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Vitamin D for COVID-19: real-time meta analysis of 91 studies
90% of 30 vitamin D treatment studies report positive effects (15 statistically significant in isolation).
Random effects meta-analysis with pooled effects using the most serious outcome reported shows 78% and 47% improvement for early treatment and for all studies (RR 0.22 [0.12-0.39] and 0.53 [0.44-0.64]). Results are similar after restriction to 27 peer-reviewed studies: 83% and 51% (RR 0.17 [0.07-0.42] and 0.49 [0.38-0.63]), and for the 18 mortality results: 78% and 57% (RR 0.22 [0.12-0.43] and 0.43 [0.29-0.63]).
Late stage treatment with calcifediol/calcitriol shows greater improvement compared to cholecalciferol: 80% versus 43% (RR 0.20 [0.13-0.31] and 0.57 [0.39-0.83]).
Heterogeneity arises from many factors including treatment delay, patient population, the effect measured, variants, the form of vitamin D used, and treatment regimens. The consistency of positive results across a wide variety of cases is remarkable.
Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta analysis of the 61 studies with pooled effects using the most serious outcome reported shows 57% improvement (RR 0.43 [0.36-0.51]).
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 7% of vitamin D treatment studies show zero events in the treatment arm.
Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. All practical, effective, and safe means should be used. Not doing so increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.
All data to reproduce this paper and the sources are in the appendix.
ImprovementStudies AuthorsPatients
Treatment RCTs 45% [-17‑74%] 5 53 482
Treatment studies 47% [36‑56%] 30 310 25,470
Cholecalciferol treatment 44% [30‑55%] 24 241 17,930
Calcifediol/calcitriol treatment 63% [24‑82%] 6 69 7,540
Treatment mortality 57% [37‑71%] 18 173 9,585
Sufficiency studies 57% [49‑64%] 61 507 32,465
A [0.03-0.48]80,000IUdeath10/575/9Improvement, RR [CI]Dose (5d)TreatmentControlAnnweiler63%0.37 [0.06-2.21]80,000IUdeath3/1610/32Loucera (PSM)72%0.28 [0.20-0.39]varies (c)death193193Sánchez-Zuno (RCT)89%0.11 [0.01-1.86]50,000IUsevere case0/224/20Tau​2 = 0.14; I​2 = 42.2%Early treatment78%0.22 [0.12-0.39]13/28819/25478% improvementTan80%0.20 [0.04-0.93]5,000IUoxygen3/1716/26Improvement, RR [CI]Dose (5d)TreatmentControlKrishnan19%0.81 [0.49-1.34]n/adeath8/1684/136Castillo (RCT)85%0.15 [0.01-2.93]0.8mg (c)death0/502/26Rastogi (RCT)53%0.47 [0.24-0.92]300,000IUviral+6/1619/24Murai (RCT)-49%1.49 [0.55-4.05]200,000IUdeath9/1196/118Ling80%0.20 [0.08-0.48]40,000IUdeath73253Jevalikar82%0.18 [0.02-1.69]60,000IUdeath1/1283/69Giannini37%0.63 [0.35-1.09]400,000IUdeath/ICU14/3629/55Nogués (QR)79%0.21 [0.10-0.43]0.8mg (c)death21/44762/391Lakkireddy (RCT)61%0.39 [0.08-1.91]300,000IUdeath2/445/43Lohia11%0.89 [0.32-1.89]n/adeath2669Alcala-Diaz81%0.19 [0.04-0.83]0.8mg (c)death4/7990/458Tau​2 = 0.37; I​2 = 75.3%Late treatment57%0.43 [0.28-0.67]68/1,051316/1,66857% improvementBlanch-Rubió8%0.92 [0.63-1.36]n/acases62/1,30347/799Improvement, RR [CI]Dose (1m)TreatmentControlAnnweiler93%0.07 [0.01-0.61]50,000IUdeath2/2910/32Cereda-73%1.73 [0.81-2.74]variesdeath7/1840/152Louca8%0.92 [0.88-0.94]n/acasesCangiano70%0.30 [0.10-0.87]50,000IUdeath3/2039/78Vasheghani30%0.70 [0.33-1.49]n/adeath7/8848/420Ma30%0.70 [0.50-0.97]n/acases49/3631,329/7,934Sulli50%0.50 [0.34-0.73]n/acases22/6643/64Meltzer36%0.64 [0.29-1.41]n/acases6/131239/3,338Ünsal71%0.29 [0.11-0.76]variespneumonia4/2814/28Oristrell43%0.57 [0.41-0.80]7.4mg (c)death2,2963,407Levitus31%0.69 [0.37-1.24]variessevere case6564Fasano42%0.58 [0.34-0.99]n/acases13/32992/1,157Oristrell-1%1.01 [0.93-1.09]varies (c)deathTau​2 = 0.04; I​2 = 77.0%Prophylaxis26%0.74 [0.63-0.86]175/4,7361,901/17,47326% improvementAll studies47%0.53 [0.44-0.64]256/6,0752,236/19,39547% improvementAll 30 vitamin D COVID-19 treatment 7/25/21Tau​2 = 0.13; I​2 = 85.9%; Z = 6.86 (p < 0.0001)Effect extraction pre-specified, see appendixLower RiskIncreased Risk
