Vitamin D deficiency correlates with a reduced number of natural killer cells in intensive care unit (ICU) and non-ICU patients with COVID-19 pneumonia
Hellenic Journal of Cardiology, https://doi.org/10.1016/j.hjc.2020.11.011
Alice G. Vassiliou, Edison Jahaj, Maria Pratikaki, Chrysi Keskinidou, Maria Detsika Eirini Grigoriou, Katherina Psarra, Stylianos E. Orfanos, Alexandra Tsirogianni, Ioanna Dimopoulou, Anastasia Kotanidou
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>3,400 medical studies on "Natural Killer" and "Vitamin D"
in Euro Pub Med as of Dec 2020
- Vitamin D, invariant natural killer T-cells and experimental autoimmune disease - 2012
- FREE PDF doi: 10.1017/S0029665111003193
- Effect of vitamin D levels on natural killer cells in diabetes mellitus patients with tuberculosis - 2014
- Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood - 2017
- Effect of Natural Compounds on NK Cell Activation - 2018
- FREE PDF https://doi.org/10.1155/2018/4868417
Regulation of immune function continues to be one of the most well recognised extra-skeletal actions of vitamin D. In vitro data have shown that vitamin D modulates immune cells and induces immune tolerance, while in vivo data from animal studies and from vitamin D supplementation human studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity.  In the present study, we examined whether vitamin D deficiency modulates the number of immune cells in COVID-19 patients.
This observational, single-centre study included consecutive COVID-19 intensive care unit (ICU) patients (N= 29), and consecutive patients hospitalised in a specialised non-ICU COVID-19 ward (N= 10), who were discharged from the hospital without being transferred to the ICU, from March 18th 2020 to May 25th 2020. The study was approved by the Hospital’s Research Ethics Committee (129/19-3-2020) and all procedures carried out on patients were in compliance with the Helsinki Declaration. Informed written consent was obtained from all patients’ next-of-kin. Total 25- hydroxyvitamin D was measured on hospital admission using the electrochemiluminescence immunoassay method (Cobas E602, Roche Diagnostics International Ltd). Immune phenotyping was performed by flow cytometric analysis (Navios EX flow cytometer, Beckman Coulter).
Vitamin D levels positively correlated with subpopulations of immune cells. Specifically, with cytotoxic T cells (r2= 0.344, p= 0.032), natural killer (NK) cells (r2= 0.496, p= 0.001), NK-T cells (r2= 0.325, p= 0.044) and regulatory T cells (r2= 0.333, p= 0.038). With respect to all other clinical and laboratory parameters, vitamin D levels correlated only with albumin (r2= 0.387, p= 0.018). To further explore these associations, we divided our cohort in two groups based on their vitamin D levels; we classified them in vitamin D deficient (<19.9 ng/ml, N= 32) and vitamin D insufficient (20-29.9 ng/ml, N= 7). Demographics, clinical and biochemical characteristics on hospital admission, and important outcomes of the two patient groups are listed in Table 1. As expected, hypertension was the most common comorbidity.  The two groups differed only in the number of NK cells (Table 1 and Figure 1). Cytotoxic T cells, NK-T cells and regulatory T cells did not differ in the two groups. It should also be noted, that the two patient groups did not differ with respect to hospital mortality, or disease severity.
The beneficial effects of vitamin D on protective immunity are due in part to its effects on the innate immune system. In vitro studies have reported contradictory results on the role of vitamin D on NK cell function, but whether vitamin D induces or inhibits NK cell function in vivo remains unclear.  NK cells are a type of cytotoxic lymphocytes critical to the innate immune system that secrete many cytokines and chemokines. Despite their vital role in viral infections, the contribution of NK cells in the immune defence against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not yet been directly investigated. The reduced circulating NK cells and exhaustion in the peripheral blood of COVID-19 patients has been suggested to be directly responsible for the progression and severity of COVID- 19. [4-6] Another study demonstrated that in SARS-CoV-2 infection, NK cell number was significantly reduced, however, the cells were strongly activated and this activation correlated with the development of severe disease. 
The immunomodulatory effects of vitamin D, have prompted researchers to consider the preventive effect of vitamin D supplementation on SARS-CoV2 viral infection [8,9]. It has been suggested that vitamin D supplementation might boost the immune system of COVID-19 patients and reduce disease severity in vitamin D deficient patients.  Indeed, bolus vitamin D3 supplementation during or just prior to COVID-19 infection was associated in frail elderly with less severe COVID-19 and better survival rate. 
Vitamin D deficiency is a widespread situation, affecting from cardiovascular- related conditions to endothelial function and the immune system.  In our pilot, single-centre, limited sample size study, we were able to demonstrate that vitamin D deficiency was associated with reduced numbers of natural killer cells; specifically, vitamin D deficient patients presented with mild NK lymphopenia (<100 cells/ul), while vitamin D insufficient patients had normal NK cell counts (>100 cells/ul). This reported lymphopenia may obstruct the important cellular barrier during early viral infections in patients with vitamin D deficiency. A larger cohort of COVID-19 patients to study the correlation between vitamin D deficiency and NK lymphopenia and activation is required.