During the natural course of sepsis, patients enter an immunosuppressed state after the initial intense inflammatory response well known to clinicians as a "cytokine storm," according to a report in the Dec. 21 issue of JAMA.
Most therapies for sepsis target this initial hyperinflammatory state and are focused on blocking inflammation and immune activation. They may be successful if used early in the course of sepsis, but harmful if used during the later, underrecognized immunosuppressed phase, said Jonathan S. Boomer, Ph.D., of the department of medicine, Washington University, St. Louis, and his associates.
This latter phase of sepsis only came to light once clinical management improved enough to allow patients to survive the early hyperinflammatory phase. Then clinicians began noting that patients who survived early sepsis often developed nosocomial infections with organisms that typically do not affect immunocompetent hosts. These patients also frequently experienced reactivation of latent viruses, Dr. Boomer and his colleagues said.
These observations lead some to hypothesize that hyperinflammation gives way to significant immunosuppression in such patients. The hypothesis has been controversial. Dr. Boomer and his associates explored the issue through rapid postmortem examination of cells from the spleens and lungs of affected patients – "a lymphoid organ and a peripheral organ that [are] frequent site[s]of nosocomial infection."
They assessed the organs of 40 patients who died while being treated for sepsis in surgical or medical ICUs, and in control samples from 29 patients who had critical illnesses that did not involve sepsis. The control tissue came from organ donors, trauma patients who required emergency splenectomy, and non–tumor-involved lung tissue from lung cancer patients who underwent lobectomies.
The causes of sepsis included ventilator-associated pneumonia, peritonitis, necrotizing fasciitis, retroperitoneal abscess, infected intravascular catheters, UTI, intrapelvic abscess, and osteomyelitis.
Compared with cells from control spleens, splenocytes from sepsis patients showed profound impairment of cytokine production when stimulated in vitro. At 5 hours after collection, the secretion of cytokines from splenocytes of sepsis patients was less than 10% of that secreted by control splenocytes, the investigators said (JAMA 2011;306:2594-605).
Splenocytes from most sepsis patients showed some recovery of cytokine production at 22 hours, but they still secreted only one-third the number of cytokines produced by control splenocytes. This result was consistent for all the cytokines tested and for all subgroups of patients, regardless of the duration of sepsis, patient age, whether or not corticosteroids had been received, and patient nutritional status at the time of death.
The researchers identified many separate mechanisms by which immune responses were inhibited in spleen cells. They found a decrease in stimulatory molecules such as CD28 on T cells, a deficiency in antigen-presenting cells such as macrophages and dendritic cells, increased expression of inhibitory ligands that suppress immune function, and an excess of inhibitory cells such as myeloid-derived suppressor cells and regulatory T cells.
Lung tissue similarly showed significant immunosuppression in sepsis patients, compared with control patients. In particular, lung alveolar epithelial cells and endothelial cells showed an excess of inhibitory receptors and ligands.
The study findings suggest that it may be possible to identify sepsis patients who enter this phase of immunocompromise and treat them with immune-enhancing therapies such as interleukin, the researchers said.
The study was limited by its small sample size and the heterogeneous nature of both the sepsis and control patients, the authors said. They further emphasized that malnutrition should be recognized for its possible effects on host immunity and that for a number of reasons, their study "must be viewed cautiously." The research "serves as a bridge between preclinical and early clinical findings," they wrote.
This study was supported by the National Institutes of Health. One of Dr. Boomer’s associates reported receiving grants from Pfizer, Bristol-Meyers Squibb, and Aurigine.