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Vitamin C for COVID-19: real-time meta analysis of 49 studies
Covid Analysis, August 19, 2022, DRAFT
https://c19vitaminc.com/meta.html
0 0.5 1 1.5+ All studies 21% 49 56,850 Improvement, Studies, Patients Relative Risk Mortality 28% 30 35,235 Ventilation 18% 4 470 ICU admission 15% 5 654 Hospitalization 14% 8 3,079 Recovery 26% 7 2,027 Cases -8% 4 15,830 Viral clearance 10% 3 256 RCTs 19% 13 1,069 RCT mortality 17% 7 588 Peer-reviewed 22% 42 37,378 High dose IV 21% 16 1,726 Symptomatic 25% 44 40,894 Prophylaxis 3% 9 35,315 Early 24% 5 571 Late 27% 35 20,964 Vitamin C for COVID-19 c19vitaminc.com Aug 2022 Favorsvitamin C Favorscontrol after exclusions
Statistically significant improvements are seen for mortality, ICU admission, and recovery. 17 studies from 17 independent teams in 10 different countries show statistically significant improvements in isolation (10 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 21% [11‑29%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral.
0 0.5 1 1.5+ All studies 21% 49 56,850 Improvement, Studies, Patients Relative Risk Mortality 28% 30 35,235 Ventilation 18% 4 470 ICU admission 15% 5 654 Hospitalization 14% 8 3,079 Recovery 26% 7 2,027 Cases -8% 4 15,830 Viral clearance 10% 3 256 RCTs 19% 13 1,069 RCT mortality 17% 7 588 Peer-reviewed 22% 42 37,378 High dose IV 21% 16 1,726 Symptomatic 25% 44 40,894 Prophylaxis 3% 9 35,315 Early 24% 5 571 Late 27% 35 20,964 Vitamin C for COVID-19 c19vitaminc.com Aug 2022 Favorsvitamin C Favorscontrol after exclusions
The treatment regimen varies widely across studies and may be high-dose IV vitamin C.
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 2% of vitamin C studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments are more effective.
No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.
All data to reproduce this paper and sources are in the appendix. [Bhowmik] present another meta analysis for vitamin C, showing significant improvements for mortality and severity.
Highlights
Vitamin C reduces risk for COVID-19 with very high confidence for mortality, recovery, and in pooled analysis, high confidence for ICU admission, low confidence for hospitalization, and very low confidence for progression.
We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 43 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Su -135% 2.35 [0.67-8.27] progression n/a n/a Improvement, RR [CI] Treatment Control Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Zhao (PSM) 72% 0.28 [0.08-0.93] progression 4/55 12/55 Ried (RCT) 31% 0.69 [0.54-0.89] no recov. 69/162 46/75 Usanma Koban 33% 0.67 [0.07-5.38] viral+ 31 (n) 95 (n) Tau​2 = 0.25, I​2 = 44.8%, p = 0.43 Early treatment 24% 0.76 [0.38-1.50] 74/296 58/275 24% improvement Krishnan 31% 0.69 [0.47-0.92] death 40/79 52/73 Improvement, RR [CI] Treatment Control Zhang (RCT) 50% 0.50 [0.20-1.50] death 6/27 11/29 ICU patients Yüksel (ICU) 19% 0.81 [0.66-0.99] death 31/42 40/44 ICU patients Patel 29% 0.71 [0.43-1.14] death 22/96 26/80 Kumari (RCT) 36% 0.64 [0.26-1.55] death 7/75 11/75 Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 ICU patients CT​2 JamaliMo.. (RCT) 0% 1.00 [0.22-4.56] death 3/30 3/30 Gao 86% 0.14 [0.03-0.72] death 1/46 5/30 Hamidi-A.