J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Review

Volume 14, Number 2, February 2022, pages 53-79

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Figure 1. Protocol for prolonged corticosteroid treatment recommended by the Corticosteroid Guideline Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).

Figure 2. Spectral computed tomography (CT) image with contrast in a coronavirus disease 2019 (COVID-19) patient. Markedly increased iodine uptake is seen (color scale on right of image), indicating increased perfusion to the ground glass opacities.

Figure 3. Therapeutic approach to hypoxemia and respiratory failure in coronavirus disease 2019 (COVID-19).

**Table 1.** MATH+ Hospital Treatment Protocol for COVID-19 (www.flccc.net)
Medication	Indication/initiation	Recommended dosing	Titration/duration
^aContinue low molecular weight heparin 1 mg/kg twice daily in ward patients transferred to intensive care units unless contraindicated. For patients with end-stage renal disease, use unfractionated heparin. ^bConsider extended thromboprophylaxis. CRP: C-reactive protein; DOAC: direct oral anti-coagulant; ICU: intensive care unit; IMV: invasive mechanical ventilation; IU: International Units; IV: intravenous; NIPPV: non-invasive positive pressure ventilation; O₂: oxygen; PO (per os): oral administration; eGFR: estimated glomerular filtration rate.
Methylprednisolone	A. Mild hypoxemia: requires O₂ via NC to maintain saturation > 92%.	40 mg IV bolus, then 20 mg IV twice daily	A1. Once off O₂, then taper with 20 mg daily for 3 days then 10 mg daily for 3 days, monitor CRP response. A2. If FiO₂, or CRP increase move to B.
	B. Moderate-severe hypoxemia (high-flow O₂, NIPPV, IMV).	COVID-19 respiratory failure protocol (Fig. 2). Preferred: 80 mg IV bolus, followed by 80 mg/240 mL normal saline IV infusion at 10 mL/h. Alternate: 40 mg IV twice daily	B1. Once off IMV, NPPV, or high-flow O₂, decrease to 20 mg twice daily. Once off O₂, then taper with 20 mg/day for 3 days then 10 mg/day for 3 days. B2. If no improvement in oxygenation in 2 - 4 days, double dose to 160 mg daily. B3. If no improvement and increase in CRP/ferritin, move to “pulse dose” below.
	C. Refractory illness/cytokine storm	“Pulse” dose with 125 mg IV every 6 - 8 h	Continue for 3 days then decrease to 80 mg IV daily dose above (B). If still no response or CRP/ferritin high/rising, consider “Salvage therapy” below
Ascorbic acid	O₂ < 4 L on hospital ward	500 - 1,000 mg oral every 6 h	Until discharge
	O₂ > 4 L or in ICU	1.5 - 3 g intravenously every 6 h	Sooner of 7 days or discharge from ICU, then switch to oral dose above
Thiamine	ICU patients	200 mg IV twice daily	Sooner of 7 days or discharge from ICU
Heparin (low molecular weight)	Hospital ward patients with moderate severity not requiring high-flow oxygen	1 mg/kg twice daily. Monitor anti-Xa, target 0.2 - 0.5 IU/mL. Adjust dose and monitor for eGFR	Until discharge then start DOAC at half dose for 4 weeks^b
	ICU patients^a	0.5 mg/kg twice daily. Monitor anti-Xa levels, target 0.6 - 1.1 IU/mL. Adjust dose and monitor for eGFR	Later of: discharge from ICU or off oxygen, then decrease to hospital ward dosing above
Vitamin D	Hospital ward patients on ≤ 4 L O₂	Calcifediol preferred: 0.532 mg PO day 1, then 0.266 mg PO day 3 and 7 and weekly thereafter. Cholecalciferol: 10,000 IU/day PO or 60,000 IU day 1, 30,000 IU days 3 and 7 and then weekly	Until discharge from ICU
	ICU patients or on > 4 L O₂	Cholecalciferol 480,000 IU (30 mL) PO on admission, then check vitamin D level on day 5, if < 20 ng/mL, 90,000 PO IU/day for 5 days	Until discharge from ICU
Spironolactone	All patients	100 mg twice daily	10 days
Dutasteride	All patients (except pregnant patients)	2 mg on day 1, then 1 mg daily (finasteride 10 mg daily	10 days
Fluvoxamine	All patients	50 - 100 mg twice daily
Atorvastatin	ICU patients	80 mg PO daily	Until discharge
Melatonin	Hospitalized patients	6 - 12 mg PO at night	Until discharge
Zinc	Hospitalized patients	75 - 100 mg PO daily	Until discharge
Famotidine	Hospitalized patients	40 - 80 PO mg twice daily	Until discharge15 days
Therapeutic plasma exchange	Patients refractory to pulse dose steroids	Five sessions, every other day	Completion of five exchanges

