Updates:

- Changes to recommendation for

fluvoxamine
- Changes to corticosteroids section
- Note about anesthesia and
contraindications
Table of Contents

Disclaimer ............................................................................................................................. 3
The Use of “Off-Label” Drugs ................................................................................................. 3
Overview of MATH+ and Key Concepts .................................................................................. 3
First Line Therapies (in order of priority) ........................................................................................................... 11
Second Line and Optional Treatments ............................................................................................................... 12

Treatment for Patients Admitted to ICU ............................................................................... 16

First line treatments ........................................................................................................................................... 16
Additional Treatment Components .................................................................................................................... 17
Second Line Treatments ..................................................................................................................................... 17
Optional Treatments (and those of uncertain benefit) ...................................................................................... 18

Patients with Severe, Life-Threatening COVID-19 Organizing Pneumonia .............................. 20

The “FULL MONTY” for Severe COVID Pulmonary Disease ................................................................................ 21

Salvage Treatments ............................................................................................................. 22

Salvage Treatments of Unproven/No Benefit .................................................................................................... 23

Monitoring .......................................................................................................................... 23
Post ICU Management ........................................................................................................................................ 24
Post Hospital Discharge Management ............................................................................................................... 24

References .......................................................................................................................... 25

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 2

Disclaimer
The information in this document is our recommended approach to COVID-19 in the
hospitalized patient, based on the best (and most recent) literature. It is provided as guidance
to healthcare providers worldwide on the prevention and early 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 provider before starting any medical treatment. As
this is a highly dynamic topic, we will update these guidelines as new information emerges.
Please ensure you are using the latest version of this protocol.

The Use of “Off-Label” Drugs

Once the FDA approves a prescription medication, federal laws allow any U.S. physician to
prescribe the duly approved drug for any reason. [1] In fact, 30 percent of all prescriptions are
for off-label uses, written by American doctors exercising their medical judgment.
Many states — including Nebraska, Tennessee, and Missouri — have asserted the right of
physicians to prescribe, and pharmacists to dispense, off-label drugs such as ivermectin and
hydroxychloroquine for the treatment of COVID-19. For example, Nebraska’s Attorney General,
Doug Peterson, released a legal opinion in October 2021 saying he did not see data to justify
legal action against healthcare professionals who prescribe ivermectin or hydroxychloroquine.
[2] In May 2022, Tennessee approved a standing order allowing ivermectin to be dispensed
over the counter.

Overview of MATH+ and Key Concepts

As the pandemic has played out over the last two years, more than six million patients have
died worldwide. Most countries across the globe have limited resources to manage this
humanitarian crisis. The FLCCC physicians developed the MATH+ protocol to provide guidance
for the treatment of the pulmonary phase of this devastating disease with the goal of reducing
hospital mortality. We are now realizing the relentless malpractice of deliberately withholding
effective early COVID treatments and forcing the use of toxic remdesivir in hospitalized patients
may have unnecessarily killed up to 800,000 Americans. [3]
The core principle of 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.
COVID is an extraordinarily complex, yet treatable, disease; many of its mysteries are still
unravelling. However, a few concepts are key to its management.
It is critically important to recognize that infection with SARS-CoV-2, the virus that causes
COVID-19, progresses through stages. Treatment approaches are therefore highly stage-specific
(see Figures 1-3 and Table 1). Antiviral therapy is likely to be effective only during the viral
replicative phase. Anti-inflammatory therapy is expected to be effective during the pulmonary
phase and possibly the post-COVID phase.
While there is no “magic bullet” for COVID-19, several therapeutic agents have shown great
promise for the treatment of this disease. These include ivermectin, Vitamin D, quercetin,

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 3

melatonin, fluvoxamine, spironolactone, corticosteroids, curcumin (turmeric), Nigella sativa
and anti-androgen therapy. A growing body of evidence suggests that many of these agents
may act synergistically in various phases of the disease. [4-6] In the midst of a global pandemic,
the use of cheap, effective, and safe repurposed drugs has and will continue to have a major
role to play. We must focus on the totality of evidence, and not just on randomized controlled
trials (RCTs) (see Figure 7).
Ivermectin has emerged as a highly effective drug for the prophylaxis and treatment of COVID-
19. Ivermectin inhibits viral replication and has potent anti-inflammatory properties. Emerging
data (including RCTs) suggest that ivermectin may have an important clinical benefit across the
spectrum of phases of the disease, i.e., pre-exposure prophylaxis, post-exposure prophylaxis,
during the symptomatic phase and during the pulmonary phase. [7-29] In the recommended
dosages, ivermectin is remarkably safe and effective against SARS-CoV-2. However, as noted
below, there is the potential for serious drug-drug interaction.
COVID-19 is essentially a clinical diagnosis supported by laboratory tests. At symptom onset, a
PCR test 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 Figure 3). [30] A PCR test remains
positive for at least two weeks. Patients who progress to the pulmonary phase are usually PCR-
positive, despite cessation of viral replication (and are therefore less likely to be infectious).
However, 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).
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).
[31]
COVID-19 patients present with a variety of phenotypes, likely dependent on inoculum size and
viral load, virus variant, genetic heterogeneity mutations and polymorphisms, biotypes, blood
type, sex and androgen status, age, race, BMI (obesity), immunological and nutritional status,
and comorbidities. [32-43] 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. [44]
The pulmonary phase is characterized by prolonged immune dysregulation, [35;45-59] a
pulmonary microvascular injury (vasculopathy), [58-62] with activation of clotting and a
procoagulant state together with the characteristics of an organizing pneumonia. [63;64]
Immune dysregulation may last weeks or even months. The early and abrupt termination of
anti-inflammatory agents will likely result in rebound inflammation. [65]
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. [59]
The pulmonary phase of COVID-19 is a treatable disease; it is inappropriate to limit therapy to
“supportive care” alone. As patients progress down the pulmonary cascade the disease
becomes more difficult to reverse. The implications of this are two-fold:

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 4

 • Early treatment of the pulmonary phase is ESSENTIAL to a good outcome.
• 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.
The radiographic and pathological findings of COVID-19 lung disease are characteristic of a
Secondary Organizing Pneumonia (and not ARDS). [63;66;67] The initial pulmonary phase
neither looks like, smells like nor is ARDS. [68-70] The ground glass infiltrates are peripheral and
patchy, [66] and do not resemble the dependent air space consolidation (sponge/baby lung)
seen with “typical ARDS”. [71] 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 an organizing
pneumonia with severe ventilation/perfusion mismatch likely due to the microvascular
narrowing, thrombosis and vasoplegia.
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 defense mechanism). [131,155] Low innate antiviral defenses and high
pro-inflammatory mediators contribute to ongoing and progressive lung injury.
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, [72;73] and necessitates pulse oximetry in
symptomatic patients managed at home.
It should be recognized that Low Molecular Weight Heparin (LWMH) has non-anticoagulant
properties that are likely beneficial in patients with COVID-19; these include anti-inflammatory
effects and inhibition of histones. [74] In addition, in vitro studies demonstrate that heparin
inhibits SARS-CoV-2 interaction with the ACE-2 receptor and viral entry, [75;76] as well as viral
replication [11;77]. Most importantly LWWH inhibits heparanase (HPSE). [78] HSE destroys the
endothelial glycocalyx increasing endothelial leakiness, activating clotting and potentiating
endothelialitis. [78] HPSE levels have been reported to be increased in patients with severe
COVID-19 infection. [79] 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).
The combination of steroids and ascorbic acid (Vitamin C) is essential. Both have powerful
synergistic anti-inflammatory actions. [80;81] Vitamin C protects the endothelium from
oxidative injury. [82-85] Furthermore, Vitamin C Increases the expression of interferon-alpha
[86] while corticosteroids (alone) decrease expression of this important protein. [87-90] 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. [91;92] It is likely that LMWH acts synergistically with
corticosteroids and Vitamin C to protect the endothelium and treat the endothelialitis of severe
COVID-19 disease.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 5

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), [93]
genomic data specific for SARS-CoV-2, [94] and a long track record of successful use in
inflammatory lung diseases (see Table 1).

Figure 1. Evaluating the Totality of Evidence

Source: FLCCC

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 6

Figure 2. The Course of COVID-19 and General Approach to Treatment

Source: FLCCC

Figure 3. Timing of the Initiation of Anti-Inflammatory Therapy

Source: FLCCC

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 7

Note: Viral replication in Figures 2 and 3 are typical for the original Wuhan SARS-CoV-2 virus
(Alpha strain). The time course of Omicron BA.4, BA.5, BQ1 and BQ1.1 appears to be
contracted/shortened compared to the Wuhan (Alpha) strain.

THIS IS A STEROID-RESPONSIVE DISEASE:

HOWEVER, TIMING IS CRITICAL.

Not too early. Not too late.

Figure 4. Time Course of Laboratory Tests for COVID-19

Source: FLCCC

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 8

Table 1. Pharmacological Therapy for COVID-19 by Stage of Illness: What has worked and
what has failed*

Source: FLCCC
** Due to extensive fraudulent activity around the design and conduct of RCTs, the benefit of
HCQ is supported largely by numerous consistently positive observational trials.

The use of Corticosteroids in the hospitalized patient.

The use of corticosteroids in the hospitalized patient with COVID-19 has been controversial
from the outset. [92;95] While we recommended the use of methylprednisolone early in the
pandemic,[96] others suggested that corticosteroids should be avoided. [97;98] Subsequently
over 100 observational, cohort and RCT have been published many with conflicting findings.
However, the landmark RECOVERY trial demonstrated that 6 mg IV dexamethasone given daily
for up to 10 days reduced the mortality of patients with respiratory failure (those requiring
supplemental oxygen or respiratory support). [99] This regimen should be regarded as the
standard of care.
While initial studies suggested that higher doses of corticosteroids (methylprednisone ≥ 1mg/kg
or dexamethasone ≥ 20 mg daily) may be beneficial, [100] this has not been borne out in more
recent studies. [101-110] Furthermore, additional studies have confirmed the lack of benefit of
corticosteroids in patients who do not require supplemental oxygen. [111] However, high dose
bolus therapy (250 mg methylprednisolone daily for 3 days) should be considered in patients
with refractory disease or upon presentation with severe, advanced disease.[112-116]
Furthermore, delayed initiation of corticosteroids is associated with a worse outcome than
early therapy (< 5 days of hospitalization). [117] While initially the superiority of

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 9

methylprednisolone over dexamethasone was supported by genomic, pharmacological, and
early clinical data, [92-94;118-120] the superiority of methylprednisolone over dexamethasone
in more recent studies of patients with COVID-19 organizing pneumonia has not been
definitively demonstrated. [104]

Table 2. Drug Interactions with Ivermectin

Patients taking any of these medications should discuss with their treating physicians.
SERIOUS (5) MONITOR CLOSELY (50)
Use Alternative
erdafitinib amiodarone lonafarnib
lasmiditan atorvastatin loratadine
quinidine berotralstat lovastatin
sotorasib bosutinib nefazodone
tepotinib clarithromycin nicardipine
clotrimazole nifedipine
dronedarone nilotinib
elagolix phenobarbital
eliglustat phenytoin
erythromycin base ponatinib
erythromycin ethylsuccinate quercetin
erythromycin lactobionate ranolazine
erythromycin stearate rifampin
felodipine ritonavir
fosphenytoin sarecycline
fostamatinib simvastatin
glecaprevir/pibrentasvir sirolimus
indinavir St John's Wort
istradefylline stiripentol
itraconazole tacrolimus
ivacaftor tolvaptan
ketoconazole trazodone
lapatinib tucatinib
levoketoconazole verapamil
lomitapide warfarin
Source: Medscape

