key: cord-0707966-mitp64yb
authors: Brito, Danilo Társio Mota; Ribeiro, Luiza Helena Coutinho; Daltro, Carla Hilário da Cunha; Silva, Roberto de Barros
title: The possible benefits of vitamin D in COVID-19
date: 2021-05-26
journal: Nutrition
DOI: 10.1016/j.nut.2021.111356
sha: 06e9d6d7c71b4d62a8e56432c4fe8ce58a870993
doc_id: 707966
cord_uid: mitp64yb

Molecular studies have demonstrated the importance of the exacerbated immune response to SARS-CoV-2 infection called cytokine storm in more severe patients with COVID-19. The pathophysiology is complex and involves several homeostatic factors; among them, the deficit of vitamin D draws attention because of the high frequency in the population. Some evidence suggests that patients with low serum vitamin D levels have a worse outcome, often requiring intensive care. This review analysed the studies available in the global literature that address the benefits of vitamin D in COVID-19, relate its serum levels to the severity of the disease, and indicate it as possible prophylaxis and therapeutic in infection.

• Vitamin D deficiency may be related to the severity of COVID-19 infection; • Adequate vitamin D concentration can prevent COVID-19 infection in the vulnerable population; • Vitamin supplementation can improve the outcome in hospitalized patients and susceptible individuals.

The pandemic caused by the SARS-CoV-2 infection, , has had a great impact on health systems and has been a great challenge for science in search of a cure. First identified in the seafood market of Wuhan-China and transmitted by airway droplets, the infection spread quickly to all continents [1] [2] [3] .

COVID-19 presents a broad clinical spectrum, ranging from absence of symptoms to acute respiratory distress syndrome (ARDS) [4] . The main symptoms observed are fever (88.5%), cough (68.6%), myalgia or fatigue (35.8%), expectoration (28.2%) and dyspnea (21.9%). Other symptoms include headache or dizziness (12.1%), diarrhoea (4.8%), and nausea and vomiting (3.9%) [2] .

Patients who evolve to ARDS need ventilatory support and other prolonged intensive care. Such respiratory complications can lead to a systemic deterioration, which confers a worse outcome to these patients [5] .

It is known that the presence of chronic comorbidities, such as diabetes mellitus, systemic arterial hypertension (SAH), obesity, and cardiovascular diseases are associated with increased morbidity and mortality in COVID-19 [6] . Current evidence states that these diseases have in common a chronic inflammatory pattern with high levels of pro-inflammatory cytokines [7] . It has been observed that patients with severe symptoms of COVID-19 have an uncontrolled production of pro-inflammatory cytokines, associated with a low serum level of vitamin D and other micronutrients, which suggests the severity of disease [6] .

Vitamin D makes up a group of molecules derived from 7-dehydrocholesterol (7-DHC), among which its active metabolite, 25-dihydroxyvitamin D (25(OH)D), and its precursors, ergocalciferol and cholecalciferol are the most important substances. Ergocalciferol or vitamin D2 is the result of ultraviolet irradiation on ergosterol. Pre-vitamin D3 or cholecalciferol originates from a photochemical cleavage suffered by the skin precursor of vitamin D (7-DHC), when exposed to ultraviolet radiation [9, 10] .

Besides its classic regulatory function in osteomineral metabolism, especially calcium metabolism, vitamin D also actively participates in blood pressure control [11] , in the synthesis of interleukins and autoimmunity modulation [12] . It also has proven to be essential in the molecular niche of innate immunity [13] and the regulation of cell multiplication and differentiation, being an antioncogenic potential [14] .

Recent studies indicate that 25(OH)D not only negatively regulates the renin-angiotensin system, but also has immunoregulatory properties with the ability to suppress interferon-gamma (INF-ɣ), tumour necrosis factor-alpha (TNF-α) and IL-6, and to stimulate anti-inflammatory cytokines such as IL-10 and IL-12 [7, 15] . In addition, there is evidence that vitamin D is effective in the prevention and treatment of influenza and other viral infections [16, 17] .

