Int-J-Clin-Pract-202175e14675-wileyonlinelibrarycomjournalijcp

Int J Clin Pract. 2021;75:e14675. wileyonlinelibrary.com/journal/ijcp | 1 of 16 https://doi.org/10.1111/ijcp.14675

Received: 12 January 2021 | Accepted: 26 July 2021 DOI: 10.1111/ijcp.14675

ME TA - A N A LY S I S

InfectiousDiseases

TheroleofvitaminDintheageofCOVID-19:Asystematic reviewandmeta-analysis

1Antimicrobial Resistance Research Center, Department of Infectious Diseases, Mazandaran University of Medical Sciences, Sari, Iran 2Department of Medical Laboratory Sciences, Student Research Committee, School of Allied Medical Science, Mazandaran University of Medical Sciences, Sari, Iran 3Gastrointestinal Cancer Research Center, Non- Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran 4Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran 5Pharmaceutical Sciences Research Center, Department of Medicinal Chemistry, School of Pharmacy, Mazandaran University of Medical Science, Sari, Iran 6School of Biomedical Engineering, University of Technology Sydney, Sydney, Ultimo, NSW, Australia 7Institute of Molecular Medicine, Sechenov First Moscow State University, Moscow, Russia 8Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran 9Neuromusculoskeletal Research Center, Department of Physical Medicine and Rehabilitation, Iran University of Medical Sciences, Tehran, Iran 10Department of Surgery, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran 11Department of Internal Medicine, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran 12Department of Psychiatry, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 13Department of Radiology, Isfahan University of Medical Sciences, Isfahan, Iran 14Department of Internal Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran 15Student Research Committee, Iran University of Medical Sciences, Tehran, Iran 16Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 17Department of Medical Laboratory Sciences, School of Allied Medical Science, Mazandaran University of Medical Sciences, Sari, Iran 18Thalassemia Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran 19Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

Correspondence Amir Shamshirian; Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran. Email: [email protected]

Danial Shamshirian, Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email: [email protected]

Abstract Background:Evidence recommends that vitamin D might be a crucial supportive agent for the immune system, mainly in cytokine response regulation against COVID- 19. Hence, we carried out a systematic review and meta- analysis in order to maximise the use of everything that exists about the role of vitamin D in the COVID- 19.

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1 | INTRODUCTION

Following the emergence of a novel coronavirus from Wuhan, China, in December 2019, the respiratory syndrome coronavirus 2 (SARS- CoV- 2) has affected the whole world and is declared a pandemic by World Health Organisation (WHO) on March 26, 2020.1 According to Worldometer metrics, this novel virus has been responsible for approxi- mately 83,848,186 infections, of which 59,355,654 cases are recovered, and 1,826,530 patients have died worldwide up to January 01, 2021.

After months of medical communities’ efforts, one of the hottest topics is still the role of Vitamin D in the prevention or treatment of COVID- 19. Several functions, such as modulating the adaptive immune system and cell- mediated immunity, as well as an increase of antioxidative- related genes expression, have been proven for Vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections.2- 4 According to available investigations, it seems that such functions lead to cytokine storm suppression and avoid Acute Respiratory Distress Syndrome (ARDS), which has been studied on other pandemics and infectious diseases in recent years.4- 7

To the best of our knowledge, unfortunately, after several months, there is no adequate high- quality data on different treatment regimens, which raise questions about gaps in scien- tific works. On this occasion, when there is an essential need for controlled randomised trials, it is surprising to see only observa- tional studies without a control group or non- randomised con- trolled studies with retrospective nature covering a small number of patients. The same issue is debatable for 25- hydroxyvitamin

D (25(OH)D); hence, concerning all of the limitations and analyse difficulties, we carried out a systematic review and meta- analysis to try for maximising the use of everything that exists about the role of this vitamin in the COVID- 19.

2 | METHODS

2.1 | SearchStrategy

The Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guideline was considered for the study plan. A systematic search through databases of PubMed, Scopus, Embase and Web of Science was done up to December 18, 2020. Moreover,

