key: cord-0843400-goy6ieue
authors: Nasiri, Maryam; Khodadadi, Javad; Molaei, Sedigheh
title: Does vitamin D serum level affect prognosis of COVID-19 patients?
date: 2021-04-30
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.04.083
sha: 7218973b1e85ef32933389404e8a926eec4735b2
doc_id: 843400
cord_uid: goy6ieue

Background Since beginning of Coronavirus disease of 2019 (COVID-19) pandemic, there were contradictions and speculations around vitamin D and COVID-19 relationship. Given that there is association between vitamin D deficiency and some diseases including cancer, autoimmune disease and some infectious diseases, COVID-19 higher incidence rate and mortality in vitamin D deficient population was not a surprise. Conversely, some research would argue this relationship. Considering these contradictions, the aim of this study was to determine the relationship between prognosis and vitamin D level in cases with COVID-19. Methods In this cross-sectional study, 329 confirmed cases of COVID-19 which admitted to Kamkar-ArabNia Hospital in Qom city, Iran from March to July 2020 were categorized into three groups according to vitamin D serum levels (ng/ml): sufficient (>30), insufficient (20-30) and deficient (<20). Prognosis was determined across the groups. Results There was significant difference in hospital stay between patients with sufficient and insufficient vitamin D levels (P = 0.007). Adjusting vitamin D levels for confounding variables, linear regression underscored significant differences in the association between length of hospitalization and lower vitamin D levels, with a longer stay noted in insufficient groups (P = 0.002). However, there was no significant difference in the time interval to return to normal oxygen level (from SpO2 below 93%) or death rate between groups (P > 0.05). Conclusion There is significant association between hospital stay and lower serum vitamin D levels. However, the relationship between vitamin D status and death rate or the time interval to return to normal oxygen levels is not significant.

Coronavirus disease of 2019 (COVID- 19) was declared a global pandemic by world health organization (WHO) on March 11, 2020. It is caused by a member of coronaviridae family named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).The symptom range is so wide from cough and dyspnea for this respiratory disease to diarrhea similar to influenza and other non specific symptoms (1) . From the beginning of this pandemic, two interesting J o u r n a l P r e -p r o o f issues that were considered were the relationship between the prognosis of COVID-19 with different blood groups and also, vitamin D ,there were contradictions and speculations around vitamin D and COVID-19 relationship, not only in literature but also in the media (2, 3) . Given that vitamin D has a supporting role in production of antimicrobial peptides in the respiratory epithelium, there arestudies suggesting vitamin D as a preventive supplement in respiratory tract infections as far as its once-daily dosing was suggested rather than bolus dosage (4) . As our knowledge of the vitamin D physiology increases, studies found about 200 genes to be regulated by this vitamin, including cellular proliferation, differentiation and apoptosis genes and also about 15 genes in innate and adaptive immunity (5) . Besides, certain cancers, some autoimmune and infectious disease have shown increased prevalence in vitamin D deficient populations diseases ( 6, 7) .Similarly, COVID-19 infection rate and mortality was higher in countries with higher vitamin D deficient population e,g. Italy versus Nordic countries with lower vitamin D deficiency rates (8) .

However, having some countries to debate this association(9, 10) and considering other influential cases, this could not be a transparent relationship. Meanwhile, some research declares no association between vitamin D deficiency and COVID-19 infection rate, hospitalization or mortality, the latter of which, while not significant statistically, was higher in vitamin D deficient populations. (11). As a result, the healthcare community still awaits a clear answer, and vitamin D is not routinely prescribed for COVID-19 patients. Also, there is a gap in research to be adjusted for confounding factors, e.g. chronic kidney disease or nursing homes residency and to be more precise, even considering all cases to be in one certain medical center to ward off another bias. So, in this study, the relationship between prognosis and vitamin D level was examined in COVID-19 patients.

In this cross-sectional study, data from 329 COVID-19 inpatients in Kamkar-ArabNia Hospital in Qom city, Iran from March to July 2020, were collected. Inclusion criteria were positive nasopharyngeal RT-PCR test for COVID-19 . Also cases with residents of nursing homes, bedridden patients, or intubation at the beginning of hospitalization were excluded. Background data including age, gender, social history, underlying disease or medical condition, including renal transplantation/dialysis, chemotherapy, etc were recorded as well as COVID-19 symptoms.

Serum 25(OH)D level (nanograms/milliliter or ng/ml) was measured by routine blood samples on the first day of hospitalization. In this study,Patients were categorized into three groups; sufficient (>30), insufficient (20-30) and deficient (<20) Serum 25(OH)D levels.

Vitamin D deficiency is considered by most studies to be under 30 ng/mL,In these studies, Serum 25(OH)D level less than 20 ng/ml is considerd as deficient and less than 30 ng/ml insufficient , 30-100 ng/ml Sufficient and more than 100 ng/ml Potential toxicity (12, 13) .

