Immunosuppression and Secondary Infection in Sepsis: Part, Not All, of the Story

Despite considerable efforts to promote early identification and treatment of sepsis, each year several million individuals worldwide develop sepsis-induced multiple organ dysfunction, requiring admission to intensive care and institution of life support, and frequently progressing to death or protracted illness and incomplete recovery. Sepsis is now the leading cause of death in US hospitals and is projected to account for more than 5 million deaths globally each year.1,2 The question is why. More specifically, why do patients with sepsis who receive appropriate antibiotics and prompt institution of life support still die? Certainly, there are instances when life support is inadequate, such as overwhelming shock unresponsive to fluids and vasopressors or severe hypoxia despite advanced mechanical ventilatory support. However, many critically ill patients simply lie in an ICU bed receiving life support while the team monitors for complications, titrates life support treatment, and waits to see what transpires. Thisclinical conundrumhasnotgoneunnoticed.Researchers have relentlessly pursued the mechanisms of persistent critical illness,postulatingnumerous theories.Formanyyears, theprevailing theorywas thatorganswere impairedbyanoveractive or hyperinflammatory innate immune response and its effect on regional and local blood flow, endothelial function, andparenchymalcellularenergyuptakeandmetabolism.However, recentworkhas focusedonamore complexunderstanding of how dysfunction in both the innate and adaptive immune systems may contribute to poor outcomes in sepsis. Specifically, the finding thatpatients appeared tobemore susceptible to secondary infections, coupled with observations of blunted immune responses tomicrobial challenges, suchas decreased major histocompatibility complex class 2 antigen expression on the surface of circulatingwhite blood cells, led researchers to speculate that the immune system could become hypoactive or “paralyzed.”3 Two broad uncertainties complicate validation of this theory. First, the immune system is protean, and the degree towhich patterns of immune function anddysfunction occur over time, involve its many components, and are uniform in all patients or in select, identifiable subsets is unknown. Second, the initial contention that suppressed immunity leads to secondary infection, which in turn leads to increased mortality and morbidity, is not well established in sepsis. The JAMA article by van Vught and colleagues4 attempts to shed light on these 2 issues. Specifically, the authors first sought to determine the incidence and attributable mortality of secondary infections among 1719 ICU admissions with a diagnosis of sepsis. Second, the authors attempted to determine whether these infections were associated with clinical risk factors or host genomic immune response patterns. The project was part of the European Union–funded Molecular Diagnosis and Risk Stratification of Sepsis (MARS) program and rested principally on the construction of a prospective cohort of ICU patients at 2 large academic medical centers in the Netherlands. Importantly, the investigators invested considerable effort in careful clinical phenotyping, both to determine whether ICU patients met criteria for sepsis on admission and to determine the occurrence of secondary infections and other noninfectious complications.5 In addition, in a subset of patients diagnosed with sepsis (n = 421), the investigators also determined gene expression in circulating white blood cell gene expression at the time of ICU admission and again on the day that infectious and noninfectious complications occurred. There were 232 admissions (13.5%) for sepsis whose ICU course was complicated by a secondary infection. Although patients who developed secondary infection had a much higher 60-day mortality rate (44.2% vs 29.1%, P < .001), this difference was largely explained by the fact that patients who developed secondary infections were also sicker on admission (Acute Physiology and Chronic Health Evaluation IV [APACHE IV] scores 90 vs 79, P < 001). In analyses that accounted for baseline differences and for competing risks over time of developing an infection, being discharged, or dying, the attributable mortality fraction of secondary infection was relatively modest, accounting for only 10.9% by day 60 (P = .03), which represents an absolute increase in mortality of only 2%. The gene expression patterns among patientswith sepsis at the time of ICU admission were markedly different from thoseofhealthycontrols, showingbroadup-regulationofboth proinflammatoryandanti-inflammatorymoleculesanddownregulation of multiple adaptive immunity pathways, similar to that seen in other patientswithmajor injury or sepsis.6 Importantly, theauthorswereunable todetectdifferencesatbaseline between patients who would later develop an ICU infection or not. However, paired analyses comparing gene expression at baseline to that on the day a secondary infection developed showed that circulatingwhite blood cells had developed expression profiles reflective of reduced glycolysis and gluconeogenesis. Glycolysis is characteristically used by tumor cells to enhance energy production via conversion Related article page 1469 Opinion