Methods:A systematic search was performed in PubMed, Scopus, Embase and Web of Science up to December 18, 2020. Studies focused on the role of vitamin D in con- firmed COVID- 19 patients were entered into the systematic review. Results:Twenty- three studies containing 11 901 participants entered into the meta- analysis. The meta- analysis indicated that 41% of COVID- 19 patients were suffering from vitamin D deficiency (95% CI, 29%- 55%), and in 42% of patients, levels of vita- min D were insufficient (95% CI, 24%- 63%). The serum 25- hydroxyvitamin D concen- tration was 20.3 ng/mL among all COVID- 19 patients (95% CI, 12.1- 19.8). The odds of getting infected with SARS- CoV- 2 are 3.3 times higher among individuals with vi- tamin D deficiency (95% CI, 2.5- 4.3). The chance of developing severe COVID- 19 is about five times higher in patients with vitamin D deficiency (OR: 5.1, 95% CI, 2.6- 10.3). There is no significant association between vitamin D status and higher mortal- ity rates (OR: 1.6, 95% CI, 0.5- 4.4). Conclusion:This study found that most of the COVID- 19 patients were suffering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS- CoV- 2 among vitamin- D- deficient individuals and about five times higher probability of developing the severe disease in vitamin- D- deficient patients. Vitamin D deficiency showed no significant association with mortality rates in this population.

ReviewCriteria

Following database search, paper screening, data extrac- tion and quality assessment were done based on inclusion and exclusion criteria by independent researchers.

MessagefortheClinic

Our study demonstrated a significant association be- tween vitamin D deficiency/insufficiency and SARS- CoV- 2 infection, which can be helpful to consider in the clinical setting.

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to obtain more data, we considered grey literature and references of eligible papers. The search strategy included all MeSH terms and free keywords found for COVID- 19, SARS- CoV- 2 and Vitamin D (Table S1). There was no time/location/language limitation in this search.

2.2 | Criteriastudyselection

Four researchers have screened and selected the papers inde- pendently, and the supervisor solved the disagreements. Studies met the following criteria included in the meta- analysis: 1) com- parative or non- comparative studies with retrospective or pro- spective nature; and 2) studies reported the role of vitamin D in confirmed COVID- 19 patients. Studies were excluded if they were: 1) in vitro studies, experimental studies, reviews, 2) dupli- cate publications.

2.3 | Dataextractionandqualityassessment

Two researchers (H.J and M.M) have evaluated the papers’ qual- ity assessment and extracted data from selected papers. The su- pervisor (D.Sh) resolved any disagreements in this step. The data extraction checklist included the name of the first author, pub- lication year, region of study, number of patients, comorbidity, vitamin D Status, serum 25- hydroxyvitamin D levels, ethnicity,

mean age, medication dosage, treatment duration, adverse ef- fects, radiological results and mortality. The Newcastle- Ottawa Scale (NOS) checklist8 and its modified version for cross- sectional studies9 and Jadad scale10 for randomised clinical trials were used to value the studies concerning various aspects of the methodol- ogy and study process.

2.4 | Vitamin D cut- off11

In this case, according to most of the studies, vitamin D cut- off points were considered as follows:

• Vitamin D sufficiency: 25(OH)D concentration greater than 30 ng/mL.

• Vitamin D insufficiency: 25(OH)D concentration of 20- 30 ng/mL. • Vitamin D deficiency: 25(OH)D level less than 20 ng/mL.

2.5 | Targetedoutcomes

(a) Frequency of Vitamin D status in COVID- 19 patients; (b) Mean 25(OH)D concentration; (c) Association between Vitamin D Deficiency and SARS- CoV- 2 infection; (d) Association between Vitamin D Deficiency and COVID- 19 severity; (e) Association between Vitamin D Deficiency and COVID- 19 mortality; (f) Comorbidity frequency; (g) Ethnicity frequency.

F IGURE 1 PRISMA flow diagram for the study selection process

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TABLE 1 Characteristics of studies entered into the systematic review

Study Country Studydesign No.ofpatients(cases) (male/female)

Controls (male/female)

Mean(±SD) Median(IQR)ageof patients(cases) Comorbidityofpatients(cases)

VitaminDstatusofpatients(cases) Ethnicityofpatients(cases)

Qualityscoreb N I D CS AC O

Im et al81 South Korea Case- control study 50 150 57.5 (34.5- 68.0) — 13 — 37 — — — 7/9

Maghbooli et al82 Iran Retrospective cross sectional 235 — 58.72 (±15.2) *mean Diabetes: 86 Hypertension: 104 Respiratory disease: 72 Cancer: 2

77 — — — — — 7/10

Baktash et al83 UK Prospective cohort study 70 (42/28) — ≥65 Hypertension: 34 Diabetes mellitus: 26 Ischaemic heart disease: 15 Chronic respiratory disease: 13 Heart failure: 12 Stroke: 9 Dementia: 6 CKD: 16 Atrial fibrillation: 14 Cancer: 3 Endocrinological disease: 3

31 — 39 50 — 20 9/10

Meltzer et al84 US Retrospective cohort study 71 — — Hypertension:261 Diabetes:137 COPD:117 Pulmonary circulation disorders: 20 Depression: 119 CKD:116 Liver disease: 56 Comorbidities with immunosuppression: 105

