D3 in patients hospitalized with severe COVID-19. [223]
7. Thiamine 200 mg IV q 12 hourly for 3-5 days then 200mg daily [224-229] Thiamine may play a role
in dampening the cytokine storm. [225]
8. ASA 325 mg. COVID infection results in profound platelet activation contributing to the severe
pro-thrombotic state and increasing the inflammatory response.[174-176] 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. B complex vitamins
10. Magnesium: 2 g stat IV. Keep Mg between 2.0 and 2.2 mmol/l. [84] Prevent hypomagnesemia
(which increases the cytokine storm and prolongs Qtc). [230-232]
11. Famotidine 40 mg BID (20–40 mg/day in renal impairment). [103-109].
12. Optional: Doxycycline 100mg daily for 5 days. Doxycycline is a broad-spectrum antibiotic which
has synergistic anti-viral and anti-inflammatory effects when combined with Ivermectin.
[21,88,93,233]

13. Optional (Consider in severe cases). Anti-serotonin agents. Platelet activation results in the release
of serotonin, which may contribute to the “cytokine storm”. [234]Therefore, the serotonin
receptor blocker cyproheptadine 4–8 mg PO q 6 hours should be considered.
14. Optional. Atorvastatin 80 mg/day. 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. [235]
Preliminary data suggests atorvastatin may improve outcome in patients with COVID-19.[236-240]
Due to numerous drug-drug interactions simvastatin should be avoided.
15. Optional: Vascepa, Lovaza or DHA/EPA 4g day (see above).
16. Not recommended: The best information to date suggests that azithromycin is of little benefit in
patients with COVID-19.[151,241,242]
17. Not recommended: Remdesivir. This drug has no benefit at this stage of the disease.
18. Not recommended. Convalescent serum [243,244] nor monoclonal antibodies. [245]
19. Not recommended. Tocilizumab. Five RCTS have now failed to demonstrate a clinical benefit from
tocilizumab. [246-250] Considering the effect of IL-6 inhibitors on the profile of dysregulated
inflammatory mediators this finding is not surprising (see Figure 11). [194]
20. 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. [251-253] While low CD4 counts are typical of severe COVID-19
infection, PJP infections have not been reported; therefore PJP prophylaxis is not required.
21. 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.
22. 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.
23. Escalation of respiratory support (steps); Try to avoid intubation if at all possible, (see Figure 12)
• Accept “permissive hypoxemia” (keep O2 Saturation > 84%); follow venous lactate and
Central Venous O2 saturations (ScvO2) in patents with low arterial O2 saturations
• N/C 1–6 L/min
• High Flow Nasal canula (HFNC) up to 60–80 L/min
• Trial of inhaled Flolan (epoprostenol)
• Attempt proning (cooperative repositioning-proning) [254,255]
• Intubation … by Expert intubator; Rapid sequence. No Bagging; Full PPE. Crash/emergency
intubations should be avoided.
• Volume protective ventilation; Lowest driving pressure and lowest PEEP as possible. Keep
driving pressures < 15 cm H2O.
• Moderate sedation to prevent self-extubation
• Trial of inhaled Flolan (epoprostenol)
• 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. 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.
Table 2: Comparison of Methylprednisolone, Dexamethasone and Hydrocortisone- Number

Need to Treat (NNT)

Figure 11. Comparison of circulating COVID-19 related biomarkers in response to
immunomodulatory therapy.[197]

Figure 12.

24. Salvage Treatments
• High dose bolus corticosteroids; 250–1000 mg/day methylprednisolone [185,187]
• Plasma exchange [256-262]. 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.[208,209] (also see https://www.youtube.com/watch?v=Au-
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.[263,264]
• 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”. [265-268]
• ECMO [269,270]. Unlike “typical ARDS” COVID-19 patients do not progress into a resolution
phase. Rather, patients with COVID-19 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. [271]
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. [243,244,272,273] Eli Lilly suspended the ACTIV-
33 clinical trial as their monoclonal antibody failed to demonstrate a clinical benefit in
hospitalized patients.[274] 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.[275] And lastly, COVID-19 pulmonary disease
is immune mediated, and it would therefore appear paradoxical to enhance the antibody
response with convalescent serum. [276]
• Janus Kinase inhibitors downregulate cytokine expression and may have a role in this disease.
[277-279] The role of the combination of Baricitinib and Remdesivir is unclear.[280]
• In patients with progressive fibrosis the combination of anti-fibrotic therapy with
corticosteroids should be considered. [281-284] It should however be recognized that unlike
all the medications in the MATH+ protocol, pirfenidone and nintedanib have complex side-
effects and drug interactions and should be prescribed by pulmonary physicians who have
experience with these drugs.
• CVVH/D with cytokine absorbing/filtering filters [285,286] This treatment strategy appears to
have an extremely limited role.

25. Treatment of Macrophage Activation Syndrome (MAS)
• A sub-group of patients will develop MAS, particularly those patients with severe COVID-19
disease.[287] While the pathophysiology of MAS in the setting of COVID-19 is unclear this
appears to be driven by SARS-CoV-2 induced inflammasome activation and increased IL-18
production as well as increased GM-CSF and INFγ production. [288-291] The role of IL-1 and
IL-6 in the pathogenesis of MAS is unclear.
• 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.[292]
• “High dose corticosteroids.” Methylprednisolone 120 mg q 6–8 hourly for at least 3 days,
then wean according to Ferritin, CRP, AST/ALT. Ferritin should decrease by at least 15%
before weaning corticosteroids.
• Consider plasma exchange.
• The role of inhibition of IL-1 (Anakinra) and IFNγ (emapalumab) is unclear (NCT04324021).
26. Monitoring
• On admission: Procalcitonin (PCT), CRP, BNP, Troponins, Ferritin, Neutrophil-Lymphocyte
ratio, D-dimer and Mg. CRP and D-dimer are important prognostic markers.[293] A PCT is
essential to rule out coexisting bacterial pneumonia.[294]
• 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. [295]
• In patients receiving IV vitamin C, the Accu-Chek™ POC glucose monitor will result in
spuriously high blood glucose values. Therefore, a laboratory glucose is recommended to
confirm the blood glucose levels. [296,297]
• A CT on admission to the ICU is useful to determine the severity/extent of the organizing
pneumonia [298] and to calculate the Ichikado Score.[299,300] Follow-up CXR and chest
ultrasound as clinically indicated.
• ECHO as clinically indicated; Patients may develop a severe “septic” cardiomyopathy and/or
COVID-19 myocarditis. [301,302]
27. Post ICU management
a. Enoxaparin 40–60 mg s/c daily

b. 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
c. Vitamin C 500 mg PO BID
d. Melatonin 3–6 mg at night
e. Vascepa, Lovaza or DHA/EPA 4g day (important for resolution of inflammation)

