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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.

Study: What is the Impact of Vitamin D Levels on COVID-19 Severity?: A Systematic Review. Image Credit: FotoHelin/Shutterstock


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, tadalafil cyclodextrin 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.

About the study

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.

*Important notice

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.

Journal reference:
  • Lydia Kersh, Kyla Geary, Michael Roberts et al. (2022). What is the impact of vitamin D levels on COVID-19 severity?: A systematic review. Research Square. doi: https://doi.org/10.21203/rs.3.rs-2219827/v1 https://www.researchsquare.com/article/rs-2219827/v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Angiotensin, Anti-Inflammatory, Calcitriol, Coronavirus, Coronavirus Disease COVID-19, covid-19, C-Reactive Protein, Cytokine, Cytokines, Enzyme, Fatigue, Hospital, Immune Response, Interferon, Interferon-gamma, Mortality, Necrosis, Peptides, Protein, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Tumor, Tumor Necrosis Factor, Virus, Vitamin D, Vitamin D Deficiency

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Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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