Source-specific host response and outcomes in critically ill patients with sepsis: a prospective cohort study
MARS Consortium
(2022) Intensive Care Medicine, volume 48, issue 1, pp. 92 - 102
(Article)
Abstract
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
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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.
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Keywords: Host response, Intensive care unit, Sepsis, Site of infection, Source of infection, Critical Care and Intensive Care Medicine
ISSN: 0342-4642
Publisher: Springer Verlag
Note: Funding Information: This research was performed within the framework of the Center for Translational Molecular Medicine (CTMM) ( www.ctmm.nl ), project Molecular Diagnosis and Risk Stratification of Sepsis (Grant 04I-201). H.P.S. was supported by the Dutch Kidney Foundation (Kolff Grant Nr. 19OK009). J.M.B. was supported by the European Commission (Horizon 2020, ImmunoSep, Grant number 847422). L.A.v.V. was supported by a VENI grant from ZonMW (Grant number 09150161910033). Members of MARS consortium are: Departments of Intensive Care Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands: Friso M. de Beer, MD, Lieuwe D. J. Bos, PhD, Gerie J. Glas, MD, Roosmarijn T. M. van Hooijdonk, MD, Janneke Horn, MD, Laura R. A. Schouten, MD, Marleen Straat, MD, Luuk Wieske, MD, Esther Witteveen, MD. Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Tom D.Y. Reijnders, MD, Alex R. Schuurman, MD, Tjitske S.R. van Engelen, MD, Liza Pereverzeva, MD, Arie J. Hoogendijk, PhD, Mischa A. Huson, MD, Maryse A. Wiewel, MD; Department of Medical Microbiology, Department of Intensive Care Medicine, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Peter M.C. Klein Klouwenberg, MD, David S.Y. Ong, MD; Department of Intensive Care Medicine and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Jos F. Frencken, MD, Maria E. Koster-Brouwer, MSc, Kirsten van de Groep, MD, Diana M. Verboom, MD. Funding Information: This research was performed within the framework of the Center for Translational Molecular Medicine (CTMM) (www.ctmm.nl ), project Molecular Diagnosis and Risk Stratification of Sepsis (Grant 04I-201). H.P.S. was supported by the Dutch Kidney Foundation (Kolff Grant Nr. 19OK009). J.M.B. was supported by the European Commission (Horizon 2020, ImmunoSep, Grant number 847422). L.A.v.V. was supported by a VENI grant from ZonMW (Grant number 09150161910033). Members of MARS consortium are: Departments of Intensive Care Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands: Friso M. de Beer, MD, Lieuwe D. J. Bos, PhD, Gerie J. Glas, MD, Roosmarijn T. M. van Hooijdonk, MD, Janneke Horn, MD, Laura R. A. Schouten, MD, Marleen Straat, MD, Luuk Wieske, MD, Esther Witteveen, MD. Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Tom D.Y. Reijnders, MD, Alex R. Schuurman, MD, Tjitske S.R. van Engelen, MD, Liza Pereverzeva, MD, Arie J. Hoogendijk, PhD, Mischa A. Huson, MD, Maryse A. Wiewel, MD; Department of Medical Microbiology, Department of Intensive Care Medicine, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Peter M.C. Klein Klouwenberg, MD, David S.Y. Ong, MD; Department of Intensive Care Medicine and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Jos F. Frencken, MD, Maria E. Koster-Brouwer, MSc, Kirsten van de Groep, MD, Diana M. Verboom, MD. Publisher Copyright: © 2021, The Author(s).
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