28. Post Hospital Discharge management
a. Patients have an increased risk of thromboembolic events post-discharge. [303] Extended

thromboprophylaxis (? with a DOAC) should be considered in high-risk patients. Risk factors
include:[304]
i. Increased D dimer (> 3 times ULN)
ii. Increased CRP (> 2 times ULN) [305]
iii. Age > 60
iv. Prolonged immobilization
b. The post-COVID-19 syndrome (Long haul syndrome) is characterized by prolonged malaise,

headaches, generalized fatigue, painful joints, dyspnea, chest pain and cognitive
dysfunction.[306-311] Up to 50% 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. The neurological symptoms may be related
micro- and/or macrovascular thrombotic disease which appears to be common in severe
COVID-19 disease.[287] Brain MRIs’ 3 months post-infection demonstrated micro-structural
changes in 55% of patients. [312] Similar to patients who have recovered from septic shock,
[313] 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 prior to discharge and a tapering course of corticosteroids should
be considered in those with an elevated CRP. It should be noted that much like omega-3
fatty acids corticosteroids have been demonstrated to increase expression of pro-resolving
lipids including Protectin D1 and Resolvin D4.[314] Other interventions that should be
considered include:
i. Recently Ivermectin has been reported to have a role in the treatment of post-
COVID-19 syndrome. [312] The anti-inflammatory properties of ivermectin may
mediate this benefit.
ii. Vascepa, Lovaza or DHA/EPA 4g day; important for resolution of inflammation by
inducing resolvin production. [112,113]
iii. Atorvastatin 40 mg daily (increase resolvin synthesis) [315]
iv. Continue melatonin.
v. Multivitamin with adequate vitamin D.
c. Post-COVID-19 pulmonary fibrosis. An unknown number of patients who have recovered

from COVID-19 organizing pneumonia will develop pulmonary fibrosis with associated
limitation of activity. These patients should be referred to a pulmonologist with expertise in
pulmonary fibrosis. Anti-fibrotic therapy may have a role in these patients, [281-284]
however additional data is required before this therapy can be more generally
recommended.

29. 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 Avoid social media as much as possible; excess social media exposure increases
the likelihood of anxiety and depression[316]
o Read the news/information from reliable sources (if you can find one)
o Have a designated time for checking information
o People share false claims about COVID-19 partly because they simply fail to
think sufficiently about whether or not the content is accurate when deciding
what to share. [317]
o Stay connected to positive people! Remotely!
o Have a plan for staying in touch with family and friends
o Identify positive influencers…limit contact with other “worriers”
o Isolation can cause rumination/anxious thinking to escalate
o Maintain a sense of hope, humanity and kindness toward others
o Seek professional help if anxiety is overwhelming
• Recognize the things you can control
o WEAR A MASK when in contact with others
o Establish social distancing; stand/sit about 6 feet away from others
o Limit attendance at large gatherings
o Eliminate your contact with those who are ill
o DON’T go to work or school if you are sick
o Practice self-care
 Good sleep, balanced diet, exercise
 Mindfulness/Meditation/Relaxation activities

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). [318]
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).[319]
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.[180,320-330] 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. [331]
7. The pulmonary phase is characterized by immune dysregulation, [277,279,287,290,291,323,332-
341] a pulmonary microvascular injury (vasculopathy),[287,341-344] with activation of clotting
and a pro-coagulant state together with the characteristics of an organizing pneumonia.
[298,345]
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. [287]
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). [298,346,347]
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.[348-350] The ground glass infiltrates are
peripheral and patchy, [346] and do not resemble the dependent air space consolidation
(sponge/baby lung) seen with “typical ARDS”.[351] 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.
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. [14,17-19,87,90-
96,153-155,215-221,352] 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.
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. [353]
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.[325,347,354-356] 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,[357,358] 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.[359]
in addition, in vitro studies demonstrate that heparin inhibits SARS-CoV-2 interaction with the
ACE-2 receptor and viral entry,[360,361] as well as viral replication [95,161]. Most importantly
LWWH inhibits heparanase (HPSE).[362] HSE destroys the endothelial glycocalyx increasing
endothelial leakiness, activating clotting and potentiating endothelialitis.[362] HPSE levels have
been reported to be increased in patients with severe COVID-19 infection. [363] 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).
20. The combination of steroids and ascorbic acid (vitamin C) is essential. Both have powerful
synergistic anti-inflammatory actions. [200,205] Vitamin C protects the endothelium from
oxidative injury.[51,364-366] Furthermore, vitamin C Increases the expression of interferon-
alpha [42] while corticosteroids (alone) decease expression of this important protein. [367-
370] 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. [182,371] 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),[372]
genomic data specific for SARS-CoV-2,[101] and a long track record of successful use in
inflammatory lung diseases. (see Table 1)

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.” [277,279,290,291,323,332,334-340] In addition, post-mortem
examination has demonstrated features of the “macrophage activation syndrome”, with
hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder.[287] 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.[287,373-375]
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.[102]
Furthermore, ACE-2 receptors are present on platelets and this may contribute to the massive
platelet aggregation characteristic of severe COVID-19 disease.[174,176,376] These blood clots
impair blood flow. [162,163,165-173,343,344,377,378] It should be noted that the thrombotic
microangiopathy appears to target predominantly the pulmonary and cerebral circulation. [287]
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.
[276,279,287,358] 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) [379,380]. 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.[177,381] 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

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.[382] 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.[149]
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 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, [178,179,185,371,383-385] as
well as a randomized controlled study.[187] It should be recognized that the mortality benefit with
methylprednisolone was not replicated in a recent Brazilian RCT. [353] However, in this study
methylprednisolone was started relatively late (day 13 after symptom onset), but most importantly was
stopped 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.[386]
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. If such early initiation of treatment could be
systematically achieved, the need for mechanical ventilators and ICU beds will decrease dramatically.
Further resources:
The reader is referred to the large autopsy series by Bruce and colleagues which clearly outlines the
pathophysiology of severe COVID-19 disease.[287]
The scientific rationale for the MATH + protocol is reviewed in this paper.[195,196]
In this U-tube video, Professor Britt Glaunsinger, PhD provides an outstanding review on the molecular
virology of SARS-CoV-2: https://www.youtube.com/watch?v=DQVpHyvz4no
Lectures by Paul Marik, MD reviewing clinical aspects of COVID-19.

