key: cord-0738441-4smy70z6 authors: Lahoor Basha, Shaik; Suresh, Sake; Ashok Reddy, V.V.; Surya Teja, S.P. title: Is the shielding effect of cholecalciferol in SARS CoV-2 infection dependable? An evidence based unraveling date: 2020-10-21 journal: Clin Epidemiol Glob Health DOI: 10.1016/j.cegh.2020.10.005 sha: f7fee92eb83f4fa4fc259207174cb6bf31905d6e doc_id: 738441 cord_uid: 4smy70z6 Despite being announced as a global health concern and emergency in January by WHO, designing specific treatment for SARS-CoV-2 is still a summit yet to be conquered. Currently, many drugs are being tested in the clinical scenario and vitamins play a significant role in therapeutic management. Based on the available evidence, we postulate that maintaining normal vitamin D(3) levels may reduce severity, mortality risk of COVID-19. This review elucidates the alarming need for randomized clinical trials to determine the role of vitamin D in patient prognosis in COVID-19 infection and on latitude bases epidemiological outcome. Vitamin D, a fat-soluble vitamin, has a crucial role in bone metabolism and calcium homeostasis. Vitamin D exists in two forms, namely, D2 (derived from plants) and D3 (cholecalciferol; derived from animals and humans). 1 Dietary and sunlight assisted (Ultra Violet-B radiation) conversion of 7-dehydrocholesterol present in the skin to cholecalciferol is the primary sources of vitamin D. [1] The produced vitamin D3 or dietary vitamin D is metabolized to 25(OH)D in the liver and then to calcitriol in the kidneys which regulate the calcium levels by negative feedback mechanism with parathyroid hormone (PTH). 2 Recent research indicates that vitamin D plays a significant role in inflammation, immunity, and host defense mechanisms; aids in the prevention of RTIs in terms of frequency and mortality. [3] The vitamin D induces the production of antimicrobial peptides, such as cathelicidins (LL-37) and β-defensins and activates innate immunity partly by toxin neutralization and chemotactic action of antimicrobial peptides. [4] [5] [6] Cathelicidins predominantly exhibit direct microbicidal activity against a spectrum of pathogens, including enveloped and nonenveloped viruses, gram-positive and gramnegative bacteria, and fungi. 7 The anti-viral activity of LL-37 was verified by Barlow PG et al in murine models and their research findings depicted that LL-37 decreased the viral replication of influenza A virus, elucidating anti-viral activity. 8 In addition, Vitamin D also governs the activities of dendritic cells and macrophages, as well as the activation of Toll-Like Receptors (TLRs). 9 This in turn leads to the expression of antimicrobial peptides and the subsequent eradication of the pathogens. 10 In COVID-19 patients, a proliferation of both anti-inflammatory and proinflammatory cytokines has been observed in response to innate immune system provoked by SARS-CoV-2. 11 In the case of adaptive immunity, the role of vitamin D has been widely established, where it exhibits a suppressive effect on T helper-1 cell proliferation and activation, in turn, produce interferon γ and lead to macrophages activation. 12 Hence, cholecalciferol modulates both the acquired and innate immune system. One in vitro study reported that interferons are responsible for acute lung injury during the late phase of the SARS-CoV pathology. 13 A proinflammatory cytokine storms haven been identified in most severe cases of MERS-CoV and SARS-CoV. 14, 15 Vitamin D reduces the cytokine storm risk by decreasing the expression of proinflammatory cytokines. 11 Hence, the effect of cholecalciferol on immune modulation for anti-viral protection cannot be ignored. search was restricted to publications in the English language. More than 500 articles were found, but only articles published in English, those related to our search criteria as well as those showing evidence-based data were included. Screening and review of articles were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) ( Figure 1 ). Statistical analysis was done using software R version 3.6.0. Normality of the data was determined using the Shapiro-Wilk test. The continuous variables with normal distribution were presented as mean±standard deviation and compared using paired t-test. Mann-Whitney U test was performed for variables without following a normal distribution. Odds ratio (OR) was used to measure the odds of COVID-19 mortality among lower (<35 o ) and higher (>35 o ) latitude countries. The correlation between case fatality ratio (CFR) and earth latitude of different countries was developed Spearman's correlation analysis. A P value of <0.05 was considered statistically significant at 95% confidence interval. J o u r n a l P r e -p r o o f A high percentage of research states that elderly persons (≥ 60 years) are at greater risk to develop vitamin D deficiency than children. Serum 25(OH)D levels tend to decline with age as aging reduces the skin's ability to produce cholecalciferol; less time outdoors and lower concentration of 7-DHC in the skin are being the key determinants of vitamin D deficiency. 