Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D 3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D 3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

The general metabolism and actions of vitamin D are well known [ 7 ]. Vitamin D 3 is produced in the skin through the action of UVB radiation reaching 7-dehydrocholesterol in the skin, followed by a thermal reaction. That vitamin D 3 or oral vitamin D is converted to 25(OH)D in the liver and then to the hormonal metabolite, 1,25(OH) 2 D (calcitriol), in the kidneys or other organs as needed. Most of vitamin D’s effect arises from calcitriol entering the nuclear vitamin D receptor, a DNA binding protein that interacts directly with regulatory sequences near target genes and that recruits chromatin active complexes that participate genetically and epigenetically in modifying transcriptional output [ 8 ]. A well-known function of calcitriol is to help regulate serum calcium concentrations, which it does in a feedback loop with parathyroid hormone (PTH), which itself has many important functions in the body [ 7 ]. Several reviews consider the ways in which vitamin D reduces the risk of viral infections [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Vitamin D has many mechanisms by which it reduces the risk of microbial infection and death. A recent review regarding the role of vitamin D in reducing the risk of the common cold grouped those mechanisms into three categories: physical barrier, cellular natural immunity, and adaptive immunity [ 16 ]. Vitamin D helps maintain tight junctions, gap junctions, and adherens junctions (e.g., by E-cadherin) [ 18 ]. Several articles discussed how viruses disturb junction integrity, increasing infection by the virus and other microorganisms [ 19 , 20 , 21 ]. Vitamin D enhances cellular innate immunity partly through the induction of antimicrobial peptides, including human cathelicidin, LL-37, by 1,25-dihdroxyvitamin D [ 22 , 23 ], and defensins [ 24 ]. Cathelicidins exhibit direct antimicrobial activities against a spectrum of microbes, including Gram-positive and Gram-negative bacteria, enveloped and nonenveloped viruses, and fungi [ 25 ]. Those host-derived peptides kill the invading pathogens by perturbing their cell membranes and can neutralize the biological activities of endotoxins [ 26 ]. They have many more important functions, as described therein. In a mouse model, LL-37 reduced influenza A virus replication [ 27 ]. In another laboratory study, 1,25(OH) 2 D reduced the replication of rotavirus both in vitro and in vivo by another process [ 28 ]. A clinical trial reported that supplementation with 4000 IU/d of vitamin D decreased dengue virus infection [ 29 ]. Vitamin D also enhances cellular immunity, in part by reducing the cytokine storm induced by the innate immune system. The innate immune system generates both pro-inflammatory and anti-inflammatory cytokines in response to viral and bacterial infections, as observed in COVID-19 patients [ 30 ]. Vitamin D can reduce the production of pro-inflammatory Th1 cytokines, such as tumor necrosis factor α and interferon γ [ 31 ]. Administering vitamin D reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages ([ 17 ] and references therein). Vitamin D is a modulator of adaptive immunity [ 16 , 32 ]; 1,25(OH) 2 D 3 suppresses responses mediated by the T helper cell type 1 (Th1), by primarily repressing production of inflammatory cytokines IL-2 and interferon gamma (INFγ) [ 33 ]. Additionally, 1,25(OH) 2 D 3 promotes cytokine production by the T helper type 2 (Th2) cells, which helps enhance the indirect suppression of Th1 cells by complementing this with actions mediated by a multitude of cell types [ 34 ]. Furthermore, 1,25(OH) 2 D 3 promotes induction of the T regulatory cells, thereby inhibiting inflammatory processes [ 35 ]. Serum 25(OH)D concentrations tend to decrease with age [ 36 ], which may be important for COVID-19 because case-fatality rates (CFRs) increase with age [ 37 ]. Reasons include less time spent in the sun and reduced production of vitamin D as a result of lower levels of 7-dehydrocholesterol in the skin [ 38 ]. In addition, some pharmaceutical drugs reduce serum 25(OH)D concentrations by activating the pregnane-X receptor [ 39 ]. Such drugs include antiepileptics, antineoplastics, antibiotics, anti-inflammatory agents, antihypertensives, antiretrovirals, endocrine drugs, and some herbal medicines. Pharmaceutical drug use typically increases with age. Vitamin D supplementation also enhances the expression of genes related to antioxidation (glutathione reductase and glutamate–cysteine ligase modifier subunit) [ 40 ]. The increased glutathione production spares the use of ascorbic acid (vitamin C), which has antimicrobial activities [ 41 , 42 ], and has been proposed to prevent and treat COVID-19 [ 43 ]. Moreover, a former director of the Center for Disease Control and Prevention, Dr. Tom Frieden, proposed using vitamin D to combat the COVID-19 pandemic on 23 March 2020 ( https://www.foxnews.com/opinion/former-cdc-chief-tom-friede