https://www.youtube.com/channel/UCz9Pvn15m4Rv1uY-aBYRVuw

Question: My Primary care physician (PCP) will not prescribe Ivermectin. Where can I get a script?
Answer: We understand and empathize with the challenges faced in obtaining a prescription for
Ivermectin during the time period prior to its use being formally adopted in national or international
COVID-19 treatment guidelines. We are anticipating these treatment guidelines to be updated in the
near future. Alternately, please know our scientific review manuscript on ivermectin in COVID-19 is
undergoing expedited peer-review at a prominent American medical journal, and if it passes peer review
and becomes published, we anticipate that this will also make access to ivermectin more
widespread. However, until such a time when its use as both a prophylactic and treatment agent is
more widely accepted, many physicians will be reluctant to prescribe. We can only recommend the
following approaches:
I. Discuss with your primary health care provider. If they are unconvinced of the data, share with
them our manuscript which can be downloaded from the FLCCC Website or from the Pre-print
server at https://osf.io/wx3zn/. Please understand that many will prefer to avoid adoption of
ivermectin treatment until such a time as the guidelines are updated or the manuscript gets
published.
II. The second option is to try one of the doctors on the list below that can provide telemedicine
consultation here: Drs Prescribing Ivermectin. https://www.exstnc.com/ Confirm the price of
any visit prior to the consultation. We have reports of some doctors charging exorbitant fees.
III. If more pills are desired than can be provided locally, you can order in bulk from the Canadian
King Pharmacy, however you will need a prescription.
https://www.canadianpharmacyking.com/
Question: Is ivermectin safe and can it be used in patients with liver disease?
Answer: The discovery of Ivermectin in 1975 was awarded the 2015 Nobel Prize in Medicine given its
global impact in reducing onchocerciasis (river blindness), lymphatic filariasis, and scabies in endemic
areas of central Africa, Latin America, India, and Southeast Asia. It has since been included on the
WHO’s “List of Essential Medicines with now over 4 billion doses administered. Numerous studies report
low rates of adverse events, with the majority mild, transient, and largely attributed to the body’s
inflammatory response to the death of parasites and include itching, rash, swollen lymph nodes, joint
paints, fever, and headache. In a study which combined results from trials including over 50,000
patients, serious events occurred in less than 1% and largely associated with administration in Loa Loa
infected patients. Further, according to the pharmaceutical reference standard Lexicomp, the only
medications contraindicated for use with ivermectin are the concurrent administration of anti-

tuberculosis and cholera vaccines while the anticoagulant warfarin would require dose monitoring.
Similarly, we suggest therapeutic monitoring of drug levels such as calcineurin inhibitors such as
tacrolimus and cyclosporin and the immunosuppressant sirolimus as potential interactions exist. A
longer list of drug interactions can be found on the drugs.com database, with nearly all interactions
leading to a possibility of either increased or decreased blood levels of ivermectin. Given studies
showing tolerance and lack of adverse effects in human subjects given escalating high doses of
ivermectin, toxicity is unlikely although a reduced efficacy due to decreased levels may be a concern.
Question: Can I request expert advice or consultation from the FLCCC?
Answer: Given the sheer volume of requests and the limited number of expert clinicians that make up
the FLCCC Alliance, the doctors are not able to respond to individual requests for expert consultation on
patients ill with COVID-19. Furthermore, we cannot provide treatment recommendations for patients
that are not under our direct care. However, we can offer interested patients, families, and health care
providers the expertise and guidance contained in our published and pre-published manuscripts which
support our understanding and approach to treatment in this disease. Given that the majority of
requests for consultation have been on cases where patients are failing standard therapies, we suggest
that those interested review the section on “salvage therapies” in this document (#24, Page 21). We also
emphasize the importance of recognizing that COVID-19 respiratory disease is not a viral pneumonia,
but rather an “organizing pneumonia”, and as such, in fulminant cases, typically require high doses of
corticosteroids as in our protocol. For support of this, please refer to our paper on “SARS-CoV-2
Organizing Pneumonia” (available on the FLCCC Website). Lastly, we recommend that patents ill with
COVID-19 at any stage of disease receive ivermectin, as per the accompanying manuscript which
compiles and reviews the large evidence base supporting this therapy.
Question: Will ivermectin interfere with the vaccine and can I continue to take ivermectin once
vaccinated?
Answer: Our understanding of the importance of ivermectin in the context of the new vaccines, is that
ivermectin prophylaxis should be thought of as complementary bridge to vaccination until the vaccines
are made available to all those in need. At this time and speaking with the vaccine experts we do not
believe that ivermectin prophylaxis interferes with the efficacy/immune response to the vaccine,
however it must also be recognized that no definitive data exists to guide use more specifically on this
question. However, given that maximal immunity from the vaccines is only achieved 2 weeks after the
second dose of vaccine, it is reasonable to take bi-weekly ivermectin until this time point. The “New’
mutated strain of SARS-CoV-2 appears to be less susceptible to pre-existent neutralizing antibodies; this
may have potential implications for the current vaccination program.