Table 1. MATH+ Hospital Treatment Protocol for COVID-19 (www.flccc.net)

Medication

Indication/initiation

Recommended dosing

Titration/duration

^aContinue low molecular weight heparin 1 mg/kg twice daily in ward patients transferred to intensive care units unless contraindicated. For patients with end-stage renal disease, use unfractionated heparin. ^bConsider extended thromboprophylaxis. CRP: C-reactive protein; DOAC: direct oral anti-coagulant; ICU: intensive care unit; IMV: invasive mechanical ventilation; IU: International Units; IV: intravenous; NIPPV: non-invasive positive pressure ventilation; O₂: oxygen; PO (per os): oral administration; eGFR: estimated glomerular filtration rate.

Methylprednisolone

A. Mild hypoxemia: requires O₂ via NC to maintain saturation > 92%.

40 mg IV bolus, then 20 mg IV twice daily

A1. Once off O₂, then taper with 20 mg daily for 3 days then 10 mg daily for 3 days, monitor CRP response. A2. If FiO₂, or CRP increase move to B.

B. Moderate-severe hypoxemia (high-flow O₂, NIPPV, IMV).

COVID-19 respiratory failure protocol (Fig. 2). Preferred: 80 mg IV bolus, followed by 80 mg/240 mL normal saline IV infusion at 10 mL/h. Alternate: 40 mg IV twice daily

B1. Once off IMV, NPPV, or high-flow O₂, decrease to 20 mg twice daily. Once off O₂, then taper with 20 mg/day for 3 days then 10 mg/day for 3 days. B2. If no improvement in oxygenation in 2 - 4 days, double dose to 160 mg daily. B3. If no improvement and increase in CRP/ferritin, move to “pulse dose” below.

C. Refractory illness/cytokine storm

“Pulse” dose with 125 mg IV every 6 - 8 h

Continue for 3 days then decrease to 80 mg IV daily dose above (B). If still no response or CRP/ferritin high/rising, consider “Salvage therapy” below

Ascorbic acid

O₂ < 4 L on hospital ward

500 - 1,000 mg oral every 6 h

Until discharge

O₂ > 4 L or in ICU

1.5 - 3 g intravenously every 6 h

Sooner of 7 days or discharge from ICU, then switch to oral dose above

Thiamine

ICU patients

200 mg IV twice daily

Sooner of 7 days or discharge from ICU

Heparin (low molecular weight)

Hospital ward patients with moderate severity not requiring high-flow oxygen

1 mg/kg twice daily. Monitor anti-Xa, target 0.2 - 0.5 IU/mL. Adjust dose and monitor for eGFR

Until discharge then start DOAC at half dose for 4 weeks^b

ICU patients^a

0.5 mg/kg twice daily. Monitor anti-Xa levels, target 0.6 - 1.1 IU/mL. Adjust dose and monitor for eGFR

Later of: discharge from ICU or off oxygen, then decrease to hospital ward dosing above

Vitamin D

Hospital ward patients on ≤ 4 L O₂

Calcifediol preferred: 0.532 mg PO day 1, then 0.266 mg PO day 3 and 7 and weekly thereafter. Cholecalciferol: 10,000 IU/day PO or 60,000 IU day 1, 30,000 IU days 3 and 7 and then weekly

Until discharge from ICU

ICU patients or on > 4 L O₂

Cholecalciferol 480,000 IU (30 mL) PO on admission, then check vitamin D level on day 5, if < 20 ng/mL, 90,000 PO IU/day for 5 days

Until discharge from ICU

Spironolactone

All patients

100 mg twice daily

10 days

Dutasteride

All patients (except pregnant patients)

