Table 1.
Characteristics of studies examining the links between vitamin D and COVID-19 *.
| Author, Year, Country [Ref] | Study Design | Sample Size | Main Findings |
|---|---|---|---|
| Whittemore et al., 2020 [114] | Correlation analysis of data | 88 countries | Countries closer to the equator had lower COVID-19 fatalities than countries further away; 16% of this effect was attributed to latitude. |
| Baktash et al., 2021, UK [115] | Cohort study | 105 | Vitamin D deficiency was associated with needing more care, and with the occurrence of cytokine storms. |
| D’Avolio et al., 2020, Switzerland [116] | Retrospective cohort study | 107 | People who tested positive for SARS-CoV-2 had lower levels of 25(OH)D. |
| Meltzer et al., 2020, USA [117] | Retrospective cohort study | 4314 | Deficient vitamin D status was linked to increased risk of COVID-19. |
| Radujkovic et al., 2020, Germany [118] | Retrospective study | 185 | Vitamin D deficiency was associated with a higher risk of invasive mechanical ventilation or death. |
| Lakkireddy et al., 2021, India [119] | Randomised prospective open-label study | 87 | Vitamin D supplementation in those with hypovitaminosis D improved inflammatory markers. |
| Ünsal et al., 2021, Turkey [120] | Retrospective cohort study | 56 | Vitamin D deficient COVID-19 patients had significantly lower haemoglobin and lymphocyte counts and higher levels of inflammatory markers. |
| Entrenas Castillo et al., 2020, Spain [121] | Parallel pilot randomized open-label trial * | 76 | High dose calcifediol reduced the severity of COVID-19 in patients requiring ICU admission. |
| Murai et al., 2021, Brazil [122] | Multi-centre parallel double-blind RCT | 240 | Single high dose cholecalciferol did not reduce hospital stay, mortality, admission to ICU or need for ventilation compared with placebo. |
| Rastogi et al., 2020, India [123] | RCT | 40 | Compared with vitamin D deficient individuals, a greater proportion of asymptomatic or mildly symptomatic patients on high dose vitamin D reaching 25(OH)D >50 ng/ml achieved a negative SARS-CoV-2 RNA at ≤ 21 days. |
| Annweiler et al., 2020, France [124] | Quasi-randomised trial | 66 | Vitamin D supplementation just before or during COVID-19 in an aged population reduced disease severity and mortality rate. |
| Munshi et al., 2021, [125] | Systematic review and meta-analysis | 6 retrospective articles | Vitamin D levels could be a useful prognostic indicator of COVID-19 outcomes. |
| Stroehlein et al., 2021 [126] | Living Cochrane systematic review |
3 RCTs | Current evidence is insufficient to conclusively determine the benefits or harms of vitamin D supplementation as a treatment for COVID-19. |
| Annweiler et al., 2020, France [127] | Open-label, multicenter, superiority RCT | Single dose of 50,000 IU of vitamin D vs Single dose of 200,000 IU of vitamin D in COVID-19 positive patients showing at least one sign of increased risk.Results pending. | |
| Annweiler et al., 2020, France [128] | Quasi-experimental study | 77 | Regular vitamin D supplementation prior to COVID-19 led to improved mortality in elderly patients at three months follow-up. |
| Pereira et al., 2020 [129] | Systematic review and meta-analysis | 21 studies | Correlation between severely ill COVID-19 patients and low vitamin D levels [130], possibly explained by 25(OH)D being inversely associated with pro-inflammatory cytokines, such as IL-6, increase in CRP, and cardiac insufficiency, which relate to severity of COVID-19 and to its unfavorable outcomes [131]. Despite the correlation between higher vitamin D levels, immune defenses, and favorable prognoses in other viral infections [132], no causal relationship has been established between 25(OH)D deficiency and vulnerability to infection by COVID-19, by testing and blood vitamin D test in SARS-CoV-2 patients. |
| Tan et al., 2020, Singapore [133] | Cohort Study | 43 | Patients were administered 1000 IU/d oral vitamin D3, 150 mg/d oral magnesium, and 500 mcg/d oral vitamin B12 upon admission if they did not require oxygen therapy. After correcting for demographics and hypertension, patients who received DMB had significantly less deterioration to the point of requiring oxygen therapy or intensive care support. |
| Meltzer et al., 2020, USA [134] | Retrospective cohort study | 499 | Other than age and non-white race, vitamin D deficient status was correlated with the incidence of COVID-19. However, the dose of vitamin D supplementation was not significantly correlated with the likelihood of testing positive to COVID-19. |
| Kaufman et al., 2020, USA [135] | Retrospective observational analysis | 191,779 | SARS-CoV-2 incidence was higher in the patients with deficient 25(OH)D scores than in patients with adequate values and those with levels ≥55 ng/mL. |
| Jain et al., 2020, India [136] | Observational study | 154 | Mean vitamin D levels were significantly higher in asymptomatic patients than severely ill. Prevalence of vitamin D deficiency was significantly higher in the severely ill. Of 154 patients, 90 were deficient in vitamin D (29 asymptomatic; 61 severely ill). Serum levels of inflammatory markers, inflammatory response and fatality rate were higher in vitamin D deficient patients (21% vs 3.1%). Vitamin D level was markedly low in severe COVID-19 patients. |
| Carpagnano et al., 2020, Italy [137] | Retrospective observational study | 42 | After 10 days of hospitalization, patients with severe vitamin D deficiency had a 50% mortality probability, while those with insufficiency or moderate deficiency had a 5% mortality risk. COVID-19 patients with acute respiratory failure treated in RICU were found to have a high prevalence of hypovitaminosis D, which correlated with a high mortality risk. |
