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Observational Study
. 2023 Oct 1;24(10):795-806.
doi: 10.1097/PCC.0000000000003292. Epub 2023 Jun 5.

Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock

L Nelson Sanchez-Pinto  1   2 , Tellen D Bennett  3 , Emily K Stroup  4 , Yuan Luo  2 , Mihir Atreya  5 , Juliane Bubeck Wardenburg  6 , Grace Chong  7 , Alon Geva  8   9   10 , E Vincent S Faustino  11 , Reid W Farris  12 , Mark W Hall  13 , Colin Rogerson  14 , Sareen S Shah  15 , Scott L Weiss  16 , Robinder G Khemani  17
Affiliations
Observational Study

Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock

L Nelson Sanchez-Pinto et al. Pediatr Crit Care Med. .

Abstract

Objectives: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies.

Design: Multicenter observational cohort study.

Setting: Thirteen PICUs in the United States.

Patients: Patients admitted with suspected infections to the PICU between 2012 and 2018.

Interventions: None.

Measurements and main results: We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS.

Conclusions: We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.

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Conflict of interest statement

Drs. Sanchez-Pinto, Bennett, and Shah’s institutions received funding from the National Institute of Child Health and Human Development. Dr. Sanchez-Pinto’s institution received funding from the National Institute of General Medical Sciences. Drs. Sanchez-Pinto, Bennett, Luo, Bubeck-Wardenburg, Faustino, Hall, Rogerson, Shah, Weiss, and Khemani received support for article research from the National Institutes of Health (NIH). Dr. Bennett’s institution received funding from the National Center for Advancing Translational Sciences and the National Heart, Lung, and Blood Institute. Drs. Luo, Bubeck-Wardenburg, Faustino, Hall, Rogerson, Weiss, and Khemani’s institutions received funding from the NIH. Dr. Bubeck-Wardenburg’s institution received funding from the National Institute of Allergy and Infectious Diseases; she disclosed that she has a financial relationship with Aridis Pharmaceuticals related to intellectual property owned by the University of Chicago. Dr. Hall received funding from Abbvie, Kiadis, and the American Board of Pediatrics. Dr. Khemani received funding from OrangeMed and Bayer. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Alluvial plots of the four SANMF groups* based on the average daily pSOFA subscores. *Of note, group 2 was further characterized as the persistent hypoxemia, encephalopathy, and shock phenotype. SANMF = subgraph-augmented nonnegative matrix factorization; pSOFA = pediatric Sequential Organ Failure Assessment.
Figure 2.
Figure 2.
Venn diagram of the overlap of persistent hypoxemia, encephalopathy, and shock with vasoactive-dependent septic shock and moderate-to-severe pediatric ARDS among patients with sepsis-associated MODS*. *Among patients with sepsis-associated MODS, there were a total of 5,048 patients with moderate-to-severe ARDS (16.6% mortality), 5,793 with vasoactive-dependent septic shock (17.8% mortality), and 4,836 with persistent hypoxemia, encephalopathy, and shock (21.6% mortality). ARDS, acute respiratory distress syndrome; dep. = dependent; MODS = multiple organ dysfunction syndrome; mort. = in-hospital mortality; OI = oxygenation index; OSI = oxygen saturation index.
See this image and copyright information in PMC

References

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