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 10

Mildly Symptomatic Patients (On hospital floor/ward)
First Line Therapies (in order of priority)
Ivermectin, low molecular weight heparin (LMWH) A note about anesthesia and
and corticosteroids form the foundation of care for surgery:
the hospitalized patient. Multiple RCTs have
demonstrated that these drugs reduce the mortality of Please notify your anesthesia
patients hospitalized with COVID-19. team if you are using the
following medications and/or
• Ivermectin 0.4–0.6 mg/kg daily for 5 days or nutraceuticals as they can
until symptoms resolve (see Figure 4). A higher increase the risk of Serotonin
dose may be required when treatment is Syndrome — a life-threatening
delayed and in patients with more severe condition — when opioids are
disease. [7-12;15-18;20;29;121-128]. administered:
Ivermectin retains full efficacy against the • Methylene blue
Omicron variants (as best we know). Ivermectin • Curcumin
is best taken with a meal or just following a
meal for greater absorption. It should be noted
• Nigella Sativa
that ivermectin has potent anti-inflammatory • Selective Serotonin
Reuptake Inhibitors
properties apart from its antiviral properties.
(SSRIs)
[13;14;23;129] Ivermectin is a remarkably safe
drug with minimal adverse reactions (almost all
minor). [29] However, potential drug-drug interactions should be reviewed before
prescribing ivermectin (see Table 2). Note that ivermectin should not be administered
with quercetin.
• Dexamethasone 6 mg IV daily or Methylprednisolone 40 mg IV daily for up to 10 days.
The role of inhaled corticosteroids (budesonide) is unclear and appears to be rather
limited. While dexamethasone/methylprednisolone is the corticosteroid of choice, in
regions/countries where these drugs are not available dosage equivalents of
prednisolone, prednisone and hydrocortisone may be utilized.
• Enoxaparin 1 mg/kg every 12 hours (see dosage adjustments and Xa monitoring below).
The ATTACC, ACTIV-4a & REMAP-CAP trials demonstrated a significant reduction of the
primary endpoint (composite of organ support days and hospital mortality) regardless of
D-dimer levels. [130]
• Zinc 75–100 mg/day.[131]
• Melatonin 6 mg at night. [132-138]
• Vitamin C 500–1000 mg every 6 hours.
• Quercetin 250–500 mg twice daily (if available). Note that ivermectin should not be
administered with quercetin.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 11

Second Line and Optional Treatments
• Nitazoxanide (NTZ) 600 mg twice daily for 7 days. [139] NTZ is considered an alternative
to ivermectin, or part of a multi-drug combination that includes ivermectin. It should be
noted that while NTZ is relatively cheap in most of the world, it is very expensive in the
United States.
• Vitamin D3/Calcifediol. For patients hospitalized with COVID-19, the dosing scheme
listed in Table 3 is suggested. Vitamin D3 requires hydroxylation in the liver to become
25(OH)D, causing a lag of about 3 to 4 days. [140] This may explain the lack of benefit of
Vitamin D3 in patients hospitalized with severe COVID-19. [141] Calcifediol is already 25-
hydroxylated, and thus, it bypasses the liver and become available in the circulation
within four hours of administration. Among other benefits, it permits boosting the
immune system and improving the functions of other systems within a day. Orally
administered, a single dose of calcifediol raises serum 25(OH)D concentration within
four hours. Therefore, calcifediol is particularly useful in acute infections like COVID-19,
and in sepsis. [142-146] The single oral calcifediol dose is calculated as 0.014 mg/kg
body weight. To be most effective, a loading dose of Vitamin D3 should be administered
with or within the first week of administration of calcifediol. We recommend against the
use of calcitriol [1,25(OH)2D], which has minimal effect on immune cells. Moreover, the
effective dose (ED50) and toxic level overlap at the dose currently suggested for COVID-
19. [147]
• Aspirin/Acetylsalicylic acid (ASA) 325 mg daily — if not contraindicated. Moderate to
severe COVID infection results in profound platelet activation, contributing to the pro-
thrombotic state and increasing the inflammatory response. [148-151]
• B complex vitamins.
• N-acetyl cysteine (NAC) 600-1200 mg by mouth twice daily. [152-156]
• Fluvoxamine 25- 50 mg twice daily. Fluoxetine 20-40 mg daily is an alternative. [157-
160] NOTE: Some individuals who are prescribed fluvoxamine experience acute anxiety
which may progress to mania, this serious side effect may occur after the first
dose.[161] Patients prescribed this medication should be carefully monitored to prevent
escalation to suicidal or violent behavior.
• Anti-androgen therapy (both men and women). Spironolactone 100 mg twice daily for
10 days. Second line anti-androgen: Dutasteride 2 mg day 1, followed by 1 mg for 10
days. AVOID IN PREGNANCY. [162-164]
• Optional: Famotidine 40 mg twice daily (20–40 mg/day in renal impairment). [165-171]
Famotidine may be useful for its protective effect on gastric mucosa, as well as its
antiviral and histamine-blocking properties.
• Optional: The anti-serotonin agent, cyproheptadine 4–8 mg by mouth every 6 hours
should be considered in patients with more severe disease. [172;173] Patients with
COVID-19 have increased circulating levels of serotonin, which is likely the result of
increased platelet activation and decreased removal by the pulmonary circulation due
to an extensive microcirculatory vasculopathy. [172;174-176] Increased circulating

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 12

 serotonin is associated with pulmonary, renal, and cerebral vasoconstriction and may
partly explain the V/Q mismatch and reduced renal blood flow noted in patients with
severe COVID-19 infection. [177-180] Furthermore, serotonin itself enhances platelet
aggregation, creating a propagating immuno-thrombotic cycle. [181] In addition,
serotonin receptor blockade may reduce progression to pulmonary fibrosis. [182]
• Optional: Vascepa (Ethyl eicosapentaenoic acid) 4 g daily or Lovaza (EPA/DHA) 4 g daily;
alternative DHA/EPA 4 g daily. [183] Vascepa and Lovaza tablets must be swallowed and
cannot be crushed, dissolved, or chewed.
• Optional: JAK inhibitors ruxolitinib or baricitinib. JAK inhibitors target JAK1, JAK2, JAK3,
and whose inhibition downregulates the JAK/STAT signaling pathway decreasing
cytokine concentrations. [184] These drugs have been shown to decrease the use of
mechanical ventilation and the risk of death. [185;186] In these studies, low doses of
corticosteroids were used. The role of JAK inhibitors with appropriate corticosteroid
dosing is unclear. JAK inhibitors should be used with caution in patients with severe
renal impairment as well as those with lymphopenia (< 500) and neutropenia (< 1000).
The safety of these drugs is uncertain, as they are nephrotoxic and myelosuppressive.
• Not recommended: Remdesivir. The SOLIDARITY trial demonstrated no mortality benefit
of this agent in the entire treatment cohort or any subgroup. [187] The VA study
showed no mortality benefit with remdesivir and a longer length of hospital stay. [188]
Most recently, the DisCoVeRy trial reported no outcome benefit from remdesivir. [189]
A meta-analysis of the six published RCTS demonstrate no mortality reduction with
remdesivir; interestingly enough, the independent studies demonstrate a trend to harm
while the two studies conducted by Gilead demonstrate a mortality benefit. (See Figure
6).
• Not recommended: Colchicine. Recruitment to the colchicine arm of the RECOVERY trial
has been closed as no mortality benefit was noted (Mortality 20% colchicine, 19%
standard of care). In addition, potentially serious drug-drug interactions exist with the
use of colchicine and CYP 3A4 and p-glycoprotein inhibitors (ivermectin, macrolide
antibiotics, cyclosporin, etc.) as well as with the use of statins. [190]

NOTE: Transfer patients to ICU as early as possible if respiratory symptoms worsen, oxygen
requirements increase, or arterial desaturation emerges.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 13

Table 3. A Single-Dose Regimen of Calcifediol to Rapidly Raise Serum 25(OH)D above 50
ng/mL

If calcifediol is not
Body Weight Body Weight Calcifediol
Equivalent in IU available, a bolus of
(lbs.) (kgs) (mg)
Vitamin D3
15 – 21 7 – 10 0.1 16,000 20,000
22 – 30 10 – 14 0.15 24,000 35,000
31 – 40 15 – 18 0.2 32,000 50,000
41 – 50 19 – 23 0.3 48,000 60,000
51 – 60 24 – 27 0.4 64,000 75,000
61 – 70 28 – 32 0.5 80,000 100,000
71 – 85 33 – 39 0.6 96,000 150,000
86 – 100 40 – 45 0.7 112,000 200,000
101 – 150 46 – 68 0.8 128,000 250,000
151 – 200 69 – 90 1.0 160,000 300,000
201 – 300 91 – 136 1.5 240,000 400,000
>300 > 137 2.0 320,000 500,000
Source: From SJ Wimalawansa with permission

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 14

Figure 5. Ivermectin for COVID-19: Real-time meta-analysis of 88 studies

Source: c19ivermectin.com

Figure 6. Meta-Analysis of the Remdesivir RCTs Grouped by Independent Studies (I) and

Those Done by Gilead™ (P)

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 15

Treatment for Patients Admitted to ICU

First line treatments

• Dexamethasone 6mg / Methylprednisolone 40mg daily.
• Ascorbic acid (Vitamin C) 50 mg/kg (or 3000 mg) IV every 6 hours for at least 7 days
and/or until transferred out of ICU. [80;81;85;191-201]. High-dose Vitamin C should be
considered in severely ill patients, those with progressive respiratory failure and as
salvage therapy: 25 g Vitamin C in 200-500 cc saline over 4-6 hours every 12 hours for 3-
5 days, then 3 g IV every 6 hours for total of 7-10 days of treatment. [202] High-dose
Vitamin C appears safe in patients with acute renal failure and end-stage renal disease.
In patients with chronic renal failure, a dose of 12.5 g every 12 hours may be suitable.
[203] In the study by Lankadeva et al, high-dose Vitamin C increased renal cortical blood
flow and renal cortical pO2; oxalate crystals were not detected. [202] Note caution with
POC glucose testing. Oral absorption is limited by saturable transport proteins, 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 1 g
every 4–6 hours.
• Anticoagulation: The ATTACC, ACTIV-4a & REMAP-CAP trials demonstrated a marginally
increased mortality in ICU patients treated with full anti-coagulation (35.3% vs. 32.6%).
[130] Critically ill COVID-19 patients frequently have impaired renal function and it is
likely that in the absence of Xa monitoring patients were over-anticoagulated. However,
full anti-coagulation should be continued on floor patients transitioned to the ICU who
have normal renal function. In all other patients, we would suggest intermediate dose
enoxaparin i.e 60 mg/day (enhanced thromboprophylaxis) or 0.5 mg/kg every 12 hours.
[204] Full anticoagulation (enoxaparin or heparin) may be required in patients with
increasing D-dimer or with thrombotic complications. Due to augmented renal clearance
some patients may have reduced anti-Xa activity despite standard dosages of LMWH.
[236] We therefore recommend monitoring anti-Xa activity aiming for an anti-Xa activity
of 0.5 – 0.9 IU/ml. Heparin is suggested with CrCl < 15 ml/min. It should also be
appreciated that Vitamin C is a prerequisite for the synthesis of collagen and Vitamin C
deficiency is classically associated with vascular bleeding. [85;193] This is relevant to
COVID-19, as Vitamin C levels are undetectable in severely ill COVID-19 patients and this
may partly explain the increased risks of anticoagulation in ICU patients (not treated
with Vitamin C). [205-207] The use of the novel oral anticoagulants (NOAC/DOAC) is not
recommended. [208]
Note: A falling SaO2 and the requirement for supplemental oxygen should be a trigger to start
anti-inflammatory treatment.
Note: Early termination of ascorbic acid and corticosteroids will likely result in a rebound effect
with clinical deterioration.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 16

Additional Treatment Components
• Highly recommended: Ivermectin 0.6 mg/kg day orally for 5 days or until recovered [7-
20;22-29;209]. Note that ivermectin has potent antiviral and anti-inflammatory effects.
As noted above, clinical outcomes are superior with multiday as opposed to single day
dosing.
• Nitazoxanide (NTZ) 600 mg twice daily for 7 days. [139] NTZ should be considered as an
alternative to ivermectin, or as part of a multi-drug combination that includes
ivermectin. It should be noted that while NTZ is relatively cheap in most of the world, it
is very expensive in the USA.
• Melatonin 10 mg at night. [133-135]
• Thiamine 200 mg IV every 12 hours for 3-5 days, then 200 mg daily [210-215] Thiamine
may play a role in dampening the cytokine storm. [211;216]
• Aspirin/Acetylsalicylic acid (ASA) 325 mg daily. COVID infection results in profound
platelet activation contributing to the severe pro-thrombotic state and increasing the
inflammatory response. [148-151] As the risk of significant bleeding is increased in
patients receiving both ASA and heparin, ASA should not be used in patients at high risk
of bleeding. In addition (as noted below) patients should receive famotidine
concurrently.
• The anti-serotonin agent, cyproheptadine. Platelet activation results in the release of
serotonin, which may contribute to the immune and vascular dysfunction associated
with COVID-19. [215-219] Therefore, the serotonin receptor blocker cyproheptadine 4–8
mg by mouth every 6 hours should be considered.
• Anti-androgen therapy (both men and women). Spironolactone 100 mg twice daily for
10 days. Second line: Dutasteride 2 mg day 1, followed by 1 mg for 10 days. Finasteride
10 mg is an alternative (dutasteride cannot be crushed). [217;218] AVOID IN
PREGNANCY. [162;163] Bicalutamide 150 mg daily is also an option.
• Fluvoxamine 25-50 mg twice daily. Fluoxetine 20-40 mg daily is an alternative.