39 — 32 — — — 9/10

Faul et al85 Ireland Retrospective cross sectional 33 (33/0) — ≥40 — 21 — 12 33 — — 5/10

Merzon et al86 Israel Case- control study 782 (385/397) 7025 (2849, 4176)

35.58 Depression/Anxiety: 73 Schizophrenia: 15 Dementia: 27 Diabetes mellitus: 154 Hypertension: 174 Cardiovascular disease: 78 Chronic lung disorders: 66 Obesity: 235

79 598 105 — — — 6/9

Panagiotou et al87 UK Retrospective cross sectional 134 (73/61) — — Hypertension: 56 Diabetes: 38 Obesity: 14 Malignancy: 15 Respiratory: 42 Cardiovascular disease: 20 Kidney and Liver diseases: 19

— — 44 132 1 1 6/10

Carpagnano et al88

Italy Retrospective cohort study 42 (30/12) — 65 (±13) *mean Hypertension: 26 Cardiovascular disease: 16 CKD: 16 Diabetes type II: 11 Cerebrovascular disease: 5 Psychosis, depression, anxiety: 10 Malignancy: 5 COPD: 5 Asthma: 2

8 11 23 — — — 8/9

Nicola et al89 Italy Retrospective cohort study 112 (52/60) — 47.2 (±16.4) — — — — — — — 6/9

Macaya et al90 Spain Retrospective cohort study 80 (35/45) — 67.65 (50- 84) Hypertension: 50 Diabetes mellitus: 32 Cardiac disease: 19

— — 45 — — — 7/9

(Continues)

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TABLE 1 Characteristics of studies entered into the systematic review

Study Country Studydesign No.ofpatients(cases) (male/female)

Controls (male/female)

Mean(±SD) Median(IQR)ageof patients(cases) Comorbidityofpatients(cases)

VitaminDstatusofpatients(cases) Ethnicityofpatients(cases)

Qualityscoreb N I D CS AC O

Im et al81 South Korea Case- control study 50 150 57.5 (34.5- 68.0) — 13 — 37 — — — 7/9

Maghbooli et al82 Iran Retrospective cross sectional 235 — 58.72 (±15.2) *mean Diabetes: 86 Hypertension: 104 Respiratory disease: 72 Cancer: 2

77 — — — — — 7/10

31 — 39 50 — 20 9/10

39 — 32 — — — 9/10

Faul et al85 Ireland Retrospective cross sectional 33 (33/0) — ≥40 — 21 — 12 33 — — 5/10

Merzon et al86 Israel Case- control study 782 (385/397) 7025 (2849, 4176)

35.58 Depression/Anxiety: 73 Schizophrenia: 15 Dementia: 27 Diabetes mellitus: 154 Hypertension: 174 Cardiovascular disease: 78 Chronic lung disorders: 66 Obesity: 235

79 598 105 — — — 6/9

— — 44 132 1 1 6/10

Carpagnano et al88

8 11 23 — — — 8/9

Nicola et al89 Italy Retrospective cohort study 112 (52/60) — 47.2 (±16.4) — — — — — — — 6/9

Macaya et al90 Spain Retrospective cohort study 80 (35/45) — 67.65 (50- 84) Hypertension: 50 Diabetes mellitus: 32 Cardiac disease: 19

— — 45 — — — 7/9

(Continues)

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Study Country Studydesign No.ofpatients(cases) (male/female)

Controls (male/female)

Mean(±SD) Median(IQR)ageof patients(cases) Comorbidityofpatients(cases)

VitaminDstatusofpatients(cases) Ethnicityofpatients(cases)

Qualityscoreb N I D CS AC O

Karahan et al91 Turkey Retrospective cohort study 149 (81/68) — 63.5 (±15.3) Coronary artery disease: 32 Hypertension: 85 Dyslipidaemia: 39 Diabetes mellitus: 61 Cerebrovascular accident: 9 COPD: 15 Malignancy: 23 CKD: 29 Chronic atrial fibrillation: 15 Congestive heart failure: 18 Acute kidney injury: 16

12 34 103 — — — 8/9

Abdollahi et al92 Iran Case- control study 201 (66/135) 201 (66/135) 48 (±16.95) Hypothyroidism: 15 Diabetes mellitus: 42 Splenectomy: 1 Heart failure and hypertension: 20 Respiratory infections: 14 Autoimmune diseases: 11 AIDS: 4

39 161 1 — — — 7/9

Arvinte et al93 US Prospective cohort study (pilot study)

