Previous studies have shown the possible relationship between vitamin D status and respiratory infections [27, 29]. Since studies have demonstrated that a sufficient vitamin D level is associated with a better immune system function, researchers posed vitamin D might have a protective effect against COVID-19 [30, 31]. In addition, patients with severe COVID-19 may share some characteristics with those with insufficient vitamin D levels, such as pre-hospital malnutrition, liver or kidney dysfunction, older age, and a poor general health condition [32]. All these factors may affect the hospitalization rate, the likelihood of ICU admission, and the mortality rate [33]. In that way, some retrospective studies have been conducted to assess this association. Although a relationship has been found between vitamin D levels and COVID-19 as well as the clinical condition of the disease, the authors reported that further studies are required [34, 35]. In the present study, the prevalence of insufficient vitamin D was 69.2%, similar to the other studies [27, 35].
Pimentel et al. assessed 26 patients and showed that the mean CRP did not differ significantly between patients with low and normal vitamin D levels, while the mean lymphocyte count was higher in patients with low vitamin D levels [36]. Lakkireddy et al. conducted a randomized clinical trial and showed that vitamin D therapy significantly reduced inflammatory factors in patients receiving vitamin D (CRP: 81 ± 66 vs. 16 ± 42; P < 0.0001, LDH: 369 ± 159 vs. 274 ± 115; P < 0.0001). This study declared that vitamin D could reduce inflammatory factors without any side effects in COVID-19 patients [37]. However, a randomized clinical trial (RCT) showed that vitamin D did not make a significant difference in CRP level (p value = 0.5) [38].
Moreover, in the present study, the pooled mean of vitamin D in patients with positive CRP (mean ± SD: 27.2 ± 17.5) was higher than in patients with negative CRP (mean ± SD: 25.1 ± 12.4), though the difference was not statistically significant [p value = 0.5, CI = (− 9.2, 5)]. Also, the pooled mean of lymphocyte and leukocyte count was higher in patients with insufficient vitamin D levels, though not statistically significant.
Davoudi et al. studied 153 COVID-19 patients and found no significant difference between the groups in terms of the need for invasive ventilation [27]. A retrospective study in Austria on 148 patients reported that vitamin D levels did not differ significantly between various types of oxygen therapy [39]. The present study showed no significant difference in intubation with the level of vitamin D (P = 0.46).
Abrishami et al. argued that the mortality rate in vitamin D deficient patients was significantly higher than in patients with sufficient vitamin D levels (34.6% vs. 6.4%, P = 0.003). A deficient vitamin D level increased the hazard of mortality rate in an adjusted model (HR = 4.15, P = 0.04). The mean O2 saturation was lower in those who died (88) than in those who survived (90), though the difference was not significant (P = 0.11). The authors suggested that vitamin D might have a protective effect against the progression of COVID-19 to a severe form [6]. Al-Daghri et al. conducted a multi-center case–control study on 220 patients and described that COVID-19 patients had lower vitamin D than patients without COVID-19 (52.8 nmol/L vs. 64.5 nmol/L; P = 0.009) although COVID-19 patients had risk factors such as low HDL-c, diabetes mellitus, and old age [40]. In addition, some trials proved the protective effect of vitamin D against COVID-19, though their results were heterogeneous among their results, which may be possibly attributed to the following reasons: (1) administration of different doses of Vitamin D, and (2) dissimilar characteristics of participators [12].
In contrast, Butler-Laporte et al. compared 14,134 individuals with COVID-19 to 1,284,876 individuals without COVID-19. They did not find any relationship between elevated levels of vitamin D and COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; P = 0.44), hospitalization (OR = 1.09; 95% CI 0.89, 1.33; P = 0.41), and severe disease (OR = 0.97; 95% CI 0.77, 1.22; P = 0.77). Their findings did not support the protective role of vitamin D in COVID-19 [41]. Moreover, another study on 502,624 participants showed that no association between vitamin D level and risk of COVID-19 [30].