Second Line Treatments

• B complex vitamins.
• Calcifediol [25-hydroxylated vitamin D; 25(OH)D]. Dosing as suggested in Table 3.
• Vascepa (Ethyl eicosapentaenoic acid) 4 g daily or Lovaza (EPA/DHA) 4 g daily;
alternative DHA/EPA 4 g daily. Vascepa and Lovaza tablets must be swallowed and
cannot be crushed, dissolved, or chewed.
• Magnesium 2 g stat IV. Keep Mg between 2.0 and 2.2 mmol/l. [219] Prevent
hypomagnesemia (which increases the cytokine storm and prolongs Qtc). [220-222]

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 17

Optional Treatments (and those of uncertain benefit)
• Optional: Famotidine 40 mg twice daily (20–40 mg/day in renal impairment). [165-171]
• Optional: JAK inhibitors ruxolitinib or baricitinib.
• Optional: Atorvastatin 40-80 mg/day (reduce dose to 40 mg if taken with ivermectin
due to possible drug-drug interaction. Preliminary data suggests atorvastatin may
improve outcome in patients with COVID-19. [238-242] Due to numerous drug-drug
interactions, simvastatin should be avoided
• Unclear benefit. Losartan 50-100 mg/day (reduce to 25-50 mg with impaired renal
function) or telmisartan 40-80 mg twice daily (reduce to 40 mg/day or twice daily with
impaired renal function). [223-225]
• Unclear benefit. Maraviroc 300 mg twice daily for 10 days. Maraviroc is a CCR5
antagonist. [226] CCR5 is a chemokine that activates macrophages/monocytes and
whose circulating levels are significantly increased in COVID-19. [227;228] Blocking the
CCR5 receptor (CCR5R) repolarizes macrophages/monocytes and decreases the
production of proinflammatory cytokines.
• Not recommended: Remdesivir. This drug has no benefit at this stage of the disease.
• Not recommended. Convalescent serum [229-234] nor monoclonal antibodies. [235]
However, convalescent serum/monoclonal antibodies may have a role in patients with
hematologic malignancies. [236] The role of bebtetovimab requires further evaluation.
[237]
• Not recommended. Colchicine (see above).
• Not recommended. Tocilizumab. Five RCTs have now failed to demonstrate a clinical
benefit from tocilizumab. [238-242] Considering the effect of IL-6 inhibitors on the
profile of dysregulated inflammatory mediators this finding is not surprising. [243]
Tocilizumab may have benefit in patients receiving an inadequate dose of
corticosteroids. [244] In patients who receive an adequate therapeutic dose of
corticosteroid the role of this drug appears limited.
• Broad-spectrum antibiotics added if complicating bacterial pneumonia is suspected
based on procalcitonin levels and respiratory 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. [245-247] Patients with non-resolving fever, increasing WBC count and
progressive pulmonary infiltrates should be screened for COVID-19-associated
pulmonary aspergillosis (CAPA). [248] Recommended first-line therapy for CAPA is either
voriconazole or isavuconazole (beware drug-drug interactions). While low CD4 counts
are typical of severe COVID-19 infection, PJP infections have not been reported;
therefore, PJP prophylaxis is not required.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 18

 • 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.
• 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.
• Escalation of respiratory support (steps); Try to avoid intubation if at all possible.
Intubation is indicated in patients who have failed non-invasive ventilation and in those
patients with excessive work of breathing. A subgroup of patients with COVID-19
deteriorates very rapidly. Intubation and mechanical ventilation may be required in
these patients.
a. Accept “permissive hypoxemia” (keep O2 Saturation > 84%); follow venous
lactate and Central Venous O2 saturations (ScvO2) in patents with low arterial O2
saturations
b. N/C 1–6 L/min
c. High Flow Nasal canula (HFNC) up to 60–80 L/min [249]
d. Trial of inhaled Flolan (epoprostenol)
e. Attempt proning (cooperative repositioning-proning) [250-253]
f. Intubation … by Expert intubator; Rapid sequence. No Bagging; Full PPE.
Crash/emergency intubations should be avoided.
g. Volume protective ventilation; Lowest driving pressure and lowest PEEP as
possible. Keep driving pressures < 15 cm H2O.
h. Moderate sedation to prevent self-extubation
i. Trial of inhaled Flolan (epoprostenol)
j. Prone positioning
There is widespread concern that using HFNC could increase the risk of viral transmission. There
is, however, no evidence to support this fear. [254;255] HFNC is a better option for the patient
and the healthcare system than intubation and mechanical ventilation. HFNC is preferred over
conventional oxygen therapy. [249] Intermittent CPAP/BiPAP may be used in select patients,
notably those with COPD exacerbation or heart failure.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 19

Figure 7. “Typical” Progression of Chest CT Findings

Source: FLCCC

Patients with Severe, Life-Threatening COVID-19

Organizing Pneumonia

The first task of the clinician is to determine the reversibility of the pulmonary disease. This is a
critical assessment. Aggressive anti-inflammatory treatment is futile in patients with advanced
fibrotic lung disease. The horse has already bolted and allowing the patient a “peaceful death”
is the most compassionate and humane approach.
The reversibility of the pulmonary disease is dependent on a number of factors superseded by a
good deal of clinical judgement; these include:
a) The length of time that has elapsed since the onset of symptoms. Early aggressive
treatment is critical to prevent disease progression. With each day the disease becomes
more difficult to reverse. The ‘traditional’ approach of supportive care alone is simply
unacceptable.
b) The level of inflammatory biomarkers, particularly the CRP. In general the CRP tracks the
level of pulmonary inflammation. [256] A high CRP is indicative of a hyper-inflammatory
state and potentially reversible pulmonary inflammation.
c) It is likely that advanced age is a moderating factor making the pulmonary disease less
reversible.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 20

d) A chest CT is extremely helpful in determining the reversibility of disease. BEWARE: this is
not ARDS but organizing pneumonia. [63] The extent of the pulmonary involvement may be
determined qualitatively or preferably quantitatively (see Figure 7). [256-263] The Ichikado
CT Score is a useful quantitative score to evaluate the extent of lung involvement with
COVID-19. [264;265] The changes in the CT follow a stereotypic progressive pattern:
I. Peripheral, patchy, predominantly basal ground glass opacification (GGO). GGO is
defined an increase in density of lung with visualization of bronchial and vascular
structures through it
II. Progressive widespread bilateral GGO
I. Crazy-paving (CGO with interlobular and intralobular septal thickening)
II. Air space consolidation (air bronchograms)
III. Dense airspace consolidation
IV. Coalescent consolidation
V. Segmental/subsegmental pulmonary vessel dilatation
VI. Bronchial wall thickening
VII. Linear opacities
VIII. Traction bronchiectasis
IX. Cavitation
X. Fibrotic changes with bullae and reticulation

GGO pattern is significantly more prevalent in early-phase disease compared with late-phase
disease while crazy-paving and consolidation patterns are significantly more common in late-
phase. [256] Therefore widespread GGO suggests reversibility while widespread consolidation
with other features of more advanced disease suggest irreversible lung disease. However, when
in doubt (borderline cases) a time-limited therapeutic trial of the aggressive “Full Monty”
approach may be warranted.

The “FULL MONTY” for Severe COVID Pulmonary Disease

I. Methylprednisolone 250 mg daily for at least 3 days, then titrate guided by clinical
status and CRP
II. Ivermectin 1 mg/kg for 5 days
III. Melatonin 10 mg by mouth at night
IV. Enoxaparin 60 mg daily; critically ill patients usually have some degree of renal
impairment and will require a renally adjusted lower dose. Patients with very high D-
dimer and or thrombotic complications may require full anticoagulant doses of Lovenox.
It may be prudent to monitor Xa levels aiming for 0.4-0.8 IU/ml (a somewhat lower anti-
Xa).

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 21

 V. Vitamin C 3 g every 6 hours to 25 g every 12 hours
VI. Cyproheptadine 4–8 mg by mouth every 6 hours
VII. Fluvoxamine 50-100 mg twice daily or fluoxetine 20-40 mg daily
VIII. Spironolactone 100 mg twice daily
IX. Thiamine 200 mg every 12 hours
X. NAC 1200 mg by mouth twice daily [154]
XI. Finasteride 10 mg daily or dutasteride 2 mg day 1 then 1 mg daily or bicalutamide 150
mg daily
XII. Omega-3 fatty acids 4 g/day
XIII. Famotidine 40 mg twice daily
XIV. Calcifediol (0.014 mg/kg) use as a single dose (see Table 3)
XV. Consider plasma exchange on admission to the ICU

All these drugs have been shown to be safe and independently to improve the outcome of
patients with COVID-19. Ultimately it is irrelevant as to the contribution of each element as long
as the patient improves and survives his/her ICU stay. In the midst of a pandemic caused by a
virus resulting in devastating lung disease, there is no place for “ivory tower medicine.”

Salvage Treatments
• High dose bolus corticosteroids: 250- 500/day methylprednisolone for 3 days then
taper. [112;113]
• Plasma exchange [266-272]. 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”.
• Calcifediol (0.014 mg/kg) use as a single dose (see Table 3).
• Mega-dose Vitamin C should be considered in severely ill patients and as salvage
therapy: 25 g Vitamin C in 200-500 cc saline over 4-6 hours, 12 hourly for 3-5 days, then
3g IV 6 hourly for total of 7-10 days of treatment. [202;203]
• 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;
25 mg of tPA over 2 hours followed by a 25 mg tPA infusion administered over the
subsequent 22 hours, with a dose not to exceed 0.9 mg/kg followed by full
anticoagulation. [273;274]
• Combination inhaled nitric oxide (or epoprostenol) and intravenous almitrine (10–16
ug/kg/min). The combination of inhaled nitric oxide, a selective pulmonary vasodilator,
MATH+: COVID Hospital Treatment Protocol (2/3/2023) 22
 and almitrine, a specific pulmonary vasoconstrictor, may improve the severe V/Q
mismatch in patients with severe COVID-19 “pneumonia”. [275-278]
• ECMO [279-281]. Unlike “typical ARDS”, COVID-19 patients may not progress into a
resolution phase. Rather, patients with COVID-19 with unresolved inflammation may
progress to a severe fibro-proliferative phase and ventilator dependency. ECMO in these
patients would likely serve little purpose. ECMO however may improve survival in
patients with severe single organ failure (lung) if initiated within 7 days of intubation.
[282]
• Lung transplantation. [283]

Salvage Treatments of Unproven/No Benefit

• Convalescent serum/monoclonal antibodies: Four RCTs failed to demonstrate a clinical
benefit with the use of convalescent serum. [229-231;233;234] Eli Lilly suspended the
ACTIV-33 clinical trial as their monoclonal antibody failed to demonstrate a clinical
benefit in hospitalized patients.[284] 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
(i.e., pulmonary phase). In addition, IgG is a large protein that penetrates tissues poorly,
and is unlikely to achieve submucosal concentrations required for mucosal immunity.
[285] Lastly, COVID-19 pulmonary disease is immune mediated, and it would therefore
appear paradoxical to enhance the antibody response with convalescent serum. [286]
• In patients with progressive fibrosis, the combination of anti-fibrotic therapy with
corticosteroids should be considered. [287-290] 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 [291;292] This treatment strategy
appears to have an extremely limited role.