2 mg on day 1, then 1 mg daily (finasteride 10 mg daily

10 days

Fluvoxamine

All patients

50 - 100 mg twice daily

Atorvastatin

ICU patients

80 mg PO daily

Until discharge

Melatonin

Hospitalized patients

6 - 12 mg PO at night

Until discharge

Zinc

Hospitalized patients

75 - 100 mg PO daily

Until discharge

Famotidine

Hospitalized patients

40 - 80 PO mg twice daily

Until discharge15 days

Therapeutic plasma exchange

Patients refractory to pulse dose steroids

Five sessions, every other day

Completion of five exchanges

**Table 2.** Review of Corticosteroid Therapy in Patients With COVID-19
Published RCTs/cohort studies of corticosteroid therapy in COVID-19	Absolute difference in mortality rate (Rx group vs. control group)	Estimated number needed to treat to save one life
Table is provided by Pierre Kory Flccc.org. COVID-19: coronavirus disease 2019.
Methylprednisolone - hospital patients [54]	5.9% vs. 42.9%	2.7
Methylprednisolone - ICU patients [44]	7.2% vs. 23.3%	6.2
Methylprednisolone - hospital patients [35]	13.6% vs. 26.3%	7.8
Methylprednisolone - ARDS patients [53]	46.0% vs. 61.8%	6.3
Methylprednisolone - percent on oxygen [36]	13.9% vs. 23.9%	10.0
CoDEX - dexamethasone - mechanical ventilation [52]	56.3% vs. 61.5%	19.2
RECOVERY trial (dexamethasone) [51]
Percent on oxygen	23.3% vs. 26.2%	28.6
Percent on mechanical ventilation	29.3% vs. 41.4%	8.4
Hydrocortisone - CAPE COVID - ICU patients [60]	14.7% vs. 27.4%	7.9
Hydrocortisone - REMAP-CAP - ICU patients [49]	28% vs. 33%	20.0

Table 2. Review of Corticosteroid Therapy in Patients With COVID-19

Published RCTs/cohort studies of corticosteroid therapy in COVID-19

Absolute difference in mortality rate (Rx group vs. control group)

Estimated number needed to treat to save one life

Table is provided by Pierre Kory Flccc.org. COVID-19: coronavirus disease 2019.

Methylprednisolone - hospital patients [54]

5.9% vs. 42.9%

2.7

Methylprednisolone - ICU patients [44]

7.2% vs. 23.3%

6.2

Methylprednisolone - hospital patients [35]

13.6% vs. 26.3%

7.8

Methylprednisolone - ARDS patients [53]

46.0% vs. 61.8%

6.3

Methylprednisolone - percent on oxygen [36]

13.9% vs. 23.9%

10.0

CoDEX - dexamethasone - mechanical ventilation [52]

56.3% vs. 61.5%

19.2

RECOVERY trial (dexamethasone) [51]

Percent on oxygen

23.3% vs. 26.2%

28.6

Percent on mechanical ventilation

29.3% vs. 41.4%

8.4

Hydrocortisone - CAPE COVID - ICU patients [60]

14.7% vs. 27.4%

7.9

Hydrocortisone - REMAP-CAP - ICU patients [49]