Question: Shouldn’t we wait for more data before widely adopting another medicine that may not
work?”
Answer: Making a risk/benefit decision at this time, with the currently available data showing consistent
high efficacy and safety with mortality benefits from 24 controlled trials, would far exceed the strength
and validity of the rationales used to adopt the entirety of currently employed therapeutics in COVID-19
given all were adopted in the setting of either:
I. Weak clinical impacts measured (Remdesivir, monoclonal antibodies, convalescent plasma),
II. High costs (Remdesivir, monoclonal antibodies, convalescent plasma, vaccines)
III. Significant adverse effects (Remdesivir, vaccines),
IV. Weak, conflicting, or non-existing evidence bases to support use (Remdesivir, monoclonal
antibodies, convalescent plasma),
V. Conflicting treatment guidelines (Remdesivir – WHO and NIH recommendations conflict)
VI. Non-peer reviewed studies (Remdesivir, monoclonal antibodies, convalescent plasma)
VII. Absence of even pre-print study data available for wider scientific review (vaccines)
Question: If ivermectin is so effective in COVID-19, how come no countries have adopted it into their
national treatment guidelines?
Answer: Multiple countries and regions have formally adopted ivermectin into their treatment
guidelines, with several having done so only recently, based on the emerging data compiled by the
FLCCC. Examples include:
I. Macedonia - December 23, 2020
II. Belize - December 22,2020
III. Uttar Pradesh in Northern India- a state with 210 million people, adopted early home
treatment kits which include ivermectin on October 10, 2020
IV. State of Alto Parana in Paraguay - September 6, 2020
V. Capital City of Lucknow in Uttar Pradesh - August 22, 2020
VI. State of Chiapas, Mexico - August 1, 2020
VII. 8 state health ministries in Peru - Spring/summer 2020
VIII. Lima, Peru - Many clinics, districts use and distribute ivermectin, as of October the hospitals
no longer use.
Question: Isn’t the promotion of ivermectin the same thing as hydroxychloroquine – everyone claims
it works when all the randomized controlled trials showed it did not?
Answer: The decision to adopt hydroxychloroquine was made early in the pandemic, when, despite the
lack of clinical trials data to support use, there existed a scientific rationale given pre-clinical data
suggesting anti-viral and anti-inflammatory properties. Thus, the decision at that time was likely a sound
one based on a risk/benefit calculation given HCQ’s low cost, minimal adverse effect profile, wide
availability/ease of compounding, and long history of use. Such a decision was also entirely in keeping
with Principle 37 of the Helsinki Agreement on Medical Research, first formulated in 1964, which
declares that “physicians may use an unproven intervention if in the physician’s judgement it offers hope
of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be
made the object of research.” In keeping with Declaration 37, immediately after the widespread
adoption of HCQ, studies were immediately conducted by many centers. Unfortunately, all of the RCT’s
reported negative results which led to rapid de-adoption with the exception of sporadic continued use

in early phase disease. Note that the current widespread non-adoption of ivermectin in the face of
hundreds of thousands of ill and dying, currently violates Declaration 37 in that adoption is being
purposely and overtly avoided despite the efficacy/risk assessment of now numerous well controlled
trials including over 3,000 total patients which report massive drops in transmission and large decreases
in mortality when used in the treatment of COVID-19 patients. The data supporting adoption is now
approaching that of corticosteroids, where widespread use began almost immediately upon the
reporting of results of the 6,000 patient RECOVERY trial which demonstrated a mortality benefit (with
only 2,000 patients treated with corticosteroids in that trial).
Question: Isn’t it a problem that all the trials were done in foreign countries and may not be
generalizable to our patients here?”
Answer: Such concerns reflect a surprising degree of ethnocentrism that we believe will lead to further
harms against humanity. We cannot deny that these concerns currently present a significant barrier for
the evidence compiled in our manuscript to influence practice. We recently learned that a COVID-19
therapeutics committee of a large hospital health care system in the Midwest recently reviewed the
existing trials data for ivermectin in November and decided not to recommend ivermectin, with one of
the stated reasons being that “many of the studies were performed abroad and are likely not
generalizable to our patients”. The belief that a potent anti-viral medicine only works in foreigners and
not in Americans is ludicrous and deserves no further comment or explanation except to note it as an
example of the most extreme skepticism that can be displayed by providers who simply “do not believe”
in the efficacy of ivermectin.
Question: Shouldn’t we wait until there are more randomized controlled trials?
Answer: Fifteen of the 24 controlled trials results are prospective and randomized and include over
3,000 patients. Again, note that the RECOVERY trial which made corticosteroids the standard of care in
COVID-19 overnight was a randomized controlled trial which included 2,000 patients treated with
dexamethasone. The number of ivermectin treated patients in the RCT’s are now approaching 2,000.
Further, the number of patients in the 9 observational controlled trials also total over 4,000 patients.
Thus, after 7,000 patients and 24 controlled trials of ivermectin in varying sizes and designs and
countries, with nearly all resulting in consistent, reproducible, large magnitude, statistically significant
findings of efficacy as a prophylactic and in early and late phase disease. Given these marked reductions
in transmission, hospitalizations, and death, any further studies using a placebo would be unethical. For
any who require more clinical trials data, well-designed observational controlled trials are a perfectly
valid alternative and will (and should) be conducted by many, even after adoption as a treatment agent.
Question: How does the NIH arrive at their recommendations for current widely used therapies and
why is the rationale for these recommendations so difficult to understand?
Answer: We are unable to identify a consistent approach to the strength and timing of NIH
recommendations and/or updates to the recommendations. However, the influence of “Big Pharma”
appears undeniable.

Question: Why does the NIH recommends against the use of ivermectin outside of clinical trials?
Answer: This recommendation is from August 27th, is graded IIIA, which means that it was expert
opinion only and reflected a “strong” opinion against. Given the amount of data available as of today,
December 27, 2020, we must ask the question, “What should the strength and level of recommendation
for Ivermectin be updated to by the NIH? First, all must understand how recommendations for medical
therapies are created by the NIH. They essentially use the below grading scale which provides an
assessment of both the strength of the recommendation and the quality of evidence to support that
recommendation.
The last NIH recommendation on ivermectin from August 27th was graded AIII against
use as per above table, indicating a strong recommendation based on expert opinion
only, despite it being one of the world’s safest, cheapest, and most widely available
drugs. No rationale or supporting evidence. Further, the grade implies that there was no
available clinical evidence at the time to make an “evidence-based” grading, yet we
know of a number of trials results available at that time.

References
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. 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.
8. 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. Fronteirs in Pharmacology 2020.
9. 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.
10. Elgazzar A, Hany B, Youssef SA et al. Efficacy and safety of ivermectin for treatment and prophylaxis of
COVID-19 pandemic. Research Square 2020.
11. 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.
12. 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.
13. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administraion
of ivermectin. Int J Antimicrob Agents 2020.
14. 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.
15. Aroke D, Tchouakam DN, Awungia AT et al. Ivermectin induced Steven-Johnsons syndrome: case report.
BMC Research Notes 2017; 10:179.
16. 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.
17. Gorial FI, Mashhadani S, Sayaly HM et al. Effectiveness of Ivermectin as add-on therapy in COVID-19
management (Pilot Trial). medRxiv 2020.
18. Khan MS, Khan MS, Debnath Cr et al. Ivermectin treatment may improve the prognosis of patients with
COVID-19. Archivos de Bronconeumologia 2020.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.