21 (15/6) — 60.2 (±17.4) 61 (20- 94)

— — — — 4 — 17 6/9

Cereda et al94 Italy Prospective cohort study 129 (70/59) — 77 (65.0- 85.0) COPD: 16 Diabetes: 39 Hypertension: 89 Ischaemic heart disease: 52 Cancer: 27 CKD: 24

— 30a 99 — — — 7/9

Hamza et al95 Pakistan Randomised controlled trial study

168 (94/74) — 42.26 (±13.69) — 22 47 98 — — — 3/5

Hernandez et al96 Spain Case- control study 19 (7/12) 197 (123/74) 60.0 (59.0- 75.0) Hypertension: 12 Diabetes: 0 Cardiovascular disease: 3 COPD: 2 Active cancer: 0 Immunosuppression: 6

— — — — — — 7/9

Jain et al97 India Prospective cohort study 154 (95/69) — 46.05 (±8.8) — — — 90 — — — 8/9

Ling et al98 UK Retrospective cohort study 444 (245/199) — 74 (63- 83) Diabetes mellitus: 129 COPD: 100 Asthma: 52 IHD: 73 ACS: 48 Heart failure: 54 Hypertension: 197 TIA: 40 Dementia: 59 Obesity: 20 Malignancy of solid organ: 71 Malignancy of skin: 8 Haematological malignancy: 8 Solid organ transplant: 4 Inflammatory arthritis: 16 Inflammatory bowel disease: 5

63 80 87 386 5 53 8/9

Luo et al99 China Retrospective cross- sectional study

335 (148/187) 560 (257/303) 56.0 (43.0- 64.0) Comorbidity status: 147 — — 218 — — — 7/10

TABLE 1 (Continued)

(Continues)

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Study Country Studydesign No.ofpatients(cases) (male/female)

Controls (male/female)

Mean(±SD) Median(IQR)ageof patients(cases) Comorbidityofpatients(cases)

VitaminDstatusofpatients(cases) Ethnicityofpatients(cases)

Qualityscoreb N I D CS AC O

12 34 103 — — — 8/9

39 161 1 — — — 7/9

Arvinte et al93 US Prospective cohort study (pilot study)

21 (15/6) — 60.2 (±17.4) 61 (20- 94)

— — — — 4 — 17 6/9

Cereda et al94 Italy Prospective cohort study 129 (70/59) — 77 (65.0- 85.0) COPD: 16 Diabetes: 39 Hypertension: 89 Ischaemic heart disease: 52 Cancer: 27 CKD: 24

— 30a 99 — — — 7/9

Hamza et al95 Pakistan Randomised controlled trial study

168 (94/74) — 42.26 (±13.69) — 22 47 98 — — — 3/5

Hernandez et al96 Spain Case- control study 19 (7/12) 197 (123/74) 60.0 (59.0- 75.0) Hypertension: 12 Diabetes: 0 Cardiovascular disease: 3 COPD: 2 Active cancer: 0 Immunosuppression: 6

— — — — — — 7/9

Jain et al97 India Prospective cohort study 154 (95/69) — 46.05 (±8.8) — — — 90 — — — 8/9

63 80 87 386 5 53 8/9

Luo et al99 China Retrospective cross- sectional study

335 (148/187) 560 (257/303) 56.0 (43.0- 64.0) Comorbidity status: 147 — — 218 — — — 7/10

TABLE 1 (Continued)

(Continues)

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2.6 | Heterogeneityassessment

I- square (I2) statistic was used for heterogeneity evaluation. Following Cochrane Handbook for Systematic Reviews of Interventions,12 the I2 was interpreted as follows: “0% to 40%: might not be important; 30% to 60%: may represent moderate het- erogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity. The importance of the ob- served value of I2 depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity (eg, P- value from the chi- squared test, or a confidence interval for I2).” Thus, the random- effects model was used for pooling the outcomes in case of het- erogeneity; otherwise, the inverse variance fixed- effect model was used. Forest plots were presented to visualise the degree of variation between studies.

2.7 | Dataanalysis

Meta- analysis was performed using Comprehensive Meta- Analysis (CMA) v. 2.2.064 software. The pooling of effect sizes was done with 95% Confident Interval (CI). The fixed/random- effects model was used according to heterogeneities. In the case of zero frequency, the correction value of 0.1 was used.

2.8 | Publicationbias

Begg's and Egger's tests were used for publication bias evaluation. A P- value of less than .05 was considered as statistically significant.

