Discussion
We reviewed 80 RCTs that examined the effects of micronutrients on the occurrence and course of ARIs among adults. Vitamin D, vitamin C and MMS reduced the risk of ARIs by 3%–21%. Vitamin D, vitamin C and zinc shortened the duration of ARI symptoms by 6%–59%. Here we explore these results and identify gaps in published studies.
Our findings indicate that vitamin D supplementation reduces ARI risk by 3% overall, and by 18% when ARI was diagnosed based on laboratory testing or clinical diagnosis. This is comparable to findings in previous meta-analyses.7–11 The current study focuses on adults and includes recent trials.36 41 Vitamin D levels are insufficient in ≥50% of the global population, even though moderate sun exposure should be enough to prevent it.107 Vitamin D modulates immunity through effects on macrophage, dendritic and T cell function.108 Vitamin D promotes T-helper 2 (Th2) response and suppresses T-helper 1 (Th1) cells by enhancing interleukin (IL)-4, IL-5 and IL-10 production.109 110 In addition, many pathogens provoke oxidative stress and vitamin D enhances the production of antioxidative enzymes that counter it.108 Notably, the trials were conducted in temperate, high-income countries, limiting the generalisability of our findings to this setting. Further, the studies did not always report baseline levels of vitamin D and any adverse events of supplementation.
Vitamin C was observed to have a modest effect of preventing ARIs and shortening the duration of ARI symptoms. This is consistent with evidence from previously published meta-analyses.12 13 Vitamin C is an important cofactor for enzymes involved in tissue repair after an insult or injury.111 Vitamin C also has critical antioxidant properties, thereby limiting inflammation and improving recovery.112 This effect is stronger in people with vitamin C deficiency, as well as those undergoing stressful conditions.113 Though frank vitamin C deficiency or scurvy is rare, recent studies have shown the potential for adverse consequences in persons with subnormal vitamin C levels.114 Notably, the effect of vitamin C to prevent ARIs was considerably stronger in middle-income countries, compared with high-income ones. There was no significant dose-response relationship of vitamin C with the risk of ARI or duration of symptoms, and included studies did not evaluate the adverse events due to vitamin C.
Evidence from the current and previous meta-analyses demonstrate that zinc supplementation shortens the duration of ARIs considerably.15 17 In addition, zinc supplementation prevents mortality related to severe pneumonia.18 Zinc deficiency is widespread, affecting almost 20% of the global population, and regular intake of adequate quantities of zinc is required to prevent it.115 Zinc is a component of hundreds of enzymes and transcription factors, and plays critical roles in gene expression, cell division and immunity.116 It regulates the proliferation, differentiation, maturation, and functioning of epithelial cells and leucocytes.117 It also modulates the production of T lymphocytes, cytokines and reactive oxygen species.117 118 In addition, zinc improves appetite and its deficiency leads to anorexia, impairing intake of macronutrients and micronutrients essential to mount a robust immune response.117
Multiple micronutrient deficiencies have been previously associated with elevated risk of respiratory infections, especially among the elderly.119 The studies included in this review used diverse formulations, and any inferences regarding the preventive effect of MMS was not possible. MMS, however, shortened the duration of symptoms considerably in the one study among older adults in India that examined it.98 It is plausible that the absence of an observed effect on prevention could be related to the dose of the micronutrients, or the extent of dietary inadequacies and nutritional deficiencies in the study population. Micronutrients are often provided at or below RDA level, which could be inadequate to address existing deficiencies. Evidence from studies of the effect of supplement administration on other viral infections such as HIV also support the potential that MMS could significantly slow disease progression and reduce mortality among HIV-infected individuals.120 121
It is possible that supplementation with vitamin C, zinc and vitamin D, possibly as part of MMS, may prevent SARS-CoV-2 infection and shorten the duration of COVID-19 symptoms. No primary studies have examined the impact of these micronutrients on the risk of SARS-CoV-2 infection. One study that examined the influence of vitamin C on any coronaviruses had only a few cases, and found no significant effect.34 In addition to their general effects as modulators of immunity discussed above, both vitamin D and zinc have antiviral effects, including through induction of cathelicidin to disrupt viral envelopes or by combining with pyrithione to inhibit RNA polymerase activity.122 123 Vitamin D also acts on cellular and genetic pathways that regulate clotting, and may ameliorate COVID-induced coagulation, especially among those with vitamin D deficiency.124 There is preliminary evidence that lower vitamin D levels are present in patients with COVID-19 in comparison to hospital controls, and that the extent of COVID-19 mortality is proportional to the national severity of vitamin D deficiency.125 This evidence is however ecological, and any significant relationships could be due to intractable confounding or systematic differences in assessment of exposure or outcome. Further, the impact of individual or combination micronutrient supplements to shorten the duration of viral respiratory illnesses may be particularly critical to free up healthcare resources, especially bed space in intensive care units and in the general hospital wards. Individuals with the most severe nutritional deficiencies are observed to receive greater benefits from supplementation,10 113 strengthening the ethical imperative to evaluate utility of different supplements in treating and preventing COVID-19. RCTs of these micronutrients among patients with COVID-19 are therefore warranted, particularly during the current stage of the pandemic which provides a unique window to enrol large study populations. These studies should carefully consider differential effects among individuals who may be replete or deficient for the relevant micronutrient, as well as the potential role for supraphysiological amounts.
Determining whether to recommend supplementation and the relevant dose is critical for clinical and public health planning, especially in the context of the ongoing response to COVID-19. We examined the effect of different dose categories on the preventive and treatment effects of the micronutrients evaluated in this meta-analysis. Notably, we found that while vitamin D was 3% protective in the general population, it was 10% protective if the daily dose was ≥2000 IU. We found that providing a monthly or loading dose was beneficial if it was <60 000 IU, but not if it was ≥60 000 IU—possibly because large doses could disrupt enzyme metabolism of vitamin D.126 We also find that weekly dosing (10 000 IU or 20 000 IU) was 30% protective. Using multiple-predictor meta-regression, we identify the best dosing regimen provided a loading dose is >0 IU to <60 000 IU, and a daily dose is ≥2000 IU for prevention of infection. We found no differential effect of dose of vitamin D when used as treatment, and it is plausible that a high loading dose may be warranted particularly among deficient individuals so as to rapidly correct vitamin D status during the narrow window of illness, followed by lower daily maintenance doses. The effects of vitamin C and zinc supplementation were not modified by the dose of supplement provided.
Our review was limited by the availability and nature of primary studies. Most of the studies were conducted in high-income countries, limiting generalisability of our findings to those settings. Many studies classified the outcomes of interest based on self-report, resulting in error which could have reduced our power to identify significant associations. Many of the included studies had high risk of bias or some concerns—partly due to a dependence on self-report for outcome assessment. In addition, there were no studies conducted among pregnant women. Furthermore, it was impractical to examine the impact of micronutrients on the severity of symptoms due to the substantially different ways that severity was assessed in the studies, and this may have contributed to heterogeneity in pooled analyses. Studies used different assays to estimate baseline micronutrient status, due to changes in laboratory standards and techniques over time. There were no significant dose-response relationships for many of the exposure-outcome relationships assessed. Adverse event information was limited, and we are therefore unable to assess the safety of supraphysiological doses. Finally, minimum clinically important differences have not been established for these outcomes, and we are unable to conclude whether these findings are clinically meaningful. Given the mix of the quality or randomised trials reviewed and the sources of bias in the primary studies, we conclude that the evidence presented likely reflects the true effect of the micronutrients on the risk of ARIs, and strength of evidence is moderate. Further research may change some of our conclusions.