(peripheral capillary oxygen saturation levels) were obtained. Considering SpO2≥93% and T≤37.4 centigrade as normal, patients with abnormal findings in each one were followed until return to normal levels. This duration showed patients' general condition and prognosis.

Intubation during hospitalization was also considered as another important index along with hospital stay and mortality. 

males and 162 females. The mean age (± standard deviation) was 64.7±18.5 ranging from 15 to 99 years. Age was under 20 in 13.1%, from 20 to 30 years in 14.6%, and above 30 years in 72.3%. Mean hospital stay (± standard deviation) was 8.27±6.04 ranging from 1 to 38 days.

A total of 297 patients (90.3%) were discharged and 32 patients (9.7%) were deceased.

Three of the most common COVID-19 symptoms were 58.7% dyspnea, 46.5% cough (7.3% productive), 38.3% fever,other symptoms of patients are shown in Table- 1. Table-2. .Also in past social history 2.1% and 3.3% were smoker and addict, respectively. r=0.553). Also, using ANOVA, the relation between groups was also significant (P=0.006) which followed by post Hoc tests, which indicated significant difference between sufficient and insufficient vitamin D groups (P=0.007) at P value level of 0.05. Finally, following chisquare tests, the relationship between vitamin D and death was not significant (P=0.928).

Tables 3 to 5 represent the regression results. Adjusting vitamin D levels for confounding variables e.g. age, sex, and underlying diseases, linear regression showed significant difference between hospitalization duration and vitamin D levels which was higher in insufficient group (P=0.002). However, there was no significant difference in the time interval to return to normal oxygen levels between serum vitamin D based-groups. Also, Logistic regression showed insignificant relationship between vitamin D levels and death rate. reported to be associated with COVID-19 mortality comparing with normal group (16) .

Knowing the role of vitamin D on immune system from its receptors on majority of immune cells to raising the anti-inflammatory cytokine production versus pro-inflammatory or even production of an antimicrobial peptide against enveloped viruses, such as corona viruses, the efficacy of adding vitamin D as a protective supplement against acute viral respiratory infections is not surprising (17), especially with 86% vitamin D deficiency in Iranian population (18) . While SARS-CoV-2 down-regulates the angiotensin-converting enzyme 2 J o u r n a l P r e -p r o o f (ACE2), exploited as an entry receptor, leading to renin-angiotensin-aldosteron system (RAS) overactivation and proinflammatory cytokines release and as a result more comorbidity, vitamin D up-regulates ACE 2 expression which in the lungs, had shown a protective effect against acute lung injury (19) .Also, senility affects this system and also vitamin D production. In consideration of these findings, there was a need for research to impact COVID-19 prognoses in different populations. Our study, through adjustment of vitamin D levels for confounding variables and underlying disease revealed significant differences in length of hospital stay and vitamin D deficiency.

However, some research reported that patients who were severe vitamin D deficient experienced the most benefit from receiving a diet base supplement (20) which in our study, very deficient vitamin D group showed no significant difference in outcomes. The limitation of our study may be the study design with the small sample size .Our sample size was low, and the larger sample size would increase the power and robustness of the comparisons.

Randomized controlled trials are warranted to show the role of vitamin D supplement on COVID-19 prognosis .

In conclusion, there was a significant difference the hospitalization duration in patients according to their vitamin D serum levels. However, the relationship between vitamin D status and death rate or the time interval to return to normal oxygen levels was not significant. Overall, considering vitamin D physiological cycle, reduced sunlight exposure and indoor living during COVID-19 era may worsen the low vitamin D status, therefore it should be more considered as a routine check-up.

J o u r n a l P r e -p r o o f

Estimated effectiveness of symptom and risk screening to prevent the spread of COVID-19

The Probable Association between Blood Groups and Prognosis of COVID-19

Vitamin D and SARS-CoV-2 virus/COVID-19 disease

Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials

Vitamin Dmediated induction of innate immunity in gingival epithelial cells

Vitamin D, autoimmune disease and rheumatoid arthritis

Vitamin D, cancer, and dysregulated phosphate metabolism

Covid-19, and vitamin D

Lockdown During COVID-19: The Greek Success. In Vivo

Serum 25-hydroxyvitamin D status, quantitative ultrasound parameters, and their determinants in Greek population

The possible role of Vitamin D in suppressing cytokine storm and associated mortality in COVID-19 patients

Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline

Optimize dietary intake of vitamin D: an epigenetic perspective

Vitamin D deficiency and co-morbidities in COVID-19 patients-A fatal relationship?

Temperature and latitude analysis to predict potential spread and seasonality for COVID-19. Available at SSRN 3550308

Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study. Available at SSRN 3585561

Editorial-Vitamin D status: a key modulator of innate immunity and natural defense from acute viral respiratory infections

Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality

This study was approved by the Ethics Committee of the Qom University of Medical Sciences (Code:IR.MUQ.REC.1399.058). We would like to thank Dr.Mohammad Aghaali and specially Dr. Mohammad Ali Nasiri.

Authors' contributions : All of the authors contributed in all parts of this study.