Vit-D in asymptomatic and critically ill Covid-19 patients and correlation

The clinical manifestations of COVID-19 varies from asymptomatic or paucisymptomatic forms to critical illness characterized by respiratory failure that warrants mechanical ventilation in an ICU⁶. Multiple organ dysfunction syndromes (MODS); sepsis and septic shock are other serious COVID-19 manifestation that warrants ICU admission. As per various studies only 10–15% of cases develop serious disease. Even in same age group without any cormorbid condition there is wide variation in the clinical severity. As till now there is no definitive treatment or vaccine is available for SARS-CoV-2., if one can identify some or other modifiable factor whose presence or absence affects the severity of disease one can definitely reduce the severity of disease. The first such factor that comes to mind is viral load itself. However, Argyropoulos et al. ruled out any association of initial viral load to the severity or chances of developing acute respiratory distress syndrome in SARS-CoV-2 patients¹⁶. There were media reports which correlates severity of COVID-19 with blood group, however the prospective multi-institutional study conducted by Latz et al. ruled out any independent association between blood type and peak inflammatory markers. The study concluded that no specific blood type is associated with the risk of intubation or mortality in COVID-19¹⁷.

Regarding, acute lung injury in COVID-19 the data so far available has indicated than an unrestricted immune reaction in the host is the main process which leads to so called 'cytokine storm' the net effect is is extensive tissue damage with dysfunctional coagulation^18,19. Just a month ago, Italian researchers introduced MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) as mechanism for underlying pulmonary injury in COVID-19²⁰. Out of several cytokines like the tumor necrosis factor α (TNF-α), IL-1β, IL-8, IL-12 play definite role in the pathogenic cascade of the disease and the most important mediator of this storm is interleukin 6 (IL-6)^19,21. IL-6 can be produced by immune system cells (B lymphocytes, T lymphocytes, macrophages, dendritic cells, monocytes, mast cells); stromal cells and by many non-lymphocytes cells including fibroblast and endothelial cells²². IL-1β and TNFα are the key activators for the secretion of the IL-6²³.

Vitamin D is usually acknowledged for the maintenance of bone health and calcium–phosphorus metabolism, many other roles like stimulation of insulin production, effects on myocardial contractility have been recently discovered. Vitamin D plays an essential role in the immune system. Vitamin D interferes with the majority of the immune systems cells such as macrophages, B and T lymphocytes, neutrophils and dendritic cells²⁴. The T and B lymphocytes can form the active metabolite of vitamin D, 1,25(OH)2D3 which inhibits T cell proliferation and activation. Beside this, vitamin D inhibits the production of pro-inflammatory cytokines and enhance the production of anti-inflammatory cytokines^25,26. Vitamin D inhibits the adaptive immune system and promotes the innate immune system which balances the immune response and provides an overall anti-inflammatory response²⁷.

In Current study authors found that vitamin D deficiency (as suggested by serum 25 (OH)D concentration < 20 ng/mL) is far more prevalent in patients with severe COVID–19 disease requiring ICU admission and thereby increased chances of mortality. For non-skeletal purpose many researchers had suggested cutoff level of serum 25 (OH)D to < 30 ng/ml for defining vitamin D deficiency¹⁵, on adopting this criterion the prevalence was almost 100% in critically ill patients (62 out of 63). On the same side the patients with vitamin D deficiency exhibit higher levels of chemical markers of inflammation. The current study is the first and the most comprehensive study in which both severe and asymptomatic COVID patients were included and vitamin D level along with inflammatory markers were estimated the so as to correlate the association. In current study authors preferred of using period-based inclusion of subject over specifying the sample size because of the reason that COVID-19 is an emerging pandemic with variable level of seropositivity in the society and none of the sample size formula fits well with satisfactory reduction in the chances of error. Authors adopted 6-week criterion for inclusion of eligible subjects which is around 10.71% of year (56 weeks). Beside this all the subjects were followed till the closure that is successful discharge or mortality.

In western countries there is a strong association of vitamin D deficiency with socioeconomic status, which doesn’t holds true in India, rather few studies have demonstrated lower prevalence of vitamin D deficiency in low socioeconomic status and correlated this to higher sunlight exposure in lower socioeconomic strata of India²⁸. Keeping this in view authors excluded accounting of socioeconomic status as independent variable.

Jun Xu, et al. in had demonstrated beneficial effect of vitamin D agonist, calcitriol, on LPS-induced acute lung injury in rats; they had demonstrated that calcitriol pretreatment significantly improved LPS-induced lung permeability. Through ELISA analysis they demonstrated that calcitriol modulates the expression of members of the renin-angiotensin system (RAS), including angiotensin I-converting enzymes (ACE and ACE2), renin and angiotensin II, to exert the protective effects on LPS-induced lung injury²⁹. Surprisingly, SARS Cov-2 also uses ACE receptors for infection.

Biesalski, in the review article emphasize the fatal relationship of Vitamin D and comorbidities in COVID-19 patients³⁰. E Laird, J Rhodes also conducted a literature search study to conclude that optimising vitamin D status certainly have benefits in COVID-19³¹.

The results of current study however be interpreted with few limitations. First, the study has been conducted in a single centre located in central India, the area has itself high prevalence of vitamin D deficiency. Second: Time elapsed between actual infection and admission has not been taken in to consideration and the quantitative variables are measured only when patient got admitted in the hospital. This may have impact over chemical markers of inflammation. Third Current study doesn’t take co morbidities in account while estimating pro-inflammatory markers as co-morbidities like diabetes and hypertension enhance the severity in COVID-19. So keeping these in view a multicentre study with large number of subjects can be carried out or a large pooled prospective datasets can be collected to re-assess the result and will generate more robust conclusions.

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