16, 17 Moreover, pharmaceutical drug usage increases with age which reduce serum 25(OH)D levels through the activation of the pregnane-X receptor. 18 Such drugs constitute antineoplastics, antiepileptics, antibiotics, antihypertensives, anti-inflammatory agents, endocrine drugs, antiretrovirals, and some herbal medicines. 18 All these factors have a major impact on pandemic (COVID-19) as CFRs are in direct proportion with age. 19 Daneshkhah et al demonstrated that the age-specific CFR of COVID-19 was highest in European countries with a greater incidence of severe vitamin D deficiency, Italy, France, and Spain. 20 Data with these characteristics are missing (or underreporting) for the majority of the cases and it is quite difficult to demonstrate age-sex specific CFR of COVID-19. Bulut et al reported that 83% mortality cases in Italy were aged ≥ 70 years old and also a similar pattern was observed in South Korea and the United states as well. 21 United States (> 7 years). 22 In contrast, in India, the majority (64%) of the coronavirus confirmed cases belong to the age group of 25-59 years and only 15% of cases are aged ≥ 60 years. 23 In an ICMR study conducted by Gupta et al reported that 82% COVID-19 cases overall were aged > 40 years. 24 India's age the structure is comparatively younger, and metropolitan cities comprise of more young population (labor/workforce). 23 By analyzing the data (as of May 13, 2020) provided by New York City Health, majority (48.7%) of the coronavirus deaths were aged ≥ 75 years J o u r n a l P r e -p r o o f following which 65-74 years (24.09%) and 45-64 years (22.4%) were the more vulnerable age groups. [25] Ningthoujam et al reported that COVID-19 can affect all age groups irrespective of whether the people are young or old with a concluding statement "strong immunity is the key weapon to fight against COVID-19". 22 Casual exposure to sun ultraviolet rays (wavelengths 290-315 nm) results in the cutaneous production of cholecalciferol. 26 During exposure to the sun, the UVB photons that enter the epidermis cause a photochemical transformation of 7-DHC (provitamin D3) to previtamin D3 and eventually cholecalciferol. 27 The skin's ability to synthesize cholecalciferol is affected by earth's rotation around the sun (season-earth is closest to the sun in January and farthest from the sun in July) and its own axis (day and night). 28 Atmospheric pollution attenuates UV solar radiation by absorbing and scattering sunlight before it reaches the earth's surface. 29 Application of sunscreen agents with the sun protection factor (SPF) ≥ 15 decreases the UVB penetration into skin epidermis by more than 95%, thereby limiting the cutaneous production of previtamin D 3 . In addition, dress code, skin pigmentation, cloudy skies, latitude and altitude, amount of ozone, and time of day, which all limit the production of cholecalciferol by the skin. 28 Occurrence of outbreak immediately after the winter season could have attributed to increased mortality. Meanwhile, seasonality of viral infections, especially URTIs, is associated with low 25(OH)D levels. For example, respiratory syncytial virus (RSV) infection is commonly observed during winter in temperate climates and the rainy season in tropical climates owing to low UVB doses. 30, 31 Many studies have documented and demonstrated the effect of season and latitude on the cutaneous synthesis of cholecalciferol. 28 Grant reported that mortality is directly proportional to latitude. 34 Marik et al also reported that cumulative CFR was significantly higher for Northern states > 40 o latitude (6.0%) compared to Southern States (3.5%; P < 0.001). 34 However, CFR is relatively low in few countries that lie above 50 o North (Nordic countries, Russia, Belarus, and Latvia), probably due to factors, such as low population density, adherence to social distancing, widespread usage of supplements, and racial makeup. 