3 | RESULTS

3.1 | Studyselectionprocess

The first search through databases resulted in 1382 papers. After removing duplicated papers and first- step screening based on title and abstract, 121 papers were assessed for eligibility. Finally, 23 ar- ticles were entered into the meta- analysis. PRISMA flow diagram for the study selection process is presented in Figure 1.

3.2 | Studycharacteristics

Among the 23 studies included in the meta- analysis, all were de- signed in retrospective nature, except for five studies in prospective nature. The studies’ sample size ranged from 19 to 7807, including 11 901 participants. Characteristics of studies entered into the sys- tematic review are presented in Table 1.

Study Country Studydesign No.ofpatients(cases) (male/female)

Controls (male/female)

Mean(±SD) Median(IQR)ageof patients(cases) Comorbidityofpatients(cases)

VitaminDstatusofpatients(cases) Ethnicityofpatients(cases)

Qualityscoreb N I D CS AC O

Radujkovic et al100

Germany Retrospective cohort study 185 (95/90) 93 (59/34) 60 (49- 70) Cardiovascular disease: 58 Diabetes: 19 Chronic kidney disease: 8 Chronic lung disease: 15 Active or history of malignancy: 17

— — 41 — — — 7/9

Vassiliou et al101 Greece Retrospective cohort study 39 (31/8) — 61.17 (±13) Hypertension: 18 COPD: 1 Hyperlipidaemia: 9 Diabetes: 6 CAD: 4 Asthma: 1

— 7 32 — — — 6/9

Ye et al102 China Case- control study 62 (23/39) 80 (32/48) 43 (32- 59) Diabetes: 5 Hypertension; 6 Liver injury: 1 COPD: 1 Asthma: 0 Renal failure: 16

— — 26 — — — 6/9

Karonova et al103 Russia Retrospective cohort study 80 (43/37) — 53.2 (±15.7) Obesity: 18 Ischaemic heart disease: 21 Diabetes: 12

7 16 57 — — — 6/9

Abbreviations: SD, standard deviation; IQR, interquartile range; US, United States; UK, United Kingdom; N, normal; I, insufficient; D, deficient; CS, Caucasian; AC, Afro- Caribbean; O, other; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; AIDS, acquired immunodeficiency syndrome; ACS, acute coronary syndrome (Current or previous); TIA, transient ischaemic attack. aIn the study defined as patients with 25(OH)Vitamin D > 20 ng/mL. bQuality assessment tools were mentioned and cited in the method section.

TABLE 1 (Continued)

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Study Country Studydesign No.ofpatients(cases) (male/female)

Controls (male/female)

Mean(±SD) Median(IQR)ageof patients(cases) Comorbidityofpatients(cases)

VitaminDstatusofpatients(cases) Ethnicityofpatients(cases)

Qualityscoreb N I D CS AC O

Radujkovic et al100

Germany Retrospective cohort study 185 (95/90) 93 (59/34) 60 (49- 70) Cardiovascular disease: 58 Diabetes: 19 Chronic kidney disease: 8 Chronic lung disease: 15 Active or history of malignancy: 17

— — 41 — — — 7/9

Vassiliou et al101 Greece Retrospective cohort study 39 (31/8) — 61.17 (±13) Hypertension: 18 COPD: 1 Hyperlipidaemia: 9 Diabetes: 6 CAD: 4 Asthma: 1

— 7 32 — — — 6/9

Ye et al102 China Case- control study 62 (23/39) 80 (32/48) 43 (32- 59) Diabetes: 5 Hypertension; 6 Liver injury: 1 COPD: 1 Asthma: 0 Renal failure: 16

— — 26 — — — 6/9

Karonova et al103 Russia Retrospective cohort study 80 (43/37) — 53.2 (±15.7) Obesity: 18 Ischaemic heart disease: 21 Diabetes: 12

7 16 57 — — — 6/9

3.3 | Qualityassessment

Results of quality assessment for studies entered into meta- analysis were fair.

3.4 | Publicationbias

The findings of Begg's and Egger's tests were as follows for publica- tion bias in main analysis: frequency of vitamin D status (PB = .38; PE = .02); mean 25(OH)D concentration (PB = .80; PE = .76); vita- min D deficiency and SARS- CoV- 2 infection (PB = 1.00; PE = .55); Vitamin D deficiency and COVID- 19 severity (PB = .12; PE = .14) and vitamin D deficiency and COVID- 19 mortality (PB = .54; PE = .62).

3.5 | Meta-analysisfindings

3.5.1 | Frequency of Vitamin D status in COVID- 19 patients

The meta- analysis of event rates in peer- reviewed papers showed that 41% of COVID- 19 patients were suffering from vitamin D de- ficiency (95% CI, 29%- 55%), in 42% of patients, levels of vitamin D were lower than the normal range (95% CI, 24%- 63%) and only 19% of patients had normal vitamin D levels (95% CI, 11%- 32%) (Figure 2).