28% vs. 33%

20.0

**Table 3.** Clinical Studies Involving IVAA in COVID-19
Study type	Intervention	Outcome IVAA vs. control	Comments/level of evidence
Based on level 5 evidence (cited in text) and current studies, we recommend the use of IVAA as adjunctive therapy in patients with COVID-19. IVAA: intravenous ascorbic acid; SOFA: sequential organ failure assessment; RCT: randomized controlled trial; HR: hazard ratio; CI: confidence interval; TNF-α: tumor necrosis factor alpha; IL-6: interleukin-6; IL-8: interleukin-8; CRP: C-reactive protein; SIRS: systemic inflammatory response syndrome; IVC: intravenous vitamin C.
RCT of 56 COVID-19 pneumonia and multiple organ injury ICU patients. Age: 67 ± 13 years. Severe COVID-19 PaO₂/FIO₂ < 300 [81]	IVAA: 24 g/day (n = 27) or placebo (n = 29) for 7 days (*corticosteroid allowed) (time to treatment 11 - 25 days to onset of symptoms)	IVAA: lower ICU and hospital mortality in patients with SOFA scores ≥ 3 (3 - 10 days, P = 0.03). No difference in ventilation-free days (26.5 vs. 10.5 days, P = 0.56)	IVAA group had higher PaO₂/FIO₂ and lower IL-6 levels on admission. Level of evidence 2
Open label RCT of 150 patients with severe COVID-19. Age: 52 - 53 years [82]	IVAA: 50 mg/kg/day + standard therapy or standard therapy (75 per group)	IVAA: sooner to symptom-free status (7.1 ± 1.8 vs. 9.6 ± 2.1) (P < 0.0001). No difference in mortality or need for mechanical ventilation	Corticosteroids allowed. Level of evidence 2
Open label RCT of 60 patients with severe COVID-19. Age: 57 - 61 years [83]	IVC 6 g/day + standard therapy or standard therapy (n = 30 per group) for 5 days	Lower body temperature on third day of hospitalization (P = 0.001) Improvement in oxygen saturation on third day of hospitalization (P = 0.014). No difference in mortality	Both groups received dexamethasone. Level of evidence 2
Retrospective cohort study of 76 patients with moderate to severe COVID-19. Age: 52 - 71 years [84]	IVAA: 6 g/12 h on first day, 6 g/day for following 4 days + standard therapy (n = 30) or standard therapy (n = 46) for 5 days	Improved oxygenation in treatment group. Decrease in pro-inflammatory biomarkers. Reduced risk of 28-day mortality (HR: 0.14, 95% CI: 0.03 - 0.72, P = 0.037)	Level of evidence 3
Propensity matched before and after retrospective analysis of 110 patients with moderate COVID-19 pneumonia. Age: 31 - 47 years [85]	IVAA: 100 mg/kg/day + standard therapy or standard therapy (55 per group) for 7 days	Fewer patients progressing to severe type of COVID-19 (P = 0.03). Reduction in incidence and progression of SIRS (P = 0.008)	Level of evidence 3
Retrospective analysis of 232 patients with COVID-19 pneumonia. Age: 46 - 74 years [86]	IVAA: 2 g/day + standard therapy (n = 153) or standard therapy (n = 170)	Shorter length of hospital stay (7 vs. 8 days, P = 0.05). No difference in re-admission rate (P = 0.94), admission to ICU, need for advanced oxygen support (P = 0.49), and mortality (P = 0.52). Need for advanced medical treatment (P < 0.001)	Level of evidence 3
Retrospective study of 34 critically ill patients with COVID-19. Age: 53 - 77 years [87]	IVAA: 1.5 g/6 h + standard therapy (n = 8) or standard therapy (n = 24) for 4 days	Higher rate of hospital mortality in treatment group (19 (79%) vs. 7 (88%), P = 0.049) and SOFA score. No difference in daily vasopressor requirement or ICU length of stay	Higher baseline SOFA score in IVAA group. Level of evidence 3
Retrospective study of 236 patients with severe COVID-19. Age: 57 - 73 years [88]	IVAA: 100 mg/kg/6 h on day 1 then 100 mg/kg/12 h for the next 5 days + standard therapy (n = 85) or standard therapy (n = 151	Reduction in inflammatory markers (CRP, P = 0.032; IL-6, P = 0.005; TNF-α, P = 0.015)	Level of evidence 3
Retrospective study of 113 patients with severe COVID-19 and cardiac injury. Age: 59 - 77 years [89]	IVAA: 100 mg/kg/6 h on day 1 then 100 mg/kg/12 h for the next 5 days + standard therapy (n = 51) or standard therapy (n = 62)	IVAA was associated with ameliorated cardiac injury (P = 0.04). Reduced levels of inflammatory markers (CRP, IL-6, IL-8, and TNF-α) at 21 days of hospitalization	Level of evidence 3

Table 3. Clinical Studies Involving IVAA in COVID-19

Study type

Intervention

Outcome IVAA vs. control

Comments/level of evidence

Based on level 5 evidence (cited in text) and current studies, we recommend the use of IVAA as adjunctive therapy in patients with COVID-19. IVAA: intravenous ascorbic acid; SOFA: sequential organ failure assessment; RCT: randomized controlled trial; HR: hazard ratio; CI: confidence interval; TNF-α: tumor necrosis factor alpha; IL-6: interleukin-6; IL-8: interleukin-8; CRP: C-reactive protein; SIRS: systemic inflammatory response syndrome; IVC: intravenous vitamin C.

