Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis

Abstract

Objectives To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol. Design Randomized, placebo-controlled, trial. Setting Medical and surgical ICUs of a single teaching hospital in Boston, MA. Patients 30 adult ICU patients. Interventions Placebo (n=10) versus 200,000 IU cholecalciferol (n=10) versus 400,000 IU cholecalciferol (n=10), within 24 hours of new-onset severe sepsis or septic shock. Measurements and Main Results Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D (25OHD), as well as vitamin D binding protein and albumin to calculate bioavailable 25OHD. Plasma LL-37 and high sensitivity C-reactive protein (hsCRP) levels were also measured. At baseline, median (IQR) plasma 25OHD was 17 (13 to 22) ng/mL and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were: 1) total 25OHD: 3 (-3 to 8)%, 49 (30 to 82)%, and 69 (55 to 106)%, (P<0.001); 2) bioavailable 25OHD: 4 (-8 to 7)%, 45 (40 to 70)%, and 96 (58 to 136)%, (P<0.01); and 3) LL-37: -17 (-9 to -23)%, 4 (-10 to 14)%, and 30 (23 to 48)%, (P=0.04). Change in hsCRP levels did not differ between groups. A positive correlation was observed between bioavailable 25OHD and LL-37 (Spearman's rho=0.44, P=0.03), but not for total 25OHD and LL-37. Conclusions High-dose cholecalciferol supplementation rapidly and safely improves 25OHD and bioavailable 25OHD levels in patients with severe sepsis or septic shock. Changes in bioavailable 25OHD are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

Impact of high-dose vitamin D 3 on plasma free 25-hydroxyvitamin D concentrations and antimicrobial peptides in critically ill mechanically ventilated adults

“…In a pilot study similar to ours, Quraishi et al administered a one-time enteral dose of vitamin D 3 (either 200,000 IU or 400,000 IU) or placebo in adults with new onset of severe sepsis or septic shock (16). Compared to baseline values, these investigators showed a modest ≈ 50% to 70% increase in plasma total 25(OH)D levels from baseline to day 5 of study with the one-time 200,000 IU and 400,000 IU vitamin D 3 doses, respectively.…”

“…Recently, several randomized clinical trials (RCT) have reported clinical effects of administration of vitamin D in adult intensive care unit (ICU) patients (5, 14–16). Three of the recent RCTs studied various high-dose regimens of vitamin D 3 (cholecalciferol) and reported some beneficial effects on secondary clinical endpoints, including mortality (15) and hospital length of stay (LOS) (5, 16), concomitant with increased total 25(OH)D levels in blood.…”

“…1,25(OH) 2 D has pleotropic effects on immune cells (17), and in many studies upregulates expression of the endogenous antimicrobial peptide (AMP) cathelicidin (LL-37) in human skin, plasma, monocytes and macrophages (12, 16, 18–21). LL-37, the C-terminal peptide fragment of human cationic antimicrobial protein (hCAP18) and human beta-defensin 2 (hBD-2) (the most abundant beta-defensin in the lung) is induced in respiratory and other epithelia and immune cells in response to infection and inflammation (22–26).…”

“…In catabolic patients, some studies have associated increased blood total 25(OH)D levels with upregulated LL-37 protein and mRNA expression of hCAP18, suggesting a possible mechanistic relationship between vitamin D status and infection (1, 14, 16, 34). However, other studies in patients with infections or lung disease did not show a relationship between blood total 25(OH)D and LL-37 concentrations (35–37).…”

Cholecalciferol Additively Reduces Serum Parathyroid Hormone and Increases Vitamin D and Cathelicidin Levels in Paricalcitol-Treated Secondary Hyperparathyroid Hemodialysis Patients

“…A high dose of oral cholecalciferol modulates disease-relevant T-cell functions and increases serum cathelicidin in patients with Human immunodeficiency virus (HIV) infection [47]. In critically ill patients with severe sepsis, high-dose cholecalciferol elevates serum cathelicidin with serum 25(OH)D 3 [48]. Therefore, supplementing nutritional vitamin D might play an adjunctive role in treating and preventing infections in dialysis patients.…”