Editorial Inflammation & Allergy - Drug Targets, 2013, Vol. 12, No.

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Editorial
Vitamin D Deficiency and Critical Illness
Critical Illnesses are significant public health issues because of the high rate of mortality and substantial health care costs.
Aggregate in-hospital mortality is 12% for patients who receive critical care and mortality approaches 30% for those with
sepsis [1]. In the United States in 2005, critical care medicine costs represented 13.4% of hospital costs, 4.1% of national health
expenditures, and 0.66% of the gross domestic product [2]. Finding factors that improve critical care outcomes would be of
significant public health and economic value. One potential modifiable factor of outcome is vitamin D status.
Vitamin D is a fat-soluble immune-modulatory vitamin. Vitamin D can both turn on and turn off inflammation, but an
important effect is antimicrobial response to fungi and bacteria. Vitamin D is both a nutrient and a hormone, with blood levels
primarily dependent on exposure to sunlight and secondarily on dietary intake. Vitamin D deficiency is well-described in
patients around the world including the critically ill, and there is growing consensus that current recommended intakes are
inadequate for the maintenance of health. Meta-analyses show that in the general population mortality risk declines as serum
25(OH)D increases, with optimal concentrations 30-35 ng/ml (7587.5 nmol/L) [3] and vitamin D supplementation appears to
improve mortality [4].
Biologic data suggests a relationship between Vitamin D and outcomes in critical care exists. Vitamin D acts as an immune
system modulator by altering the excessive expression of inflammatory cytokines and by increasing the 'oxidative burst'
potential of macrophages, which improves bacterial killing. Vitamin D receptors (VDR) and vitamin D metabolic enzymes
have been identified in many other tissues aside from bone and the intestine, suggesting involvement in the metabolism and
function of many cell types. VDR is expressed in cells of the immune system, such as T, activated B cells, and dendritic cells.
Vitamin D deficiency promotes defective macrophage function, such as impaired phagocytosis, chemotaxis and the altered
production of pro-inflammatory cytokines. Specifically, in vitro, Vitamin D modulates TNF- and IL-6, reduces bacterial
growth, and inhibits vascular endothelium activation by lipopolysaccharides. In murine sepsis, Vitamin D supplementation
improves coagulation parameters and appears to inhibit endotoxemia.
Much of the work highlighted in this issue supports the concept that vitamin D deficiency can serve as a biomarker of illness
severity, organ dysfunction and mortality of critically ill patients and raise vitamin D as a potential therapeutic agent. The
immunomodulatory and antimicrobial effects of vitamin D likely require 25(OH)D levels over 30 ng/ml, achieved through
more aggressive dosing. Low 25(OH) levels in critically ill patients can be normalized quickly following supplementation with
single high-dose oral Vitamin D. Expert opinion notes that vitamin D toxicity in the form of hypercalcemia only results when
25(OH)D concentrations are consistently above 160-200 ng/ml. Studies on supplementation of single high-dose Vitamin D
3
have not shown adverse events with the exception of rare mild hypercalcemia. Randomized controlled trials that utilized
100,000 IU single dose oral Vitamin D
3
have not demonstrated adverse outcomes. While some existing data on vitamin D
trials support an anti-inflammatory and immunomodulatory role [5], improved outcomes with Vitamin D supplementation in
bacterial [6-8] and viral infections [9, 10], other studies have not shown improvements in outcomes [11] or have even shown
harm [12]. At present it is not clear if hypovitaminosis D is a marker for mortality and morbidity risk in critically ill patients. It
is also not clear if Vitamin D treatment to achieve a sufficiency target can improve outcomes in the ICU [13].
This special issue of Inflammation & Allergy - Drug Targets will address important issues regarding Vitamin D status in the
critically ill including the prevalence and risk factors of Vitamin D deficiency; caveats of Vitamin D measurement; Vitamin D
and associations with Acute Lung Injury, Acute Kidney Injury, and Sepsis; Vitamin D treatment in the prevention and
treatment of infection and Vitamin D Interventional Trials. The contributing authors to this special issue and others around the
world are a diverse set of highly skilled investigators who are working towards understanding the importance of vitamin D in
critical illness.
