While several studies have assessed the relationship between vitamin D and COVID-19, the results vary. This is the first multi-center observational study of hospitalized COVID-19 patients that examines the association between acute infection and vitamin D status and explores the potential mechanism of this relationship.
COVID-19 disease severity and death correlate with high levels of acute phase reactants[19]. These results are in agreement with the findings of Favaloro et al.[20] that elevated LDH, D-dimer, CRP, and IL-6 levels at the time of diagnosis are linked to severe outcomes. In the current study, levels of the primary lymphocyte subsets were lower in critical and deceased patients with COVID-19, with way below normal T and B cell counts. Chen et al.[21] found that the concentrations of PCT and high-sensitivity CRP were significantly higher in deceased patients. While PCT levels were lower in deceased patients in the current study, however, this was not statistically significant. Serum 25-hydroxyvitamin D [25(OH)D] was also significantly lower in the deceased group than in the other groups, and IL-5 was higher in both the critical and deceased groups than in the general and severe groups. Low serum 25(OH)D levels in COVID-19 patients are associated with a more severe disease course[2; 4]. Vitamin D deficiency is one of many factors involved in determining the outcome of COVID-19 disease that can be corrected safely and cheaply. The current study also found that elevated serum IL-5 levels were linked to poor disease outcomes. To our knowledge, few short-term case studies have measured the association between serum 25(OH)D levels and acute phase COVID-19 disease severity following in-patient admission, and no study has addressed the mechanism by which 25(OH)D status affects disease severity.
This study further clarified the impact of serum 25(OH)D levels on the clinical characteristics of COVID-19 patients. Patients were divided into three groups based on their serum 25(OH)D level: a normal group, a vitamin D insufficient group, and a vitamin D deficient group. Only 24 patients (6%) had normal 25(OH)D status, while 15% and 77% were insufficient and deficient, respectively. This study may have observed such low levels of 25(OH)D because it was conducted in winter when the incidence of acute upper respiratory virus infection is high. Other studied groups that traditionally exhibit vitamin D deficiency or insufficiency, such as older adults and people, stay at home because of cold weather and the pandemic. These are also the populations that are most vulnerable to COVID-19. This study found that 20% and 16% of vitamin D deficient and vitamin D insufficient patients, respectively developed critical disease. This may be the result of 25(OH)D levels that were unable to provide enough substrate for effective intracrine conversion to the active form of vitamin D, 1, 25(OH)2D3[22]. The levels of D-dimer and IL-5 were higher in patients with vitamin D deficiency than in those in the vitamin D normal and insufficient groups, while the number of CD8+ T cells was significantly lower in the vitamin D deficient group. Except for COVID-19 patients with diabetes, this study found no significant difference in the levels of coronary heart disease and hypertension by 25(OH)D status. Despite this heterogeneity, most of the clinical trials analyzed in this study found statistical differences in these parameters among vitamin D insufficient or deficient patients with COVID-19.
The logistic analysis results reported here are in agreement with those of Karonova et al.[4] that low 25(OH)D levels are associated with a severe course of COVID-19 and a poor prognosis. These findings suggest that vitamin D insufficiency may be a contributing factor, due to the lack of sunlight during the winter months which limits outdoor activity and the opportunity to receive sufficient levels of vitamin D. Other studies have linked disease severity to older age[10]. The findings of the current study are consistent with those of Han et al.[23] and Sun et al.[24] that LDH and CD8+ T cell count are independent predictors of disease severity in COVID-19 patients. However, studies of whole blood are needed to more fully understand the mechanism that links vitamin D status to COVID-19 disease severity, as well as any corresponding serological markers. Results from the current study show that serum IL-5 expression is an independent risk factor for the severity of COVID-19. IL-5 levels were higher in patients with vitamin D deficiency than in those with normal or insufficient vitamin D. A few studies have suggested that anti-IL-5 drugs can reverse aberrant immune response, and thus protect infected subjects from severe COVID-19-related complications[25; 26], however, it remains unknown whether vitamin D can affect COVID-19 severity by regulating IL-5.
Studies have indicated a possible relationship between serum 25(OH)D levels and COVID-19 disease outcomes. Bilezikian et al.[27] found that individuals with 25(OH)D levels ≥ 38 ng/mL had a two-fold lower risk of viral acute respiratory infections than those with levels < 38 ng/ml. Other studies have also observed a link between lower concentrations of 25(OH)D and a higher risk of acute respiratory infections[22; 28]. The current study identified the 25(OH)D level < 36.04 ng/mL that was able to predict COVID-19 mortality. When combined with IL-5 levels and Eos counts, the predictive value was even higher, indicating the advantage of using a 25(OH)D level < 36.04 ng/mL combined with an IL-5 level > 1.70 pg/mL and an Eos count > 0.015 in place of 25(OH)D alone to predict COVID-19-related death. The current study also found that peripheral blood Eos counts, IL-5 levels, and 25(OH)D levels alone should be considered when predicting the risk of death. A very large, multi-center study conducted by Ling et al.[2] found a reduced risk of mortality in acute COVID-19 inpatients who received cholecalciferol treatment, regardless of baseline serum 25(OH)D levels.
Serum 1,25(OH)2D3 is also active in signaling cascades that promote innate antiviral immune responses, including induction of the antimicrobial peptide, CAMP/LL37, which was originally characterized for its antibacterial properties. Cytokines are important markers of infection and immune status. Interestingly, COVID-19 patients with severe disease also had a marked Th2 immune response concurrent with a cytokine storm. Increased IL-5, IL-13, and immunoglobulin E (IgE) levels are observed in these patients, which also correlates with the severity of the clinical course[29]. This is consistent with the upregulation of IL-5 observed in the critical and deceased patients in the current study. Our findings further showed that 25(OH)D levels in the serum of patients with COVID-19 correlated negatively with the expression of IL-5. Wang et al.[16] found that vitamin D supplementation can reduce the levels of IL-5 in patients with asthma and chronic obstructive pulmonary disease (COPD). Thus, it is possible that vitamin D reverses disease in COVID-19 patients by reducing IL-5 production. Vitamin D supplementation is a promising low-cost, low-risk method of controlling COVID-19. The serum 25(OH)D status correlated positively with the CD8+ T cell count, this suggests that vitamin D is involved in regulating the immune response of COVID-19 patients. The specific mechanism for this association is worth further exploration.
As with all retrospective studies, there were several limitations to this study. For example, data distribution was somewhat heterogeneous since not every patient had information available for all studied biomarkers. Power may have been improved with more data values. In addition, this study only included hospitalized patients with known COVID-19 diagnoses. A longitudinal analysis of outcomes is needed to assess whether vitamin D status is also associated with the risk of developing SARS-CoV-2 infection and to identify any long-term sequelae of deficient vitamin D status during acute disease. Finally, the role of vitamin D supplementation requires further study using randomized controlled studies, both to establish its efficacy and to determine its optimal dose and duration of treatment.