RCT of 56 COVID-19 pneumonia and multiple organ injury ICU patients. Age: 67 ± 13 years. Severe COVID-19 PaO₂/FIO₂ < 300 [81]

IVAA: 24 g/day (n = 27) or placebo (n = 29) for 7 days (*corticosteroid allowed) (time to treatment 11 - 25 days to onset of symptoms)

IVAA: lower ICU and hospital mortality in patients with SOFA scores ≥ 3 (3 - 10 days, P = 0.03). No difference in ventilation-free days (26.5 vs. 10.5 days, P = 0.56)

IVAA group had higher PaO₂/FIO₂ and lower IL-6 levels on admission. Level of evidence 2

Open label RCT of 150 patients with severe COVID-19. Age: 52 - 53 years [82]

IVAA: 50 mg/kg/day + standard therapy or standard therapy (75 per group)

IVAA: sooner to symptom-free status (7.1 ± 1.8 vs. 9.6 ± 2.1) (P < 0.0001). No difference in mortality or need for mechanical ventilation

Corticosteroids allowed. Level of evidence 2

Open label RCT of 60 patients with severe COVID-19. Age: 57 - 61 years [83]

IVC 6 g/day + standard therapy or standard therapy (n = 30 per group) for 5 days

Lower body temperature on third day of hospitalization (P = 0.001) Improvement in oxygen saturation on third day of hospitalization (P = 0.014). No difference in mortality

Both groups received dexamethasone. Level of evidence 2

Retrospective cohort study of 76 patients with moderate to severe COVID-19. Age: 52 - 71 years [84]

IVAA: 6 g/12 h on first day, 6 g/day for following 4 days + standard therapy (n = 30) or standard therapy (n = 46) for 5 days

Improved oxygenation in treatment group. Decrease in pro-inflammatory biomarkers. Reduced risk of 28-day mortality (HR: 0.14, 95% CI: 0.03 - 0.72, P = 0.037)

Level of evidence 3

Propensity matched before and after retrospective analysis of 110 patients with moderate COVID-19 pneumonia. Age: 31 - 47 years [85]

IVAA: 100 mg/kg/day + standard therapy or standard therapy (55 per group) for 7 days

Fewer patients progressing to severe type of COVID-19 (P = 0.03). Reduction in incidence and progression of SIRS (P = 0.008)

Level of evidence 3

Retrospective analysis of 232 patients with COVID-19 pneumonia. Age: 46 - 74 years [86]

IVAA: 2 g/day + standard therapy (n = 153) or standard therapy (n = 170)

Shorter length of hospital stay (7 vs. 8 days, P = 0.05). No difference in re-admission rate (P = 0.94), admission to ICU, need for advanced oxygen support (P = 0.49), and mortality (P = 0.52). Need for advanced medical treatment (P < 0.001)

Level of evidence 3

Retrospective study of 34 critically ill patients with COVID-19. Age: 53 - 77 years [87]

IVAA: 1.5 g/6 h + standard therapy (n = 8) or standard therapy (n = 24) for 4 days

Higher rate of hospital mortality in treatment group (19 (79%) vs. 7 (88%), P = 0.049) and SOFA score. No difference in daily vasopressor requirement or ICU length of stay

Higher baseline SOFA score in IVAA group. Level of evidence 3

Retrospective study of 236 patients with severe COVID-19. Age: 57 - 73 years [88]

IVAA: 100 mg/kg/6 h on day 1 then 100 mg/kg/12 h for the next 5 days + standard therapy (n = 85) or standard therapy (n = 151

Reduction in inflammatory markers (CRP, P = 0.032; IL-6, P = 0.005; TNF-α, P = 0.015)

Level of evidence 3

Retrospective study of 113 patients with severe COVID-19 and cardiac injury. Age: 59 - 77 years [89]

IVAA: 100 mg/kg/6 h on day 1 then 100 mg/kg/12 h for the next 5 days + standard therapy (n = 51) or standard therapy (n = 62)

IVAA was associated with ameliorated cardiac injury (P = 0.04). Reduced levels of inflammatory markers (CRP, IL-6, IL-8, and TNF-α) at 21 days of hospitalization

