Abstract
BackgroundAcute respiratory distress syndrome (ARDS) is heterogeneous and may be amenable to sub-phenotyping to improve enrichment for trials. We aimed to identify subtypes of pediatric ARDS based on whole blood transcriptomics.MethodsThis was a prospective observational study of children with ARDS at the Children’s Hospital of Philadelphia (CHOP) between January 2018 and June 2019. We collected blood within 24 h of ARDS onset, generated expression profiles, and performed k-means clustering to identify sub-phenotypes. We tested the association between sub-phenotypes and PICU mortality and ventilator-free days at 28 days using multivariable logistic and competing risk regression, respectively.ResultsWe enrolled 106 subjects, of whom 96 had usable samples. We identified three sub-phenotypes, dubbed CHOP ARDS Transcriptomic Subtypes (CATS) 1, 2, and 3. CATS-1 subjects (n = 31) demonstrated persistent hypoxemia, had ten subjects (32%) with immunocompromising conditions, and 32% mortality. CATS-2 subjects (n = 29) had more immunocompromising diagnoses (48%), rapidly resolving hypoxemia, and 24% mortality. CATS-3 subjects (n = 36) had the fewest comorbidities and also had rapidly resolving hypoxemia and 8% mortality. The CATS-3 subtype was associated with lower mortality (OR 0.18, 95% CI 0.04–0.86) and higher probability of extubation (subdistribution HR 2.39, 95% CI 1.32–4.32), relative to CATS-1 after adjustment for confounders.ConclusionsWe identified three sub-phenotypes of pediatric ARDS using whole blood transcriptomics. The sub-phenotypes had divergent clinical characteristics and prognoses. Further studies should validate these findings and investigate mechanisms underlying differences between sub-phenotypes.
Highlights
Acute respiratory distress syndrome (ARDS) is characterized by acute onset of bilateral pulmonary edema and hypoxemia not fully explained by cardiac dysfunction [1, 2]
We identified three sub-phenotypes of pediatric ARDS with distinct biologic pathways and prognoses using whole blood transcriptomics within 24 h of ARDS onset
The sub-phenotypes demonstrated some overlap of traditional clinical characteristics of ARDS severity, with immunocompromised status, stem cell transplant, and severe hypoxemia seen at differing proportions across all subtypes
Summary
Acute respiratory distress syndrome (ARDS) is characterized by acute onset of bilateral pulmonary edema and hypoxemia not fully explained by cardiac dysfunction [1, 2]. ARDS is heterogeneous, with patients having distinct comorbidities and inciting etiologies. This heterogeneity has contributed to negative trial results, as therapies. Methods to reduce heterogeneity, including sub-phenotyping using protein and mRNA biomarkers, have been proposed for improving patient selection for future clinical trials [10]. Extensive work in adult ARDS has demonstrated differential response to positive end-expiratory pressure [11], conservative fluid management [12], and simvastatin [13] depending on subtypes defined, in part, by protein biomarkers. The presence of subtypes in pediatric ARDS is largely unexplored [14]. Acute respiratory distress syndrome (ARDS) is heterogeneous and may be amenable to sub-phenotyping to improve enrichment for trials. We aimed to identify subtypes of pediatric ARDS based on whole blood transcriptomics
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