Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

Abstract

Background: The role of site of infection in sepsis has been poorly characterized. Additionally, sepsis epidemiology has evolved. Early mortality has decreased, but many survivors now progress into chronic critical illness (CCI). This study sought to determine if there were significant differences in the host response and current epidemiology of surgical sepsis categorized by site of infection.

Study design: This is a longitudinal study of surgical sepsis patients characterized by baseline predisposition, insult characteristics, serial biomarkers, hospital outcomes, and long-term outcomes. Patients were categorized into five anatomic sites of infection.

Results: The 316 study patients were predominantly Caucasian; half were male, with a mean age of 62 years, high comorbidity burden, and low 30-day mortality (10%). The primary sites were abdominal (44%), pulmonary (19%), skin/soft tissue (S/ST, 17%), genitourinary (GU, 12%), and vascular (7%). Most abdominal infections were present on admission and required source control. Comparatively, they had more prolonged proinflammation, immunosuppression, and persistent organ dysfunction. Their long-term outcome was poor with 37% CCI (defined as > 14 in ICU with organ dysfunction), 49% poor discharge dispositions, and 30% 1-year mortality. Most pulmonary infections were hospital-acquired pneumonia. They had similar protracted proinflammation and organ dysfunction, but immunosuppression normalized. Long-term outcomes are similarly poor (54% CCI, 47% poor disposition, 32% 1-year mortality). S/ST and GU infections occurred in younger patients with fewer comorbidities, less perturbed immune responses, and faster resolution of organ dysfunction. Comparatively, S/ST had better long-term outcomes (23% CCI, 39% poor disposition, 13% 1-year mortality) and GU had the best (10% CCI, 20% poor disposition, 10% 1-year mortality). Vascular sepsis patients were older males, with more comorbidities. Proinflammation was blunted with baseline immunosuppression and organ dysfunction that persisted. They had the worst long-term outcomes (38% CCI, 67% poor disposition, 57% 1-year mortality).

Conclusion: There are notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection in surgical sepsis. While previous studies have focused on differences in hospital mortality, this study provides unique insights into the host response and long-term outcomes associated with different sites of infection.

Trial registration: ClinicalTrials.gov NCT02276417.

Keywords: Chronic critical illness; Functional outcomes; Heterogeneity; Immunosuppression; Long-term outcomes; Organ dysfunction; Phenotypes; Proinflammation; Site of infection; Surgical sepsis.

Conflict of interest statement

None to report.

Figures

Fig. 1

Serial biomarkers of proinflammation. Biomarkers of proinflammation (a interleukin-6, b interleukin-8) in each infection subgroup were measured for inpatients at 1, 4, 7, and 14 days post sepsis onset and compared to each other as well as matched healthy controls. An asterisk indicates significant intergroup differences (excluding controls, p < 0.05) at that time point

Fig. 2

Serial biomarkers of immunosuppression. Biomarkers of immunosuppression (a soluble programmed death ligand-1, b absolute lymphocyte count) in each infection subgroup were measured for inpatients at 1, 4, 7, and 14 days post sepsis onset and compared to each other as well as matched healthy controls or normal reference range. An asterisk indicates significant intergroup differences (excluding controls, p < 0.05) at that time point

Fig. 3

Summarizes the subgroups, their serial first 14-day SOFA scores, 1-year survival, and 1-year Zubrod performance status. a Depicts daily SOFA scores following sepsis onset (day 0) by subgroup. An asterisk indicates significant intergroup differences (p < 0.05) at that time point (only tested days 1, 4, 7, and 14). b Depicts 1-year survival by subgroup. An asterisk indicates significant intergroup differences (p < 0.005) by log-rank test. c Depicts performance status changes from baseline as measured by World Health Organization (WHO)/Zubrod score. Higher score indicates worse performance status (see the “Methods” section). An asterisk indicates significant intergroup differences at that time point

Fig. 4

Depicts relative risk of 12-month mortality by sites of infection. Odds ratios and 95% confidence intervals are from multivariate logistic regression analyses done to assess the relative risk of 12-month mortality for abdominal, S/ST, GU, and vascular infections compared to pulmonary infections