This study aimed to analyse the studies available in the global literature that address the benefits of vitamin D in COVID-19, relate its serum levels to the severity of the disease, and indicate it as possible prophylaxis and therapeutic in infection.

This paper is a narrative review of the literature for studies that have considered the benefits of vitamin D in patients with COVID-19.

It was sought to evaluate studies on the prophylactic and therapeutic role of vitamin D in COVID-19. Two independent reviewers read the titles and abstracts of the articles, and the common conclusions were summarised. In case of divergences, a third reviewer defined the inclusion of the study in the results.

An electronic search was done using Medline and Lilacs with the combination of terms/descriptors: "vitamin D" AND "COVID-19" and "vitamin D" AND "SARS-CoV-2" without restrictions of language between March and November, 2020. Those studies that did not directly refer to the benefits and/or consequences of vitamin D levels in COVID-19 were excluded from the analysis. Letters and Editorials were also excluded. In the first analysis, the immunomodulatory role of vitamin D was correlated as a protective factor against SARS-CoV-2 infection and, in individuals with low serum levels, showed a higher probability to evolve to the severe forms of the disease, in an inversely proportional way. Other functions and consequences of vitamin D deficiency in COVID-19 have also been described in the literature. These results are summarised in Table 1 . 

Observational evidence was found that vitamin D can be an important ally against COVID-19.

The pilot randomised clinical trial indicates that low levels of vitamin D are associated with severity and mortality from infection.

It is observed that mortality and lethality rates by COVID-19 have been higher in countries of low and high latitudes. This is probably due to a lower incidence of UVB rays, especially in winter [34] and consequently, a large proportion of the elderly population with severe vitamin D deficiency compared to the countries closest to the equator [35, 36] .

The vitamin D immunological function found in a short time has shown great value against bacterial and viral infections, especially in the respiratory tract, with a satisfactory level of evidence [37, 38] , stimulating the production of cathelicidin and defensins which decrease cell death in HEp-2 human epithelial cells, and modulate the immune response from Th1 to Th2, suppressing IFN-γ and TNF-β and producing IL-4, IL-5, IL-10, and IL-13 [39] . In addition, its deficiency is an important factor in the direct contribution to the progression of the patient with the acute infectious disease for ARDS [40] , at COVID-19 is not being different, in which its deficiency is showing an important inverse relation to the severity of the clinical condition [24] .

Patients who progress to ARDS, and consequently need intensive care, have in common the cytokine storm, a phase of infection characterised by uncontrolled production of inflammatory cytokines [6, 41] . Studies claim that vitamin D has an immunoregulatory potential at this stage, suppressing the production of INF-ɣ, TNF-α and IL-6 and other pro-inflammatory cytokines, besides stimulating anti-inflammatory factors [27, 29] .

However, previous systematic reviews have shown that vitamin D has no significant effect in the treatment of Acute Respiratory Tract Infections [42] , as well as Randomized Clinical Trial (RCT)

found not to improve insulin sensitivity in patients with obesity not reducing the risk of type 2 diabetes [43] . These results may be a consequence of Glutathione (GSH) deficiency, observed in animal models fed a high fat diet, and in patients with chronic diseases, including diabetes and immunological diseases, implying oxidative stress and vitamin D metabolism. It was noted that L-cysteine supplementation improved serum GSH levels which may be an adjuvant therapeutic strategy [44] [45] [46] [47] . Therefore, combined supplementation of vitamin D and L-cysteine may be a significant therapeutic strategy to reduce oxidative stress and treat vitamin D deficiency and its systemic complications [48] [49] [50] [51] .

The immunomodulatory role of vitamin D in the natural history of viral and bacterial respiratory infections is relevant. These benefits should be extended to COVID-19 as patients with its deficiency have presented worse clinical outcome. There is still no robust evidence on the prophylactic and therapeutic role of vitamin D in COVID-19, and more clinical trials are needed to prove its efficacy against infection. Considering that its pharmacological safety profile is well known, it is prudent to keep its mean serum concentration >30 ng/mL in patients on COVID-19 and the susceptible population.

None

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