B studiesTreatment studiesmin, Q1, median, Q3, maxLower RiskIncreased 7/25/21
100+ 75 50 25 25 50 75 100 Tanoxygen, p=0.04Krishnandeath, p=0.42Castillodeath, p=0.11Annweilerdeath, p=0.002Blanch-Rubiócases, p=0.68Annweilerdeath, p=0.02Annweilerdeath, p=0.28Ceredadeath, p=0.14Rastogiviral+, p=0.02Muraideath, p=0.43Loucacases, p=0.0007Lingdeath, p<0.001Cangianodeath, p=0.04Jevalikardeath, p=0.12Gianninideath/ICU, p=0.13Vasheghanideath, p=0.45Noguésdeath, p=0.001Macases, p=0.03Lakkireddydeath, p=0.27Sullicases, p=0.0002Lohiadeath, p=0.75Meltzercases, p=0.38Ünsalpneumonia, p=0.009Oristrelldeath, p=0.001Louceradeath, p<0.0001Levitussevere case, p=0.25Alcala-Diazdeath, p=0.02Sánchez-Zunosevere case, p=0.04Fasanocases, p=0.05Oristrelldeath, p=0.91Treatment studies% Lower Risk% Increased 7/25/21
100+ 75 50 25 25 50 75 100 Lau, ICU, p=0.29Mendy, death, p=0.89Panagiotou, ICU, p=0.02Faul, ventilation, p=0.03Merzon, hosp., p=0.06Carpagnano, death, p=0.05Im, cases, p=0.003Hastie, death, p=0.31Baktash, death, p=0.50Meltzer, cases, p=0.02Israel, cases, p<0.001Radujkovic, death, p=0.001Kaufman, cases, p<0.001Maghbooli, death, p=0.08Karahan, death, p<0.0001Yılmaz, severe case, p=1.00Faniyi, seropositive, p=0.003Ye, hosp., p=0.03Macaya, severe case, p=0.07Hernández, death/ICU, p<0.0001Abrishami, death, p=0.04Cereda, death, p=0.04Walk, int./death, p=1.00Luo, progression, p=0.01Jain, ICU, p<0.0001De Smet, death, p=0.02Katz, cases, p<0.001Alguwaihes, death, p=0.007Vassiliou, death, p=0.04Abdollahi, cases, p=0.001Szeto, death, p=1.00Karonova, death, p=0.07Amin, progression, p=0.20Angelidi, death, p=0.01Li, severe case, p<0.0001Bennouar, death, p=0.002Orchard, ICU, p=0.001Barassi, death, p=0.44Demir, severe case, p<0.001Susianti, death, p=0.32Infante, death, p=0.05Gavioli, death, p=0.83Sulli, cases, p<0.0001Ricci, death, p=0.07Lohia, death, p=0.56Mazziotti, progression, p=0.006Charoenngam, death, p=0.19Vanegas-Cedillo, death, p=0.006Meltzer, cases, p=0.11Freitas, death, p=0.02Bayramoğlu, severe case, p=0.0008Livingston, cases, p<0.0001Ünsal, death, p=0.23Savitri, symp. case, p<0.0001Li, cases, p=0.21AlSafar, death, p=0.05Sánchez-Zuno, severe case, p=1.00Diaz-Curiel, ICU, p=0.02Dror, severe case, p<0.0001Campi, death, p=0.53Jude, hosp., p<0.0001Sufficiency studies% Lower Risk% Increased 7/25/21
Figure 1. A. Random effects meta-analysis of treatment studies. This plot shows pooled effects, analysis for individual outcomes is below, and more details on pooled effects can be found in the heterogeneity section. Effect extraction is pre-specified, using the most serious outcome reported. Simplified dosages are shown for comparison, these are the total dose in the first five days for treatment, and the monthly dose for prophylaxis. Calcifediol or calcitriol treatment is indicated with (c). For details of effect extraction and full dosage information see the appendix. B. Scatter plot showing the distribution of effects reported in serum level analysis (sufficiency) studies and treatment studies (the vertical lines and shaded boxes show the median and interquartile range). C and D. Chronological history of all reported effects for treatment studies and sufficiency studies.