25. Lau FH, Majumder R, Torabi R et al. Vitamin D insufficiency is prevalent in severe COVID-19. medRxiv
2020.
26. Marik PE, Kory P, Varon J. Does vitamin D status impact mortlality from SARS-CoV-2 infection? Medicine in
Drug Discovery 2020.
27. 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).
28. 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.
29. 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.
30. Daneshkhah A, Eshein A, Subramanian H. The role of vitamin D in suppressing cytokine storm of COVID-19
patients and associated mortality. medRxiv 2020.
31. 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.
32. 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.
33. Israel A, Cicurel A, Feldhamer I et al. The link between vitamin D deficiency and Covid-19 in a large
population. medRxiv 2020.
34. Radujkovic A, Hippchen T, Tiwari-Heckler S et al. Vitamin D deficiency and outcome of COVID-19 patients.
Nutrients 2020; 12:2757.
35. Rizzoli R. Vitamin D supplementation: upper limit for safety revisited. Aging Clin Exp Res 2020.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. Colunga Biancatelli RM, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert Rev Anti Infect
Ther 2020; 18:99-101.
43. 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.
44. Khaerunnisa S. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant
compuns by molecular docking study. medRxiv 2020.
45. 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.
46. Nain Z, Rana HK, Lio P et al. Pathogenic profiling of COVID-19 and SARS-like viruses. Briefings in
Bioinformatics 2020.
47. 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.
48. 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.
49. Calder PC. Nutrition, immunity and COVID-19. BMJ Nutrition, Prevenion & Health 2020; 3.
50. 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.

51. Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) for the treatment of sepsis. Focus on
ascorbic acid. Nutrients 2018; 10:1762.
52. Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Therapeut 2018;
189:63-70.
53. 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.
54. Ono K, Nakane H. Mechanisms of inhibition of various cellular DNA and RNA polymerases by several
flavonoids. J Biochem 1990; 108:609-13.
55. Kaul TN, Middleton E, Pgra PL. Antiviral effects of flavonoids on human viruses. J Med Virol 1985; 15:71-
79.
56. Shinozka K, Kikuchi Y, Nishino C et al. Inhibitory effect of flavonoids on DNA-dependent DNA and RNA
polymerases. Experientia 1988; 44:882-85.
57. 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;
68:266-74.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. 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.
65. 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.
66. 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.
67. 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.
68. Colombo D, Lunardon L, Bellia G. Cyclosporine and herbal supplement interactions. Journal of Toxicology
2014; 2014:145325.
69. 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.
70. 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.
71. 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.
72. Zhang R, Wang X, Ni L et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci 2020;
250:117583.
73. Kleszczynski K, Slominski AT, Steinbrink K et al. Clinical trials for use of melatonin to fight COVID-19 are
urgently needed. Nutrients 2020; 12.
74. 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.
75. 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.

76. Shneider A, Kudriavtsev A, Vakhusheva A. Can melatonin reduce the severity of COVID-19 pandemic.
medRxiv 2020.
77. 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.
78. Gammoh NZ, Rink L. Zinc in Infection and Inflammation. Nutrients 2017; 9.
79. 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.
80. 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.
81. Shakoor H, Freehan J, Mikkelsen K et al. Be well: A potential role for vitamin B in COVID-19. Maturitas
2020.
82. dos Santos LM. Can vitamin B12 be an adjuvant to COVID-19 treatment? GSC Biological and
Pharmaceutical Sciences 2020; 11.
83. Kandeel M, Al-Nazawi M. Virtual screening and repurposing of FDA approved drugs against COVID-19
main protease. Life Sci 2020; 251:117627.
84. 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.
85. 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.
86. 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.
87. 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.
88. 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.
89. 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.
90. Chamie J. Real-World evidence: The case of Peru, casuality between Ivermectin and COVID-19 infection
fatality rate. ResearchGate 2020.
91. 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.
92. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to
ACE2. In Vivo 2020; 34:3023-26.
93. 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.
94. 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.
95. Dayer MR. Coronavirus (2019-nCoV) deactivation via spike glycoprotein shielding by old drugs,
bioinformatic study. Preprints 2020.
96. 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.
97. 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.
98. 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.
99. 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.
100. Muller C, Karl N, Ziebuhr J et al. D,L-lysine acetylsalicylate + glycine impairs coronavirus replication. J
Antivir Antiretovir 2020.
101. 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.

102. 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.
103. 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.
104. 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.
105. Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of hospitalized COVID-19
patients. Am J Gastroenterol 2020.
106. Malone RW, Tisdall P, Fremont-Smith P et al. COVID-19: Famotidine, Histamine, Mast Cells, and
mechanisms. Research Square 2020.
107. Sethia R, Prasad M, Mahapatra SJ et al. Efficacy of famotidine for COVID-19: A systematic review and
meta-analysis. medRxiv 2020.
108. Shoaibi A, Fortin S, Weinstein R et al. Comparative effectiveness of famotidine in hospitalized COVID-19
patients. medRxiv 2020.
109. 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.
110. Hammock BD, Wang W, Gilligan MM et al. Eicosanoids. The overlooked storm in Coronavirus Disease 2019
(COVID-19)? Am J Pathol 2020.
111. Das UN. Can bioactive lipids inactivate coronavirus (COVID-19)? Arch Med Res 2020; 51:282-86.
112. Lee CR, Zeldin DC. Resolvin infectious inflammation by targeting the host response. N Engl J Med 2015;
373:2183-85.
113. Serhan CN. Novel pro-resolving lipid mediators in inflammation are leads for resolution physiology.
Nature 2014; 510:92-101.
114. 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.
115. 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.
116. 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.
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. 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.
119. 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.
120. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home: Potential pitfalls
and practical guidance. Ann Thorac Med 2020.
121. 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.
122. 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.
123. 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.
124. Boulware DR, Pullen MF, Bangdiwala AS et al. A randomized trial of hydroxychloroquine as postexposure
prophylaxis for Covid-19. N Engl J Med 2020.
125. 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.
126. 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.
127. 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.

128. 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.
129. Skipper CP, Pastick KA, Engen NW. Hydroxychlooquine in nonhospitalized adults with early COVID-19. Ann
Intern Med 2020; 173:623-31.
130. 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.
131. Geleris J, Sun Y, Platt J et al. Observational study of hydroxychloroquine in hospitalized patients with
Covid-19. N Engl J Med 2020.
132. Magagnoli J, Narendran S, Pereira F. Outcomes of hydroxychloroquine usage in United states veterans
hospitalized with COVID-19. medRxiv 2020.
133. 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.
134. 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.
135. 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.
136. 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.
137. 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.
138. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020; 383:2030-2040.
139. 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.
140. Rajasingham R, Bangdiwala AS, Nicol MR et al. Hydroxychloroquine as pre-exposure prophylaxis for
COVID-19 in healthcare workers: a randomized trial. medRxiv 2020.
141. 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.
142. Tett SE, Cutler DJ, Day RO et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J
Clin Pharmac 1989; 27:771-79.
143. MacGowan A, Hamilton F, Bayliss M et al. Hydroxychloroquine serum concentrations in non-critical care
patients infected with SARS-CoV-2. medRxiv 2020.
144. 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.
145. 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.
146. 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.
147. 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.
148. 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.
149. Effect of Dexamethasone in hospitalized patients with COVID-19-Preliminary report. N Engl J Med 2020.
150. 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.
151. Azithromycin in hospitalized patients with COVID-19 (RECOVERY) a randomised, controlled, open-label,
platform trial. medRxiv 2020.
152. 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.
153. 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.

