Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study

Abstract

Objectives: The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.

Design: Cross-sectional study.

Setting and participants: Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009-2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples.

Outcome measures: Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality.

Results: Vitamin D insufficiency (total 25(OH)D 25-50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators.

Conclusions: Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes.

Keywords: COVID-19; immunology; intensive & critical care; respiratory infections.

Figure 1

Total 25(OH)D in COVID-19 and influenza A and in survivors of critical illness. (A) Total 25(OH)D concentrations in patients with COVID-19 (n=295) stratified by receipt of IMV. (B) Total 25(OH)D concentrations from patients with COVID-19 were divided into quartiles and the proportion of patients who received IMV in each quartile was compared by χ² test. (C) Total 25(OH)D concentrations in patients with influenza A (from 2009 H1N1 pandemic, n=93) stratified by receipt of IMV. For (A) and (C), groups were compared by Mann-Whitney test. The stacked bar charts represent the proportion of patients in each subgroup with sufficient (green), insufficient (orange) or deficient (red) total vitamin D status, compared by χ² test. (D) Total 25(OH)D concentrations in non-selected critical illness survivors (n=139, recruited prior to the COVID-19 pandemic) at the time of ICU discharge. On violin plots of total 25(OH)D concentrations (nmol/L), the solid line within the plot represents the median and the dashed lines represent the IQR. The dotted lines on the y-axis represent the thresholds for total vitamin D insufficiency (25–50 nmol/L) and deficiency (<25 nmol/L). 25(OH)D, 25-hydroxy vitamin D; ICU, intensive care unit; IMV, invasive mechanical ventilation.

Figure 2

Total and free 25(OH)D and outcomes in COVID-19 and influenza A. Smoothed predicted probability of outcomes (invasive mechanical ventilation (A. B and C) or in-hospital mortality (D)) versus total (A and B) or free (C and D) 25(OH)D concentration (with other covariates at mean values) from the binary logistic regression multivariable models. The grey ribbon represents the estimated 95% CI and the x-axis ticks show the observations. 25(OH)D, 25-hydroxy vitamin D.

Figure 3

Free 25(OH)D in COVID-19. (A) Simple linear regression line and 95% CI (dashed lines) representing the correlation between total and free 25(OH)D concentrations in COVID-19. (B) Violin plot of free 25(OH)D concentrations (pg/mL) in patients with COVID-19 stratified by receipt of invasive mechanical ventilation. The solid line within the plot represents the median and the dashed lines represent the IQR. Groups are compared by Mann-Whitney test. 25(OH)D, 25-hydroxy vitamin D.