We analyze all significant studies regarding vitamin D and COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random-effects meta-analysis results for studies analyzing outcomes based on sufficiency, for all treatment studies, for mortality results only, and for treatment studies within each treatment stage.
Vitamin D.
Vitamin D undergoes two conversion steps before reaching the biologically active form as shown in Figure 2. The first step is conversion to calcidiol, or 25(OH)D, in the liver. The second is conversion to calcitriol, or 1,25(OH)2D, which occurs in the kidneys, the immune system, and elsewhere. Calcitriol is the active, steroid-hormone form of vitamin D, which binds with vitamin D receptors found in most cells in the body. Vitamin D was first identified in relation to bone health, but is now known to have multiple functions, including an important role in the immune system [Carlberg, Martens]. There is a significant delay involved in the conversion from cholecalciferol, therefore calcifediol (calcidiol) or calcitriol may be preferable for treatment.
Figure 2. Simplified view of vitamin D sources and conversion.
Many vitamin D studies analyze outcomes based on serum vitamin D levels which may be maintained via sun exposure, diet, or supplementation. We refer to these studies as sufficiency studies, as they typically present outcomes based on vitamin D sufficiency. These studies do not establish a causal link between vitamin D and outcomes. In general, low vitamin D levels are correlated with many other factors that may influence COVID-19 susceptibility and severity. Therefore, beneficial effects found in these studies may be due to factors other than vitamin D. On the other hand, if vitamin D is causally linked to the observed benefits, it is possible that adjustments for correlated factors could obscure this relationship. For these reasons, we analyze sufficiency studies separately from treatment studies. We include all sufficiency studies that provide a comparison between two groups with low and high levels. A few studies only provide results as a function of change in vitamin D levels [Butler-Laporte, Raisi-Estabragh], which may not be indicative of results for deficiency/insufficiency versus sufficiency (increasing already sufficient levels may be less useful than going from deficient to sufficient). A few studies show the average vitamin D level for patients in different groups [Al-Daghri, D'avolio, Kerget, Vassiliou], all of which show lower D levels for worse outcomes. Other studies analyze vitamin D status and outcomes in geographic regions [Jayawardena, Marik, Papadimitriou, Rafailia, Rhodes, Sooriyaarachchi, Walrand, Yadav], all finding worse outcomes to be more likely with lower D levels.
For studies regarding treatment with vitamin D, we distinguish three stages as shown in Figure 3. Prophylaxis refers to regularly taking vitamin D before being infected in order to minimize the severity of infection. Due to the mechanism of action, vitamin D is unlikely to completely prevent infection, although it may prevent infection from reaching a level detectable by PCR. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 3. Treatment stages.
Figure 1 shows the effects reported in sufficiency studies and treatment studies. Figure 4 and 5 show results by treatment stage. Figure 6 shows a forest plot for random effects meta-analysis of sufficiency studies, while Figure 7, 8, 9, 10, 11, 12, 13, and 14 show forest plots for all treatment studies with pooled effects, RCT studies, calcifediol/calcitriol studies, cholecalciferol studies, and for studies reporting mortality, case results, and viral clearance results only. Table 1 summarizes the results.
Study typeNumber of studies reporting positive results Total number of studiesPercentage of studies reporting positive results Random effects meta-analysis results
Analysis of outcomes based on sufficiency 56 61 91.8% 57% improvement
RR 0.43 [0.36‑0.51]
p < 0.0001
Early treatment 4 4 100% 78% improvement
RR 0.22 [0.12‑0.39]
p < 0.0001
Late treatment 11 12 91.7% 57% improvement
RR 0.43 [0.28‑0.67]
p = 0.00019
Prophylaxis 12 14 85.7% 26% improvement
RR 0.74 [0.63‑0.86]
p = 0.00022
All treatment studies 27 30 90.0% 47% improvement
RR 0.53 [0.44‑0.64]
p < 0.0001
Table 1. Results. treatment studiesProphylaxisLate treatmentEarly treatmentmin, Q1, median, Q3, maxLower RiskIncreased 7/25/21
Figure 4. Results by treatment stage.
