Peripheral blood transcriptomic sub-phenotypes of pediatric acute respiratory distress syndrome
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RESEARCH
Peripheral blood transcriptomic sub‑phenotypes of pediatric acute respiratory distress syndrome Nadir Yehya1,2* , Brian M. Varisco3,4, Neal J. Thomas5, Hector R. Wong3,4, Jason D. Christie6,7,8 and Rui Feng9
Abstract Background: 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. Methods: This 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 subphenotypes and PICU mortality and ventilator-free days at 28 days using multivariable logistic and competing risk regression, respectively. Results: We enrolled 106 subjects, of whom 96 had usable samples. We identified 3 sub-phenotypes, dubbed CHOP ARDS Transcriptomic Subtypes (CATS) 1, 2, and 3. CATS-1 subjects (n = 31) demonstrated persistent hypoxemia, had 10 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, 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. Conclusions: We identified three sub-phenotypes of pediatric ARDS using whole blood transcriptomics. The subphenotypes had divergent clinical characteristics and prognoses. Further studies should validate these findings and investigate mechanisms underlying differences between sub-phenotypes. Keywords: Children, ARDS, PARDS, Endotypes, Gene expression, Sub-phenotypes Introduction Acute respiratory distress syndrome (ARDS) is characterized by acute onset of bilateral pulmonary edema and hypoxemia not fully explained by cardiac dysfunction [1, 2]. Primarily defined for adults, ARDS affects 45,000 *Correspondence: [email protected] 1 Department of Anesthesiology and Critical Care Medicine, 6040A Wood Building, Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA Full list of author information is available at the end of the article
children in the United States annually [3], representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs) [4], with a mortality rate of 20% in the United States and 30% worldwide [5, 6]. There are no specific pharmacological therapies for adult or pediatric ARDS despite several trials, and supportive care with lung-protective ventilation [7] and fluid restriction [8] remains the mainstay of treatment. ARDS is heterogeneous, with patients having distin
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