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]
• As indicated above (corticosteroid section), a chest CT scan on admission to the ICU is
very useful for risk stratification and for the initial corticosteroid dosing strategy. The
Ichikado Score is a quantitative method to assess the extent of lung involvement on the
CT scan. [264;295] Follow-up CXR, CT scan (if indicated) and chest ultrasound as
clinically indicated.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 23

 • 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. [296]
• 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. [297;298]
• ECHO as clinically indicated; Patients may develop a severe “septic” cardiomyopathy
and/or COVID-19 myocarditis. [299;300]

Post ICU Management

• Enoxaparin 40–60 mg s/c daily
• Methylprednisolone 40 mg day, then wean slowly, follow CRP and oxygen requirements
– wean off over two weeks once oxygen is discontinued to prevent relapse/recurrence
• Vitamin C 500 mg PO BID
• Melatonin 3–6 mg at night
• Vascepa, Lovaza or DHA/EPA 4g day
• Atorvastatin 40mg daily

Post Hospital Discharge Management

• Patients have an increased risk of thromboembolic events post-discharge. [301;302]
Extended thromboprophylaxis (with a DOAC) should be considered in high-risk patients.
Risk factors include: [303]
i. Increased D dimer (> 3 times ULN)
ii. Increased CRP (> 2 times ULN) [304]
iii. Age > 60
iv. Prolonged immobilization
• Patients with unresolved pulmonary infiltrates and/or those who remain dyspneic
and/or oxygen dependent should be discharged on a tapering course of corticosteroids
(prednisone).
• Patients should continue to receive Vitamin C, melatonin, Omega-3 fatty acids and a
statin. These agents may reduce this risk of developing long COVID.
• Nigella sativa and Kefir.
• Patients should be followed/monitored for developing long COVID.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 24

References

1. Wittich CM, Burkle CM, Lanier WL. Ten common questions (and their answers) about
off-label drug use. Mayo Clin Proc 2012; 87:982-990.
2. Peterson DJ. Prescription of ivermectin or hydroxychloroquine as off-label medicines for
the prevention and treatment of Covid-19. https://ago nebraska gov/sites/ago nebraska
gov/files/docs/opinions/21-017_0 pdf [ 2021 [cited 2022 Jan. 14];
3. Kennedy RF. The Real Anthony Fauci. Bill Gates, Big Pharma, and the Global War on
Democracy and Public Health. New York, NY: Skyhorse Publishing; 2021.
4. Fatima S, Zaidi SS, Alsharidah AS, Alijaser FS, Banu N. 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.
5. Arslan B, Ergun NU, Topuz S, Semerci SY, Suner N. Synergistic effect of quercetin and
vitamin C against COVID-19: Is a possible guard for front liners? ssrn 2020.
6. Ahmed AK, Albalawi YS, Shora HA, Abelseed HK, Al-Kattan AN. 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.
7. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug Ivermectin
inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020.
8. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding
domain attached to ACE2. In Vivo 2020; 34:3023-3026.
9. 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.
10. Yang SN, Atkinson SC, Wang C, Lee A. The broad spectrum antiviral ivermectin targets
the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res 2020;
177:104760.
11. Dayer MR. Coronavirus (2019-nCoV) deactivation via spike glycoprotein shielding by old
drugs, bioinformatic study. Preprints 2020.
12. 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.
13. Zhang X, Song Y, Ci X, An N, Ju Y. Ivermectin inhibits LPS-induced production of
inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res 2008;
57:524-529.
14. Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N 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; 23:449-455.
15. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. ICON (Ivermectin in COvid
Ninteen) study: Use of ivermectin is associated with lower mortality in hospitalized
patients with COVID-19. Chest 2020.
16. Gorial FI, Mashhadani S, Sayaly HM, Dakhil BD, AlMashhadani MM. Effectiveness of
Ivermectin as add-on therapy in COVID-19 management (Pilot Trial). medRxiv 2020.
17. Khan MS, Khan MS, Debnath Cr, Nath PN, Mahtab MA. Ivermectin treatment may
improve the prognosis of patients with COVID-19. Archivos de Bronconeumologia 2020.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 25

 18. Hashim HA, Maulood MF, rasheed AM, Fatak DF, Kabah KK. Controlled randomized
clinical triaal on using Ivermectin with Doxycycline for treating COVID-19 patients in
Bagdad, Iraq. medRxiv 2020.
19. Murshed MR, Bhiuyan E, Saber S, Alam RF, Robin RF. A case series of 100 COVID-19
positive patients treated with combination of Ivermectin and Doxycycline. Bangladesh
Coll Phys Surg 2020; 38:10-15.
20. Chamie J. Real-World evidence: The case of Peru, casuality between Ivermectin and
COVID-19 infection fatality rate. ResearchGate 2020.
21. Patel AN, Desai SS, Grainger DW, Mehra MR. Usefulness of ivermectin in COVID-19
illness. medRxiv 2020.
22. Jans DA, Wagstaff KM. Ivermectin as a broad-spectrum host directed anti-viral: The real
deal. Cells 2020; 9:2100.
23. 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.
24. Sharun K, Dhama K, Patel SK, Pathak M, Tiwari R. Ivermectin, a new candidate
therapeutic against SARS-CoV-2/COVID-19. Ann Clin Microbiol Antimicrob 2020; 19:23.
25. Peralta EG, Fimia-Duarte R, Cardenas JW, Dominguez DV, Segura RB. 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.
26. Al-Jassim KB, Jawad AA, Al-Masoudi EA, Majeed SK. 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.
27. Mudatsir M, Yufika A, Nainu F, Frediansyah A, Megawati D. Antiviral activity of
ivermectin against SARS-CoV-2: an old-fashioned dog with a new trick- Literature
review. Sci Pharm 2020; 88:36.
28. Carvallo H, Hirsch R, Farinella ME. Safety and efficacy of the combined use of Ivermectin,
dexamethasone, enoxaparin and aspirin against COVID-19. medRxiv 2020.
29. Kircik LH, Del Rosso JQ, Layton AM, schauber J. Over 25 years of clinical experience with
Ivermectin: An overview of safety for an increasing number of indications. J Drugs
Dermatol 2016; 15:325-332.
30. Kurcicka L, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate
of reverse transcriptase polmerase chain reacion-based SARS-CoV-2 tests by time since
exposure. Ann Intern Med 2020; 173:262-267.
31. Cheng HY, Jian SW, Liu DP, Huang WT, Lin HH. 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; 180:1156-1163.
32. Zhao J, Yang Y, Huang H, Li D, Gu D. Relationship between ABO blood group and the
COVID-19 susceptibility. medRxiv 2020.
33. Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A. Estimating excess 1-year mortality
associated with the COVID-19 pandemic according to underlying conditions and age: a
population-based cohort study. Lancet 2020; 395:1715-1725.
34. Goren A, Vamo-Galvan S, Wambier CG, McCoy J. 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.
35. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan,China. Lancet 2020; 395:497-506.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 26

 36. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J. Clinical characteristics of Coronavirus disease
2019 in China. N Engl J Med 2020.
37. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S. Risk factors associated with acute respiratory
distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in
Wuhan,China. JAMA Intern Med 2020.
38. von der Thusen J, van der Eerden M. Histopathology and genetic susceptibility in COVID-
19 pneumonia. Eur J Clin Invest 2020.
39. Sweeney TE, Liesenfeld O, Wacker J, He YD, rawling D, Remmel M. Validation of
inflammopathic, adaptive, and coagulopathic sepsis endotypes in Coronavirus disease
2019. Crit Care Med 2020.
40. Tartof SY, Qian L, Hong V, Wei R, Nadjafi RF, Fischer H. Obesity and mortality among
patients diagnosed with COVID-19: Results from an integrated health care organization.
Ann Intern Med 2020.
41. Pujadas E, Chaudhry F, McBride R, Richter F, Zhao S. SARS-CoV-2 viral load predictes
COVID-19 mortality. Lancet Resp Med 2020.
42. Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science 2020; 369.
43. Zhang Q, Bastard P, Liu Z, Le Pen J, Chen J, Korol C. Inborn errors of type I IFN immunity
in patients with life-threatening COVID-19. Science 2020.
44. Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a
wide variety of human tissues. Infectious Diseases of Poverty 2020; 9:45.
45. Zhou Y, Fu B, Zheng X, Wang D, Zhao C. Pathogenic T cellls and inflammatory monocytes
incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev 2020; 7:998-1002.
46. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S. Imbalanced host response to SARS-
CoV-2 drives development of COVID-19. Cell 2020; 181:1036-1045.
47. Giamarellos-Bouboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A,
Antonakos N et al. Complex immune dysregulation in COVID-19 patients with severe
respiratory failure. Cell Host & Microbe 2020.
48. McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including
interleukin-6 in COVID-19 induces pneumonia and macrophage activation syndrome-like
disease. Autoimmunity Reviews 2020; 19:102537.
49. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z. Clinical course and risk factor for mortality of adult
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020.
50. Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of
JAK2 inhibitor Febratinib. J Microbiol Immunol Infect 2020.
51. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K. Complex immune
dysregulation in COVID-19 patients with severe respiratory failure. medRxiv 2020.
52. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19:
consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395:1033-
1034.
53. Qin C, Zhou L, Hu Z, Zhang S. Dysregulation of the immune response in patiens with
COID-19 in Wuhan, China. Lancet Infect Dis 2020.
54. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. 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.
55. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the "Cytokine Storm" in
COVID-19. J Infection 2020.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 27

 56. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020.
57. Tay MZ, Poh CM, Renia L, MacAry PA. The trinity of COVID-19: immunity, inflammation
and intervention. Nature Reviews 2020; 20:363-374.
58. Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular
dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med 2020;
46:1105-1108.
59. Bryce C, Grimes Z, Pujadas E, Ahuja S, Beasley MB, Albrecht R 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.
60. Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed.
Nature Reviews 2020.
61. Varga Z, Flammer AJ, Steiger P, Habrecker M, Andermatt R, Zinkernagel AS. Endothelial
cell infection and endotheliitis in COVID-19. Lancet 2020.
62. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T. Pulmonary vascular
endothelialitis, Thrombosis, and Angiogenesis in COVID-19. N Engl J Med 2020; 383:120-
128.
63. 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.
64. Torrealba JR, Fisher S, Kanne JP, Butt YM, Glazer C, Kershaw C. Pathology-radiology
correlation of common and uncommon computed tomographic patterns of organizing
pneumonia. Human Pathology 2018; 71:30-40.
65. Jeronimo CM, Farias ME, Almeida FF, Sampaio VS, Alexandre MA, Melo GC.
Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19
(Metcovid): A ramdomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect
Dis 2020.
66. Kanne JP, Little BP, Chung JH, Elicker BM. Essentials for radiologists on COVID-19: an
Update-Radiology Scientific Expert Panel. Radiology 2020.
67. Copin MC, Parmentier E, Duburcq T, Poissy J, Mathieu D. Time to consider histologic
pattern of lung injury to treat critically ill patietns with COVID-19 infection [letter].
Intensive Care Med 2020.
68. Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L. COVID-19 pneumonia:
different respiratory treatment for different phenotypes? Intensive Care Med 2020;
46:1099-1102.
69. Chiumello D, Cressoni M, Gattinoni L. Covid-19 does not lead to a "typical" Acute
Respiratory Distress syndrome. Lancet 2020.
70. Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care 2020;
24:154.
71. Gattinoni L, Pesenti A. The concept of "baby lung". Intensive Care Med 2005; 31(6):776-
784.
72. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians.
Am J Respir Crit Care Med 2020.
73. Schurink B, Roos E, Radonic T, Barbe E, Bouman CS. Viral presence and
immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.
Lancet Microbe 2020.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 28