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​2 Al Sulaiman (PSM) 15% 0.85 [0.61-1.12] death 46/142 59/142 Mulhem -32% 1.32 [1.07-1.62] death 157/794 359/2,425 Gadhiya -1% 1.01 [0.48-1.91] death 19/55 36/226 Hakamifard (RCT) 46% 0.54 [0.14-2.08] ICU 3/38 5/34 CT​2 Elhadi (ICU) -12% 1.12 [0.96-1.31] death 175/277 106/188 ICU patients Suna 21% 0.79 [0.44-1.41] death 17/153 24/170 Pourhoseingholi 13% 0.87 [0.63-1.19] death 54/199 285/2,269 Li (ICU) -11% 1.11 [0.79-1.54] death 7/8 19/24 ICU patients Vishnuram 54% 0.46 [0.24-0.86] death 164/8,634 10/241 Özgünay (ICU) 9% 0.91 [0.63-1.30] death 17/32 75/128 ICU patients Tan 25% 0.75 [0.10-2.98] death/int. 1/46 14/115 CT​2 Zheng (PSM) -157% 2.57 [0.39-16.8] death 12/70 7/327 Simsek 44% 0.56 [0.23-1.35] death 6/58 15/81 Shousha 94% 0.06 [0.01-0.37] death 22/340 31/207 Tehrani (RCT) 87% 0.13 [0.01-2.25] death 0/18 4/26 Majidi (DB RCT) 14% 0.86 [0.74-1.01] death 26/31 67/69 ICU patients Baguma -48% 1.48 [0.41-4.70] death 385 (n) 96 (n) Tu 83% 0.17 [0.08-0.35] death 8/116 26/64 Yang (RCT) 15% 0.85 [0.68-1.06] recov. time 10 (n) 10 (n) LD​3 Gavrielatou (ICU) 58% 0.42 [0.12-1.48] death 2/10 49/103 ICU patients Salehi (ICU) 10% 0.90 [0.65-1.25] death 22/40 52/85 ICU patients Coppock (RCT) 5% 0.95 [0.16-7.84] progression 4/44 2/22 Hess (PSW) 20% 0.80 [0.40-1.60] death 10/25 37/75 Zangeneh (ICU) 4% 0.96 [0.64-1.45] death n/a n/a ICU patients Izzo 41% 0.59 [0.50-0.69] recovery 869 (n) 521 (n) LONG COVID OT​1 CT​2 Fogleman (DB RCT) 4% 0.96 [0.65-1.40] recovery 32 (n) 34 (n) Tau​2 = 0.16, I​2 = 83.7%, p = 0.00026 Late treatment 27% 0.73 [0.61-0.86] 889/12,871 1,442/8,093 27% improvement Behera 18% 0.82 [0.45-1.57] cases case control Improvement, RR [CI] Treatment Control Louca 0% 1.00 [0.97-1.04] cases Mahto -26% 1.26 [0.63-2.28] IgG+ 34/140 59/549 Holt -3% 1.03 [0.77-1.39] cases 49/1,580 397/13,647 Abdulateef 19% 0.81 [0.37-1.78] hosp. 8/132 22/295 Mohseni -44% 1.44 [1.22-1.71] cases 34/43 307/560 Nimer 25% 0.75 [0.54-1.04] hosp. 52/651 167/1,497 Shehab 4% 0.96 [0.46-1.99] severe case 14/139 12/114 Loucera 28% 0.72 [0.58-0.88] death 840 (n) 15,128 (n) Tau​2 = 0.04, I​2 = 76.2%, p = 0.77 Prophylaxis 3% 0.97 [0.83-1.15] 191/3,525 964/31,790 3% improvement All studies 21% 0.79 [0.71-0.89] 1,154/16,692 2,464/40,158 21% improvement 49 vitamin C COVID-19 studies c19vitaminc.com Aug 2022 Tau​2 = 0.09, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment3 LD: comparison with low dose treatment 2 CT: study uses combined treatment Favors vitamin C Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Su -135% progression Improvement Relative Risk [CI] Thomas (RCT) -204% death Zhao (PSM) 72% progression Ried (RCT) 31% recovery Usanma Koban 33% viral- Tau​2 = 0.25, I​2 = 44.8%, p = 0.43 Early treatment 24% 24% improvement Krishnan 31% death