3.5.2 | Mean serum 25- hydroxyvitamin D concentration

The meta- analysis of mean 25(OH)D concentration was 20.3 ng/mL among all COVID- 19 patients (95% CI, 11.5- 28.1), 16.0 ng/mL in se- vere cases (95% CI, 12.1- 19.8) and 24.5 ng/mL in non- severe cases (95% CI, 20.0- 29.0) (Figure 3).

3.5.3 | Vitamin D Deficiency and SARS- CoV- 2 infection

The meta- analysis indicated that odds of getting infected with SARS- CoV- 2 increase by 3.3 times in individuals with vitamin D deficiency (95% CI, 2.5- 4.3) (Figure 4).

3.5.4 | Vitamin D Deficiency and COVID- 19 severity

The meta- analysis showed that the probability of developing severe stages of COVID- 19 is 5.1 times higher in patients with vitamin D deficiency (95% CI, 2.6- 10.3) (Figure 5).

3.5.5 | Vitamin D Deficiency and COVID- 19 mortality

The meta- analysis indicated no significant higher COVID- 19 mortality re- lated to vitamin- D- deficient patients (OR: 1.6, 95% CI, 0.5- 4.4) (Figure 6).

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3.6 | Comorbidities

Meta- analysis of available data on comorbidities frequency in COVID- 19 patients was as follows: in non- severe cases, 13% can- cer, 12% chronic kidney disease (CKD), 18% cardiovascular dis- eases (CVD), 21% diabetes, 29% hypertension (HTN), 12% obesity and 13% respiratory diseases (Figure S1); in severe cases, 13% cancer, 34% CKD, 31% CVD, 35% diabetes, 64% HTN, 33% obe- sity and 17% respiratory diseases (Figure S2); in overall, 8% cancer, 20% CKD, 26% CVD, 5% dementia, 15% depression/anxiety, 22%

obesity, 26% diabetes, 49% HTN and 15% respiratory diseases (Figure S3).

3.7 | Ethnicityfrequency

Pooling available data regarding ethnicity distribution among COVID- 19 patients resulted in 2% Afro- Caribbean, 13% Asian and 87% Caucasian (Figure S4). The results for severe cases were as fol- lows: 2% Asian, 68% Caucasian and 81% Hispanic (Figure S5).

F IGURE 2 Forest plot for pooling events of vitamin D status

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4 | DISCUSSION

4.1 | Epidemiologicalandclinicalaspects

Although comparing global statistics of COVID- 19 outcomes is dif- ficult, it is clear that the mortality rate is higher in several countries. It seems that among various factors such as age, healthcare system qual- ity, general health status, socioeconomic status, etc, one of the under- estimated factors that might be associated with COVID- 19 outcome is the vitamin D status in every population. In recent years, vitamin D de- ficiency/insufficiency has become a global health issue, and its impact has been studied on respiratory viral infections. Most of the epide- miological studies have been reported a higher risk of developing the infection to the severe stages and death in patients with low levels of vitamin D.13- 16 Besides, vitamin D clinical interventions have demon- strated a significantly reduced risk of respiratory tract infection (RTI),

further proposed as a prophylactic or treatment approach against RTIs by WHO in 2017.17- 19

Concerning all of the limitations and lack of high- quality data about the relation of vitamin D status and COVID- 19 after sev- eral months, we have conducted this systematic review and meta- analysis to maximise the use of every available data, which would give us an overview towards further studies like what we have done recently on the effectiveness of hydroxychloroquine in COVID- 19 patients,20 which have underestimated first, but the value was re- vealed after a while.

According to available data entered into our meta- analysis, we could find that approximately 43% of the patients infected with SARS- CoV- 2 were suffering from vitamin D deficiency, and this vi- tamin was insufficient in about 42% of them. We have also found that mean 25(OH)D levels were low (~20 ng/mL) in all COVID- 19 patients. More importantly, our analysis showed that the chance of

F IGURE 3 Forest plot for pooling mean 25(OH)D concentrations

F IGURE 4 Forest plot for pooling odds ratios of vitamin D deficiency and SARS- CoV- 2 infection

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infecting with SARS- CoV- 2 is about three times higher in individuals with vitamin D deficiency and the probability of developing the se- vere disease in such patients is about five times higher than others. However, vitamin D deficiency did not substantially affect mortality rates in such patients.

