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Sepsis remains one of the most challenging and deadly illnesses confronting modern medicine. In ICUs in westernized countries, sepsis is the leading cause of mortality Citation[1]. Human-activated protein C (drotrecogin-a, Xigris®), which was approved by the US FDA in 2001 for the treatment of severe sepsis, was recently withdrawn from the worldwide market following the results of the PROWESS-SHOCK study, which failed to show a benefit in survival Citation[2]. This has left clinicians with one fewer option in an area bereft of effective biological-based therapies. The treatment paradigm for sepsis and septic shock has essentially remained unchanged over the past 20 years. It includes source identification and control, adequate intravenous fluid resuscitation, administration of appropriate antibiotics and organ support methods. These interventions are unfortunately inadequate for a significant number of severely ill patients with sepsis.
Vitamin D has been increasingly recognized for its intricate role in the function of the immune system Citation[3]. Humans usually obtain vitamin D through conversion in the skin caused by exposure to sunlight and diet. Until recently, a person’s vitamin D status was determined by the presence or absence of rickets (osteomalacia in adults). The condition is now more precisely defined by the serum concentration of 25-hydroxyvitamin D, with insufficiency as a level between 20 and 29 ng/ml and deficiency as less than 20 ng/ml. Approximately 1 billion people worldwide are thought to be vitamin D deficient Citation[4]. In one of the first reports to associate vitamin D and innate immunity, Rook et al. found that treatment with the active form of vitamin D inhibited the growth of Mycobacterium tuberculosis in human monocytes Citation[5]. It took 20 years for the biological mechanism to be elucidated: Toll-like receptor activation of macrophages upregulates expression of the vitamin D receptor and vitamin D-1 hydroxylases genes, leading to the induction of the antimicrobial protein cathelicidin Citation[6]. The adaptive immune response is also dependent on vitamin D, with more than 100 genes identified as targets of vitamin D in mature T-helper cells Citation[7]. Moreover, T-helper cytokine production, including IL-2, IFN-g and TNF is downregulated by 1,25-dihydroxyvitamin D Citation[8].
Sepsis represents a dysregulated proinflammatory host response to infection that results in damage to tissues and organs. Lipopolysaccharide from Gram-negative bacteria promotes the development of thrombosis and disseminated intravascular coagulation through the induction of TNF-a. In an animal model, administration of 1,25-dihydroxyvitamin D improved blood coagulation parameters in sepsis-induced disseminated intravascular coagulation Citation[9]. It was observed that critically ill patients with sepsis have lower serum vitamin D levels compared with controls and higher risk for mortality Citation[10,11]. A recent report found that critically ill surgery patients with serum vitamin D levels less than 20 ng/ml had longer lengths of stay, higher rates of infection and higher incidence of sepsis Citation[12]. Another study included 81 patients suspected of having sepsis in the emergency department Citation[13]. It showed that those with serum 25 (OH)D concentrations less than 75 nmol/l were more likely at enrollment and 24-h postenrollment to have more severe sepsis and organ dysfunction compared with patients with higher vitamin D levels. Fatality rates for sepsis are higher in the winter and lower in the summer, during which time most people have more exposure to sunlight and presumably higher serum vitamin D levels Citation[14]. However, it remains uncertain if the correlation between sepsis and decreased vitamin D levels is a dilutional effect resulting from resuscitation with large volumes of fluid. In addition, free vitamin D levels may be diminished as a result of decreased serum vitamin D-binding protein in sepsis, which is similar to what happens to serum albumin.
Although observational studies are promising, prospective, randomized, placebo-controlled clinical trials with vitamin D are needed to determine whether supplementation in patients with deficiency will lead to improved outcomes, such as mortality and length of hospital stay. A placebo-controlled trial among Finnish military recruits who were given 400 IU vitamin D3 daily found that a higher proportion remained healthy with fewer respiratory infections than the placebo group (p = 0.045) Citation[15]. Furthermore, serum levels of vitamin D were higher in the intervention group at the end of the study compared with those who did not get the supplement (p < 0.001). Adjustments for influenza vaccination and smoking were included in the Cox regression analysis. The severity of subjective symptoms of respiratory illness did not vary between the groups, nor was it found to be dependent on the number of days patient remained absent from duty. Whether a higher dose of vitamin D, that is, 1000 IU daily, would have led to more robust differences between the groups is an open question. Since respiratory infections are the leading cause of sepsis in the USA, further studies on the preventative effects of vitamin D supplementation are warranted. A recent randomized trial of vitamin D supplementation in patients undergoing treatment for pulmonary tuberculosis identified a possible benefit (more rapid sputum conversion) only in patients with the TT genotype of the TaqI vitamin D receptor polymorphism Citation[16]. These polymorphisms could be examined in therapeutic trials of vitamin D in sepsis.
Given the progress that has been made from basic science in understanding the pathophysiology of vitamin D deficiency in sepsis, preliminary research has begun in critically ill patients in ICUs. However, no interventional trial data have yet been reported, although such findings will probably have widespread interest throughout both the critical care and infectious disease communities. Although basic science has shown that vitamin D has an intricate role in the proper function of the innate and adaptive immune systems, it is less clear whether repletion of low vitamin D levels will be an effective strategy for treating infection or reversing organ damage in critically ill septic patients. For such a trial to demonstrate this and other meaningful outcomes, a large number of patients at multiple centers will probably be necessary along with significant financial and material resources. Alternatively, one could argue that since vitamin D deficiency is a well-established medical condition with known adverse consequences, correcting it should be done regardless in order to improve the overall health status of the patient.
Although basic science and translational research data on the beneficial effects of vitamin D appear promising, carefully designed and conducted clinical trials are needed to clarify its role in the treatment and prevention of sepsis. A recently published review made several recommendations for effective clinical trials, including that they stratify subjects and results according to ethnicity, age, geographic location and seasonal variability; high-dose vitamin D supplementation is used; consensus on target serum vitamin D levels ≥75 nmol/l; correlation of immunological and clinical outcomes with serum vitamin D levels; and inclusion of functional immunological studies, such as cytokine production Citation[17]. I would also suggest that trials be randomized, placebo-controlled and ideally conducted at multiple centers to account for the confounding effect of location. Dose responses need to be carefully monitored prospectively so that optimal therapeutic doses and serum vitamin D concentrations in septic patients can be determined.
Acknowledgements
The author would like to thank T Lemonovich and S Deresinski for their valuable comments on the manuscript.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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