Zhang (RCT) 50% death ICU patients Yüksel (ICU) 19% death ICU patients Patel 29% death Kumari (RCT) 36% death Darban (RCT) 33% progression ICU patients CT​2 JamaliMo.. (RCT) 0% death Gao 86% death Hamidi-A.. (RCT) 44% death CT​2 Al Sulaiman (PSM) 15% death Mulhem -32% death Gadhiya -1% death Hakamifard (RCT) 46% ICU admission CT​2 Elhadi (ICU) -12% death ICU patients Suna 21% death Pourhoseingholi 13% death Li (ICU) -11% death ICU patients Vishnuram 54% death Özgünay (ICU) 9% death ICU patients Tan 25% death/intubation CT​2 Zheng (PSM) -157% death Simsek 44% death Shousha 94% death Tehrani (RCT) 87% death Majidi (DB RCT) 14% death ICU patients Baguma -48% death Tu 83% death Yang (RCT) 15% recovery LD​3 Gavrielatou (ICU) 58% death ICU patients Salehi (ICU) 10% death ICU patients Coppock (RCT) 5% progression Hess (PSW) 20% death Zangeneh (ICU) 4% death ICU patients Izzo 41% recovery LONG COVID OT​1 CT​2 Fogleman (DB RCT) 4% recovery Tau​2 = 0.16, I​2 = 83.7%, p = 0.00026 Late treatment 27% 27% improvement Behera 18% case Louca 0% case Mahto -26% IgG positive Holt -3% case Abdulateef 19% hospitalization Mohseni -44% case Nimer 25% hospitalization Shehab 4% severe case Loucera 28% death Tau​2 = 0.04, I​2 = 76.2%, p = 0.77 Prophylaxis 3% 3% improvement All studies 21% 21% improvement 49 vitamin C COVID-19 studies c19vitaminc.com Aug 2022 Tau​2 = 0.09, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specifiedRotate device for footnotes/details Favors vitamin C Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of vitamin C for 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 all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Preclinical Research
3 In Silico studies support the efficacy of vitamin C [Kumar, Malla, Pandya].
2 In Vitro studies support the efficacy of vitamin C [Goc, Hajdrik].
An In Vivo animal study supports the efficacy of vitamin C [Zuo].
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Figure 3 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, high dose IV studies, peer reviewed studies, and non-symptomatic vs. symptomatic results.
0 0.5 1 1.5+ ALL STUDIES MORTALITY VENTILATION ICU ADMISSION HOSPITALIZATION RECOVERY CASES VIRAL CLEARANCE RANDOMIZED CONTROLLED TRIALS RCT MORTALITY PEER-REVIEWED HIGH DOSE IV After Exclusions ALL STUDIES All Prophylaxis Early Late Vitamin C for COVID-19 C19VITAMINC.COM AUG 2022
Figure 3. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 3 5 60.0% 24% improvement
RR 0.76 [0.38‑1.50]
p = 0.43
Late treatment 28 35 80.0% 27% improvement
RR 0.73 [0.61‑0.86]
p = 0.00026
Prophylaxis 5 9 55.6% 3% improvement
RR 0.97 [0.83‑1.15]
p = 0.77
All studies 36 49 73.5% 21% improvement
RR 0.79 [0.71‑0.89]
p < 0.0001
Table 1. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 4924% [-50‑62%]27% [14‑39%]3% [-15‑17%] 56,850 539
With exclusions 333% [-95‑52%]35% [19‑48%]12% [-8‑27%] 26,021 376
Peer-reviewed 4224% [-50‑62%]32% [16‑45%]-3% [-22‑13%] 37,378 451
Randomized Controlled TrialsRCTs 1330% [10‑46%]16% [5‑25%] 1,069 149