35, 36 Majority of the studies indicate that preventive vitamin D supplementation during early spring seasons and winter can reduce the frequency and incidence of RTIs, especially seasonal influenza A. 37 The National Heart, Lung, and Blood Institute (NHBLI) conducted an RCT to evaluate whether the single large dose of cholecalciferol (540,000 IU) would be beneficial in critically ill patients with severe vitamin D deficiency. But NHBLI failed to demonstrate any benefit from high dose of cholecalciferol. 47 Many studies reported no adverse effects with high doses of vitamin D. 46, 48 Currently, large doses of vitamin D are not supported by clinical evidence and therefore, standard vitamin D dosage may be beneficial in providing adequate clinical response. 34 LRTIs is the most common and leading cause of child mortality. 49 Literature indicates that children have shown low susceptibility to infection by MERS-CoV, SARS-CoV-1, and SARS-CoV-2 compared to other viruses, such as RSV and influenza. 50 According to the CDC report, fewer children were hospitalized (5.7%-20%) and admitted to ICU (0.58%-2.0%) compared to adults (>30%); among them infants had a higher hospitalization rate (15%-62%) compared to children aged 1-17 years (4.1%-14%). 51 A recent UNICEF report entitled "Lives Upended: How COVID-19 threatens the futures of 600 million South Asian Children" states that more than 8,80,000 children could die due to COVID-related issues in the next 12 months; most deaths likely in India. 52 The report also says that lack of nutritious diet to children (due to dwindling incomes and massive job loss) would be a predisposing factor. 52 A well-established association has been found between vitamin D deficiency and respiratory illness from tuberculosis to RSV. 53 Onwuneme et al reported a high prevalence of low 25(OH)D levels (<30 nmol/L [64%] and ≤50 nmol/L [92%]) in preterm infants which were significantly associated with acute respiratory illness in preterm infants immediately after birth; preterm infants with vitamin D insufficiency required increased resuscitation at delivery and assisted ventilation. 54 Few recent observational studies have demonstrated that Vitamin D levels are significantly lower in children with latent TB and TB infection than in children without TB in the absence of any differences in dietary habits, sunlight exposure, or ethnic or social background. [55] [56] [57] In developing countries, vitamin D or calcium deficiency may be potential predisposing factors for pneumonia in children under 5 years and vitamin D or calcium supplementation may lead to a significant reduction in CAP-related morbidity and mortality. 58 In an Indian study on 150 children, a significant association was found between severe lower RTI and sub-clinical vitamin D deficiency. 59 A Canadian study reported that mean serum 25(OH)D levels was significantly lower in LRTI subjects admitted to ICU (49 ± 24 J o u r n a l P r e -p r o o f nmol/L) than subjects admitted to general ward (87 ± 39 nmol/L). 60 Boosting children's immunity in the amidst COVID-19 is prerequisite and therefore, prophylactic measures and treatment guidelines deserve further research and attention. Patients with chronic medical conditions have a significantly higher risk of mortality from RTIs than healthy people. By analyzing the data (as of May 13, 2020) provided by New York City Health, patients with underlying conditions had a higher mortality rate (75%) than patients without underlying conditions; among them 46% were aged ≥ 75 years followed by 24.6% and 25.1% in age groups of 65-74 years and 45-64 years, respectively. 25 A well-established association has been found between vitamin D deficiency and co-morbidities. 61 69 Increased secretion of renin in the early stages of vitamin D deficiency results in more fluid and salt reabsorption and a rise in vascular pressure. 70 Hypertension and DM (16.2%) were the most comorbidities seen in critically ill COVID patients. 71, 72 Majority of the corona deaths in China were due to CVS, chronic RTIs, DM, and hypertension. 19 Hypertensive patients (13±11 and 13±10 ng/ml in males and females, respectively) had lower 25(OH)D concentrations compared to controls (21±11 and 20±11 ng/ml in males and females, respectively). 73 Prediabetics had significantly lower 25(OH)D levels than controls as well as higher C-reactive protein as 25(OH)D levels decreased. 74 In a large cohort study (n = 3296), a significant rise in angiotensin II and plasma renin was observed with decreased 25(OH)D levels, but not with aldosterone levels. 67 Most cases (92%, 1657/1801) with metabolic syndrome had low serum 25(OH)D levels and 22.2% patients had very low 25(OH)D levels (< 25 nmol/L). 