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 hospitalacquired 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.

Circulating Th1 and Th2 Subset Accumulation Kinetics in Septic Patients with Distinct Infection Sites: Pulmonary versus Nonpulmonary

“…Our results confirmed the hypothesis and showed that pulmonary sepsis presented Th2 dominance while nonpulmonary sepsis was characterized with Th1 subset dominance. The current results partly supported the findings of notable differences in host responses by the site of infection during sepsis in Stortz et al's study [ 13 ], in which abdominal infections experienced robust proinflammation, partly in line with our findings of proinflammatory Th1 predominance in the nonpulmonary sepsis, while immunosuppression biomarkers of pulmonary sepsis normalized faster which was likely due to the distinct resources of hospital-acquired pneumonia in Stortz et al's study and community-acquired severe sepsis in our study.…”

“…Sepsis-induced adaptive immune dysfunction should be evaluated comprehensively, including other immune cell types like Th17 and multilevels in transcription and protein as well as the function of these immune cells, not limited to the number or frequency. Given the recent study by Stortz et al [ 13 ], the impact on host response by sepsis is site-dependent and may occur later in the clinical course. Future studies need to be done at multiple levels of immunological behaviours for long-term outcomes.…”

“…Sepsis is the result of host immune response to infection, and the original site of infection might be the main driver of secondary organ injury or even death. A prospective longitudinal study recently published [ 13 ] demonstrated notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection during sepsis. Phenotypic heterogeneity was partly induced by the site of infection during sepsis.…”

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

“…Finally, we should consider that not all sepsis is the same-that is, community-versus hospital-acquired, medical versus surgical sepsis or pneumonia versus abdominal sepsis. 45,46 We compared an animal model of surgical sepsis to both human surgical sepsis and community-acquired sepsis in our work. Further studies to compare the genomic response of different murine models of sepsis to specific corresponding types of human sepsis are warranted.…”

“…[40][41][42][43][44] Importantly, our collective data illustrate the importance of further evaluating preclinical models of sepsis and emphasizes that with modifications more relevant rodent models can be engendered to achieve better and more appropriate comparisons (as all sepsis is not equivalent). 45,46 There are many possible explanations as to why there have been no interventional therapies, proven successful in murine models of sepsis, translated in clinical trials. First, biomedical research has traditionally used young male mice despite human sepsis population being predominantly older adults with a significant proportion being female.…”