154. 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.
155. 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.
156. Quesada-Gomez JJ, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation?
Osteoporosis International 2018; 29:1697-711.
157. Cesareo R, Falchetti A, Attanasio R et al. Hypovitaminosis D: Is it time to consider the use of calcifediol?
Nutrients 2019; 11:1016.
158. Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med 2019; 381:2529-40.
159. 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.
160. Hsu A, Liu Y, Zayac AS et al. Intensity of anticoagulation and survival in patients hospitalized with COVID-
19 pneumonia. Thrombosis Research 2020.
161. Kwon PS, Oh H, Kwon SJ et al. Sulphated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell
Discovery 2020; 6:50.
162. 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.
163. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020.
164. Nadkarni GN, Lala A, Bagiella E et al. Anticoagulation, mortality, bleeding and pathology among patients
hospitalized with COVID-19: A single Health System Study. J Am Coll Cardiol 2020.
165. 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.
166. 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.
167. 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.
168. Iba T, Levy JH, Levi M et al. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020.
169. 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.
170. 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.
171. 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.
172. 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.
173. 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.
174. 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.
175. 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.
176. 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.
177. 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.
178. Fadel R, Morrison AR, Vahia A et al. Early course corticosteroids in hospitalized patients with COVID-19.
Clin Infect Dis 2020; 71:2114-20.
179. Chroboczek T, Lacoste M, Wackenheim C et al. Beneficial effect of corticosteroids in severe COVID-19
pneumonia: a propensity score matching analysis. medRxiv 2020.
180. 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.
181. 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.

182. Liu J, Zheng X, Huang Y et al. Successful use of methylprednisolone for treating severe COVID-19. J Allergy
Clin Immunol 2020.
183. 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.
184. Association between administration of systemic corticosteroids and mortality among critically ill patients
with COVID-19. A meta-analysis. JAMA 2020.
185. 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.
186. 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.
187. 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.
188. 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.
189. 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.
190. 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.
191. Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the treatment of Covid-19-Preliminary report. N
Engl J Med 2020;ePub.
192. 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.
193. Pan H, Peto R, Karim QA et al. Repurposed antiviral drugs for COVID-19 - interim WHO SOLIDARITY trial.
medrx 2020.
194. 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.
195. 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.
196. 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.
197. Wang SY, Chang CH, Meizlish ML et al. Changes in inflammatory and immune drivers in response to
immunmodulatory therapies in COVID-19. medRxiv 2020.
198. 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.
199. 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.
200. 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.
201. Cheng RZ. Can early and high-dose vitamin C prevent and treat coronavirus disease 2019 (COVID-19).
Medicine in Drug Discovery 2020.
202. 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.
203. Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress
syndrome. PharmaNutrition 2020; 12:100190.
204. 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.
205. 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.
206. Zhang J, Rao X, Li Y et al. High-dose vitamin C infusion for the treatment of critically ill COVID-19. Research
Square 2020.

207. Kumari P, Dembra S, Dembra P et al. The role of vitamin C as adjuvant therapy in COVID-19. Cureus 2020;
12:e11779.
208. 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.
209. 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.
210. Jonmarker S, Hollenberg J, Dahlberg M et al. Dosing of thromboprophylaxis and mortality in critically ill
COVID-19 patients. medRxiv 2020.
211. 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.
212. Tomassa-Irriguible TM, Lielsa-Berrocal L. COVID-19: Up to 87% critically ill patients had low vitamin C
values. Research Square 2020.
213. 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.
214. Tomasa-Irriguible TM, Martinez-Vega S, Mor-Marco E et al. Low molecular weight heparins in COVID-19
patients: beware of augmented renal clearance! Crit Care 2020; 24:325.
215. 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.
216. Jans DA, Wagstaff KM. Ivermectin as a broad-spectrum host directed anti-viral: The real deal. Cells 2020;
9:2100.
217. 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.
218. 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.
219. 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.
220. 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.
221. Carvallo H, Hirsch R, Farinella ME. Safety and efficacy of the combined use of Ivermectin, dexamethasone,
enoxaparin and aspirin against COVID-19. medRxiv 2020.
222. 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.
223. 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.
medRxiv 2020.
224. 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.
225. 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.
226. Mallat J, Lemyze M, Thevenin D. Do not forget to give thiamine to your septic shock patient! J Thorac Dis
2016; 8:1062-66.
227. Moskowitz A, Donnino MW. Thiamine (vitamin B1) in septic shock: a targeted therapy. J Thorac Dis 2020;
12 (suppl 1):S78-S83.
228. 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.
229. Marik PE. Thiamine: An essential component of the metabolic resuscitation protocol. Crit Care Med 2018;
46:1869-70.
230. Lee CY, Jan WC, Tsai PS et al. Magnesium sulfate mitigates acute lung injury in endotoxemia rats. J Trauma
2011; 70:1177-85.
231. 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.

