Significant association between vitamin D deficiency and sepsis: a systematic review and meta-analysis

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Abstract

Background

A number of observational studies have found an association between low vitamin D levels and risk of sepsis. We conducted a systematic review and meta-analysis to determine the overall estimate of risk.

Methods

This was a systematic review and meta-analysis conducted by online searches (CENTRAL, PubMed/MEDLINE, and EMBASE) was registered in PROSPERO (CRD42014014767). Primary outcome was incidence, prevalence, relative risk or odds ratio of having sepsis or bloodstream infection between patients with vitamin D deficiency and controls.

Results

The initial search yielded 647 articles. Twenty-one articles underwent full-length review and data were extracted from 10 observational studies. Pooled odds ratio of sepsis in participants with vitamin D deficiency was 1.78 (95 % confidence interval [CI] = 1.55 to 2.03, p < 0.01) compared with controls in studies that reported participant numbers and was 1.45 (95 % CI = 1.26 to 1.66, p < 0.01) in studies that reported an adjusted odds ratio of vitamin D deficiency for developing sepsis. Statistical between-study heterogeneity was low (I ² = 0 % and 5 %, respectively). Standardized mean difference of 25-hydroxyvitamin D levels in patients with sepsis and controls was −0.24 (95 % CI = −0.49 to 0.00, p = 0.05) and lower in the sepsis group compared with non-sepsis or control participants. The statistical between-study heterogeneity (I ²) was 0 %.

Conclusion

Vitamin D deficiency were associated with an increased susceptibility of sepsis.

Electronic supplementary material

The online version of this article (doi:10.1186/s12871-015-0063-3) contains supplementary material, which is available to authorized users.

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Most cited references 20

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Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.

Tian-Tian Wang, Frederick Nestel, Véronique Bourdeau … (2004)

The hormonal form of vitamin D(3), 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)(2)D(3) signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)(2)D(3) is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin beta2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)(2)D(3)-dependent gene expression. 1,25(OH)(2)D(3) induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)(2)D(3) along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)(2)D(3) induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)(2)D(3) thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.

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Human neutrophils contain two structurally distinct types of antimicrobial peptides, beta-sheet defensins (HNP-1 to HNP-4) and the alpha-helical peptide LL-37. We used radial diffusion assays and an improved National Committee for Clinical Laboratory Standards-type broth microdilution assay to compare the antimicrobial properties of LL-37, HNP-1, and protegrin (PG-1). Although generally less potent than PG-1, LL-37 showed considerable activity (MIC, <10 microgram/ml) against Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, Listeria monocytogenes, Staphylococcus epidermidis, Staphylococcus aureus, and vancomycin-resistant enterococci, even in media that contained 100 mM NaCl. Certain organisms (methicillin-resistant S. aureus, Proteus mirabilis, and Candida albicans) were resistant to LL-37 in media that contained 100 mM NaCl but were susceptible in low-salt media. Burkholderia cepacia was resistant to LL-37, PG-1, and HNP-1 in low- or high-salt media. LL-37 caused outer and inner membrane permeabilization of E. coli ML-35p. Chromogenic Limulus assays revealed that LL-37 bound to E. coli O111:B4 lipopolysaccharide (LPS) with a high affinity and that this binding showed positive cooperativity (Hill coefficient = 2.02). Circular dichroism spectrometry disclosed that LL-37 underwent conformational change in the presence of lipid A, transitioning from a random coil to an alpha-helical structure. The broad-spectrum antimicrobial properties of LL-37, its presence in neutrophils, and its inducibility in keratinocytes all suggest that this peptide and its precursor (hCAP-18) may protect skin and other tissues from bacterial intrusions and LPS-induced toxicity. The potent activity of LL-37 against P. aeruginosa, including mucoid and antibiotic-resistant strains, suggests that it or related molecules might have utility as topical bronchopulmonary microbicides in cystic fibrosis.

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H Looker, C Pfeiffer, Rosemary L Schleicher … (2011)

The Institute of Medicine (IOM) recently released new dietary reference intakes for calcium and vitamin D. The IOM defined four categories of vitamin D status based on serum 25-hydroxyvitamin D (25OHD): (i) risk of deficiency, (ii) risk of inadequacy, (iii) sufficiency, and (iv) above which there may be reason for concern. This brief presents the most recent national data on vitamin D status in the U.S. population based on these IOM categories. Results are presented by age, sex, race and ethnicity, and, for women, by pregnancy and lactation status. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

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Author and article information

Contributors

Sikarin Upala: sikarin.upala@bassett.org

Anawin Sanguankeo: anawin.sanguankeo@bassett.org

Nitipong Permpalung: nitipong.permpalung@bassett.org

Journal

Journal ID (nlm-ta): BMC Anesthesiol

Journal ID (iso-abbrev): BMC Anesthesiol

Title: BMC Anesthesiology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2253

Publication date (Electronic): 4 June 2015

Publication date PMC-release: 4 June 2015

Publication date Collection: 2015

Volume: 15

Electronic Location Identifier: 84

Affiliations

[ ]Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY USA

[ ]Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

Article

Publisher ID: 63

DOI: 10.1186/s12871-015-0063-3

PMC ID: 4455341

PubMed ID: 26041306

SO-VID: b9cc5c08-0dc6-4652-aeca-84833deb3bcb

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.