Level of evidence 3

**Table 4.** Clinical Studies Involving Melatonin in the Treatment of COVID-19
Trial details	Dose	Outcomes	Comments/level of evidence
Based on level 5 evidence (cited in text) and current studies, we recommend the use of melatonin as adjunctive therapy in patients with COVID-19. CRP: C-reactive protein.
Randomized single blind trial. Treatment: n = 14. Control: n = 17. Age: 25 - 65 years. Hospitalized mild moderate COVID-19 [145]	6 mg melatonin at bedtime for 14 days	Improved declined CRP in treatment group. Percentage of recovery (based on symptoms) in patients who took melatonin was higher than that of patients in the control group (85.7% vs. 47.1%)	Corticosteroids given. Level of evidence 2
Double blind randomized controlled trial. Treatment: n = 24. Control: n = 20. Age: 36 - 64 years. Mild to moderate COVID-19 [146]	3 mg melatonin three times a day for 14 days	Faster time to symptom resolution, faster time to discharge. Improvement in CRP	Unclear if standard of care included corticosteroids. Level of evidence 2
Randomized open label study. Treatment: n = 48. Control: n = 48. Age: 36 - 69 years. Mild to moderate COVID-19 [147]	3 mg at bedtime for 7 days	Improvement in oxygenation	Higher usage of methylprednisolone in control group. Level of evidence 2
Retrospective study. Patients: n = 791. Mean age: 56 years. Patients received melatonin: n = 112 [148]	112 patients received melatonin	Improved survival in those patients who received melatonin	Study adjusted for comorbidities and therapy including corticosteroids. Level of evidence 3

Table 4. Clinical Studies Involving Melatonin in the Treatment of COVID-19

Trial details

Dose

Outcomes

Comments/level of evidence

Based on level 5 evidence (cited in text) and current studies, we recommend the use of melatonin as adjunctive therapy in patients with COVID-19. CRP: C-reactive protein.

Randomized single blind trial. Treatment: n = 14. Control: n = 17. Age: 25 - 65 years. Hospitalized mild moderate COVID-19 [145]

6 mg melatonin at bedtime for 14 days

Improved declined CRP in treatment group. Percentage of recovery (based on symptoms) in patients who took melatonin was higher than that of patients in the control group (85.7% vs. 47.1%)

Corticosteroids given. Level of evidence 2

Double blind randomized controlled trial. Treatment: n = 24. Control: n = 20. Age: 36 - 64 years. Mild to moderate COVID-19 [146]

3 mg melatonin three times a day for 14 days

Faster time to symptom resolution, faster time to discharge. Improvement in CRP

Unclear if standard of care included corticosteroids. Level of evidence 2

Randomized open label study. Treatment: n = 48. Control: n = 48. Age: 36 - 69 years. Mild to moderate COVID-19 [147]

3 mg at bedtime for 7 days

Improvement in oxygenation

Higher usage of methylprednisolone in control group. Level of evidence 2

Retrospective study. Patients: n = 791. Mean age: 56 years. Patients received melatonin: n = 112 [148]

112 patients received melatonin

Improved survival in those patients who received melatonin

Study adjusted for comorbidities and therapy including corticosteroids. Level of evidence 3

