key: cord-321817-z9oj9nmv
authors: Cereda, Emanuele; Bogliolo, Laura; Lobascio, Federica; Barichella, Michela; Zecchinelli, Anna Lena; Pezzoli, Gianni; Caccialanza, Ricardo
title: Vitamin D supplementation and outcome in COVID-19 patients from the outbreak area of Lombardy, Italy
date: 2020-11-11
journal: Nutrition
DOI: 10.1016/j.nut.2020.111055
sha: 
doc_id: 321817
cord_uid: z9oj9nmv

• Vitamin D has anti-inflammatory and immunoregulatory functions. • The involvement of vitamin in the pathophysiology of COVID-19 is still not clear; • Some studies support a link between vitamin D deficiency and worse COVID-19 outcome; • Vitamin D may also enhance macrophages activation and aberrant immune response; • In our study vitamin D supplementation was associated with a trend to higher mortality; • Supplementation trials are crucial to clarify the role of vitamin D in COVID-19.

Recent literature has substantially raised the interest in the immune-modulating properties of vitamin D against coronavirus disease 2019 (COVID-19). Although several viewpoints have been published, data supporting the hypothesized beneficial role are limited and controversial [1, 2] .

Consistently with systematic review reporting the protective role of 25-hydroxyvitamin D (25OHD) supplementation [3] , in a recent survey conducted in Parkinson's disease (PD) patients, cases were more likely to be not-supplemented than unaffected patients [4] . The observation of lower mortality rates at lower degrees of latitude, along with other preliminary reports on the association between serum levels of 25OHD and the risk of having the disease or a critical outcome, have suggested that vitamin D could modulate the risk and mitigate the severity of COVID-19 [1, 2, 5] . There is evidence that vitamin D has immunomodulatory functions and plays an anti-inflammatory role particularly in viral infections. It was also demonstrated to be inversely correlated to acute respiratory distress syndrome (ARDS) and increased levels of C-reactive protein [6] . On the other hand, the higher prevalence of 25OHD deficiency in many disease conditions is questionable according to a reversed causality hypothesis, as the underlying disease and related inflammatory background may negatively influence 25OHD metabolism, particularly of its binding protein, resulting in substantial bias in the assessment of its status [7, 8] . This is also suggested by differences in serum levels between PCR-positive and negative patients, which might not only be interpreted as a higher susceptibility to infection in patients with deficiency status [5, 9] . Therefore, we aimed to evaluate whether vitamin 25OHD supplementation, which may be a better surrogate of real 25OHD status, is associated with prognosis in COVID-19 patients from the Italian outbreak area of Lombardy.

The study was approved by local Institutional Ethics Committees and written informed consent was obtained from every patient.

Two sets of data collected prospectively during the outbreak of the pandemic in the north of Italy were pooled and analyzed. The first consisted of COVID-19 PD patients (Group 1) and COVID-19 PD caregivers (Group 2) identified from a pool of 2693 PD patients (N=1486) and caregivers (N=1207) which were approached in a recent phone survey and interview conducted between March and May 2020 [4] . The second included consecutive COVID-19 patients (Group 3) admitted to a referral hospital between April and May 2020 (unpublished data). Information on supplementation with 25OHD (defined as at least 25.000 IU/month in the last 3 months [800 IU/day]), weight status, comorbidities, serum 25OHD, COVID-19 diagnosis and related hospitalization and in-hospital mortality were gathered by direct interview and validated through the consultation of institutional electronic charts and linkage to the regional register of healthcare data. In hospital inpatients, fasting venous serum samples were collected within 48 hours since admission for the assessment of 25OHD (chemiluminescence immunoassay [Abbott Diagnostics, Lake Forest, IL, USA]).

Hospitalization and in-hospital mortality for COVID-19 were the study endpoints.

Analyses were conducted using Stata 16 (StataCorp, College Station, TX, USA). Comparisons (supplemented vs. non-supplemented patients) of continuous variables were performed using parametric or non-parametric tests, while categorical variables were analyzed by the Fisher's exact test. Then, adjusted logistic regression was used to investigate the association between supplementation and study outcomes.

Overall, 324 COVID-19 cases were included: Group 1 (PD patients), 105 cases; Group 2 (PD caregivers), N=92; Group 3 (hospital inpatients), N=127. The characteristics of the study patients are summarized in Table 1 died. The use of 25OHD supplements was not associated nor with hospitalization neither with inhospital mortality, although a trend to a 2-fold higher risk of death was found for supplements users, particularly after adjusting for potential confounders ( Table 2 ).

In our study, 25OHD supplementation was not associated with the severity of COVID-19. On the other hand, a trend to a 2-fold higher mortality in users was found.

Vitamin D could boost mucosal defenses and protect against infections [1] [2] [3] [4] [5] [6] and it has been suggested to down-regulate the inflammatory burden contributing to acute respiratory distress syndrome and lung injury [2, 10, 11] , the main cause of death in COVID-19 patients. Enhanced ACE2 expression is considered a protective factor in acute lung injury [10, 11] . Vitamin D increases the expression of ACE2 [6] , and this may apply not only to airway epithelium but also to other organs and monocyte-derived macrophages. However, ACE2 is the binding site of SARS-CoV2 and increased ACE2 expression may result in enhanced viral homing and organ damage, as well as in an aberrant innate immune response with hyper-activation of macrophages [11] , perhaps at least in highly complicated patients, as those admitted in our outbreak area.

Our data may appear in contrast with recent literature suggesting that higher serum 25OHD is associated with more favorable COVID-19 outcomes, with lower progression of respiratory and to critical illness, as well as lower mortality rates [1, 2, 5, 12] , although no association has been also reported [13] . However, disease-related inflammation may negatively affect 25OHD metabolism, particularly of its binding protein, resulting in reduced circulating levels and assessment bias [7, 8] .

In this perspective, also the timing of assessment in relation to the onset of symptoms could play a role [13] . It is with this background that we have decided to evaluate the association between supplementation rather than serum levels and outcome. Nonetheless, we have evaluated s erum 25OHD in a subgroup of consecutive patient demonstrating that supplementation results in substantially higher and adequate circulating levels.

Therefore, although the potential utility of vitamin D in the prevention of respiratory tract infections is more substantial [3] , its benefits on COVID-19 (prevention and management) still need to be clarified by appropriate intervention trials.

We recognize the following limitations. First, a larger study population along with a multicenter participation would have resulted in increased statistical power and bias reduction. However, we were not able to perform a valid calculation of the sample size due to the emergency crisis and the heterogeneity in published data on outcome and use of supplements. Indeed, we recognize that the emergency crisis was a source of bias itself as it is likely that only the worst cases have been hospitalized in our outbreak area. Finally, in agreement with Italian recommended dietary allowances [14] we have decided to define supplementation as an intake of at least 25.000 IU (800 IU/day) in the previous three months. It is not at all clear that supplements of <1000 IU/day are likely to make much difference compared to larger ones. However, the mean intake in supplemented patients was >54.000 IU (>1800 IU/day), resulting in adequate circulating levels in most patients assessed.

In conclusion, 25OHD supplementation was not associated with hospitalization but appeared to be a risk factor for higher in-hospital mortality for COVID-19. Further studies are needed to clarify the role of vitamin D supplementation and status in modulating the severity of COVID-19, as well as its prevention. 

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Author Contributions: Dr. Cereda had full access to all of the data in the study and take
