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Vitamin D for COVID-19: real-time meta analysis of 75 studies
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96% of 23 vitamin D treatment studies report positive effects (13 statistically significant in isolation).
Random effects meta-analysis with pooled effects using the most serious outcome reported shows 78% and 53% improvement for early treatment and for all studies (RR 0.22 [0.12-0.43] and 0.47 [0.36-0.60]). Results are similar after restriction to 17 peer-reviewed studies: 81% and 55% (RR 0.19 [0.06-0.61] and 0.45 [0.33-0.61]).
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. The only treatment study reporting a negative effect is a very late stage cholecalciferol study.
Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta analysis of the 52 studies with pooled effects using the most serious outcome reported shows 53% improvement (RR 0.47 [0.40-0.55]).
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 4% of vitamin D treatment studies show zero events in the treatment arm. Multiple approaches are required to protect everyone from all existing and future variants.
All data to reproduce this paper and the sources are in the appendix.
ImprovementStudies AuthorsPatients
Treatment RCTs 50% [14‑71%] 5 56 1,370
Treatment studies 53% [40‑64%] 23 236 23,046
Calcifediol/calcitriol treatment 62% [43‑75%] 4 43 7,095
Treatment mortality 63% [45‑75%] 14 127 8,818
Sufficiency studies 53% [45‑60%] 52 419 12,067
    
  
A
00.250.50.7511.251.51.752+Annweiler0.11[0.03-0.48]80,000IUdeath10/575/9RRCIDose (5d)TreatmentControlAnnweiler0.37[0.06-2.21]80,000IUdeath3/1610/32Loucera (PSM)0.28[0.20-0.39]varies (c)death193193Tau​2 = 0.19; I​2 = 58.8%Early treatment0.22[0.12-0.43]13/26615/23478% improvementTan0.20[0.04-0.93]5,000IUoxygen3/1716/26RRCIDose (5d)TreatmentControlCastillo (RCT)0.15[0.01-2.94]0.8mg (c)death0/502/26Rastogi (RCT)0.47[0.24-0.92]300,000IUviral+6/1619/24Murai (RCT)1.49[0.55-4.05]200,000IUdeath9/1196/118Ling0.20[0.08-0.48]40,000IUdeath73253Jevalikar0.18[0.02-1.70]60,000IUdeath1/1283/69Giannini0.63[0.35-1.09]400,000IUdeath/ICU14/3629/55Nogués (CLUS. RCT)0.36[0.19-0.67]0.8mg (c)death36/55157/379CS​1Lakkireddy (RCT)0.39[0.08-1.91]300,000IUdeath2/445/43Lohia0.89[0.32-1.89]n/adeath2669Tau​2 = 0.23; I​2 = 65.8%Late treatment0.48[0.31-0.72]71/1,060137/1,06252% improvementBlanch-Rubió0.92[0.63-1.36]n/acases62/1,30347/799RRCIDose (1m)TreatmentControlAnnweiler0.07[0.01-0.61]50,000IUdeath2/2910/32Louca0.92[0.88-0.94]n/acasesCangiano0.30[0.10-0.87]50,000IUdeath3/2039/78Vasheghani0.70[0.33-1.49]n/adeath7/8848/420Ma0.70[0.50-0.97]n/acases49/3631,329/7,934Sulli0.50[0.34-0.73]n/acases22/6643/64Meltzer0.64[0.29-1.41]n/acases6/131239/3,338Ünsal0.29[0.11-0.76]variespneumonia4/2814/28Oristrell0.57[0.41-0.80]7.4mg (c)death2,2963,407Tau​2 = 0.11; I​2 = 78.6%Prophylaxis0.60[0.46-0.79]155/4,3241,769/16,10040% improvementAll studies0.47[0.36-0.60]239/5,6501,921/17,39653% improvementAll 23 vitamin D COVID-19 treatment studiesvdmeta.com 5/12/211 CS: preprint censoredTau​2 = 0.24; I​2 = 85.9%; Z = 5.82 (p < 0.0001)Lower RiskIncreased Risk
    
