Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19?

Background: Hypovitaminosis D has been suggested to play a possible role in coronavirus disease 2019 (COVID-19) infection. Methods: The aim of this study is to analyze the relationship between vitamin D status and a biochemical panel of inflammatory markers in a cohort of patients with COVID-19. A secondary endpoint was to evaluate the correlation between 25OHD levels and the severity of the disease. Ninety-three consecutive patients with COVID-19-related pneumonia were evaluated from March to May 2020 in two hospital units in Pisa, in whom biochemical inflammatory markers, 25OHD levels, P/F ratio at nadir during hospitalization, and complete clinical data were available. Results: Sixty-five percent of patients presented hypovitaminosis D (25OHD ≤ 20 ng/ml) and showed significantly higher IL-6 [20.8 (10.9-45.6) vs. 12.9 (8.7-21.1) pg/ml, p = 0.02], CRP [10.7 (4.2-19.2) vs. 5.9 (1.6-8.1) mg/dl, p = 0.003], TNF-α [8.9 (6.0-14.8) vs. 4.4 (1.5-10.6) pg/ml, p = 0.01], D-dimer [0.53 (0.25-0.72) vs. 0.22 (0.17-0.35) mg/l, p = 0.002], and IL-10 [3.7 (1.8-6.9) vs. 2.3 (0.5-5.8) pg/ml, p = 0.03]. A significant inverse correlation was found between 25OHD and all these markers, even adjusted for age and sex. Hypovitaminosis D was prevalent in patients with severe ARDS, compared with the other groups (75% vs. 68% vs. 55%, p < 0.001), and 25OHD levels were lower in non-survivor patients. Conclusions: The relationship between 25OHD levels and inflammatory markers suggests that vitamin D status needs to be taken into account in the management of these patients. If vitamin D is a marker of poor prognosis or a possible risk factor with beneficial effects from supplementation, this still needs to be elucidated.

Vitamin D Status as a Potential Modifiable Risk Factor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

In March 2020, the infection COVID-19 spread as a pandemic emergence. Among multiple biological and environmental factors, hypovitaminosis D is a credible candidate. The aim of this study is to shed light on the pathogenic role of vitamin D deficiency in the susceptibility to SARS-CoV-2 and in the aggressive immune and inflammatory response by the host. We retrospectively analyzed the biochemical panel of immune system markers and the tandem mass spectrometry coupled to liquid chromatography (LC-MS-MS) measured vitamin D, in the serum samples of patients with SARS-CoV-2 studied in all aspects of clinical relevant parameters. RESULTS between 18th March and 20th April 2020 we enrolled 29 consecutive patients with COVID-19. They were 17 (58.6%) males and 12 (41.4) females, and the median age was 79 (69–88) years. Mean 25OHD was 17.3±2.1 ng/ml, with a median of 15.7 1 ng/ml (i.r. 6.7–25). Twenty-five patients (86.2%) had 25OHD levels &lt;30 ng/ml, 18 patients (62.0%) had 25OHD levels &lt;20 ng/ml and 10 patients (34.5%) had severe vitamin D deficiency (&lt;10 ng/ml). In the group of patients with severe disease (ARDS, cardiovascular complications, CID) 69.2% (n=9/13) of patients presented hypovitaminosis D (&lt;20 ng/ml). All patients who dead for COVID-19 during hospitalization (n=6) had 25OHD≤30 ng/ml and 5/6 had 25OHD≤20 ng/ml. IL-6 and CRP were measured in all patients and were considered surrogate markers of cytokines storm. The majority of patients had levels of IL-6 (n=22, 75.8%) and CRP (n=25, 86.2%) above the upper limit of the reference range of our laboratory (IL6 6.59 and CRP 1 mg/dl) and the median was IL 6=16.1 (i.r. 7.3–36.3) and CRP=6.67 (2.64–11.52). Patients with 25OHD &lt;20 ng/ml had higher levels of IL-6 (p=0.004;19.9 vs 10.4) and CRP (p=0.009, 9.85 vs 1.40) and did not differ for the other clinical and biochemical variables. If we considered as 25OHD cut-off the mean value in our population (17.3 ng/ml), patients with lower levels of 25OHD had higher age (p=0.033) and higher levels of IL6 (p=0.016), CRP (p=0.04), troponin (p=0.04) and D-dimer (p=0.017), compared to the others. An inverse correlation was found between 25OHD levels and IL-6, CRP, and troponin. In a univariate regression analysis hypovitaminosis D (&lt;20 ng/ml) was a predictive factor for IL6 (expressed as LnIL6) levels (β=0.57, P=0.003) and for PCR levels (β=0.42, P=0.034). We also performed a multivariate regression analysis with hypovitaminosis D (&lt;20 ng/ml), sex, BMI, age (&lt;70 years) and ARDS as independent variables. Notably, hypovitaminosis D (β=0.49, P&lt;0.02), BMI (β=0.4, P=0.04) and ARDS (β=0.44, P=0.02) were confirmed to be significant variables for IL6 (expressed as LnIL6) level prediction. In the same multivariate model hypovitaminosis D (β=0.49, P=0.034) was confirmed as independent predictor of CRP levels. In conclusion, hypovitaminosis D is related to the negative prognostic inflammatory status in patients with SARS-Cov2.

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives.

Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.

An Update on Vitamin D Metabolism.

Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.