75 A bi-directional genetic approach (26 studies; n = 42,024) showed that lower serum 25(OH)D levels lead to higher body mass index (BMI). 65 Obesity could be a potential risk factor in patients with metabolic syndrome, coronary disorders, and hypertension since adipose tissue may lead to RAS overreaction. 76, 77 Qingxian et al conducted a cohort study on 383 SARS-CoV-2 infected patients and reported that overweight (BMI: 24-27.9) and obese patients (BMI > 28) had 86% and 142% greater risk of developing pneumonia, respectively compared to normal weight patients. 78 According to a federal report (CDC), patients with comorbidities, such as CVD and DM were six and twelve times more likely to hospitalize and die, respectively compared to healthy individuals infected with SARS-CoV-2; most commonly reported underlying conditions in SARS-CoV-2 infected patients were heart disease (32%), DM (30%) and chronic lung disease (18%). 79 Cholecalciferol supplementation should be started before winter to reach the target serum 25(OH)D range to reduce the risk of RTIs and COVID during winter. 64 The half-life of calcitriol is about 15 days and that of calcidiol is between 13 and 15 days. 80 Consequently, strict lockdown (longer time indoors and home quarantine) and there may be a risk of developing vitamin D deficiency. Although, the protective effect is directly proportional to serum 25(OH)D levels, the optimal 25(OH)D level should be in the range of 100-150 nmol/l (40-60 ng/mL). 81 Endocrine Society recommended that 1000-4000 IU/d of vitamin D would be beneficial for patients with any chronic illness to maintain a serum 25(OH)D levels ≥30 ng/mL. 82 On Mar 23, 2020, a former director of CDC, Dr. Tom Frieden proposed that vitamin D supplementation may reduce the risk of coronavirus infection. 83 The U.S. Institute of Medicine reported that no adverse effects have been reported with supplementation of daily doses of vitamin D (<10,000 IU/d). 84 Along with vitamin D, supplementation of 250-500 mg/d magnesium is recommended because it acts as a cofactor for most enzymatic reactions and helps in the activation of vitamin D. 85 Naturally, we can get abundant vitamin D from sunshine. 28 Exposure of arms and legs (18% body surface) to sun rays between 11 A.M. and 2 P.M. until skin turns into slight pinkness is equivalent to supplementation of about 3600 IU cholecalciferol; weekly three times can provide adequate levels of vitamin D. 28 Vitamin D supplementation, moderate sun exposure, and control of immune diseases Vitamin D deficiency A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response Vitamin d-directed rheostatic regulation of monocyte antibacterial responses Vitamin D and respiratory infection in adults The role of cathelicidin and defensins in pulmonary inflammatory diseases Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37 A review of micronutrients and the immune System-Working in harmony to reduce the risk of infection Role of vitamin D in children with respiratory tract infection Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China 1, 25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro A probable role for IFN-γ in the development of a lung immunopathology in SARS MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome Low vitamin D levels among patients at Semmelweis University: retrospective analysis during a one-year period Aging decreases the capacity of human skin to produce vitamin D3 Influence of drugs on vitamin D and calcium metabolism The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China The role of vitamin D in suppressing cytokine storm of COVID-19 patients and associated mortality Epidemiology of COVID-19 Older people are at highest risk from COVID-19": Should the hypothesis be corroborated or rejected Case-Fatality Ratio and Recovery Rate of COVID-19: Scenario of Most Affected Countries and Indian States Severe acute respiratory illness surveillance for coronavirus disease COVID-19) Vitamin D requirements for the elderly Vitamin D: a millenium perspective Vitamin D status and sun exposure in India Reduction of solar photovoltaic resources due to air pollution in China Respiratory syncytial virus infection in adults Respiratory syncytial virus seasonality in tropical Australia The possible roles of solar ulraviolet-B radiation and vitamin D in reducing case fatality rates from the 1918-1919 influenza pandemic in the United States Does vitamin D status impact mortality from SARS-CoV-2 infection? 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