Late Sepsis Associated With Immunosuppression

Norra MacReady

December 21, 2011

December 21, 2011 — Patients who die in the late stages of sepsis show evidence of immunosuppression compared with patients who die of nonseptic causes, a new study shows.

These findings support the hypothesis that patients evolve from a hyperinflammatory state early in sepsis to a hypoinflammatory, hypoimmune state later on, lead author Jonathan S. Boomer, PhD, from the Washington University School of Medicine in St. Louis, Missouri, and colleagues write in the December 21 issue of JAMA.

Current therapies for sepsis focus on blocking immune activation and modulating the early, hyperinflammatory "cytokine storm," the authors explain. This has allowed many patients to survive that phase, only to succumb to nosocomial infections from organisms that are not pathogenic in healthier people, leading some observers to suspect that septic patients eventually lose immunocompetence. The new findings "may allow for targeted therapeutic immune interventions to restore host immunity," they write.

Dr. Boomer and colleagues performed rapid, postmortem analyses of lungs and spleens harvested from 40 intensive care patients who died of sepsis-related causes and compared them with spleens from 29 patients who either underwent emergent splenectomy or died of nonseptic causes, and lungs from 20 patients who were transplant donors or underwent lung resection because of cancer. The mean ages of the septic and the control patients were 71.7 and 52.7 years, respectively. The septic patients had been in the intensive care unit for a median of 8 days (range, 1 - 195 days) compared with a median of 4 days (range, 1 - 40 days) for the control patients.

The organs of the septic patients showed evidence of immunosuppression. For example, splenocytes from the septic patients showed significant reductions in the secretion of cytokines, tumor necrosis factor, interferon gamma, and interleukins 6 and 10 compared with in control patients (P < .001 for all comparisons). "Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status," the authors report.

This reduction in cytokine secretion suggests that the splenocytes from the septic patients had significant functional impairments, they add.

In an accompanying editorial, Peter A. Ward, MD, from the University of Michigan Medical School, Ann Arbor, writes that this study is "perhaps the most authoritative investigation exclusively involving humans and confirming the onset of immunosuppression developing during septic shock or severe sepsis." The observations "provide compelling evidence for development of immunosuppression in patients with sepsis, albeit with the important caveat that all of the study patients died of sepsis — those who survived may well have had a different immunologic course."

The authors note that the study had several important limitations, including the small sample size and the heterogeneous nature of both the study and the control populations. In addition, many of the septic patients were hypoalbuminemic. Not only was poor nutritional status "undoubtedly" a contributing factor to their demise, but "malnutrition has numerous effects on host immunity that could be responsible for some of the observed immunologic findings," the authors write.

In addition, the study patients all died in intensive care, some after a lengthy bout with sepsis, and findings may differ for patients who recover from sepsis, who die earlier in the course of the illness, or who die in other surroundings.

Finally, the observed phenomena may have been prodromal events that do not reflect changes in all septic patients, but only those in patients who do not respond successfully to initial supportive measures.

Nevertheless, the authors conclude that these findings suggest that "immune-enhancing therapy may be a valid approach in selected patients with sepsis."

The study was supported by the National Institutes of Health. One study author has disclosed receiving grant support from Pfizer, Bristol-Myers Squibb, and Aurigene. The other authors and Dr. Ward have disclosed no relevant financial relationships.

JAMA. 2011;306:2594-2605, 2618-2619.