Interventional studies on vitamin D replacement in the critically ill are timely, given the scientific rationale, and innovative,
given the lack of clinical studies in the area and the increasing economic burden of critical illness. If the safety profile of high
dose vitamin D can be established in the critically ill, a future placebo controlled trial powered to relevant clinical outcomes is
warranted. Such a study could have potential wide-ranging public health implications, not only for the possible prevention of
secondary infections but also for overall mortality of the critically ill.
REFERENCES
[1] Angus, D.C.; Pereira, C.A.; Silva, E.; Epidemiology of severe sepsis around the world. Endocr. Metab. Immune Disord. Drug Targets, 2006, 6, 207-
212.
[2] Halpern, N.A.; Pastores, S.M. Critical care medicine in the United States 2000-2005: an analysis of bed numbers, occupancy rates, payer mix, and
costs. Crit. Care Med., 2010, 38, 65-71.
[3] Zittermann, A.; Iodice, S.; Pilz, S.; Grant, W.B.; Bagnardi, V.; Gandini, S. Vitamin D deficiency and mortality risk in the general population: a
metaanalysis of prospective cohort studies. Am. J. Clin. Nutr., 2012, 95(1), 91-100.
[4] Autier, P.; Gandini, S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007, 167,
1730-1737.
[5] Coussens, A.K.; Wilkinson, R.J.; Hanifa, Y.; Nikolayevskyy, V.; Elkington, P.T.; Islam, K.; Timms, P.M.; Venton, T.R.; Bothamley, G.H.; Packe,
G.E.; Darmalingam, M.; Davidson, R.N.; Milburn, H.J.; Baker, L.V.; Barker, R.D.; Mein, C.A.; Bhaw-Rosun, L.; Nuamah, R.; Young, D.B.;
222 Inflammation & Allergy - Drug Targets, 2013, Vol. 12, No. 4 Editorial
Drobniewski, F.A.; Griffiths, C.J.; Martineau, A.R. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
Proc.Natl. Acad. Sci. U S A, 2012, 109(38), 15449-15454.
[6] Camargo, C.A. Jr. Vitamin D and cardiovascular disease: time for large randomized trials. J. Am. Coll. Cardiol., 2011, 58, 1442-1444.
[7] Marchisio, P.; Consonni, D.; Baggi, E.; Zampiero, A.; Bianchini, S.; Terranova, L.; Tirelli, S.; Esposito, S.; Principi, N. Vitamin D supplementation
reduces the risk of acute otitis media in otitis-prone children. Pediatr. Infect. Dis. J., 2013, [Epub ahead of print].
[8] Bergman, P.; Norlin, A.C.; Hansen, S.; Rekha, R.S.; Agerberth, B.; Bjrkhem-Bergman, L.; Ekstrm, L.; Lindh, J.D.; Andersson, J. Vitamin D3
supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open, 2012, 2(6),
pii:e001663.
[9] Aloia, J.F.; Li-Ng M: Re: epidemic influenza and vitamin D. Epidemiol. Infect., 2007, 135, 1095-1096; author reply 1097-1098.
[10] Urashima, M.; Segawa, T.; Okazaki, M.; Kurihara, M.; Wada, Y.; Ida, H. Randomized trial of vitamin D supplementation to prevent seasonal
influenza A in schoolchildren. Am. J. Clin. Nutr., 2010, 91, 1255-1260.
[11] Murdoch, D.R.; Slow, S.; Chambers, S.T.; Jennings, L.C.; Stewart, A.W.; Priest, P.; Florkowski, C.M.; Livesey, J.H.; Camargo, C.A.; Scragg, R.
Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA, 2012,
308, 1333-1339.
[12] Sanders, K.M.; Stuart, A.L.; Williamson, E.J.; Simpson, J.A.; Kotowicz, M.A.; Young, D.; Nicholson, G.C. Annual high-dose oral vitamin D and falls
and fractures in older women: a randomized controlled trial. JAMA, 2010, 303, 1815-1822.
[13] Amrein, K.; Venkatesh, B. Vitamin D and the critically ill patient. Curr. Opin. Clin. Nutr. Metab. Care, 2012, 15, 188-193.
Kenneth B. Christopher
(Guest Editor)
Renal Division
Brigham and Womens Hospital
Harvard Medical School
Boston
MA 02445
USA
E-mail: KBCHRISTOPHER@partners.org