A study in Iran showed mortality rate in the vitamin D sufficient patients was higher than in the vitamin D deficient patients (3.5% vs. 3.1%). Additionally, the mean hospitalization days in the vitamin D sufficient patients (6.36) was higher than the vitamin D deficient patients (6.25), though the difference was not statistically significant. In addition, univariate and multivariate linear regression analyses showed no association between vitamin D level with hospitalization duration and long-term complications [27]. Azadeh et al. demonstrated that the number of patients with insufficient or deficient vitamin D levels was not significant in both groups (dead/survived) (p value = 0.35) [42]. However, a single-center cohort study declared vitamin D deficiency increases the rate of in-hospital mortality after adjusting age and sex (OR = 1.73, CI = 1.11, 2.69) [43].
An observational study in Spain assessed 1549 patients. After adjusting gender and age, they concluded that low levels of vitamin D increase the risk of hospitalization and critical care, but not the mortality rate [35]. Additionally, another study in Iran showed that vitamin D insufficiency or deficiency was not significantly different between ICU and non-ICU patients [42]. A systematic review in Brazil studied all of the RCTs, which showed no association between the vitamin D group and placebo in terms of mortality, length of hospitalization stay, and duration of invasive ventilation. However, they included a few studies, and the dose of Vitamin D was different in 3 studies may confound their conclusion [44]. In contrast, two systematic reviews and meta-analyses proved a significant relationship between vitamin D deficiency and the severity of disease [45, 46]. However, these systematic reviews did not consider age and sex, included heterogeneous studies, and most parts of included studies were observational, avoiding causality conclusions. However, the rate of severe disease and the duration of hospitalization were higher in the patients with sufficient vitamin D levels than in patients with insufficient vitamin D levels [P = 0.74, P = 0.9 (8.1 ± 7 vs. 7.4)]. No significant differences were found between groups in terms of O2 saturation and mortality rate.
Some previous studies reported that low vitamin D levels might lead to coronary artery dysfunction, postinfarction complications, vasculitis, and adverse cardiovascular outcomes [47, 48]. Similarly, distinct research regarding the effectiveness of vitamin D on heart failure showed controversial results [49]. Christina et al. reported vitamin D can efficiently decrease the risk of ischemia (odds ratio = 0.934, confidence interval [0.882, 0.989]) [50]. On top of that, scientists have found that vitamin D deficiency may increase the risk of atrial fibrillation (AF), possibly since vitamin D can reduce inflammation by inducing interleukin 10 (IL-10) production and reducing the production of interferon-γ, and tumor necrosis factor-alpha (TNF-α), IL-6, and IL-12 [51], and vitamin D inhabitant the renin-angiotensin system (RAS) [52]. A review study in 2019 on the effect of vitamin D on atrial fibrillation reported that further basic and precise studies are required in this area [53].
On the other hand, researchers have shown the association between COVID-19 and cardiovascular complications, which posed the potential role of vitamin D levels and cardiovascular complications in COVID-19 patients. Zheng et al. demonstrated that COVID-19 could cause myocarditis through an uncertain specific mechanism [54]. Dinis et al. declared that COVID-19 patients with a critical condition had higher rates of arrhythmia. Moreover, atrial fibrillation and other supraventricular arrhythmia were the most prevalent amongst these patients. However, vitamin D levels were not related to increased cardiac mortality [55]. Additionally, a systematic review and meta-analysis demonstrated that QTc prolongation, ST-changes, and arrhythmia could be observed in COVID-19 patients. They also reported that cardiac arrhythmia was associated with poor prognosis [56]. Some studies reported an increased rate of myocardial infarction and heart failure due to vitamin D deficiency [57]. A systematic review and meta-analysis reported that COVID-19 might affect the cardiovascular system [58]. Consequently, in the present study, the cardiovascular factors were assessed in different levels of vitamin D. Findings of the present study showed no statistically significant difference between serum vitamin D levels in terms of blood pressure, arrhythmia, reduced LVEF, pericardial effusion, and abnormal ST-segment changes.