These findings are in the same line with studies that have de- bated the association of vitamin D and COVID- 19.21- 25 Recently, Kaufman et al26 studied the relation of SARS- CoV- 2 positivity rates with circulation 25(OH)D among 191,779 patients retro- spectively. They found the highest SARS- CoV- 2 positivity rate among patients with vitamin D deficiency (12.5%, 95% CI, 12.2%- 12.8%). Overall, the study indicated a significant inverse relation between SARS- CoV- 2 positivity and circulating 25(OH)D levels in COVID- 19 patients.

Along with all observational studies, a pilot randomised clinical trial performed by Castillo et al27 on 76 hospitalised COVID- 19 patients indicated a promising result for calcifediol therapy in these individuals. In this study, high- dose oral calcifediol signifi- cantly reduced the need for intensive care unit (ICU) treatment. However, because of the small sample size, more extensive, well- organised clinical trials are needed to robust and confirm this study's findings.

Additionally, in the case of vitamin D supplements’ benefits against acute respiratory tract infections, Martineau et al conducted a meta- analysis of randomised controlled on 10.933 participants and resulted in an inverse association between vitamin D levels and risk of acute respiratory tract infections. Thus, it can be concluded that patients with lower vitamin D levels or patients with vitamin D

F IGURE 5 Forest plot for pooling odds ratios of vitamin D deficiency and COVID- 19 severity

F IGURE 6 Forest plot for pooling odds ratios of vitamin D deficiency and COVID- 19 mortality

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deficiency are at higher risk of developing the disease to the severe form.17

4.2 | Comorbidities

After months of investigation on COVID- 19, several factors, such as male sex, older age, CVD, HTN, chronic lung disease, obesity and CKD, are proposed to be risk factors towards deteriorating COVID- 19 patients’ outcomes.28- 31 Interestingly, one of the condi- tions that lead to most of the considered risk factors is vitamin D deficiency. Studies indicated that malignancies, diabetes, HTN and CVDs are significantly related to vitamin D deficiency. Also, studies reported the important role of vitamin D deficiency in older males.32- 34 Evidence shows that ageing, physical activity, obesity, seasonal variation, less vitamin D absorption, pregnancy, thyroid disorders, prolonged use of corticosteroids and ethnicity/race can substantially affect the circulating 25(OH)D levels.35- 41

Hence, although studies reported vitamin D deficiency as one of the critical risk factors in clinical outcomes of COVID- 19 patients, it seems that it can also be in a strong relationship with basic underly- ing risk factors and diseases in such patients.

In this case, our analyses indicated that HTN, CVDs, CKDs, dia- betes, obesity and respiratory diseases were the most frequent co- morbidities in COVID- 19 patients. According to the facts mentioned above and our findings, it is plausible that both vitamin D deficiency and underlying diseases, which affect each other, may worsen the condition of these patients more than others.

4.3 | Ethnicity

From the beginning of the COVID- 19 pandemic, different studies have been reported probable associations between COVID- 19 and the ethnicity of these patients. Most studies found that the mortal- ity rate among black people is higher than the other ethnic groups.42- 46 However, other challenges, such as human resources, healthcare systems budgetary, poor management, etc, have to be considered among such people and low- income countries,47- 49 which unavoid- ably affects the subject significantly. In recent years, many studies have focused on vitamin D mechanisms and status among various ethnic groups to find the roles of vitamin D and its relationships with any factors or disorders in various ethnicities.50- 53

Herein, our findings demonstrated that the most frequent eth- nic group has belonged to Caucasians, followed by Hispanic, Asian and Afro- Caribbean. Although there is some evidence on the role of genetic variants in COVID- 19 patients, the subject is still not clear enough.54,55

In contrast to many studies about vitamin D status in different ethnicities, Aloia et al have reported that serum 25(OH)D concen- tration is the same in cross- racial comparison. They found an incon- sistency between monoclonal and polyclonal assays for detecting

vitamin D- binding protein.56 Hence, the approach for considering serum 25(OH)D concentration is much important.