Table 2. Results by treatment stage for all studies and with different exclusions.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Su -135% 2.35 [0.67-8.27] progression n/a n/a Improvement, RR [CI] Treatment Control Thomas (RCT) -204% 3.04 [0.13-72.9] death 1/48 0/50 Zhao (PSM) 72% 0.28 [0.08-0.93] progression 4/55 12/55 Ried (RCT) 31% 0.69 [0.54-0.89] no recov. 69/162 46/75 Usanma Koban 33% 0.67 [0.07-5.38] viral+ 31 (n) 95 (n) Tau​2 = 0.25, I​2 = 44.8%, p = 0.43 Early treatment 24% 0.76 [0.38-1.50] 74/296 58/275 24% improvement Krishnan 31% 0.69 [0.47-0.92] death 40/79 52/73 Improvement, RR [CI] Treatment Control Zhang (RCT) 50% 0.50 [0.20-1.50] death 6/27 11/29 ICU patients Yüksel (ICU) 19% 0.81 [0.66-0.99] death 31/42 40/44 ICU patients Patel 29% 0.71 [0.43-1.14] death 22/96 26/80 Kumari (RCT) 36% 0.64 [0.26-1.55] death 7/75 11/75 Darban (RCT) 33% 0.67 [0.14-3.17] progression 2/10 3/10 ICU patients CT​2 JamaliMo.. (RCT) 0% 1.00 [0.22-4.56] death 3/30 3/30 Gao 86% 0.14 [0.03-0.72] death 1/46 5/30 Hamidi-A.. (RCT) 44% 0.56 [0.20-1.51] death 5/40 9/40 CT​2 Al Sulaiman (PSM) 15% 0.85 [0.61-1.12] death 46/142 59/142 Mulhem -32% 1.32 [1.07-1.62] death 157/794 359/2,425 Gadhiya -1% 1.01 [0.48-1.91] death 19/55 36/226 Hakamifard (RCT) 46% 0.54 [0.14-2.08] ICU 3/38 5/34 CT​2 Elhadi (ICU) -12% 1.12 [0.96-1.31] death 175/277 106/188 ICU patients Suna 21% 0.79 [0.44-1.41] death 17/153 24/170 Pourhoseingholi 13% 0.87 [0.63-1.19] death 54/199 285/2,269 Li (ICU) -11% 1.11 [0.79-1.54] death 7/8 19/24 ICU patients Vishnuram 54% 0.46 [0.24-0.86] death 164/8,634 10/241 Özgünay (ICU) 9% 0.91 [0.63-1.30] death 17/32 75/128 ICU patients Tan 25% 0.75 [0.10-2.98] death/int. 1/46 14/115 CT​2 Zheng (PSM) -157% 2.57 [0.39-16.8] death 12/70 7/327 Simsek 44% 0.56 [0.23-1.35] death 6/58 15/81 Shousha 94% 0.06 [0.01-0.37] death 22/340 31/207 Tehrani (RCT) 87% 0.13 [0.01-2.25] death 0/18 4/26 Majidi (DB RCT) 14% 0.86 [0.74-1.01] death 26/31 67/69 ICU patients Baguma -48% 1.48 [0.41-4.70] death 385 (n) 96 (n) Tu 83% 0.17 [0.08-0.35] death 8/116 26/64 Yang (RCT) 15% 0.85 [0.68-1.06] recov. time 10 (n) 10 (n) LD​3 Gavrielatou (ICU) 58% 0.42 [0.12-1.48] death 2/10 49/103 ICU patients Salehi (ICU) 10% 0.90 [0.65-1.25] death 22/40 52/85 ICU patients Coppock (RCT) 5% 0.95 [0.16-7.84] progression 4/44 2/22 Hess (PSW) 20% 0.80 [0.40-1.60] death 10/25 37/75 Zangeneh (ICU) 4% 0.96 [0.64-1.45] death n/a n/a ICU patients Izzo 41% 0.59 [0.50-0.69] recovery 869 (n) 521 (n) LONG COVID OT​1 CT​2 Fogleman (DB RCT) 4% 0.96 [0.65-1.40] recovery 32 (n) 34 (n) Tau​2 = 0.16, I​2 = 83.7%, p = 0.00026 Late treatment 27% 0.73 [0.61-0.86] 889/12,871 1,442/8,093 27% improvement Behera 18% 0.82 [0.45-1.57] cases case control Improvement, RR [CI] Treatment Control Louca 0% 1.00 [0.97-1.04] cases Mahto -26% 1.26 [0.63-2.28] IgG+ 34/140 59/549 Holt -3% 1.03 [0.77-1.39] cases 49/1,580 397/13,647 Abdulateef 19% 0.81 [0.37-1.78] hosp. 8/132 22/295 Mohseni -44% 1.44 [1.22-1.71] cases 34/43 307/560 Nimer 25% 0.75 [0.54-1.04] hosp. 52/651 167/1,497 Shehab 4% 0.96 [0.46-1.99] severe case 