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A recent review posted to the Research Square* preprint server examined published studies for a consistent association between vitamin D levels and coronavirus disease 2019 (COVID-19) severity.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the body through the respiratory system, where the SARS-CoV-2 spike protein binds to the angiotensin-converting enzyme-2 (ACE-2) receptors on the bronchial and nasal epithelia.
The entry and rapid replication of the virus disrupt the epithelial-endothelial barrier, causing inflammatory response dysregulation and triggering a cytokine storm. The increased immune response during the cytokine storm can damage tissues and organs and has been linked to long-term fatigue and systemic complications experienced after recovery.
Cytokine storm is an imbalance in the levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and interleukins 6 (IL-6) and 1 beta (IL-1β), and anti-inflammatory factors such IL-10. Vitamin D regulates the balance between pro- and anti-inflammatory cytokines, with studies showing significant protective effects of vitamin D supplementation against acute respiratory infections. The active form of vitamin D, calcitriol, is also known to activate antiviral peptides. Understanding the association between vitamin D levels and COVID-19 severity could provide methods to protect individuals against severe outcomes proactively.
In the present study, the researchers conducted a systematic review of studies that examined the progression of COVID-19 severity based on the vitamin D levels of patients. The review included case-controlled, cross-sectional, observational, clinical, retrospective, and prospective cohort studies that compared median serum vitamin D levels to COVID-19 positivity rates, hospitalizations, COVID-19 severity, and survivors and survivors non-survivors.
The study analyzed the means and standard deviations of vitamin D levels in COVID-19 positive and negative individuals using a meta-analysis effect size calculator. Additionally, the P-value and 95% confidence intervals were also calculated. The researchers also used the t-test to determine differences in vitamin D levels between severe and moderate COVID-19 cases and between COVID-19 survivors and those who succumbed to the disease. Furthermore, they explored studies that examined vitamin D levels concerning hospitalization duration.
The results were near significant when median serum vitamin D levels in COVID-19-positive individuals were compared to those in COVID-19-negative individuals. However, when vitamin D levels were compared with the progression of COVID-19 severity, the results were not statistically significant. The serum vitamin D levels were also not significantly different when compared between COVID-19 survivors and mortalities.
The average median serum vitamin D values for COVID-19-positive patients was 27.08 nmol/L, compared to the 48.67 nmol/L among COVID-19-negative individuals. With a p-value of 0.059, this difference was considered near significant.
The review examined a study that evaluated the impact of vitamin D on inflammatory cytokine levels and found significantly higher levels of pro-inflammatory cytokine IL-6 in individuals with vitamin D deficiency. Patients whose vitamin D levels were higher than 75 nmol/L showed lower inflammatory markers such as C-reactive protein. However, studies showed no significant direct association between C-reactive protein and vitamin D levels. The study also reported lower COVID-19 survival probability among patients with vitamin D levels below 30 nmol/L.
A study comparing vitamin D levels between inpatients who exhibited severe symptoms of COVID-19 and outpatients with milder disease symptoms found that patients with severe symptoms had significantly lower median vitamin D levels (less than 12 ng/mL). Although the difference was not statistically significant, the review found that individuals with higher vitamin D levels had fewer median hospitalization days. However, three contrasting studies also found that patients with higher vitamin D levels stayed hospitalized for longer.
Furthermore, no statistically significant difference was found in the vitamin D levels of individuals with moderate and severe COVID-19 symptoms. The t-test results also reported no significant difference in the vitamin D levels of COVID-19 survivals and mortalities.
To summarize, the review examined various studies that compared median serum vitamin D levels to factors such as COVID-19-positive cases, the severity of the infection, disease survivors, deaths, levels of inflammatory cytokines and markers such as C-reactive protein, and the number of days spent in the hospital.
Overall, the results reported no significant associations between vitamin D levels and COVID-19 severity, mortality, or hospitalization duration. Vitamin D deficiency seemed to be associated with the likelihood of being COVID-19 positive, but the nearly significant association decreased when examined at a larger scale.
Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.