232. 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.
233. Spoorthi V, Sasank S. Utility of Ivermectin and Doxycycline combination for the treatment of SARS-CoV-2.
International Archives of Integrated Medicine 2020; 7.
234. 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.
235. 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.
236. 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.
237. 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.
238. 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.
239. Kow CS, Hasan SS. Meta-analysis of effectiveness of statins in patients with severe COVID-19. Am J Cardiol
2020.
240. Tan WY, Young BE, Lye DC et al. Statin use is assocaited with lower disease severity in COVID-19 infection.
Nature Research 2020.
241. Oldenburg CE, Doan T. Azithromycin for severe COVID-19. Lancet 2020.
242. 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.
243. 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.
244. Simonovich VA, Pratx LD, Scibona P et al. A randomized trial of convalescent plasma in COVID-19 severe
pneumonia. N Engl J Med 2020.
245. Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria Jurnal 2003; 3 (Suppl I):S8.
246. Rosas IO, Brau N, Waters M et al. Tocilizumab in hospitalized patients with COVID-19 pneumonia. medRxiv
2020.
247. 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.
248. Stone JH, Frigault MJ, Sterling-Boyd NJ et al. Efficacy of tocilizumab in patients hospitalized with Covid-19.
N Engl J Med 2020.
249. 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.
250. Salama C, Han J, Yau L et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med
2020.
251. Bassetti M, Kollef MH, Timsit JF. Bacterial and fungal superinfections in critically ill patients with COVID-
19. Intensive Care Med 2020.
252. Rawson TM, Wilson RC, Holmes A. Understanding the role of bacterial and fungal infection in COVID-19.
Clinical Microbiology & Infection 2021; 27:9-11.
253. 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.
254. 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.
255. 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.
256. 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.
257. 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.
258. 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.

259. Morath C, Weigand MA, Zeier M et al. Plasma exchange in critically ill COVID-19 patients. Crit Care 2020;
24:481.
260. 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.
261. 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.
262. 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.
263. 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.
264. 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.
265. 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.
266. 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.
267. 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.
268. Payen D. Coronavirus disease 2019 acute respiratory failure: Almitrine drug resuscitaion or resuscitating
patients by almitrine? Crit Care Med 2020.
269. 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.
270. Abrams D, Lorusso R, Vincent JL et al. ECMO during the COVID-19 pandemic: when is it unjustified. Crit
Care 2020; 24:507.
271. 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.
272. 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.
273. Avendano-Sola C, Ramos-Martinez A, Munez-Rubio E et al. Convalescent plasma for COVID-19: A
multicenter, randomized clinical trial. medRxiv 2020.
274. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med 2020.
275. Cerutti A, Chen K, Chorny A. Immunoglobulin responses at the mucosal interface. Annu Rev Immunol
2011; 29:273-93.
276. Jacobs JJ. Neutralizing antibodies mediate virus-immue pathology of COVID-19. Med Hypotheses 2020;
143:109884.
277. Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor
Febratinib. J Microbiol Immunol Infect 2020.
278. Favalli EG, Biggioggero M, Maioli G et al. Baricitinib for COVID-19: a suitable treatment? Lancet Infect Dis
2020.
279. Mehta P, McAuley DF, Brown M et al. COVID-19: consider cytokine storm syndromes and
immunosuppression. Lancet 2020; 395:1033-34.
280. Kalil AC, Patterson TF, Mehta AK et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N
Engl J Med 2020.
281. Seifirad S. Pirfenidone: A novel hypothetical treatment for COVID-19. Medical Hypotheses 2020;
144:11005.
282. 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.
283. 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.
284. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antibibrotic
therapy. Lancet Resp Med 2020; 8:807-15.
285. 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.

286. 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;
24:605.
287. 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.
288. Slaats J, ten Oever J, van de Veerdonk FL et al. Il-1B/Il-6/CRP and IL-18/ferritin: Distinct inflammatory
programs in infections. PLos Pathog 2016; 12:e1005973.
289. Colafrancesco S, Alessandri C, Conti F et al. COVID-19 gone bad: A new character in the spectrum of the
hyperferritinemic syndrome? Autoimmunity Reviews 2020; 19:102573.
290. Giamarellos-Bouboulis EJ, Netea MG, Rovina N et al. Complex immune dysregulation in COVID-19 patients
with severe respiratory failure. Cell Host & Microbe 2020.
291. McGonagle D, Sharif K. The role of cytokines including interleukin-6 in COVID-19 induces pneumonia and
macrophage activation syndrome-like disease. Autoimmunity Reviews 2020.
292. 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.
293. 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.
294. 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;
60:135-39.
295. 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.
296. 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.
297. Stephenson E, Hooper MH, Marik PE. Vitamin C and Point of Care glucose measurements: A retrospective,
Observational study [Abstract]. Chest 2018; 154 (suppl.):255a.
298. 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.
299. 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.
300. 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.
301. 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.
302. Ma KL, Liu ZH, Cao CF et al. COVID-19 myocarditis and severity factors: An adult cohort study. medRxiv
2020.
303. Brosnahan SB, Bhatt A, Berger JS et al. COVID-19 pneumonia hospitalizations followed by re-presentation
for presumed thrombotic event. Chest 2020.
304. 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.
305. 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.
306. Carfi A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA 2020.
307. Prescott HC, Girard TD. Recovery from Severe COVID-19. Leveraging the lessons of survival from sepsis.
JAMA 2020.
308. Greenhalgh T, Knight M, A'Court C et al. Management of post-acute Covid-19 in primary care. BMJ 2020.
309. Chopra V, Flanders SA, O'Malley M. Sixty-day outcomes among patients hospitalized with COVID-19. Ann
Intern Med 2020.
310. 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.

311. Michelen M, Manoharan L, Elkheir N et al. Characterising long-term covid-19: a rapid living systematic
review. medRxiv 2020.
312. 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.
313. Riche F. Protracted immune disorders at one year after ICU discharge in patients with septic shock. Crit
Care 2018; 22:42.
314. Andreakos E, Papadaki M, Serhan CN. Dexamethasone, pro-resolving lipid mediators and resolution of
inflammation in COVID-19. Allergy 2020.
315. Dalli J, Chiang N, Serhan CN. Elucidation of novel 13-series resolvins that increase with atorvastatin and
clear infections. Nat Med 2015; 21:1071-75.
316. Gao J, Zheng P, Jia Y et al. Mental health problems and social media exposure during COVID-19 outbreak.
PloS ONE 2020; 15:e0231924.
317. 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.
318. 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.
319. 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.
320. Zhao J, Yang Y, Huang H et al. Relationship between ABO blood group and the COVID-19 susceptibility.
medRxiv 2020.
321. 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.
322. 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.
323. 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.
324. Guan W, Ni Z, Hu Y et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020.
325. von der Thusen J, van der Eerden M. Histopathology and genetic susceptibility in COVID-19 pneumonia.
Eur J Clin Invest 2020.
326. Sweeney TE, Liesenfeld O, Wacker J et al. Validation of inflammopathic, adaptive, and coagulopathic
sepsis endotypes in Coronavirus disease 2019. Crit Care Med 2020.
327. 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.
328. Pujadas E, Chaudhry F, McBride R et al. SARS-CoV-2 viral load predictes COVID-19 mortality. Lancet Resp
Med 2020.
329. Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science 2020; 369.
330. Zhang Q, Bastard P, Liu Z et al. Inborn errors of type I IFN immunity in patients with life-threatening
COVID-19. Science 2020.
331. 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.
332. 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.
333. Blanco-Melo D, Nilsson-Payant BE, Liu WC et al. Imbalanced host response to SARS-CoV-2 drives
development of COVID-19. Cell 2020.
334. 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.
335. Giamarellos-Bourboulis EJ, Netea MG, Rovina N et al. Complex immune dysregulation in COVID-19
patients with severe respiratory failure. medRxiv 2020.
336. 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.