14/139 12/114 Loucera 28% 0.72 [0.58-0.88] death 840 (n) 15,128 (n) Tau​2 = 0.04, I​2 = 76.2%, p = 0.77 Prophylaxis 3% 0.97 [0.83-1.15] 191/3,525 964/31,790 3% improvement All studies 21% 0.79 [0.71-0.89] 1,154/16,692 2,464/40,158 21% improvement 49 vitamin C COVID-19 studies c19vitaminc.com Aug 2022 Tau​2 = 0.09, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment3 LD: comparison with low dose treatment 2 CT: study uses combined treatment Favors vitamin C Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Su -135% progression Improvement Relative Risk [CI] Thomas (RCT) -204% death Zhao (PSM) 72% progression Ried (RCT) 31% recovery Usanma Koban 33% viral- Tau​2 = 0.25, I​2 = 44.8%, p = 0.43 Early treatment 24% 24% improvement Krishnan 31% death Zhang (RCT) 50% death ICU patients Yüksel (ICU) 19% death ICU patients Patel 29% death Kumari (RCT) 36% death Darban (RCT) 33% progression ICU patients CT​2 JamaliMo.. (RCT) 0% death Gao 86% death Hamidi-A.. (RCT) 44% death CT​2 Al Sulaiman (PSM) 15% death Mulhem -32% death Gadhiya -1% death Hakamifard (RCT) 46% ICU admission CT​2 Elhadi (ICU) -12% death ICU patients Suna 21% death Pourhoseingholi 13% death Li (ICU) -11% death ICU patients Vishnuram 54% death Özgünay (ICU) 9% death ICU patients Tan 25% death/intubation CT​2 Zheng (PSM) -157% death Simsek 44% death Shousha 94% death Tehrani (RCT) 87% death Majidi (DB RCT) 14% death ICU patients Baguma -48% death Tu 83% death Yang (RCT) 15% recovery LD​3 Gavrielatou (ICU) 58% death ICU patients Salehi (ICU) 10% death ICU patients Coppock (RCT) 5% progression Hess (PSW) 20% death Zangeneh (ICU) 4% death ICU patients Izzo 41% recovery LONG COVID OT​1 CT​2 Fogleman (DB RCT) 4% recovery Tau​2 = 0.16, I​2 = 83.7%, p = 0.00026 Late treatment 27% 27% improvement Behera 18% case Louca 0% case Mahto -26% IgG positive Holt -3% case Abdulateef 19% hospitalization Mohseni -44% case Nimer 25% hospitalization Shehab 4% severe case Loucera 28% death Tau​2 = 0.04, I​2 = 76.2%, p = 0.77 Prophylaxis 3% 3% improvement All studies 21% 21% improvement 49 vitamin C COVID-19 studies c19vitaminc.com Aug 2022 Tau​2 = 0.09, I​2 = 83.1%, p < 0.0001 Effect extraction pre-specifiedRotate device for footnotes/details Favors vitamin C Favors control
Figure 4. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Thomas (RCT) -204% 3.04 [0.13-72.9] 1/48 0/50 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.5 Early treatment -204% 3.04 [0.13-72.9] 1/48 0/50 -204% improvement Krishnan 31% 0.69 [0.47-0.92] 40/79 52/73 Improvement, RR [CI] Treatment Control Zhang (RCT) 50% 0.50 [0.20-1.50] 6/27 11/29 ICU patients Yüksel (ICU) 19% 0.81 [0.66-0.99] 31/42 40/44 ICU patients Patel 29% 0.71 [0.43-1.14] 22/96 26/80 Kumari (RCT) 36% 0.64 [0.26-1.55] 7/75 11/75 JamaliMo.. (RCT) 0% 1.00 [0.22-4.56] 3/30 3/30 Gao 86% 0.14 [0.03-0.72] 1/46 5/30 Hamidi-A.. (RCT) 44% 0.56 [0.20-1.51] 5/40 9/40 CT​1 Al Sulaiman (PSM) 15% 0.85 [0.61-1.12] 46/142 59/142 Mulhem -32% 1.32 [1.07-1.62] 157/794 359/2,425 Gadhiya -1% 1.01 [0.48-1.91] 19/55 36/226 Elhadi (ICU)