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Source-specific host response and outcomes in critically ill patients with sepsis: a prospective cohort study
Hessel Peters-Sengers1,2, Joe M Butler3,4, Fabrice Uhel3,4
1Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Room T1.240, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. h.peterssengers@amsterdamumc.nl.
Purpose:
There is limited knowledge on how the source of infection impacts the host response to sepsis. We aimed to compare the host response in sepsis patients with a single, known source at admission (< 24 h) to the intensive care unit.
Methods:
From the molecular diagnosis and risk stratification of sepsis (MARS) prospective cohort, we measured 16 plasma host response biomarkers reflective of key host response pathways in 621 sepsis patients. In a subgroup (n = 335), blood leukocyte transcriptomes were compared between the sources. Differences in clinical patient profiles and survival were compared in the whole sepsis cohort (n = 2019).
Results:
The plasma biomarker cohort was categorized into sepsis originating from the respiratory tract (n = 334, 53.8%), abdomen (n = 159, 25.6%), urinary tract (n = 44, 7.1%), cardiovascular (n = 41, 6.6%), central nervous system (CNS) (n = 18, 2.9%), or skin (n = 25, 4%). This analysis revealed stronger inflammatory and cytokine responses, loss of vascular integrity and coagulation activation in abdominal sepsis relative to respiratory. Endothelial cell activation was prominent in urinary, cardiovascular and skin infections, while CNS infection was associated with the least host response aberrations. The leukocyte transcriptional response showed the largest overlap between abdominal and pulmonary infections (76% in common); notable differences between the sources were detected regarding hemostasis, cytokine signaling, innate and adaptive immune, and metabolic transcriptional pathways. After adjustment for confounders, the source of infection remained an independent contributor to 30-day mortality (unadjusted p = 0.001, adjusted p = 0.028).
Conclusion:
Sepsis heterogeneity is partly explained by source-specific host response dysregulations and should be considered when selecting patients for trials testing immune modulatory drugs.
Insights
Sepsis source significantly impacts host response, with abdominal sepsis showing heightened inflammation and coagulation. Understanding these source-specific differences is crucial for targeted sepsis treatments and clinical trials.
Area of Science:
- Critical Care Medicine
- Immunology
- Genomics
Background:
- Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.
- The impact of infection source on host response in sepsis remains incompletely understood.
- Identifying source-specific host responses can refine diagnostic and therapeutic strategies.
Purpose of the Study:
- To compare host responses in sepsis patients based on the identified source of infection.
- To investigate differences in plasma biomarkers and leukocyte transcriptomes across various sepsis origins.
- To determine if infection source independently influences sepsis patient outcomes.
Main Methods:
- Analysis of 16 plasma host response biomarkers in 621 sepsis patients from the MARS cohort.
- Comparison of blood leukocyte transcriptomes in a subgroup of 335 patients stratified by infection source.
- Evaluation of clinical profiles and 30-day survival in 2019 sepsis patients.
Main Results:
- Abdominal sepsis exhibited stronger inflammatory, cytokine, and coagulation responses compared to respiratory sepsis.
- Urinary, cardiovascular, and skin infections showed prominent endothelial cell activation.
- Central nervous system infections presented with minimal host response aberrations.
- Leukocyte transcriptional analysis revealed significant differences in immune and metabolic pathways between infection sources.
- Infection source was an independent predictor of 30-day mortality in sepsis patients.
Conclusions:
- Sepsis exhibits heterogeneity driven by source-specific host response dysregulations.
- Tailoring patient selection for immune modulatory drug trials based on infection source is recommended.
- Further research into source-specific sepsis pathophysiology is warranted.
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