  
B
00.250.50.7511.251.51.752+Sufficiency studiesTreatment studiesmin, Q1, median, Q3, maxLower RiskIncreased Riskvdmeta.com 5/12/21
    
  
C
100+ 75 50 25 25 50 75 100 Tanoxygen, p=0.04Castillodeath, p=0.11Annweilerdeath, p=0.002Blanch-Rubiócases, p=0.68Annweilerdeath, p=0.02Annweilerdeath, p=0.28Rastogiviral+, 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<0.0001Treatment studies% Lower Risk% Increased Riskvdmeta.com 5/12/21
    
  
D
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=0.002Barassi, 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=0.23Sufficiency studies% Lower Risk% Increased Riskvdmeta.com 5/12/21
Figure 1. A. Random effects meta-analysis of treatment studies. This plot shows pooled effects using the most serious outcome reported. Analysis for individual outcomes is below, and more details on pooled effects can be found in the heterogeneity section. 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 full details see the appendix. Note that [Nogués] was censored, see [Covid Analysis] for more details. 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.
Introduction
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 [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.
Sufficiency.
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 groups having sufficient and insufficient levels.
Treatment.
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.
Results
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, and 13 show forest plots for all treatment studies with pooled effects, RCT studies only, calcifediol/calcitriol studies only, 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 47 52 90.4% 53% improvement
RR 0.47 [0.40‑0.55]
p < 0.0001
Early treatment 3 3 100% 78% improvement
RR 0.22 [0.12‑0.43]
p < 0.0001
Late treatment 9 10 90.0% 52% improvement
RR 0.48 [0.31‑0.72]
p = 0.0005
Prophylaxis 10 10 100% 40% improvement
RR 0.60 [0.46‑0.79]
p = 0.00026
All treatment studies 22 23 95.7% 53% improvement
RR 0.47 [0.36‑0.60]
p < 0.0001
Table 1. Results.
    
  
00.250.50.7511.251.51.752+All treatment studiesProphylaxisLate treatmentEarly treatmentmin, Q1, median, Q3, maxLower RiskIncreased Riskvdmeta.com 5/12/21
Figure 4. Results by treatment stage.
    
  
100+ 75 50 25 25 50 75 100 Annweilerdeath, p=0.002Annweilerdeath, p=0.28Louceradeath, p<0.0001Early treatmentTanoxygen, p=0.04Castillodeath, 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=0.75Late treatmentBlanch-Rubiócases, p=0.68Annweilerdeath, p=0.02Loucacases, p=0.0007Cangianodeath, p=0.04Vasheghanideath, p=0.45Macases, p=0.03Sullicases, p=0.0002Meltzercases, p=0.38Ünsalpneumonia, p=0.009Oristrelldeath, p=0.001Prophylaxis% Lower Risk% Increased Riskvdmeta.com 5/12/21
Figure 5. Results by treatment stage.
    