The first step in developing a hypothesis is to outline the epidemiological and clinical findings regarding the disease of interest and their relationship with 25(OH)D concentrations. From the recent journal literature, it is known that COVID-19 infection is associated with the increased production of pro-inflammatory cytokines [ 58 ], C-reactive protein [ 30 ], increased risk of pneumonia [ 58 ], sepsis [ 59 ], acute respiratory distress syndrome [ 59 ], and heart failure [ 59 ]. CFRs in China were 6%–10% for those with cardiovascular disease, chronic respiratory tract disease, diabetes, and hypertension [ 37 ]. Two regions hard hit by COVID-19 are regions of high air pollution in China [ 60 ] and northern Italy [ 61 ]. The possible roles of vitamin D for the clinical and epidemiological characteristics of diseases associated with the increased risk of COVID-19 CFR are given in Table 2 . Most of the beneficial effects of vitamin D given in Table 2 are from observational studies of disease incidence or prevalence with respect to serum 25(OH)D concentrations. RCTs comparing outcomes for participants treated or given a placebo are preferred to establish causality related to health outcomes. However, most vitamin D RCTs have not reported that vitamin D supplementation reduced the risk of disease [ 62 , 63 ]. Reasons for the lack of agreement between observational studies and RCTs seems to be due to several factors, including enrolling participants with relatively high 25(OH)D concentrations and using low vitamin D doses and not measuring baseline and achieved 25(OH)D concentrations. Previous studies proposed that RCTs of nutrients such as vitamin D be based on nutrient status, such as 25(OH)D concentration, seeking to enroll participants with low values, supplementing them with enough agent to raise the concentration to values associated with good health, and measuring achieved concentrations as well as cofactors such as vitamin C, omega-3 fatty acids, and magnesium [ 64 , 65 ],. Two recently completed RCTs reported significantly reduced incidence in the secondary analyses for cancer [ 66 ] and diabetes mellitus [ 67 ]. Table 3 lists some findings for vitamin D supplementation in reducing the clinical effects of COVID-19 infection found from treating other diseases. A possible reason for the monotonic increase in CFR with increasing age could be that the presence of chronic diseases increases with age. For example, the global prevalence of diabetes mellitus increases from about 1% below the age of 20 years, to ~10% at 45 years and to 19% at 65 years, decreasing to 14% by 95 years [ 94 ]. Invasive lung cancer incidence rates for females in the United States in 2015 increased from 1.1/100,000 for those aged 30–34 years, to 51.0/100,000 for those aged 50–54 years, 204.1/100,000 for those aged 65–79 years, and 347.3 for those aged 75–79 years [ 95 ]. Several studies report that people with chronic diseases have lower 25(OH)D concentrations than healthy people. A study in Italy reported that male chronic obstructive pulmonary disease patients had mean 25(OH)D concentrations of 16 (95% CI, 13–18) ng/mL, whereas female patients had concentrations of 13 (95% CI, 11–15) ng/ml [ 96 ]. A study in South Korea reported that community-acquired pneumonia (CAP) patients had a mean 25(OH)D concentration at admission of 14 ± 8 ng/mL [ 97 ]. A study in Iran reported that hypertensive patients had lower 25(OH)D concentrations than control subjects: males, 13 ± 11 vs. 21 ± 11 ng/mL; females, 13 ± 10 vs. 20 ± 11 ng/mL [ 98 ]. Another factor that affects immune response with age is reduced 1,25-dihydroxyvitamin D (1,25(OH) 2 D, or calcitriol), the active vitamin D metabolite, with increased age. Parathyroid hormone (PTH) concentration increases with age. A U.S. study was based on 312,962 paired serum PTH and 25(OH)D concentration measurements from July 2010 to June 2011. For participants with 20-ng/mL 25(OH)D concentration, PTH increased from 27 pg/mL for those <20 years to 54 pg/mL for those >60 years [ 99 ]. Serum calcitriol concentrations are inversely related to PTH concentrations. In a study conducted in Norway on patients with a mean age of 50 (SD, 21) years, calcitriol decreased from 140 pmol/L for those aged 20–39 years to 98 pmol/L for those >80 years despite an increase in serum 25(OH)D from 24 ng/mL for those 20–39 years to 27 ng/mL for those >80 years [ 100 ]. The seasonality of many viral infections is associated with low 25(OH)D concentrations, as a result of low UVB doses owing to the winter in temperate climates and the rainy season in tropical climates—such as respiratory syncytial virus (RSV) infection [ 101 , 102 ],. This is the case for influenza [ 45 , 46 ], and SARS-CoV [ 103 ]. However, MERS showed a peak in the April–June quarter [ 104 ], probably affected by both Hajj pilgrims gathering and the fact that 25(OH)D concentrations show little seasonal variation in the Middle East [ 105 ]. In the trop

4.1. Hospital-Acquired Infections Hospitals are a source of RTIs for both patients and medical personnel. For example, during the SARS-CoV epidemic, a woman returned to Toronto from Hong Kong with SARS-CoV in 2003 and went to a hospital. The disease was transmitted to other people, leading to an outbreak among 257 people in several Greater Toronto Area hospitals [ 129 ]. During the 2014–2015 influenza season, 36% of health care workers in a German hospital developed influenza infection [ 130 ]. Working in a hospital dealing with COVID-19 patients is associated with increased risk of COVID-19 infection. For example, 40 of 138 hospitalized COVID-19 patients in Wuhan in the Zhongnan Hospital from 1 to 28 January were medical staff, and 17 more were infected while in the hospital [ 58 ]. It was announced on February 14, 2020, that more than 1700 Chinese health workers were infected by COVID-19 and six had died ( https://www.huffpost.com/entry/chinese-health-workers-infected-by virus_n_5e46a0fec5b64d860fc97c1b). Vitamin D supplementation to raise serum 25(OH)D concentrations can help reduce hospital-associated infections [ 131 ]. Concentrations of at least 40–50 ng/mL (100–125 nmol/L) are indicated on the basis of observational studies [ 132 , 133 ]. During the COVID-19 epidemic, all people in the hospital, including patients and staff, should take vitamin D supplements to raise 25(OH)D concentrations as an important step in preventing infection and spread. Trials on that hypothesis would be worth conducting.