337. 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.
338. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the "Cytokine Storm" in COVID-19. J Infection
2020.
339. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020.
340. Tay MZ, Poh CM, Renia L et al. The trinity of COVID-19: immunity, inflammation and intervention. Nature
Reviews 2020; 20:363-74.
341. 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.
342. Teuwen LA, Geldhof V, Pasut A et al. COVID-19: the vasculature unleashed. Nature Reviews 2020.
343. Varga Z, Flammer AJ, Steiger P et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020.
344. 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.
345. 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.
346. Kanne JP, Little BP, Chung JH et al. Essentials for radiologists on COVID-19: an Update-Radiology Scientific
Expert Panel. Radiology 2020.
347. 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.
348. Gattinoni L, Chiumello D, Caironi P et al. COVID-19 pneumonia: different respiratory treatment for
different phenotypes? Intensive Care Med 2020; 46:1099-102.
349. Chiumello D, Cressoni M, Gattinoni L. Covid-19 does not lead to a "typical" Acute Respiratory Distress
syndrome. Lancet 2020.
350. Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care 2020; 24:154.
351. Gattinoni L, Pesenti A. The concept of "baby lung". Intensive Care Med 2005; 31:776-84.
352. Patel AN, Desai SS, Grainger DW et al. Usefulness of ivermectin in COVID-19 illness. medRxiv 2020.
353. 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.
354. 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.
355. 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.
356. Xu Z, Shi L, Wang Y et al. Pathological findings of COVID-19 associated with acute respiratory distress
syndrome. Lancet Resp Med 2020.
357. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care
Med 2020.
358. 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.
359. Buijsers B, Yanginlar C, Maciej-Hulme ML et al. Beneficial non-anticoagulant mechanisms underlying
heparin treatment of COVID-19 patients. EBioMedicine 2020.
360. 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.
361. Clausen TM, Sandoval DR, Spliid CB et al. SARS-CoV-2 infection depends on cellular heparan sulphate and
ACE2. bioRxiv 2020.
362. 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.
363. Buijsers B, Yanginlar C, de Nooijer A et al. Increased plasma heparanase activity in COVID-19 patients.
medRxiv 2020.
364. May JM, Qu ZC. Ascorbic acid prevents oxidant-induced increases in endothelial permeability. Biofactors
2011; 37:46-50.
365. 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.

366. 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.
367. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 2004; 1024:138-46.
368. Shodell M, Siegal FP. Corticosteroids depress INF-alpha-producing plasmacytoid dentritic cells in human
blood. J Allergy Clin Immunol 2001; 108:446-48.
369. Thomas BJ, Porritt RA, Hertzog PJ et al. Glucocorticosteroids enhance replication of respiratory viruses:
effect of adjuvant interferon. Scientific Reports 2014; 4:7176.
370. 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.
371. Salton F, Confalonieri P, Santus P et al. Prolonged low-dose methylprednisolone in patients with severe
COVID-19 pneumonia. medRxiv 2020.
372. Braude AC, Rebuck AS. Prednisone and methylprednisolone disposition in the lung. Lancet 1983;995-97.
373. 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.
374. 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.
375. Dorward DA, Russell CD, Um IH et al. Tissue-specific immunopathology in fatal COVID-19. Am J Respir Crit
Care Med 2020.
376. 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.
377. Tang N, Bai H, Chen X et al. Anticoagulant treatment is associated with decreased mortality in severe
coronavirus disease 2019 with coagulopathy. medRxiv 2020.
378. Sardu C, Gambardella J, Morelli MB et al. Is COVID-19 an endothelial disease? Clinical and basic evidence.
medRxiv 2020.
379. World Health Organization: Coronavirus Disease 2019 (COVID-19): Situation Report -54 (14th March
2020). https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200314-sitrep-54-
covid-19.pdf . 2020. 7-9-2020.
380. Clinical management of COVID-19. Interim guidance. 27th May 2020.
https://www.who.int/publications/i/item/clinical-management-of-covid-19 WHO/2019-
nCoV/clinical/2020.5 . 2020. World Health Organization. 7-10-2020.
381. Yam LY, Lau AC, Lai FY et al. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong.
J Infection 2007; 54:28-39.
382. Siemieniuk RA, Bortoszko JJ, Ge L et al. Drug treatments for Covid-19: living systematic review and
network meta-analysis. BMJ 2020.
383. 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.
384. 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.
385. 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.
386. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone. A potential strategy to avoid steroid-
related Strongyloides hyperinfection. JAMA 2020; 324:623-24.

Marik Critical Care COVID-19 Protocol

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COVID-19 MANAGEMENT PROTOCOL

An overview of the MATH+ and I-MASK+ Protocols

Disclaimer: The information in this document is provided as guidance to physicians World-Wide

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THIS IS A STEROID RESPONSIVE DISEASE:

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

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

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Figure 5. Treatment Phases of COVID-19

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

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Components of the I-MASK Prophylactic Protocol

• Ivermectin for postexposure prophylaxis (see ClinTrials.gov NCT04422561). 0.2 mg/kg

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MATH + PRTOCOL (for patients admitted to the ICU) [195,196]

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Additional Treatment Components (the Full Monty)

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Table 2: Comparison of Methylprednisolone, Dexamethasone and Hydrocortisone- Number

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Salvage treatments of unproven/no benefit.

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27. Post ICU management

a. Enoxaparin 40–60 mg s/c daily

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a. Patients have an increased risk of thromboembolic events post-discharge. [303] Extended

b. The post-COVID-19 syndrome (Long haul syndrome) is characterized by prolonged malaise,

c. Post-COVID-19 pulmonary fibrosis. An unknown number of patients who have recovered

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1) Hyper-inflammation (“Cytokine storm”) – a dysregulated immune system whose cells infiltrate

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Lectures by Paul Marik, MD reviewing clinical aspects of COVID-19.

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Question: Can I request expert advice or consultation from the FLCCC?

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