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Multicenter Study
. 2019 Aug 2;2(8):e198686.
doi: 10.1001/jamanetworkopen.2019.8686.

Long-term Host Immune Response Trajectories Among Hospitalized Patients With Sepsis

Sachin Yende  1   2 , John A Kellum  3 , Victor B Talisa  2 , Octavia M Peck Palmer  4 , Chung-Chou H Chang  5 , Michael R Filbin  6 , Nathan I Shapiro  7 , Peter C Hou  8 , Arvind Venkat  9 , Frank LoVecchio  10 , Katrina Hawkins  11   12 , Elliott D Crouser  13 , Anne B Newman  14 , Derek C Angus  2
Affiliations
Multicenter Study

Long-term Host Immune Response Trajectories Among Hospitalized Patients With Sepsis

Sachin Yende et al. JAMA Netw Open. .

Abstract

Importance: Long-term immune sequelae after sepsis are poorly understood.

Objective: To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge.

Design, settings, and participants: This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals.

Exposures: Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified.

Main outcomes and measures: Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality.

Results: A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P < .001), 6-month all-cause readmission or mortality (hazard ratio [HR], 1.53; 95% CI, 1.10-2.13; P = .01), and 6-month readmission or mortality attributable to cardiovascular disease (HR, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (HR, 5.15; 95% CI, 1.25-21.18; P = .02). These associations were adjusted for demographic characteristics, chronic diseases, illness severity, organ support, and infection site during sepsis hospitalization and were robust in sensitivity analyses.

Conclusions and relevance: In this study, persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yende reported receiving personal fees from Atox Bio and grants from Bristol-Myers Squibb and Roche outside the submitted work. Dr Chang reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Filbin reported receiving grants from University of Pittsburgh during the conduct of the study. Dr Hou reported receiving grants from the NIH during the conduct of the study. Dr Venkat reported receiving grants from the NIH during the conduct of the study. Dr Crouser reported receiving grants from the NIH during the conduct of the study and grants from Bristol-Myers Squibb outside the submitted work. Dr Angus reported receiving grants from the NIH during the conduct of the study; receiving personal fees from Ferring Pharmaceuticals Inc, Bristol-Myers Squibb, Bayer AG, and Beckman Coulter Inc; receiving stock and stock options from Alung Technologies Inc outside the submitted work; having a pending patent to Selepressin (compounds, compositions, and methods for treating sepsis); and having a pending patent to proteomic biomarkers of sepsis in elderly patients. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Inflammatory and Immunosuppression Biomarker Values Collected at Each Scheduled Collection Time Point
Horizontal dotted lines represent the estimated 95th percentile of biomarker distribution among individuals without an infection. The lowest whisker indicates the minimum value; bottom border of the box, 25th percentile; line bisecting the shaded region of each box, median; top border of the box, 75th percentile; and highest whisker, maximum value. hs-CRP indicates highly sensitive C-reactive protein; IL, interleukin; and sPD-L1, soluble programmed death ligand 1.
Figure 2.
Figure 2.. Latent Trajectory Classes for Biomarkers of Inflammation and Immunosuppression Estimated During 1 Year Using Joint Latent Class Mixture Models (JLCMM)
Horizontal dotted lines represent the estimated 95th percentile of biomarker distribution among individuals without an infection. The solid and dashed lines indicate latent mean longitudinal biomarker trajectories corresponding to the 2 classes identified by separate joint latent class mixture models fit to each set of biomarker data. hs-CRP indicates highly sensitive C-reactive protein; IL, interleukin; and sPD-L1, soluble programmed death ligand 1.
See this image and copyright information in PMC

References

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