Sepsis (coming from the Greek meaning putrefaction and decay) is a severe inflammatory state caused by an infection that can deteriorate into organ failure and death if not contained by the immune system or medical intervention. Sepsis is caused by the immune system’s response to an infection in the blood, urinary tract, lungs, skin, or other tissues.
Sepsis causes millions of deaths globally each year. In the United States, sepsis contributes to more than 200,000 deaths per year. There were 4.07 million cases of septicemia – infection of the blood – from 1995 to 2000, of which 730,000 died. In 1995, the average costs per case were $22,100, with annual total costs in the U.S. of $16.7 billion. It is the second-leading cause of death in the ICU, and the tenth-most-common cause of death overall (the first being heart disease). Premature infants and elderly have the highest incidence of severe sepsis. It accounts for about 25% of all ICU bed utilization.
In the United States, septicemia is characterized by being more common in the winter, having a highest incidence in the cloudy northeast and lowest in the sunny West; having higher rates among the dark skinned (the ratio of black to white incidence is almost 2). It also shows a rapid increase in incidence with age (as vitamin D skin production wanes); and a rapid rise in incidence over the last several decades, concurrent with increasing sun avoidance.
Vitamin D Council Board Director, Dr. Bill Grant, was the first to give evidence that vitamin D is related to septicemia.
Recently, Doctor Jordan Kempker, working under senior author Professor Greg Martin of Emory University School of Medicine in Atlanta, summarized what we know about sepsis and vitamin D.
Here’s what we know:
On disease incidence
- The strength of the seasonal variation is contingent on latitude. That is, the further from the equator, the stronger the seasonal variation.
- An analysis of the large group (NHANES III) showed that prevalence of various infections were higher in blacks when compared to whites when controlling for socioeconomic status. That is, poverty does not explain the higher rates in Blacks.
- Vitamin D is integral to the innate immune system’s production of naturally occurring antimicrobial peptides (AMP) in response to various infections. The most studied AMP is cathelicidin and its activated form, LL-37.
- LL-37 directly kills various disease causing bacteria in the test tube, including Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, Listeria monocytogenes, Staphylococcus epidermidis, Staphylococcus aureus, and vancomycin-resistant enterococci.
- In healthy volunteers, serum 25(OH)D concentrations appear to have a positive correlation with LL-37 levels at 25(OH)D concentrations < 32 ng/mL but not > 32 ng/mL, possibly indicating a leveling of beneficial effects above 32 ng/ml.
- In one study, vitamin D supplementation increased LL-37 levels, but only in those with the greatest 25(OH)D response, perhaps indicating the dose of vitamin D used in the study was inadequate.
On observational studies
- In one retrospective study of 81 ICU patients, low 25(OH)D concentrations at admission were predictive of worsening organ dysfunction at 24 hours.
- Another retrospective study of 170 ICU patients found an association between low vitamin D and mortality in sepsis patients, but this association did not remain significant in the statistical multivariate analysis.
On clinical trials
- There are no reported clinical trials in sepsis.
- There are currently two registered trials underway of vitamin D supplementation in sepsis. One of them will look at the effects of vitamin D on cathelicidin levels and other inflammatory biomarkers, while the other will look at sepsis in neonates treated with vitamin D in the ICU.
For future study, the researchers point out that there are some barriers in studying vitamin D and sepsis. While vitamin D’s role in the functioning of the innate immune system is well established, vitamin D kills some pathogens that cause sepsis but not other pathogens. Also, there is no gold standard inflammatory marker in sepsis like there is in some other medical conditions, thus making it hard to study the impact of an intervention on sepsis. Third, it may be hard to develop a true vitamin D placebo group when studying vitamin D, as most populations will likely have some baseline levels of sufficiency.
In addition, I believe it is also increasingly hard ethically to withhold adequate vitamin D from placebo groups.