From the Journals

Sepsis survivors’ persistent immunosuppression raises mortality risk



Inflammation and immunosuppression could persist for some patients up to a year after a hospitalization for sepsis, and these patients were more likely to experience worsened long-term outcomes, readmission after discharge, and mortality, according to a study published in JAMA Network Open.

Sachin Yende, MD 141820

Sachin Yende, MD

“Individuals with persistent biomarkers of inflammation and immunosuppression had a higher risk of readmission and death due to cardiovascular disease and cancer compared with those with normal circulating biomarkers,” Sachin Yende, MD, of the VA Pittsburgh Healthcare System and the University of Pittsburgh and colleagues wrote in their study. “Our findings suggest that long-term immunomodulation strategies should be explored in patients hospitalized with sepsis.”

Dr. Yende and colleagues performed a multicenter, prospective cohort study of 483 patients who were hospitalized for sepsis at 12 different sites between January 2012 and May 2017. They measured inflammation using interleukin-6, high-sensitivity C-reactive protein (hs-CRP), and soluble programmed death-ligand 1 (sPD-L1); hemostasis using plasminogen activator inhibitor 1 and D-dimer; and endothelial dysfunction using intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. The patients included were mean age 60.5 years, 54.9% were male, the mean Sequential Organ Failure Assessment score was 4.2, and a total of 376 patients (77.8%) had one or more chronic diseases.

Overall, there were 485 readmissions in 205 patients (42.5%). The mortality rate was 43 patients (8.9%) at 3 months, 56 patients (11.6%) at 6 months, and 85 patients (17.6%) at 12 months. At 3 months, 23 patients (25.8%) had elevated hs-CRP levels, which increased to 26 patients (30.2%) at 6 months and 40 patients (44.9%) at 12 months. sPD-L1 levels were elevated in 45 patients (46.4%) at 3 months, but the number of patients with elevated sPD-L1 did not appear to significantly increase at 6 months (40 patients; 44.9%) or 12 months (44 patients; 49.4%).

From these results, researchers developed a phenotype of hyperinflammation and immunosuppression that consisted of 326 of 477 (68.3%) patients with high hs-CRP and elevated sPD-L1 levels. Patients with this phenotype of hyperinflammation and immunosuppression had more than eight times the risk of 1-year mortality (odds ratio, 8.26; 95% confidence interval, 3.45-21.69; P less than .001) and more than five times the risk of readmission or mortality at 6 months related to cardiovascular disease (hazard ratio, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (hazard ratio, 5.15; 95% CI, 1.25-21.18; P = .02), compared with patients who had normal hs-CRP and sPD-L1 levels. This hyperinflammation and immunosuppression phenotype also was associated with greater risk of 6-month all-cause readmission or mortality (HR, 1.53; 95% CI, 1.10-2.13; P = .01), compared with patients who had the normal phenotype.

“The persistence of hyperinflammation in a large number of sepsis survivors and the increased risk of cardiovascular events among these patients may explain the association between infection and cardiovascular disease in a prior study,” the authors said. “Although prior trials tested immunomodulation strategies during only the early phase of hospitalization for sepsis, immunomodulation may be needed after hospital discharge,” and suggest points of future study for patients who survive sepsis and develop long-term sequelae.

This study was funded by grants from National Institutes of Health and resources from the VA Pittsburgh Healthcare System. The authors reported personal and institutional relationships in the form of personal fees, grants, and patents for Alung Technologies, Atox Bio, Bayer AG, Beckman Coulter, BristolMyers Squibb, Ferring, NIH, Roche, Selepressin, and the University of Pittsburgh.


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