 74. Buijsers B, Yanginlar C, Maciej-Hulme ML, de Mast Q. Beneficial non-anticoagulant
mechanisms underlying heparin treatment of COVID-19 patients. EBioMedicine 2020.
75. Kim SY, Jin W, Sood A, Montgomery DW, Grant OC, Fuster MM. Characterization of
heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2)
spike glycoprotein binding interactions. Antiviral Res 2020; 181:104873.
76. Clausen TM, Sandoval DR, Spliid CB, PiHl J, Painter CD, Thacker BE et al. SARS-CoV-2
infection depends on cellular heparan sulphate and ACE2. bioRxiv 2020.
77. Kwon PS, Oh H, Kwon SJ, Jin W, Zhang F, Fraser K et al. Sulphated polysaccharides
effectively inhibit SARS-CoV-2 in vitro. Cell Discovery 2020; 6:50.
78. Huang X, Han S, Liu x, Wang T, Xu H. Both UFH and NAH alleviate shedding of
endothelial glycocalyx and coagulopathy in LPS-induced sepsis. Exp Thera Med 2020;
19:913-922.
79. Buijsers B, Yanginlar C, de Nooijer A, Grondman I, Jonkman I, Rother N. Increased
plasma heparanase activity in COVID-19 patients. medRxiv 2020.
80. Barabutis N, Khangoora V, Marik PE, Catravas JD. Hydrocortisone and Ascorbic Acid
synergistically protect and repair lipopolysaccharide-induced pulmonary endothelial
barrier dysfunction. Chest 2017; 152:954-962.
81. 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.
82. May JM, Qu ZC. Ascorbic acid prevents oxidant-induced increases in endothelial
permeability. Biofactors 2011; 37:46-50.
83. Utoguchi N, Ikeda K, Saeki K, Oka N, Mizuguchi H, Kubo K et al. Ascorbic acid stimulates
barrier function of cultured endothelial cell monolayer. Journal of Cellular Physiology
1995; 163(2):393-399.
84. Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. Ascorbate protects
endothelial barrier function during septic insult: Role of protein phosphatase type 2A.
Free Radic Biol Med 2010; 48:128-135.
85. Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) for the treatment
of sepsis. Focus on ascorbic acid. Nutrients 2018; 10:1762.
86. Colunga Biancatelli RM, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert
Rev Anti Infect Ther 2020; 18:99-101.
87. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 2004; 1024:138-
146.
88. Shodell M, Siegal FP. Corticosteroids depress INF-alpha-producing plasmacytoid dentritic
cells in human blood. J Allergy Clin Immunol 2001; 108:446-448.
89. Thomas BJ, Porritt RA, Hertzog PJ, Bardin PG. Glucocorticosteroids enhance replication
of respiratory viruses: effect of adjuvant interferon. Scientific Reports 2014; 4:7176.
90. Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A. Corticosteroid
suppression of antiviral immunity increases bacterial loads and mucus production in
COPD exacerbations. Nature Communications 2018; 9:2229.
91. Liu J, Zheng X, Huang Y, Shan H, Huang J. Successful use of methylprednisolone for
treating severe COVID-19. J Allergy Clin Immunol 2020.
92. Salton F, Confalonieri P, Santus P, Harari S, Scala R, Lanini S et al. Prolonged low-dose
methylprednisolone in patients with severe COVID-19 pneumonia. Open Forum
Infectious Diseases 2020; 7:421.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 29

 93. Braude AC, Rebuck AS. Prednisone and methylprednisolone disposition in the lung.
Lancet 1983;995-997.
94. Draghici S, Nguyen TM, Sonna LA, Ziraldo C, Vanciu R, Fadel R et al. COVID-19: disease
pathways and gene expression chnages predict methylprednisolone can improve
outcome in severe cases. Bioinformatics 2020.
95. Shang L. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet 2020; 395:683.
96. Villar J, Confalonieri M, Pastores SM, Meduri GU. Rationale for prolonged corticosteroid
tratment in the acute respiratory distress syndrome (ARDS) caused by COVID-19. Crit
Care Expl 2020; 2:e0111.
97. Russell CD, Millar JE, Bailllie JK. Clinical evidence does not support corticosteroid
treatment for 2019-nCoV lung injury. Lancet 2020; 395:473-475.
98. Tang C, Wang Y, Lv H, Guan Z. Caution against corticosteroid-based COVID-19 treatment.
Lancet 2020; 395:1759-1760.
99. Effect of Dexamethasone in hospitalized patients with COVID-19. N Engl J Med 2021;
384:693-704.
100. Taboada M, Rodriguez N, Varela PM, Rodriguez MT, Casal A. Effect of high versus low
dose dexamethasone on clinical worsening in patients hospitalised with moderate or
severe COVID-19 pneumonia: an open-label, randomised clinical trial. Eur Resp J 2022.
101. Mora-Lujan JM, Tuells M, Montero A, Formiga F, Homs NA, Alba-Albalate J et al. High-
dose methylprednisolone pulses for 3 days vs. low dose dexamethasone for 10 days in
severe, non-critical COVID-19: A retrospective propensity score matched analysis. J Clin
Med 2021; 10:4465.
102. Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not
requiring ventilatory support (RECOVERY): a randomised, controlled, open-label,
platform trial. medRxiv 2022.
103. Sahraei Z, Panahi P, Afaghi S, Amirdosara M, Salamzadeh J. The efficacy of high-dose
pulse-therapy versus low-dose intravenous methylprednisolone on severe to critical
COVID-19 clinical outcomes: A randomized clinical trial study. Research Square 2022.
104. Salton F, Confalonieri P, Centanni S, Mondoni M, Petrosillo N, Meduri GU. Prolonged
higher dose methylprednisolone vs. conventional dexamethasone in COVID-19
pneumonia: a randomised controlled trial (MEDEAS). Eur Respir J 2023.
105. Corral-Gudino L, Cuascovich I, Martin-Gonzalez JI, Muela-Molinero A, Abadia-Otero J.
Effect of intravneous pulses of methylprednisolone 250 mg versus dexamethasome 6
mg in hospitalized adults with severe COVID-19 pneumonia: an open-label randomized
trial. Eur J Clin Invest 2023; 53:e13881.
106. Wu H, Daouk S, Kebbe J, Chaudry F, Harper J, Brown B. Low-dose versus high-dose
dexamethasone for hospitalized patietns with COVID-19 pneumonia: a randomized
clinical trial. PloS ONE 2022; 17:e0275217.
107. Saha AK, Das S, Biswas D, Sain B, Mitra M, Chakraborty R et al. Treatment outcome with
high versus low-to-moderate dosing of corticosteroids in early vis-a-vis late-onset
hypoxic cases of COVID-19: A multicentric retrospective cohort study. IJID Regions 2022.
108. Effect of 12mg vs 6 mg dexamethasone on the number of days alive without life support
in adults with COVID-19 and severe hypoxemia. The COVID STEROID 2 randomized Trila.
JAMA 2021; 326:1-11.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 30

 109. Granholm A, Munch MW, Myatra SN, Cronhjort M. Long-term outcomes of
dexamethasone 12mg versus 6 mg in patients with COVID-19 and severe hypoxaemia.
Intensive Care Med 2022; 48:680-689.
110. Joshi S, Smith Z, Soman S, Jain S, Yako A. Low-versus high-dose methylprednisolone in
adult patients with coronavirus disease 2019: Less is more. Open Forum Infectious
Diseases 2022.
111. Les I, Loureiro-Amigo J, Capdevila F, Oriol I, Elejalde I, Modesto J et al.
Methylprednisolone pulses in hospitalized COVID-19 patients without respiratory
failure: A randomized controlled trial. Frontiers in Medicine 2022; 9:807981.
112. Ruiz-Irastorza G, Pijoan JI, Bereciatua E, Dunder S, Dominguez J, Garcia-Escudero P.
Second week methyl-prednisolone pulses improve prognosis in patients with severe
coronavirus disease 2019 pneumonia: An observational comparative study using routine
care data. PloS ONE 2020; 15:e0239401.
113. Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S. Intravenous
methylprednisolone pulse as a treatment for hospitalized severe COVID-19 patients:
results from a randomised controlled clinical trial. Eur Respir J 2020; 56:2002808.
114. Cusacovich I, Aparisi A, Marcos M, Lopez-Veloso M. A comparison of
methylprednisolone and dexamethasone in intensive care patients with COVID-
19Corticosteroid pulses for hospitalized patients with COVID-19:effects on mortality.
Mediators of Inflammation 2021; 2021:6637227.
115. Dafni M, Karampeli M, Michelakis I, Manta A, Spanoudaki A, Mantzos D. Treatment with
3-day methylprednisolone pulses in severe cases of COVID-19 compared with the
standard regimen protocol of dexamethasone. J Investig Med 2022.
116. Et T, Korkusuz M, Yarimoglu R. Different dose corticosteroid treatment protocols for
COVID-19 patients admitted to intensive care: Comparison of the effects on efficacy and
mortality. J Crit Intensive Care 2022; 13:84-89.
117. Al Sulaiman K, Korayem GB, Eljaaly K, Altebainawi AF, Al HArbi O, Badreidin HA. Early
dexamethasone use as a protective measure in non-mechanically ventilated critically ill
patients with COVID-19: a multicenter, cohort study. Scientific Reports 2023; 12:9766.
118. Ranjbar K, Shahriarad R, erfani A, Khodamoradi Z, Saadi MH. Methylprednisolone or
dexamethasone, which one is the superior corticosteroid in the treatment of
hospitalized COVID-19 patients: A triple-blinded randomized controlled trial. BMC Infect
Dis 2021; 21:337.
119. Ko JJ, Wu C, Mehta N, Wald-Dickler N, Yang W. A comparison of methylprednisolone
and dexamethasone in intensive care patients with COVID-19. J Intensive Care Med
2021; 36:673-680.
120. Gutam PB, Kumar A, Kannoujia BL, Chaudhary R. A comparative study of the efficacy and
outcome of methylprednisolone and dexamethasone in moderate to severe COVID-19
disease. Asian Journal of Medical Sciences 2021; 12:17-22.
121. Niaee MS, Gheibl N, Namdar P, Allami A, Javadi A. Ivermectin as an adjunct treatment
for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial.
Research Square 2020.
122. Alam MT, Murshed R, Bhiuyan E, Saber S, Alam RF, Robin RC. A case series of 100
COVID-19 positive patients treated with combination of Ivermectin and Doxycycline.
Bangladesh Coll Phys Surg 2020; 38:10-15.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 31

