Source-specific host response and outcomes in critically ill patients with sepsis: a prospective cohort study,Intensive Care Medicine

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Source-specific host response and outcomes in critically ill patients with sepsis: a prospective cohort study
Intensive Care Medicine ( IF 27.1 ) Pub Date : 2021-12-13 , DOI: 10.1007/s00134-021-06574-0
Hessel Peters-Sengers _{1,

2} , Joe M Butler _{1,

2} , Fabrice Uhel _{1,

2} , Marcus J Schultz _{3,

4,

5,

6} , Marc J Bonten _{7,

8} , Olaf L Cremer ₉ , Brendon P Scicluna _{1,

2,

10} , Lonneke A van Vught _{1,

2} , Tom van der Poll _{1,

2,

11} ,

Affiliation

Center 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.
The Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Department of Intensive Care Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand.
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Division of Infectious Diseases, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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.

中文翻译：

脓毒症危重患者的源特异性宿主反应和结果：一项前瞻性队列研究

目的

关于感染源如何影响宿主对败血症的反应的知识有限。我们旨在比较脓毒症患者在进入重症监护病房时（< 24 小时）具有单一已知来源的宿主反应。

方法

从脓毒症 (MARS) 前瞻性队列的分子诊断和风险分层，我们测量了 621 名脓毒症患者的 16 种血浆宿主反应生物标志物，这些生物标志物反映了关键宿主反应途径。在一个亚组 ( n = 335) 中，比较了来源之间的血液白细胞转录组。在整个脓毒症队列 ( n = 2019)中比较了临床患者概况和生存率的差异。

结果

血浆生物标志物队列分为起源于呼吸道的败血症 ( n = 334, 53.8%)、腹部 ( n = 159, 25.6%)、泌尿道 ( n = 44, 7.1%)、心血管 ( n = 41, 6.6 ) %)、中枢神经系统 (CNS) ( n = 18, 2.9%) 或皮肤 ( n = 25, 4%)。该分析揭示了与呼吸系统相关的腹部脓毒症中更强的炎症和细胞因子反应、血管完整性丧失和凝血激活。内皮细胞激活在泌尿、心血管和皮肤感染中很突出，而中枢神经系统感染与宿主反应异常最少相关。白细胞转录反应显示腹部和肺部感染之间的重叠最大（共有 76%）；在止血、细胞因子信号、先天性和适应性免疫以及代谢转录途径方面，检测到来源之间的显着差异。调整混杂因素后，感染源仍然是 30 天死亡率的独立因素（未调整的p = 0.001，调整后的p = 0.028）。