Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients.

CRP is produced primarily in the liver in response to inflammation to minimize damage to tissues. It is generally considered to be a non-specific marker of inflammation. Vitamin D may modulate inflammation and reduce the intensity of cytokine storm in severe COVID patients. However, the authors do not have data to show that vitamin D is therapeutic or preventive. Future studies of the role of vitamin D in reducing cytokine storm and COVID-19 mortality are warranted.

• hs-CRP in healthy subjects indicated an OR of 1.8 with 95% CI (1.2 to 2.6) among the elderly (age ≥ 60 years) in low-income families and an OR of 1.9 with 95% CI (1.4 to 2.7) among the elderly (age ≥ 60 years) in high-income families. This is indirect evidence supporting the association of vitamin D with cytokines and unregulated inflammation.
• In severe COVID-19 cases, a cytokine storm notably increases the production of CRP, and as such a stronger correlation between cytokine storm and high CRP is achieved. Patient level data shows a notable OR of 3.4 with 95% CI (2.15 to 5.4) for high CRP in severe COVID-19 patients.
• Data suggested a possible link between Vitamin D deficiency and A-CMR among countries with similar testing strategies.

COVID-19 affected and deceased cases from a wide range of populations identified from data published by governments, researchers and agencies (like the World Health Organization).

• One important limitation of the present country-level analysis is the assumption that vitamin D levels in COVID-19 patients follow the same distribution with subjects in other previous vitamin D studies. The authors did not have access to vitamin D status and cytokine levels in individual COVID-19 patients before and after infection and therefore, do not have the data to suggest that vitamin D is therapeutic.
• The difference in age range, ethnicity, gender, social status, geographic latitude, measurement variations, the season of sample collection and year of study may impact the reported value of vitamin D status in different studies. The authors reduced some of these impacts by analyzing data from more recent studies which have collected a large number of samples through the entire year, however the distribution of samples collected in each season may not be equal across all studies.
• Different laboratory methods used in the estimation of 25(OH)D concentrations in different studies across the world is another limiting factor that introduces uncertainty.
• The cross-sectional nature of this study does not prove a relationship between 25(OH)D levels, hs-CRP levels, cytokine storm and severe COVID-19.
• Other underlying conditions associated with the populations at risk of vitamin D deficiency makes it more challenging to assess the actual impact of vitamin D in comparison to other factors.

Future studies on VitD’s role in reducing cytokine storm and COVID-19 mortality are warranted.

• The concentration of 25-hydroxyvitamin D (25(OH)D) among the elderly population in each country (US, UK, France, Italy, Spain, Switzerland as well as WHO and CDC) was obtained from prior studies
• Vitamin D and high-sensitivity C-reactive protein (hs-CRP) data from the US National Health and Nutrition Examination Survey (NHANES) 2009–2010 dataset was combined with clinical data from COVID-19 patients to assess a possible role of vitamin D in regulating inflammation and cytokine production, which is a major risk factor for severe COVID-19 across many different countries.
• CRP is the marker for bioactivity of IL-6 which plays a major role in the development of a cytokine storm.
• hs-CRP in severe COVID-19 patients (hs-CRP ≥ 1 mg/dL) was used as a surrogate of a cytokine storm.
• Normal high-sensitivity CRP in healthy subjects was defined as hs-CRP ≥ 0.2 mg/dL.

Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy HK, Backman V. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res. 2020 Oct;32(10):2141-2158. doi: 10.1007/s40520-020-01677-y. Epub 2020 Sep 2. PMID: 32876941; PMCID: PMC7465887.