 123. Chowdhury AT, Shahabz M, Karim MR, Islam J, Guo D, He D. A randomized trial of
ivermectin-doxycycline and hydrochloroquine-azithromycin therapy on COVID-19
patients. Research Square 2020.
124. Kory P, Meduri GU, Iglesias J, Varon J, Berkowitz K, Wagshul F 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.
125. Chamie-Quintero JJ, Hibberd JA, Scheim DE. Ivermectin for COVID-19 in Peru: 14-fold
reduction in nationwide excess deaths, p=0.002 for effect by state, then 13-fold increase
after ivermectin use restricted. medRxiv 2021.
126. Hazan S, Dave S, Gunaratne AW, Dolai S, Clancy RL, McCullough PA et al. Effectiveness of
ivermectin-based multidrug therrapy in severe hypoxic ambulatory COVID-19 patients.
medRxiv 2021.
127. Bryant A, Lawrie TA, Dowswell T, Fordham E, Mitchell S, Hill SR et al. Ivermectin for the
prevention and treatment of COVID-19 infection: a systematic review and meta-analysis.
Lancet 2021.
128. Hill A, Garratt A, Levi J, Falconer J, Ellis L, McCann K et al. Meta-analysis of randomized
trials of ivermectin to treat SARS-CoV-2 infection. Open Forum Infectious Diseases 2021.
129. DiNicolantonio JJ, Barroso-Aranda J, McCarty MF. Anti-inflammatory activity of
ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors.
Open Heart 2021; 8:e001655.
130. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N
Engl J Med 2021; 389:790-802.
131. BenAbdallah S, Mhalla Y, Trebeisi I, Sekma A, Youssef R, Soltane HB et al. Twice-dailey
oral zinc in the treatment of patients with Coronavirus Disease 2019: a randomized
double-blind controlled trial. Clin Infect Dis 2022.
132. Gandolfi JV, Di Bernardo AP, Chanes DA, Martin DF, Joles VB, Amendola CP 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.
133. Castillo RR, Quizon GR, Juco MJ, Roman AD, de Leon DG, Punzalan FE et al. Melatonin as
adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring
hospitalization (MAC-19 PRO): a case series. Melatonin Res 2021; 3:297-310.
134. Ramiall V, Zucker J, Tatonetti N. Melatonin is significantly associated with survival of
intubated COVID-19 patients. medRxiv 2021.
135. Farnoosh G, Akbaariqomi M, Badri T, Bagheri M, Izadi M. Efficacy of a low dose of
melatonin as an adjunctive therapy in hospitalized patients with COVID-19: A
randomized, double-blind clinical trial. medRxiv 2021.
136. Hasan ZT, AlAtrakji MQ, Mehuaiden AK. The effect of melatonin on thrombosis, sepsis
and mortality rate in COVID-19 patients. International Journal of Infectious Diseases
2022; 114:79-84.
137. Farnoosh G, Akbariqomi M, Badri T, Bagheri M, Izadi M, rezaie E. Efficacy of a low dose
of melatonin as an adjunctive therapy in hospitalized patietns with COVID-19: A
randomized, double-blind clinical trial. Archives of Medical Research 2021.
138. Darban M, Malek F, Memarian M, Gohari A, Kiani A, Emadi A. Efficacy of high dose
vitamin C, melatonin and zinc in Iranian patients with acute respiratory sydrome due to
Coronavirus infection: A pilot randomized trial. Journal of Cellular & Molecular
Anesthesia 2021; 6:164-167.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 32

 139. Blum VF, Cimerman S, Huneter JR, Tierno P, Lacerda A, Soeiro A. Nitazoxanide
superioroty to placebo to treat moderate COVID-19 - A pilot prove of concept
randomized double-blind clinical trial. EClinicalMedicine 2021; 37:100981.
140. Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-hydroxylation of
vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin
Nutr 2008; 87:1738-1742.
141. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF. Effect of vitamin D3
supplementaion vs placebo on hospital length of stay in patients with severe COVID-19:
A multicenter, double-blind, randomized controlled trial. JAMA 2020.
142. Castillo ME, Costa LM, Barrios JM, Diaz JF, Miranda JL, Bouillon R et al. Effect of
calcifediol treatment and best available therapy versus best available therapy on
intensive care unit admission and mortality among patients hospitalized for COVID-19: a
pilot randomized clinical study. J Steroid Biochem Mol Biol 2020; 203:105751.
143. Loucera C, Pena-Chilet M, Esteban-Medina M, Villegas R, Lopez-Miranda J. Real world
evidence of calcifediol use and mortality rate of COVID-19 hospitalized in a large cohort
of 16,401 Adalusian patients. medRxiv 2021.
144. Nogues X, Overjero D, Pineda-Moncus M, Bouillon R. Calcifediol treatment and COVId-
19-related outcomes. medRxiv 2021.
145. Loucera C, Pena-Chilet M, Esteban-Medina M, Villegas R, Tunez I. Real world evidence of
calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective
cohort of hospitalized Andalusian patients. Scientific Reports 2021; 11:23380.
146. Henriquez MS, de Tejada Romero MJ. Cholecalciferol or calcifediol in the management
of vitamin D deficiency. Nutrients 2020; 12:1617.
147. Elamir YM, Amir H, Lim S, Rana Y, Lopez CG, Omar A. A randomized pilot study using
calcitriol in hospitalized patients. Bone 2022; 154:116175.
148. Hottz ED, Azevedo-Quintanilha Ig, Palhinha L, Teixeira L, Barreto EA. Platelet activation
and platelet-monocyte aggregate formation trigger tissue factor expression in patients
with severe COVID-19. Blood 2020; 136:1330-1341.
149. Barrett TJ, Lee AH, Xia Y, Lin LH, Black M, Cotzia P. Platelet and vascular biomarkers
associate with thrombosis and death in coronavirus disease. Circulation Research 2020;
127:945-947.
150. Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y. SARS-CoV-2 binds platelet ACE2 to enhance
thrombosis in COVID-19. Journal of hematology & oncology 2020; 13:120.
151. Cloutier N, Allaeys I, Marcoux G, Machius KR, Mailhot B. Platelets release pathogenic
serotonin and return to circulation after immune complex-mediated sequestration.
PNAS 2018;E1550-E1559.
152. De Flora S, Balansky R, La Maestra S. Rationale for the use of N-acetylcysteine in both
prevention and adjuvant therapy of COVID-19. FASEB J 2020.
153. Shi Z, Puyo CA. N-Acetylcysteine to combat COVID-19: an evidence review. Therapeutics
and Clinical Risk Management 2020; 16:1047-1055.
154. Assimakopoulos SF, Aretha D, Kominos D, Dimitropoulou D, Lagadinou M. N-acetyl-
cysteine reduces the risk for mechanical ventilation and mortality in patients with
COVID-19 pneumonia: a two-center retrospective cohort study. Infectious Diseases
2021; 53(11):847-854.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 33

 155. Kumar P, Osahon O, Vides DB, Hanania N, Minard CG. Severe glutathione deficiency,
oxidative stress and oxidant damage in adults hospitalized with COVID-19: implications
for GlyNac (Glycine and N-acetylcysteine) supplementaion. Antioxidants 2022; 11(50).
156. Izquierdo JL, Soriano JB, Gonzalez Y, Lumbreras S. Use of N-Acetylcysteine at high doses
as an oral treatment for patients with COVID-19. Science Progress 2022; 105.
157. Calusic M, Marcec R, Luksa L, Jurkovic I, Kovac N, Likic R. Safety and efficacy of
fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with
matched controls. Br J Clin Pharmacol 2021.
158. Reis G, Moreira-Silva EA, Silva DC, Thabane L, Guyatt GH, Mills EJ. Effect of early
treatment with fluvoxamine on risk of emergency care and hospitalization among
patients with COVID-19: the TOGETHER randomized, platform clinical trial. Lancet Glob
Health 2021.
159. Sukhatme VP, Reiersen AM, Vayttaden SJ, Sukhatme VV. Fluvoxamine: A review of its
mechanism of action and its role in COVID-19. Fronteirs in Pharmacology 2021;
12:652688.
160. Oskotsky T, Maric I, Tang A, Oskotsky B, Wong RJ, Sirota M. Mortality risk among
patients with COVID-19 prescribed selective serotonin reuptake inhibitor
antidepressants. JAMA Network Open 2021; 4:e2133090.
161. Breggin PR. Fluvoxamine as a cuase of stimulation, mania and agression with a critical
analysis of the FDA-approved label. International Journal of Risk & Safety Mediciine
2001; 14:71-86.
162. McCoy J, Goren A, Cadegiani FA, Vano-Galvan S, Kovacevic M, Situm M et al.
Proxalutamide reduces the rates of hospitalization for COVID-19 male outpatients: A
randomized double-blinded placebo-controlled trial. Front Med 2021; 8:668698.
163. Cadegiani FA, McCoy J, Zimerman A, Mirza FN, Barros RN. Efficacy of proxalutamide in
hospitalized COVID-19 patients: A randomized, double-blind, placebo-controlled,
parallel-design clinical trial. medRxiv 2021.
164. Cadegiani FA, McCoy J, Wambier CG, Goren A. Early antiandrogen therapy with
dutasteride reduces viral shedding, inflammatory responses, and time-to remission in
males with COVID-19: A randomized, double-blind, placebo-controlled interventional
trial (EAT-DUTA AndroCoV Trial- Biochemical). Cureus 2021.
165. Freedberg DE, Conigliaro J, Sobieszczyk ME, Markowitz DD. Famotidine use is associated
with impoved clinical outcomes in hospitalized COVID-19 patients: A propensity score
matched retrospective cohort study. medRxiv 2020.
166. Janowitz T, Baglenz E, Pattinson D, Wang TC, Conigliaro J. Famotidine use and
quantitative symptom tracking for COVID-19 in non-hospitalized patients: a case series.
Gut 2020; 69:1592-1597.
167. Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of
hospitalized COVID-19 patients. Am J Gastroenterol 2020.
168. Malone RW, Tisdall P, Fremont-Smith P, Liu Y, Huang XP, White KM. COVID-19:
Famotidine, Histamine, Mast Cells, and mechanisms. Research Square 2020.
169. Sethia R, Prasad M, Mahapatra SJ, Nischal N, Soneja M. Efficacy of famotidine for
COVID-19: A systematic review and meta-analysis. medRxiv 2020.
170. Shoaibi A, Fortin S, Weinstein R, Berlin JA. Comparative effectiveness of famotidine in
hospitalized COVID-19 patients. medRxiv 2020.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 34

