Applied nutritional investigationImpact of high-dose vitamin D3 on plasma free 25-hydroxyvitamin D concentrations and antimicrobial peptides in critically ill mechanically ventilated adults
Introduction
The potential benefit of vitamin D administration in critically ill patients is being investigated given the high rate of vitamin D deficiency in this patient population [1], [2], [3], [4], [5] and its strong association between low blood levels of total 25-hydroxyvitamin D [25(OH)D] and adverse clinical outcomes such as increased risk for mortality [6], [7], [8], [9], [10], [11], [12], [13]. Recently, several randomized clinical trials (RCTs) have reported clinical effects of administration of vitamin D in adult patients in the intensive care unit (ICU) [5], [14], [15], [16]. Three of the recent RCTs studied various high-dose regimens of vitamin D3 (cholecalciferol) and reported some beneficial effects on secondary clinical endpoints, including mortality [15] and hospital length of stay [5], [16], concomitant with increased total 25(OH)D levels in blood.
Vitamin D administration has been a focus for intervention because of benefits to the immune system. 1,25(OH)2D 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], [19], [20], [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], [23], [24], [25], [26]. LL-37 and other AMPs, such as defensins, exhibit direct antimicrobial effects against microorganisms and modulate various innate and adaptive immune functions, including chemotaxis and phagocytosis [24], [27]. hBD-2 is upregulated in epithelia during infections, inflammation, or when both are present [24], [26]. Studies in humans with respiratory infections demonstrate upregulation of these AMPs in lung [28], [29], [30]. Limited data suggests that 1,25(OH)2D may upregulate hBD-2 [17], [31], [32]. This is relevant to studies of vitamin D administration in ICU patients because induction of hBD-2 is impaired in patients with severe sepsis [33]. Additionally, to our knowledge, no studies have explored the relationship between circulating AMPs and lung macrophage phagocytosis.
In catabolic patients, some studies have associated increased plasma 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 this relationship [35], [36], [37]. Thus far, the strongest evidence supporting vitamin D administration in critically ill patients are from the large RCT of Amrein et al. [15] and a meta-analysis of vitamin D trials in ICUs by Putzu et al. [38]. Taken together, these data suggest that administration of high-dose vitamin D may be associated with reduced mortality in some patient subgroups (e.g., those with frank vitamin D deficiency) without improvement in other clinical outcomes; thus, vitamin D therapy in this setting remains controversial and there is a need for further investigations [15], [38]. In a recent RCT in mechanically ventilated adults, high-dose vitamin D3 increased plasma total 25(OH)D levels by two- to threefold, but did not alter plasma LL-37 concentrations [5].
Total 25(OH)D concentrations in plasma reflects 25(OH)D tightly bound to vitamin D-binding protein (DBP), the major 25(OH)D carrier protein; the rest is loosely bound to albumin or is free in circulation, defined as bioavailable 25(OH)D [39], [40]. Recently, immunoassays have been developed to accurately and directly measure free (nonprotein–bound) 25(OH)D in human blood [39]. Direct measurement of free 25(OH)D may be advantageous in ICU patients, in whom the catabolic response results in a marked decline in blood albumin concentrations and circulating levels of DBP [1], [41]. To our knowledge, no studies in ICU patients have yet evaluated the effects of vitamin D administration on directly measured free 25(OH)D levels or relationships to AMP expression in blood. In the present study, we determined the following in critically ill adults with respiratory failure:
- 1.
The effect of previous high-dose regimens of vitamin D3 on free 25(OH)D concentrations;
- 2.
The relationship of free 25(OH)D to circulating LL-37 and hBD-2; and
- 3.
Associations between plasma levels of free 25(OH)D and these AMPs to alveolar macrophage phagocytosis function.
Section snippets
Trial design
The parent RCT was approved by the Emory University Institutional Review Board and published previously [5]. Written informed consent was obtained from all participants or their legally authorized representative. Participants were enrolled at two Emory University School of Medicine teaching hospitals, Emory University Hospital Midtown and Emory University Hospital. Full details of trial design, inclusion and exclusion criteria, safety criteria, and other methodologic details have been provided
Results
The CONSORT diagram, clinical outcomes, and concentrations of total 25(OH)D and LL-37 in plasma over time and in baseline BALF were previously published [5]. For illustration purposes, selected baseline demographic characteristics of the same individuals in this substudy, and the baseline vitamin D and AMP endpoints from plasma and BALF are shown in Table 1. Baseline clinical and demographic indexes, baseline plasma total 25(OH)D, and LL-37 concentrations were similar between groups at
Discussion
This pilot study was designed to demonstrate the effects of high-dose vitamin D3 administration (either 250 000 or 500 000 IU versus placebo) on serial plasma free 25(OH)D concentrations. At baseline (before vitamin D3 or placebo administration), plasma values ranged between 4.1 and 5.8 pg/mL, similar to serum free 25(OH)D levels in a recent report with healthy adults (4.7 pg/mL) and noncritical ill adults with cystic fibrosis (4.6–5.9 pg/mL) [39]. The three groups in the present study were
Conclusions
To our knowledge, the present study was the first to provide data on directly measured, nonprotein-bound, free 25(OH)D levels in response to high-dose vitamin D3 in critically ill adult patients with respiratory failure. Additionally, we related the administration of vitamin D3 to changes in circulating antimicrobial molecules that may have an effect on critical illness infectious and inflammatory outcomes. Additionally, we demonstrated that plasma LL-37 levels may affect alveolar macrophage
Acknowledgments
The authors acknowledge Frank Harris for his technical assistance.
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2020, Archives of Oral BiologyCitation Excerpt :Interestingly, in line with our findings, in critically ill ventilator-dependent adults who received enteral vitamin D supplementation, although no change was observed in plasma LL-37 and hBD-2, the percent change in mRNA expression of cathelicidin was positively associated with percent change in free 25(OH)D over time. This study (Han et al., 2017) gives credit to the concept that vitamin D may regulate LL-37. However, further studies with larger sample size are required to investigate the role of vitamin D supplementation on gingival AMP levels.
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This work was supported, in part, by National Institutes of Health grants: NIH R21 HL110044 (GSM, TRZ), K24 DK096574 (TRZ), UL1 TR000454 (JEH, GSM, TRZ, VT), K01 DK102851 (JAA), T32 DK007298 (JLJ), T32 AA013528 (JEH). JEH, JAA, JLJ, LAB, VT, GSM, and TRZ were responsible for the conception and design of the study, conduct of trial, analysis and interpretation, and drafting and revising the manuscript. MAB and LH were involved in conducting the trial, interpretation of the data, and drafting work of intellectual content. The authors have no conflicts of interest to declare.