**Table 5.** Clinical Studies Involving Vitamin D Therapy in COVID-19
Trial details	Dose	Outcomes	Comments
Based on level 5 evidence (cited in text) and current studies we recommend use of vitamin D as adjunctive therapy. BMI: body mass index; CRP: C-reactive protein; LDH: lactate dehydrogenase; ICU: intensive care unit; IL-6: interleukin-6.
Randomized single blind trial. Treatment: n = 14 Control: n = 17. Age: 25 - 65 years. Hospitalized mild COVID-19. Mean age 51 ± 15 years, healthy cohorts no comorbidities. Asymptomatic to mild COVID-19 [225]	Oral cholecalciferol 60,000 IU daily for 7 days (if target 25(OH)D concentration > 50 ng/mL not achieved on day 7; same dose continued, if target achieved weekly 60,000 IU)	Significant rapid disappearance of viral mRNA in treatment group at 21 days (62%vs. 20%) significant decrease in fibrinogen. No difference in procalcitonin, CRP, ferritin or D-dimer	Level of evidence 2. Placebos were not identical
Double masked randomized open label trial. Treatment: n = 50. Control: n = 26. Age: 43 - 63 years. Moderately severe COVID-19 [14]	Oral calcifediol 0.532 mg on day of admission and 0.266 on day 3, 7 and weekly until discharge	Need for ICU admission was lower in the group receiving intervention (2% vs. 50%, P < 0.001). Two patients in control group died, none in the intervention group died	Level of evidence 2
Randomized open label study. Treatment: n = 44. Control: n = 43. Age: 20 - 83 years. Vitamin level less than 30. Mild to moderate COVID-19 [226]	Cholecalciferol 60,000 IU daily for 8 days in participants with BMI 18 - 25 kg/m² and 10 days for participants with BMI > 25 kg/m²	Significant reduction of inflammatory markers (CRP, LDH, ferritin, IL-6, N/L ratio) in intervention group compared to control group. No difference in hospital stay or mortality	Level of evidence 2. Adjustment made for comorbidities
Double blind randomized trial. Treatment: n = 119. Control: n = 118. Mean age: 56 ± 15 years. Moderate to severe COVID-19 [227]	Single dose of oral cholecalciferol 200,000 IU	No significant difference between groups in median length of hospital stay (7 vs. 7, P = 0.94), mortality (7.6% vs. 5.1%, P = 0.43). No significant difference in need for ventilation or length of ventilation. No significant difference in post-hoc analysis on patients with vitamin D deficiency.	Level of evidence 2. Patient could enroll for up to 10 days from development of symptoms; 60% of patients in both groups received corticosteroids

Table 5. Clinical Studies Involving Vitamin D Therapy in COVID-19

Trial details

Dose

Outcomes

Comments

Based on level 5 evidence (cited in text) and current studies we recommend use of vitamin D as adjunctive therapy. BMI: body mass index; CRP: C-reactive protein; LDH: lactate dehydrogenase; ICU: intensive care unit; IL-6: interleukin-6.

Randomized single blind trial. Treatment: n = 14
Control: n = 17. Age: 25 - 65 years. Hospitalized mild COVID-19. Mean age 51 ± 15 years, healthy cohorts no comorbidities. Asymptomatic to mild COVID-19 [225]

Oral cholecalciferol 60,000 IU daily for 7 days (if target 25(OH)D concentration > 50 ng/mL not achieved on day 7; same dose continued, if target achieved weekly 60,000 IU)

Significant rapid disappearance of viral mRNA in treatment group at 21 days (62%vs. 20%) significant decrease in fibrinogen. No difference in procalcitonin, CRP, ferritin or D-dimer

Level of evidence 2. Placebos were not identical

Double masked randomized open label trial. Treatment: n = 50. Control: n = 26. Age: 43 - 63 years. Moderately severe COVID-19 [14]

Oral calcifediol 0.532 mg on day of admission and 0.266 on day 3, 7 and weekly until discharge

Need for ICU admission was lower in the group receiving intervention (2% vs. 50%, P < 0.001). Two patients in control group died, none in the intervention group died

Level of evidence 2

Randomized open label study. Treatment: n = 44. Control: n = 43. Age: 20 - 83 years. Vitamin level less than 30. Mild to moderate COVID-19 [226]

Cholecalciferol 60,000 IU daily for 8 days in participants with BMI 18 - 25 kg/m² and 10 days for participants with BMI > 25 kg/m²

Significant reduction of inflammatory markers (CRP, LDH, ferritin, IL-6, N/L ratio) in intervention group compared to control group. No difference in hospital stay or mortality

Level of evidence 2. Adjustment made for comorbidities

Double blind randomized trial. Treatment: n = 119. Control: n = 118. Mean age: 56 ± 15 years. Moderate to severe COVID-19 [227]

Single dose of oral cholecalciferol 200,000 IU

No significant difference between groups in median length of hospital stay (7 vs. 7, P = 0.94), mortality (7.6% vs. 5.1%, P = 0.43). No significant difference in need for ventilation or length of ventilation. No significant difference in post-hoc analysis on patients with vitamin D deficiency.

Level of evidence 2. Patient could enroll for up to 10 days from development of symptoms; 60% of patients in both groups received corticosteroids