 171. Yeramaneni S, Doshi P, Sands K, Cooper M, Kurbegov D, Fromell G. 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.
172. Jalali F, Rezaie S, Rola P, Kyle-Sidell C. COVID-19 pathophysiology: Are platelets and
serotonin hiding in plain sight? ssrn 2021.
173. Lin OA, Karim ZA, Vemana HP, Espinosa EV, Khasawneh FT. The antidepressant 5-HT2a
receptor antagonists Pizotifen and cyproheptadine inhibit serotonin-enhanced platelet
function. PloS ONE 2014; 9:e87026.
174. Zaid Y, Guessous F, Puhm F, Elhamdani W, Chentoufi L, Morris AC. Platelet reactivity to
thrombin differs between patients with COVID-19 and those with ARDS unrelated to
COVID-19. Blood Advances 2021; 5:635-639.
175. Zaid Y, Puhm F, Allaeys I, Naya A, Oudghiri M. Platelets can associate with SARS-CoV-2
RNA and are hyperactivated in COVID-19. Circ Res 2020; 127:1404-1418.
176. Dawson C, Christensen CW, Rickaby DA, Linehan JH, Johnston MR. Lung damage and
pulmonary uptake of serotonin in intact dogs. J Appl Physiol 1985; 58:1761-1766.
177. MacLean MR, Herve P, Eddahibi S, Adnot S. 5-hydroxytryptamine and the pulmonary
circulation: receptors, transporters and the relevance to pulmonary arterial
hypertension. Br J Pharmacol 2000; 131:161-168.
178. Blackshear JL, Orlandi C, Hollenberg NK. Constrictive effect of serotonin on visible renal
arteries: a pharmacoangiographic study in anesthetized dogs. J Cardiovasc Pharmacol
1991; 17:68-73.
179. Watchorn J, Hang DY, Joslin J, Bramham K, Hutchings SD. Critically ill COVID-19 patients
with acute kidney injury have reduced renal blood flow and perfusion despite preserved
cardiac function: A case-control study using contrast enhanced ultrasound. Lancet Resp
Med 2021.
180. McGoon MD, Vanhoutte PM. Aggregating platelets contract isolated canine pulmonary
arteries by releasing 5-hydroxytryptamine. J Clin Invest 1984; 74:823-833.
181. Almqvist P, Skudder P, Kuenzig M, Schwartz SI. Effect of cyproheptadine on endotoxin-
induced pulmonary platelet trapping. Am Surg 1984; 50:503-505.
182. Skurikhin EG, Andreeva TV, Khnelevskaya ES, Ermolaeva LA, Pershina OV, Krupin VA.
Effect of antiserotonin drug on the development of lung fibrosis and blood system
reactions after intratracheal administration of bleomycin. Bull Exp Biol Med 2012;
152:519-523.
183. Doaei S, Gholami S, Rastgoo S, Bourbour F, Ghorat F, Joola P. The effect of omega-3 fatty
acid supplementation on clinical and biochemical parameters of critically ill patients
with COVID-19: a randomized clinical trial. J Transl Med 2021; 19:128.
184. Spinelli FR, Conti F, Gadina M. HiJAKing SARS-C0V-2? The potential role of JAK inhibitors
in the management of COVID-19. Sci Immunol 2020; 5:eabc5367.
185. Chen CX, Wang JJ, Li H, Yuan LT, Gale RP. JAK-inhibitors for coronavirus disease-2019
(COVID): a meta-analysis. Leukemia 2021.
186. Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V. Efficacy and safety of
baricitinib for the treament of hospitalized adults with COVID-19 (COV-BARRIER): a
randomised, double-blind,parallel-group, placebo-controlled phase 3 trial. Lancet Resp
Med 2021.
187. Pan H, Peto R, Karim QA, Alejandria M, Henao-Restrepo AM. Repurposed antiviral drugs
for COVID-19 - interim WHO SOLIDARITY trial. medrx 2020.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 35

 188. Ohl ME, Miller DR, Lund BC, Kobayashi T, Miell KR. Association of remdesivir treatment
with survival and length of hospital stay among US veterans hospitalized with COVID-19.
JAMA Network Open 2021; 4:e2114741.
189. Ader F, Hites M, Poissy J, Belhadi D, Diallo A, Staub T. Remdesivir plus standard of care
versus standard of care alone for the treatment of patients admitted to hospital with
COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect
Dis 2021.
190. Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Pollak U. Colchicine poisoning:
the dark side of an acient drug. Clinical Toxicology 2010; 48:407-414.
191. Fowler AA, Truwit JD, Hite D, Morris PE, DeWilde C, Priday A et al. Vitamin C Infusion for
TReatment In Sepsis-Induced Acute Lung Injury- CITRIS-ALI: A Randomized, Placebo
Controlled Clinical Trial. JAMA 2018; 322:1261-1270.
192. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C and
Thiamine for the treatment of severe sepsis and septic shock: A retrospective before-
after study. Chest 2017; 151:1229-1238.
193. Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol
Therapeut 2018; 189:63-70.
194. Cheng RZ. Can early and high-dose vitamin C prevent and treat coronavirus disease 2019
(COVID-19). Medicine in Drug Discovery 2020.
195. Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of
critically ill patients: a meta-analysis. Ann Intensive Care 2019; 9:58.
196. Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute
respiratory distress syndrome. PharmaNutrition 2020; 12:100190.
197. Iglesias J, Vassallo AV, Patel V, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic
resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of
sepsis. Chest 2020; 158:164-173.
198. Hiedra R, Lo KB, Elbashabsheh M, Gul F, Wright RM. The use of IV vitamin C for patients
with COVID-19: a case series. Exp Rev Anti Infect Ther 2020.
199. Zhang J, Rao X, Li Y, Zhu Y, Liu G, Guo G et al. High-dose vitamin C infusion for the
treatment of critically ill COVID-19. Research Square 2020.
200. Kumari P, Dembra S, Dembra P, Bhawna F, Gul A, Ali B. The role of vitamin C as adjuvant
therapy in COVID-19. Cureus 2020; 12:e11779.
201. Al Sulaiman K, Al Juhani O, Badreldin HA, Salah KB, Alharbi A, Arabi YM. Adjunctive
therapy with ascorbic in critically ill patients with COVID-19: A multicenter propensity
score matched study. Crit Care 2021.
202. Lankadeva YR, Peiris RM, Okazaki N, Birchall IE, Doenom A, Evans RG et al. Reversal of
the pathophysiological responses to Gram-negative sepsis by megadose Vitamin C. Crit
Care Med 2020.
203. Zhang J, Rao X, Li Y, Zhu Y, Liu G, Guo G et al. Pilot trial of high-dose vitamin C in critically
ill COVID-19 patients. Ann Intenisve Care 2020.
204. Lavinio A, Ercole A, Battaglini D, Magnoni S, Badenes R, Thomas W et al. Safety profile of
enhanced thromboprophylaxis strategies for critically ill COVID-19 patients during the
first wave of the pandemic: observational report from 28 European intensive care units.
Crit Care 2021; 25:155.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 36

 205. 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.
206. Tomassa-Irriguible TM, Lielsa-Berrocal L. COVID-19: Up to 87% critically ill patients had
low vitamin C values. Research Square 2020.
207. 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.
208. Lopes RD, Furtado RH, Bronhara B, Damiani LP, Barbosa LM. Therapeutic versus
prophylactic anticoagulation for patients admitted to hospital with COVID-19 and
elevated D-dimer concentraion (ACTION): an open-label, multicentre, randomised,
controlled trial. Lancet 2021; 397:2253-2263.
209. Kalfas S, Visvanathan K, Chan K, Drago J. The therapeutic potential of ivermectin for
COVID-19: A systematic review of mechanisms and evidence. medRxiv 2020.
210. Menezes RR, Godin AM, Rodrigues FF, Coura GM, Melo IS, Brito AM. 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; 69:1036-1043.
211. Vatsalya V, Li F, Frimodig J, Gala KS, Srivastava S, Kong M. 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.
212. Mallat J, Lemyze M, Thevenin D. Do not forget to give thiamine to your septic shock
patient! J Thorac Dis 2016; 8:1062-1066.
213. Moskowitz A, Donnino MW. Thiamine (vitamin B1) in septic shock: a targeted therapy. J
Thorac Dis 2020; 12 (suppl 1):S78-S83.
214. Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of
thiamine administration on lactate clearance and mortality in patients with septic shock.
Crit Care Med 2018; 46:1747-1752.
215. Marik PE. Thiamine: An essential component of the metabolic resuscitation protocol.
Crit Care Med 2018; 46:1869-1870.
216. Al Sulaiman K, Aljuhani O, Al Dossari M, Alshahrani A, Alharbi A. Evaluation of thiamine
as adjunctive therapy in COVID-19 critically ill patients: A multicenter propensity score
matched study. Research Square 2021.
217. Zarehoseinzade E, Allami A, Ahmadi M, Bijani B. Finasteride in hospitalized adult males
with COVID-19: A risk factor for severity of the disease or an adjunct treatment: A
randomized controlled clinical trial. Medical Journal of the Islamic Republic of Iran 2021;
35:30.
218. Chen L, Jiang X, Huang L, Lan K, Wang H, Hu L et al. Bioequivalence of a single 10-mg
dose of finasteride 5-mg oral disintegrating tablets and standard tablets in healthy adult
male Han Chinese volunteers: A randomized sequence, open-label, two-way crossover
study. Clinical Therapeutics 2009; 31:2242-2248.
219. Tan CW, Ho LP, Kalimuddin S, Cherng BP, Teh YE. 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.
220. Lee CY, Jan WC, Tsai PS, Huang CJ. Magnesium sulfate mitigates acute lung injury in
endotoxemia rats. J Trauma 2011; 70:1177-1185.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 37

 221. Salem M, Kasinski N, Munoz R, Chernow B. Progressive magnesium deficiency inceases
mortality from endotoxin challenge:Protective effects of acute magnesium replacement
therapy [abstract]. Crit Care Med 1995;A260.
222. Jiang P. Does hypomagnesemia impact on the outcome of patients admitted to the
intensive care unit? A systematic review and meta-analysis. Shock 2019; 47:288-295.
223. Duarte M, Pelorosso F, Nicolosi L, Salgado V, Vetulli H. Telmisartan for treatment of
COVID-19 patients: an open multicenter randomized clinical trial. EClinicalMedicine
2021; 37:100962.
224. Rothlin RP, Vetulli HM, Duarte M, Pelorosso FG. Telmisartan as tentative angiotensin
receptor blocker therapeutic for COVID-19. Drug Dev Res 2020; 81:768-770.
225. Nejat R, Sadr AS, Freitas BT, Murray J, Pegan SD. Losartan inhibits SARS-CoV-2
replication in vitro. J Pharm Pharm Sci 2021; 24:390-399.
226. Patterson BK, seethamraju H, Dhody K, Corley MJ, Kazempour K, Lalezari J et al. CCR5
inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8
T-cells, and deceases SARS-CoV2 RNA in plasma by day 14. International Journal of
Infectious Diseases 2021; 103:25-32.
227. Patterson BK, Guevara-Coto J, Yogendra R, Francisco E, Long E, Pise A. Immune-based
prediction of COVID-19 severity and chronicity decoded using machine learning. Front
Immunol 2021.
228. Li S, Jiang L, Li X, Lin F, Wang Y, Li B. Clinical and pathological investigation of patients
with severe COVID-19. JCI Insight 2020; 5:e138070.
229. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnager T. 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.
230. Simonovich VA, Pratx LD, Scibona P, Beruto MV, Vallone MG. A randomized trial of
convalescent plasma in COVID-19 severe pneumonia. N Engl J Med 2020.
231. Avendano-Sola C, Ramos-Martinez A, Munez-Rubio E, Ruiz-Antoran B, de Molina RM.
Convalescent plasma for COVID-19: A multicenter, randomized clinical trial. medRxiv
2020.
232. Balcells ME, Rojas L, Le Corre N, Ceballos ME, Ferres M, Chang M. Early versus deferred
anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized
phase II clinical trial. PLOS Med 2021; 18:e1003415.
233. Janiaud P, Axfors C, Schmitt AM, Glory V, Moher D. Association of convalescent plasma
treatment with clinical outcomes in patients with COVID-19. A systematic review and
meta-analysis. JAMA 2021.
234. Li L, Zhang W, Hu Y, Tong X, Zeng S, Yang J. 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.
235. Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria Jurnal
2003; 3 (Suppl I):S8.
236. Thompson MA, Henderson JP, Shah PK, Rubenstein SM, Joyner MJ, Flora DB.
Convalescent plasma and improved survival in patients with hematologic malignancies
and COVID-19. medRxiv 2021.
237. Westendorf K, Zentelis S, Wang L, Foster D, Wiggin M, Lovett E. LY-CoV1404
(bebtelovimab) potently neuralizes SARS-CoV-2 variants. bioRxiv 2022.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 38