| Padhi et al., 2020, India [138] | Observational study | NA | Mean vitamin D levels reported in different states and territories correlated inversely with mortality data collected via government statistics. |
| Ling et al., 2020, UK [139] | Retrospective observational study | 444 | Administration of cholecalciferol booster was correlated with a reduced risk of COVID-19 mortality |
| De Smet et al., 2021, Belgium [140] | Retrospective observational trial | 186 | Vitamin D deficiency on admission was associated with mortality, independently of age, chronic lung disease, and the extent of lung damage seen from chest CT severity score. |
| Karahan et al., 2021, Turkey [141] | Retrospective observational study | 149 | Serum 25(OH)D deficiency was associated with increased mortality in COVID-19 patients. |
| AlSafar et al., 2021, UAE, [142] | Retrospective observational study | 464 | After ruling out sex as a predictor for COVID-19 severity or mortality, 25(OH)D levels below 12 ng/mL were significantly correlated with increased risk of severe illness and mortality. |
| Orchard et al., 2021, UK [143] | Cohort study | 646 | No significant correlation reported between low vitamin D levels and severity of COVID-19 or mortality. |
| Osman et al., 2021, Oman [144] | Observational cohort study | 445 | While no correlation between vitamin D and disease severity and progression was observed, there was an association between hypocalcaemia and COVID-19 severity. The relationship between calcium and vitamin D is also acknowledged. |
| Diaz-Curiel et al., 2021, Spain [145] | Retrospective observational study | 1549 | Vitamin D deficiency was correlated with an increased risk of hospital admission and critical care, but not mortality. |
| Angelidi et al., 2021, USA [146] | Retrospective cohort study | 144 | Mortality in hospital and need for mechanical ventilation were inversely correlated with serum vitamin D level |
| Jevalikar et al., 2021, Indian [147] | Prospective observational study | 410 | No association between vitamin D deficiency and incidence of severe COVID-19, increased oxygen requirement, ICU admissions or mortality. In vitamin D deficient patients who received cholecalciferol treatment, there was no significant improvement in outcome. |
| Alcala-Diaz et al., 2021, Spain [148] | Retrospective, multicentre, non-randomised cohort study | 537 | Calcifediol treatment after COVID-19 diagnosis was significantly associated with reduced 30-day mortality |
| Cangiano et al., 2020, Italy [149] | Observational study | 157 | Mortality in COVID-19 patients was found to be inversely associated with vitamin D supplementation |
| Fasano et al., 2020, Italy [150] | Cohort study | 1486 | Among Parkinson’s Disease patients, COVID-19 incidence was greater among those who were younger, obese and those with COPD. It was less likely among patients who had vitamin D supplementation. |
| Giannini et al., 2021, Italy [151] | Retrospective study | 91 | Two doses of 200,000 IU of vitamin D administered on consecutive days can improve outcomes (ICU admission, mortality) in patients with comorbidities. |
| Israel et al., 2021, Israel [152] | Case-control study | 60,039 | The only statins that exerted a protective effect in COVID-19 were those that increased levels of 25(OH)D, such as rosuvastatin. |
| Loucera et al., 2021, Andalusia [153] | Retrospective survival study | 16,401 | There was significant reduction in mortality after administration of vitamin D (calcifediol) 15–30 days before hospitalisation |
| Sabico et al., 2021, Saudi Arabia [154] | RCT | 69 | 5000 IU, but not 1000 IU, daily administration of vitamin D for 2 weeks reduced recovery time for COVID-19 patients with mild to moderate symptoms. Both groups showed decreases in levels of IL-6 and BMI over time. |
| Oristell et al., 2021, Catalonia [155] | Population based cohort study | 108,343 | Reduced serum 25(OH)D levels were associated with an increased incidence of infection rather than disease severity or mortality. Groups compared were supplemented vitamin D sufficient versus non-supplemented vitamin D deficient patients who contracted COVID-19 |
| Ohaegbulam et al., 2020, USA [156] | Clinical case series | 4 | Patients who received high dose supplementation in the form of cholecalciferol or ergocalciferol had faster recovery, seen from reduced inflammatory markers, comparative lower oxygen requirements and reduced duration of hospital stay. |
| Nogues et al., 2021, Spain [157] | Observational study | 838 | In hospitalised COVID-19 patients, treatment with calcifediol significantly reduced mortality and admission to ICU |
| Ma et al. 2021, UK [158] | Prospective study | 8297 | Habitual vitamin D supplementation was correlated with a reduction in COVID-19 incidence. |
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BMI, body mass index; COPD, chronic obstructive pulmonary disorder; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CT, computed tomography; DMB, combination of vitamin D3, magnesium and vitamin B12; ICU, intensive care unit; IL, interleukin; IU, international units; RCT, randomised controlled trial; RICU, respiratory intensive care unit; SARS-CoV-2, coronavirus severe acute respiratory syndrome. This list is representative of most observational and clinical studies conducted, not exhaustive. * open-label for hydroxychloroquine and azithromycin, double-blind for vitamin D.