Nadir Yehya1,2, Julie C Fitzgerald1,2, Katie Hayes1,2, Donglan Zhang1, Jenny Bush1, Natalka Koterba3,4,5, Fang Chen3,4,5, Florin Tuluc6, David T Teachey7, Fran Balamuth2,7, Simon F Lacey3,4,5, Jan Joseph Melenhorst3,4,5, Scott L Weiss1,2. 1. Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 2. Pediatric Sepsis Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 3. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 5. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. 6. Flow Cytometry Research Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 7. Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract
OBJECTIVE: Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 h have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 h, and compare cytokine, immune function, and immunometabolic markers across subgroups. METHODS: This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 h of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration. RESULTS: We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3-11%; P = 0.26). CONCLUSIONS: Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.
OBJECTIVE: Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 h have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 h, and compare cytokine, immune function, and immunometabolic markers across subgroups. METHODS: This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 h of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration. RESULTS: We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3-11%; P = 0.26). CONCLUSIONS: Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.
Authors: Theodore J Iwashyna; James F Burke; Jeremy B Sussman; Hallie C Prescott; Rodney A Hayward; Derek C Angus Journal: Am J Respir Crit Care Med Date: 2015-11-01 Impact factor: 21.405
Authors: Mark W Hall; Susan M Geyer; Chao-Yu Guo; Angela Panoskaltsis-Mortari; Philippe Jouvet; Jill Ferdinands; David K Shay; Jyotsna Nateri; Kristin Greathouse; Ryan Sullivan; Tram Tran; Shannon Keisling; Adrienne G Randolph Journal: Crit Care Med Date: 2013-01 Impact factor: 7.598
Authors: Stéphane Leteurtre; Alain Martinot; Alain Duhamel; François Proulx; Bruno Grandbastien; Jacques Cotting; Ronald Gottesman; Ari Joffe; Jurg Pfenninger; Philippe Hubert; Jacques Lacroix; Francis Leclerc Journal: Lancet Date: 2003-07-19 Impact factor: 79.321
Authors: Joseph A Carcillo; Robert A Berg; David Wessel; Murray Pollack; Kathleen Meert; Mark Hall; Christopher Newth; John C Lin; Allan Doctor; Tom Shanley; Tim Cornell; Rick E Harrison; Athena F Zuppa; Ron W Reeder; Russell Banks; John A Kellum; Richard Holubkov; Daniel A Notterman; J Michael Dean Journal: Pediatr Crit Care Med Date: 2019-12 Impact factor: 3.624
Authors: Sivasubramanium V Bhavani; Krysta S Wolfe; Cara L Hrusch; Jared A Greenberg; Paulette A Krishack; Julie Lin; Paola Lecompte-Osorio; Kyle A Carey; John P Kress; Craig M Coopersmith; Anne I Sperling; Philip A Verhoef; Matthew M Churpek; Bhakti K Patel Journal: Crit Care Med Date: 2020-11 Impact factor: 9.296
Authors: Anne M Drewry; Enyo A Ablordeppey; Ellen T Murray; Evan R Beiter; Andrew H Walton; Mark W Hall; Richard S Hotchkiss Journal: Crit Care Date: 2016-10-20 Impact factor: 9.097