 238. Rosas IO, Brau N, Waters M, Go R, Hunter BD, Bhagani S et al. Tocilizumab in
hospitalized patients with COVID-19 pneumonia. medRxiv 2020.
239. Hermine O, Mariette X, Tharaux PL, Resche-Rignon M, Porcher R. 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.
240. Stone JH, Frigault MJ, Sterling-Boyd NJ, Fernandes AD, Harvey FL. Efficacy of tocilizumab
in patients hospitalized with Covid-19. N Engl J Med 2020.
241. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S. Effect of tocilizumab vs standard
care on clinical worsening in patients hospitalized with COVID-19 pneumonia. A
randomized clinical trial. JAMA Intern Med 2020.
242. Salama C, Han J, Yau L, Reiss WG, Kramer B. Tocilizumab in patients hospitalized with
Covid-19 pneumonia. N Engl J Med 2020.
243. Jeffreys L, Pennington SH, Duggan J, Breen A, Jinks J. Remdesivir-Ivermectin combination
displays synergistic interactions with improved in vitro antiviral activity against SARS-
CoV-2. bioRxiv 2020.
244. Gordon AC, Mouncey PR, Rowan KM, Nichol AD, Arabi YM, Annane D. Interleukin-6
receptor antagonists in critically ill patients with COVID-19 - Preliminary report. medRxiv
2021.
245. Bassetti M, Kollef MH, Timsit JF. Bacterial and fungal superinfections in critically ill
patients with COVID-19. Intensive Care Med 2020.
246. Rawson TM, Wilson RC, Holmes A. Understanding the role of bacterial and fungal
infection in COVID-19. Clinical Microbiology & Infection 2021; 27:9-11.
247. Le Balc'h P, Pinceaux K, Pronier C, Seguin P, Reizine F. Herpes simplex virus and
cytomegalovirus reactivations among severe COVID-19 patients. Crit Care 2020; 24:530.
248. Koehler P, Bassetti M, Chen SC, Colombo AL, Perfect JR. Defining and managing COVID-
19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for
research and clinical guidance. Lancet Infect Dis 2021.
249. Ospina-Tascon GA, Calderon-Tapia LE, Garcia AF, Zarama V, Vargas MP, Vaaron J. Effect
of high-flow oxygen therapy vs conventional oxygen therapy on invasive mechanical
ventilation and clinical recovery in patients with severe COVID-19. A randomized clinical
trial. JAMA 2021; 326:2161-2171.
250. Xu Q, Wang T, Quin X, Zha L. Early awake prone position combined with high-flow nasal
oxygen therapy in severe COVID-19; a case series. Crit Care 2020; 24:250.
251. Elharrar X, Trigui Y, Dois AM, Touchon F. Use of prone positioning in nonintubated
patients with COVID-19 and hypoxemic acute respiratory failure. JAMA 2020.
252. Reddy MP, Subramaniam A, Afroz A, Billah B, Lim ZJ, Wong SN. Prone positioning of
nonintubated patients with Coronavirus Disease 2019- A systematic review and meta-
analysis. Crit Care Med 2021.
253. Xin Y, Martin K, Morais CC, Gerard SE, Abate N, Sidhu U et al. Diminishing efficacy of
prone positioning with late application in evolving lung injury. Crit Care Med 2021.
254. Haymet A, Bassi GL, Fraser JF. Airborne spread of SARS-CoV-2 while using high-flow
nasal cannula oxygen therapy: myth or reality. Intensive Care Med 2020; 46:2248-2251.
255. Winslow RL, Zhou J, Windle EF, Nur I, Lall R, Ji C. SARS-CoV-2 environmental
contamination from hospitalized patients with COVID-19 receiving erosol-generating
procedures. Thorax 2021.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 39

 256. Francone M, Lafrate F, Masci GM, Coco S, Cilia F, Manganaro L et al. Chest CT score in
COVID-19 patients: correlation with disease severity and short-term prognosis.
European Radiology 2020; 30:6808-6817.
257. Parry AH, Wani AH, Shah NN, Yaseen M, Jehangir M. Chest CT features of coronavirus
disease-19 (COVID-19) pnemonia: which findings on initial CT can predict an adverse
short-term outcome? BJR Open 2020; 2:20200016.
258. Zhang J, Meng G, Li W, Shi B, Dong H, Su Z. Relationship of chest CT score with clinical
characteristics of 108 patients hospitalized with COVID-19 in Wuhan, China. Respiratory
Research 2020; 21:180.
259. Yang R, Li X, Liu H, Zhen Y, Zhang X, Xiong Q et al. Chest CT severity score: An imaging
tool for assessing severe COVID-19. Radiology: Cardiothoracic Imaging 2020;
2:e2000047.
260. Li K, Wu J, Wu F, Guo D, Cen L, Fang Z et al. The clinical and chest CT features associated
with severe and critical COVID-19 pneumonia. Investigative Radiology 2020; 55:1-5.
261. Pan F, Ye T, Sun P, Gui S, Liang B, Li L. Time course of lung changes at Chest CT during
recovery from Coronavirus Disease 2019 (COVID-19). Radiology 2021; 295:715-721.
262. Ding X, Xu J, Zhou J, Long Q. Chest CT findings of COVID-19 pneumonia by duration of
symptoms. European Journal of Radiology 2020; 127:109009.
263. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N et al. Chest CT findings in
Coronavirus disease 2019 (COVID-19): relationship to duration of infection. Radiology
2020; 295:685-691.
264. Ichikado K, Suga M, Muranka H, Gushima Y, Miyakawa H. Prediction of prognosis for
acute respiratory distress syndrome with thin-section CT: Validation in 44 cases.
Radiology 2006; 238:321-329.
265. Ichikado K, Suga M, Muller NL, Tangiguchi H, Kondoh Y, akira M. Acute interstitial
pneumonia. Comparison of high-resolution computed tomography findings between
survivors and nonsurvivors. Am J Respir Crit Care Med 2002; 165:1551-1556.
266. Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel treatment approach to the
novel coronavirus: an argument for the use of therapeutic plasma exchange for
fulminant COVID-19. Crit Care 2020; 24:128.
267. Keith P, Wells AH, Hodges J, Fast SH. The therapeutic efficacy of adjunct therapeutic
plasma exchange for septic shock with multiple organ failure: A single center
experience. Crit Care 2020; 24:518.
268. Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and
septic shock: a prospective, randomised, controlled trial. Intensive Care Med 2002;
28:1434-1439.
269. Morath C, Weigand MA, Zeier M, Speer C, Tiwari-Heckler S. Plasma exchange in critically
ill COVID-19 patients. Crit Care 2020; 24:481.
270. Khamis F, Al-Zakwani I, Al Hashmi S, Al Dowaiki S, Al Bahrani M. Therapeutic plasma
exchange in adults with severe COVID-19 infection. Int J Infect DIs 2020; 99:214-218.
271. Fernandez J, Gratacos-Gines J, Olivas P, Costa M, Nieto S, Mateo D. Plasma exchange: An
effective rescue therapy in critically ill patients with Coronavirus Disease 2019 infection.
Crit Care Med 2020.
272. Gucyetmez B, Atalan HK, Sertdemir I, Cakir U, Telci L. Therapeutic plasma exchange in
patients with COVID-19 pneumonia in intensive care unit: a retrospective study. Crit
Care 2020; 24:492.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 40

 273. Poor HD, Ventetuolo CE, Tolbert T, Chun G, Serrao G. COVID-19 critical illness
pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial
dysfuncion responsive to thrombolysis. medRxiv 2020.
274. Wang J, Najizadeh N, Moore EE, McIntyre RC, Moore PK, Veress LA. Tissue plasminogen
activator (tPA) treatment for COVID-19 associated respiratory distress syndrome (ARDS):
A case series. J Thromb Haemost 2020.
275. Abou-Arab O, Huette P, Debouvries F, Dupont H, Jounieaux V. Inhaled nitric oxide for
critically ill Covid-19 patients: a prospective study. Crit Care 2020; 24:645.
276. Bagate F, Tuffet S, Masi P, Perier F, Razazi K. Rescue thearpy with inhaled nitric oxide
and almitrine in COVID-19 patients with severe acute respiratory distress syndrome.
Ann Intensive Care 2020.
277. Caplan M, Goutay J, Bignon A, Jaillette E, Favory R. Almitrine infusion in severe acute
respiratory syndrome coronavirus-2 indued acute respiratory distress syndrome: A
single-center observational study. Crit Care Med 2020.
278. Payen D. Coronavirus disease 2019 acute respiratory failure: Almitrine drug resuscitaion
or resuscitating patients by almitrine? Crit Care Med 2020.
279. 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.
280. Abrams D, Lorusso R, Vincent JL, Brodie D. ECMO during the COVID-19 pandemic: when
is it unjustified. Crit Care 2020; 24:507.
281. Supady A, Taccone FS, Lepper PM, Ziegeler S, Staudacher DL. Survival after
extracorporeal membrane oxygenation in severe COVID-19 ARDS: results from an
international multicenter registry. Crit Care Med 2021; 25:90.
282. Barbaro RP, MacLaren G, Boonstra PS, Iwashyna TJ, Slutsky AS. Extracorporeal
membrane oxygenation support in COVID-19: an international cohort study of the
Extracorporeal Life Support Organization registry. Lancet 2020.
283. Cypel M, Keshavjee S. When to consider lung transplantation for COVID-19. Lancet Resp
Med 2021; 8:944-946.
284. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J
Med 2020.
285. Cerutti A, Chen K, Chorny A. Immunoglobulin responses at the mucosal interface. Annu
Rev Immunol 2011; 29:273-293.
286. Jacobs JJ. Neutralizing antibodies mediate virus-immue pathology of COVID-19. Med
Hypotheses 2020; 143:109884.
287. Seifirad S. Pirfenidone: A novel hypothetical treatment for COVID-19. Medical
Hypotheses 2020; 144:11005.
288. Saba A, Vaidya PJ, Chavhan VB, Achlerkar A, Leuppi J. Combined pirfenidone,
azithromycin and prednisolone in post-H1N1 ARDS pulmonary firbosis. Sarcoidosis Vasc
Diffuse Lung Dis 2018; 35:85-90.
289. Spagnolo P, Balestro E, Aliberti S, Cocconcelli E, Biondini D, Casa GD. Pulmonary fibrosis
secondary to COVID-19: a call to arms? Lancet Resp Med 2020; 8:750-752.
290. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role
for antibibrotic therapy. Lancet Resp Med 2020; 8:807-815.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 41

 291. Brouwer WP, Duran S, Kuijper M, Inc C. 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.
292. Villa G, Romagnoli S, De Rosa S, Greco M, Resta M. 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.
293. Ahmad Q, DePerrior SE, Dodani S, Edwards JF, Marik PE. 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; 60:135-139.
295. Ichikado K, Muranaka H, Gushima Y, Kotani T, Nader HM, Fujimoto K 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.
296. Tan C, Huang Y, Shi F, Tan K, Ma Q, Chen Y. C-reactive protein correlates with computed
tomographic findings and predicts severe COVID-19 early. J Med Virol 2020; 92:856-862.
297. 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.
298. Stephenson E, Hooper MH, Marik PE. Vitamin C and Point of Care glucose
measurements: A retrospective, Observational study [Abstract]. Chest 2018; 154
(suppl.):255a.
299. Hekimian G, Kerneis M, Zeitouni M, Cohen-Aubart F, Chommeloux J. COVID-19 acute
myocarditis and multisystem inflanmmatory syndrome in Adult Intensive and cardiac
Care Units. Chest 2020.
300. Ma KL, Liu ZH, Cao CF, Liu MK, Liao J. COVID-19 myocarditis and severity factors: An
adult cohort study. medRxiv 2020.
301. Brosnahan SB, Bhatt A, Berger JS, Yuriditsky E, Iturrate E. COVID-19 pneumonia
hospitalizations followed by re-presentation for presumed thrombotic event. Chest
2020.
302. Giannis D, allen SL, Tsang J, Flint S, Pinhasov T, Williams S. Post-discharge
thromboembolic outcomes and mortality of hospitalized COVID-19 patients: The CORE-
19 registry. Blood 2021.
303. Spyropoulos AC, Lipardi C, Xu J, Peluso C, Spiro TE. 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.
304. Kunutsor SK, Seidu S, Blom AW, Khunti K. Serum C-reactive protein increases the risk of
venous thromboembolism: a prospective study and meta-analysis of published
prospective evidence. Eur J Epidemiol 2017; 32:657-667.

MATH+: COVID Hospital Treatment Protocol (2/3/2023) 42