100+ 75 50 25 25 50 75 100 Annweilerdeath, p=0.002Annweilerdeath, p=0.28Louceradeath, p<0.0001Sánchez-Zunosevere case, p=0.04Early treatmentTanoxygen, p=0.04Krishnandeath, p=0.42Castillodeath, p=0.11Rastogiviral+, p=0.02Muraideath, p=0.43Lingdeath, p<0.001Jevalikardeath, p=0.12Gianninideath/ICU, p=0.13Noguésdeath, p=0.001Lakkireddydeath, p=0.27Lohiadeath, p=0.75Alcala-Diazdeath, p=0.02Late treatmentBlanch-Rubiócases, p=0.68Annweilerdeath, p=0.02Ceredadeath, p=0.14Loucacases, p=0.0007Cangianodeath, p=0.04Vasheghanideath, p=0.45Macases, p=0.03Sullicases, p=0.0002Meltzercases, p=0.38Ünsalpneumonia, p=0.009Oristrelldeath, p=0.001Levitussevere case, p=0.25Fasanocases, p=0.05Oristrelldeath, p=0.91Prophylaxis% Lower Risk% Increased 7/25/21
Figure 5. Results by treatment stage. [0.18-1.68]ICU2/511/15Improvement, RR [CI]TreatmentControlMendy7%0.93 [0.33-2.47]death21/6005/89Panagiotou52%0.48 [0.24-0.95]ICU8/4434/90Faul69%0.31 [0.10-0.95]ventilation4/218/12Merzon46%0.54 [0.23-1.02]hosp.79703Carpagnano71%0.29 [0.10-0.85]death5/344/8Im73%0.27 [0.11-0.69]cases98102Hastie17%0.83 [0.57-1.20]deathBaktash29%0.71 [0.18-2.78]death4/316/39Meltzer44%0.56 [0.36-0.89]cases39/31732/172Israel21%0.79 [0.75-0.84]casesRadujkovic93%0.07 [0.01-0.37]death14412Kaufman53%0.47 [0.29-0.76]casesMaghbooli52%0.48 [0.22-1.05]death7/7227/134Karahan83%0.17 [0.08-0.41]death5/4664/103Yılmaz73%0.27 [0.01-5.14]severe case0/112/29Faniyi29%0.71 [0.59-0.86]seropositive170/33144/61Ye93%0.07 [0.01-0.81]hosp.2/368/26Macaya55%0.45 [0.15-1.06]severe case11/3520/45Hernández83%0.17 [0.07-0.43]death/ICU35162Abrishami76%0.24 [0.06-0.93]death3/479/26Cereda-120%2.20 [1.01-3.22]death10/3024/99Walk-0%1.00 [0.60-1.67]int./death48/11010/23Luo63%0.37 [0.17-0.81]progression335560Jain95%0.05 [0.01-0.18]ICU2/6461/90De Smet70%0.30 [0.10-0.80]death7/7720/109Katz78%0.22 [0.17-0.27]casesAlguwaihes86%0.14 [0.04-0.59]death111328Vassiliou91%0.09 [0.01-1.51]death0/155/15Abdollahi54%0.46 [0.28-0.75]cases108294Szeto-6%1.06 [0.49-2.26]death14/588/35Karonova79%0.21 [0.03-1.28]death1/2312/57Amin-32%1.32 [0.88-1.89]progressionAngelidi88%0.12 [0.02-0.60]death6/6520/79Li36%0.64 [0.53-0.78]severe caseBennouar86%0.14 [0.04-0.50]death4/3015/32Orchard59%0.41 [0.22-0.76]ICU9/4041/75Barassi65%0.35 [0.05-2.69]death1/318/87Demir89%0.11 [0.03-0.44]severe case1399Susianti91%0.09 [0.01-1.34]death0/89/42Infante55%0.45 [0.19-1.10]death4/1955/118Gavioli-5%1.05 [0.78-1.40]death80/26052/177Sulli51%0.49 [0.35-0.69]cases28/7937/51Ricci88%0.12 [0.01-2.28]death0/303/22Lohia15%0.85 [0.47-1.41]death8895Mazziotti37%0.63 [0.40-0.90]progression72/18797/161Charoenngam34%0.66 [0.32-1.33]death12/10029/187Vanegas-Cedillo53%0.47 [0.28-0.81]death95/49421/57Meltzer35%0.65 [0.39-1.10]cases61/1,097118/1,251Freitas41%0.59 [0.38-0.91]death23/17968/311Bayramoğlu70%0.30 [0.09-0.77]severe case10/6024/43Livingston51%0.49 [0.25-0.83]cases16/5231/52Ünsal81%0.19 [0.01-3.87]death0/292/27Savitri88%0.12 [0.05-0.32]symp. case3/2517/17Li9%0.91 [0.79-1.06]cases610/13,650290/4,498AlSafar59%0.41 [0.16-0.99]death16/33710/127Sánchez-Zuno6%0.94 [0.44-2.02]severe case4/818/34Diaz-Curiel73%0.27 [0.07-0.67]ICU3/21491/1,017Dror85%0.15 [0.04-0.44]severe case109/12076/133Campi24%0.76 [0.31-1.83]death6/3913/64Jude72%0.28 [0.25-0.32]hosp.All studies57%0.43 [0.36-0.51]1,535/20,1711,559/12,29457% improvementAll 61 vitamin D COVID-19 sufficiency 7/25/21Tau​2 = 0.35; I​2 = 92.4%; Z = 9.02 (p < 0.0001)Effect extraction pre-specified, see appendixLower RiskIncreased Risk
Figure 6. Random effects meta-analysis for sufficiency studies. This plot pools studies with different effects and vitamin D cutoff levels, and studies may be within hospitalized patients, excluding the risk of hospitalization. However, the prevalence of positive effects is notable. [0.03-0.48]80,000IUdeath10/575/9Improvement, RR [CI]Dose (5d)TreatmentControlAnnweiler63%0.37 [0.06-2.21]80,000IUdeath3/1610/32Loucera (PSM)72%0.28 [0.20-0.39]varies (c)death193193Sánchez-Zuno (RCT)89%0.11 [0.01-1.86]50,000IUsevere case0/224/20Tau​2 = 0.14; I​2 = 42.2%Early treatment78%0.22 [0.12-0.39]13/28819/25478% improvementTan80%0.20 [0.04-0.93]5,000IUoxygen3/1716/26Improvement, RR [CI]Dose (5d)TreatmentControlKrishnan19%0.81 [0.49-1.34]n/adeath8/1684/136Castillo (RCT)85%0.15 [0.01-2.93]0.8mg (c)death0/502/26Rastogi (RCT)53%0.47 [0.24-0.92]300,000IUviral+6/1619/24Murai (RCT)-49%1.49 [0.55-4.05]200,000IUdeath9/1196/118Ling80%0.20 [0.08-0.48]40,000IUdeath73253Jevalikar82%0.18 [0.02-1.69]60,000IUdeath1/1283/69Giannini37%0.63 [0.35-1.09]400,000IUdeath/ICU14/3629/55Nogués (QR)79%0.21 [0.10-0.43]0.8mg (c)death21/44762/391Lakkireddy (RCT)61%0.39 [0.08-1.91]300,000IUdeath2/445/43Lohia11%0.89 [0.32-1.89]n/adeath2669Alcala-Diaz81%0.19 [0.04-0.83]0.8mg (c)death4/7990/458Tau​2 = 0.37; I​2 = 75.3%Late treatment57%0.43 [0.28-0.67]68/1,051316/1,66857% improvementBlanch-Rubió8%0.92 [0.63-1.36]n/acases62/1,30347/799Improvement, RR [CI]Dose (1m)TreatmentControlAnnweiler93%0.07 [0.01-0.61]50,000IUdeath2/2910/32Cereda-73%1.73 [0.81-2.74]variesdeath7/1840/152Louca8%0.92 [0.88-0.94]n/acasesCangiano70%0.30 [0.10-0.87]50,000IUdeath3/2039/78Vasheghani30%0.70 [0.33-1.49]n/adeath7/8848/420Ma30%0.70 [0.50-0.97]n/acases49/3631,329/7,934Sulli50%0.50 [0.34-0.73]n/acases22/6643/64Meltzer36%0.64 [0.29-1.41]n/acases6/131239/3,338Ünsal71%0.29 [0.11-0.76]variespneumonia4/2814/28Oristrell43%0.57 [0.41-0.80]7.4mg (c)death2,2963,407Levitus31%0.69 [0.37-1.24]variessevere case6564Fasano42%0.58 [0.34-0.99]n/acases13/32992/1,157Oristrell-1%1.01 [0.93-1.09]varies (c)deathTau​2 = 0.04; I​2 = 77.0%Prophylaxis26%0.74 [0.63-0.86]175/4,7361,901/17,47326% improvementAll studies47%0.53 [0.44-0.64]256/6,0752,236/19,39547% improvementAll 30 vitamin D COVID-19 treatment 7/25/21Tau​2 = 0.13; I​2 = 85.9%; Z = 6.86 (p < 0.0001)Effect extraction pre-specified, see appendixLower RiskIncreased Risk
Figure 7. Random effects meta-analysis for treatment studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.