  
00.250.50.7511.251.51.752+Lau0.55[0.18-1.68]ICURRCIMendy0.93[0.33-2.47]deathPanagiotou0.48[0.24-0.95]ICUFaul0.31[0.10-0.95]ventilationMerzon0.54[0.23-1.02]hosp.Carpagnano0.29[0.10-0.85]deathIm0.27[0.11-0.69]casesHastie0.83[0.57-1.20]deathBaktash0.71[0.18-2.78]deathMeltzer0.56[0.36-0.89]casesIsrael0.79[0.75-0.84]casesRadujkovic0.07[0.01-0.37]deathKaufman0.47[0.29-0.76]casesMaghbooli0.48[0.22-1.05]deathKarahan0.17[0.08-0.41]deathYılmaz0.27[0.01-5.14]severe caseFaniyi0.71[0.59-0.86]seropositiveYe0.07[0.01-0.81]hosp.Macaya0.45[0.15-1.06]severe caseHernández0.17[0.07-0.43]death/ICUAbrishami0.24[0.06-0.93]deathCereda2.20[1.01-3.22]deathWalk1.00[0.60-1.67]int./deathLuo0.37[0.17-0.81]progressionJain0.05[0.01-0.18]ICUDe Smet0.30[0.10-0.80]deathKatz0.22[0.17-0.27]casesAlguwaihes0.14[0.04-0.59]deathVassiliou0.09[0.01-1.51]deathAbdollahi0.46[0.28-0.75]casesSzeto1.06[0.49-2.26]deathKaronova0.21[0.03-1.28]deathAmin1.32[0.88-1.89]progressionAngelidi0.12[0.02-0.60]deathLi0.64[0.53-0.78]severe caseBennouar0.14[0.04-0.50]deathBarassi0.35[0.05-2.69]deathDemir0.11[0.03-0.44]severe caseSusianti0.09[0.01-1.34]deathInfante0.45[0.19-1.10]deathGavioli1.05[0.78-1.40]deathSulli0.49[0.35-0.69]casesRicci0.12[0.01-2.28]deathLohia0.85[0.47-1.41]deathMazziotti0.63[0.40-0.90]progressionCharoenngam0.66[0.32-1.33]deathVanegas-Cedillo0.47[0.28-0.81]deathMeltzer0.65[0.39-1.10]casesFreitas0.59[0.38-0.91]deathBayramoğlu0.30[0.09-0.77]severe caseLivingston0.49[0.25-0.83]casesÜnsal0.19[0.01-3.87]deathAll studies0.47[0.40-0.55]53% improvementAll 52 vitamin D COVID-19 sufficiency studiesvdmeta.com 5/12/21Tau​2 = 0.17; I​2 = 80.4%; Z = 9.52 (p < 0.0001)Lower RiskIncreased Risk
Figure 6. Random effects meta-analysis for sufficiency studies.
    