4.4 | VitaminDmechanismsandCOVID-19

Vitamin D metabolism has been well studied throughout history. Numerous investigations indicate vitamin D’s roles in reducing mi- crobial infections through a physical barrier, natural immunity and adaptive immunity.2,57- 62 For example, investigations on respiratory infections indicated that 25(OH)D could effectively induce the host defence peptides against bacterial or viral agents. Vitamin D insuf- ficiency/deficiency can lead to non- communicable and infectious diseases.2,63,64 The other potential role of vitamin D is reducing in- flammatory induced following SARS- CoV- 2 infection by suppressing inflammatory cytokines, reducing leukocytes’ infiltration, interac- tion with polymorphonuclear leukocytes and inhibiting complement component C3.13,65- 69 Also, according to the available evidence for infections and malignancies,70,71 vitamin D may enhance the se- rological response and CD8+ T lymphocytes performance against COVID- 19 when the T cells’ exhaustion is related to the critical stages of the disease.72- 74

Besides, according to the revealed association of SARS- CoV- 2 and angiotensin- converting enzyme 2 (ACE2), this virus can sub- stantially down- regulate the ACE2 expression, which seems to lead the COVID- 19 patients to deterioration.75- 77 In contrast, vitamin D affects the renin- angiotensin system pathway and promotes the ex- pression of ACE2.78,79 However, since the high expression of ACE2 can be a risk factor for the severity of the disease,80 it is not yet clear enough to conclude how much vitamin D helps the condition. Hence, more evidence and trials are needed to design a treatment plan for three groups of mild, moderate and severe patients.

It is worth noticing that the current meta- analysis includes the following limitations: (a) most of studies entered into the meta- analysis were retrospective in nature; (b) There are inevitable chal- lenges with the reliability of data due to different strategies in a testing (eg, vitamin D measurement, COVID- 19 test, etc), various subpopulations, etc; (c) other immunomodulatory factors (eg, vita- min C, zinc, selenium, etc), which might be influential in the outcome of COVID- 19 patients, have not considered in included studies and (d) type II statistical errors following studies with small sample size. Eventually, to overcome the limitations and bias, the study's results should be confirmed by robustly large multicentre randomised clin- ical trials.

5 | CONCLUSION

The conditional evidence recommends that vitamin D might be a critical supportive agent for the immune system, mainly in cytokine response regulation against pathogens. In this systematic review and meta- analysis, we found that mean serum 25(OH)D level was low

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(~20 ng/mL) in all COVID- 19 patients and most of them were suf- fering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS- CoV- 2 among vitamin- D- deficient individuals and five times higher prob- ability of developing the severe disease in such patients. Vitamin D deficiency showed no significant association with mortality rates in these population. The Caucasian was the dominant ethnic group, and the most frequent comorbidities in COVID- 19 patients were HTN, CVDs, CKDs, diabetes, obesity and respiratory diseases, which might be affected by vitamin D deficiency directly or indi- rectly. However, further large clinical trials following comprehensive meta- analysis should be taken into account to achieve more reliable findings.

ACKNOWLEDGEMENTS We would like to express our appreciation to the Student Research Committee of Mazandaran University of Medical Sciences for ap- proving this student research proposal with the code 7904. It is also remarkable that the manuscript was published on a pre- print server (available at https://doi.org/10.1101/2020.06.05.201235 54).

DISCLOSURES The authors declare that they have no competing interests.

ETHICSAPPROVALANDCONSENTTOPARTICIPATE Not applicable.

CONSENTFORPUBLICATION Not applicable.

DATAAVAILABILITYSTATEMENT Not applicable.

ORCID Roya Ghasemian https://orcid.org/0000-0001-7330-7749 Amir Shamshirian https://orcid.org/0000-0002-2735-0209 Keyvan Heydari https://orcid.org/0000-0002-2843-7832 Mohammad Malekan https://orcid.org/0000-0002-5622-0294 Reza Alizadeh- Navaei https://orcid.org/0000-0003-0580-000X Mohammad Ali Ebrahimzadeh https://orcid. org/0000-0002-8769-9912 Majid Ebrahimi Warkiani https://orcid. org/0000-0002-4184-1944 Hamed Jafarpour https://orcid.org/0000-0003-0652-2363 Sajad Razavi Bazaz https://orcid.org/0000-0002-6419-3361 Ehsan Dadgostar https://orcid.org/0000-0002-4041-7324 Marzieh Aalinezhad https://orcid.org/0000-0002-3365-2844 Meghdad Sedaghat https://orcid.org/0000-0002-3966-0597 Amirhossein Hessami https://orcid.org/0000-0002-1219-1081 Soheil Azizi https://orcid.org/0000-0002-8802-4255 Ali Reza Mohseni https://orcid.org/0000-0001-9347-5096 Danial Shamshirian https://orcid.org/0000-0001-8461-3477

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SUPPORTINGINFORMATION Additional Supporting Information may be found online in the Supporting Information section.

Howtocitethisarticle: Ghasemian R, Shamshirian A, Heydari K, et al. The role of vitamin D in the age of COVID- 19: A systematic review and meta- analysis. Int J Clin

Pract. 2021;75:e14675. https://doi.org/10.1111/ijcp.14675

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