  
00.250.50.7511.251.51.752+Annweiler0.11[0.03-0.48]80,000IUdeath10/575/9RRCIDose (5d)TreatmentControlAnnweiler0.37[0.06-2.21]80,000IUdeath3/1610/32Loucera (PSM)0.28[0.20-0.39]varies (c)death193193Tau​2 = 0.19; I​2 = 58.8%Early treatment0.22[0.12-0.43]13/26615/23478% improvementTan0.20[0.04-0.93]5,000IUoxygen3/1716/26RRCIDose (5d)TreatmentControlCastillo (RCT)0.15[0.01-2.94]0.8mg (c)death0/502/26Rastogi (RCT)0.47[0.24-0.92]300,000IUviral+6/1619/24Murai (RCT)1.49[0.55-4.05]200,000IUdeath9/1196/118Ling0.20[0.08-0.48]40,000IUdeath73253Jevalikar0.18[0.02-1.70]60,000IUdeath1/1283/69Giannini0.63[0.35-1.09]400,000IUdeath/ICU14/3629/55Nogués (CLUS. RCT)0.36[0.19-0.67]0.8mg (c)death36/55157/379CS​1Lakkireddy (RCT)0.39[0.08-1.91]300,000IUdeath2/445/43Lohia0.89[0.32-1.89]n/adeath2669Tau​2 = 0.23; I​2 = 65.8%Late treatment0.48[0.31-0.72]71/1,060137/1,06252% improvementBlanch-Rubió0.92[0.63-1.36]n/acases62/1,30347/799RRCIDose (1m)TreatmentControlAnnweiler0.07[0.01-0.61]50,000IUdeath2/2910/32Louca0.92[0.88-0.94]n/acasesCangiano0.30[0.10-0.87]50,000IUdeath3/2039/78Vasheghani0.70[0.33-1.49]n/adeath7/8848/420Ma0.70[0.50-0.97]n/acases49/3631,329/7,934Sulli0.50[0.34-0.73]n/acases22/6643/64Meltzer0.64[0.29-1.41]n/acases6/131239/3,338Ünsal0.29[0.11-0.76]variespneumonia4/2814/28Oristrell0.57[0.41-0.80]7.4mg (c)death2,2963,407Tau​2 = 0.11; I​2 = 78.6%Prophylaxis0.60[0.46-0.79]155/4,3241,769/16,10040% improvementAll studies0.47[0.36-0.60]239/5,6501,921/17,39653% improvementAll 23 vitamin D COVID-19 treatment studiesvdmeta.com 5/12/211 CS: preprint censoredTau​2 = 0.24; I​2 = 85.9%; Z = 5.82 (p < 0.0001)Lower RiskIncreased Risk
Figure 7. Random effects meta-analysis for treatment studies.
00.250.50.7511.251.51.752+Annweiler0.11[0.03-0.48]80,000IUdeath10/575/9RRCIDose (5d)TreatmentControlAnnweiler0.37[0.06-2.21]80,000IUdeath3/1610/32Tau​2 = 0.48; I​2 = 65.3%Early treatment0.19[0.06-0.61]13/7315/4181% improvementTan0.20[0.04-0.93]5,000IUoxygen3/1716/26RRCIDose (5d)TreatmentControlCastillo (RCT)0.15[0.01-2.94]0.8mg (c)death0/502/26Rastogi (RCT)0.47[0.24-0.92]300,000IUviral+6/1619/24Murai (RCT)1.49[0.55-4.05]200,000IUdeath9/1196/118Ling0.20[0.08-0.48]40,000IUdeath73253Jevalikar0.18[0.02-1.70]60,000IUdeath1/1283/69Giannini0.63[0.35-1.09]400,000IUdeath/ICU14/3629/55Lohia0.89[0.32-1.89]n/adeath2669Tau​2 = 0.24; I​2 = 63.7%Late treatment0.51[0.31-0.82]33/46575/64049% improvementBlanch-Rubió0.92[0.63-1.36]n/acases62/1,30347/799RRCIDose (1m)TreatmentControlAnnweiler0.07[0.01-0.61]50,000IUdeath2/2910/32Cangiano0.30[0.10-0.87]50,000IUdeath3/2039/78Ma0.70[0.50-0.97]n/acases49/3631,329/7,934Sulli0.50[0.34-0.73]n/acases22/6643/64Meltzer0.64[0.29-1.41]n/acases6/131239/3,338Ünsal0.29[0.11-0.76]variespneumonia4/2814/28Tau​2 = 0.15; I​2 = 69.3%Prophylaxis0.51[0.35-0.75]148/1,9401,721/12,27349% improvementAll studies0.45[0.33-0.61]194/2,4781,811/12,95455% improvementAll 17 vitamin D COVID-19 peer reviewed trialsvdmeta.com 5/12/21Tau​2 = 0.23; I​2 = 72.1%; Z = 5.09 (p < 0.0001)Lower RiskIncreased Risk
Figure 8. Random effects meta-analysis for peer-reviewed treatment studies.
00.250.50.7511.251.51.752+Castillo (RCT)0.15[0.01-2.94]0.8mg (c)death0/502/26RRCIDose (5d)TreatmentControlRastogi (RCT)0.47[0.24-0.92]300,000IUviral+6/1619/24Murai (RCT)1.49[0.55-4.05]200,000IUdeath9/1196/118Nogués (CLUS. RCT)0.36[0.19-0.67]0.8mg (c)death36/55157/379CS​1Lakkireddy (RCT)0.39[0.08-1.91]300,000IUdeath2/445/43Tau​2 = 0.15; I​2 = 44.9%Late treatment0.50[0.29-0.86]53/78089/59050% improvementAll studies0.50[0.29-0.86]53/78089/59050% improvementAll 5 vitamin D COVID-19 Randomized Controlled Trialsvdmeta.com 5/12/211 CS: preprint censoredTau​2 = 0.15; I​2 = 44.9%; Z = 2.51 (p = 0.0061)Lower RiskIncreased Risk
Figure 9. Random effects meta-analysis for treatment RCTs.
00.250.50.7511.251.51.752+Loucera (PSM)0.28[0.20-0.39]varies (c)death193193RRCIDose (5d)TreatmentControlTau​2 = 0.00; I​2 = 0.0%Early treatment0.28[0.20-0.39]0/1930/19372% improvementCastillo (RCT)0.15