Zhaozhong Zhu1, Carlos A Camargo2, Yoshihiko Raita2, Michimasa Fujiogi2, Liming Liang3, Eugene P Rhee4, Prescott G Woodruff5, Kohei Hasegawa2. 1. Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Electronic address: zzhu5@mgh.harvard.edu. 2. Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. 3. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Mass; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Mass. 4. Nephrology Division and Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. 5. Division of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, Calif.
Abstract
BACKGROUND: Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. OBJECTIVES: We sought to identify biologically distinct subgroups based on the metabolome signatures (metabotypes) in infants with severe bronchiolitis and to examine the longitudinal relationships of metabotypes with asthma development. METHODS: In a multicenter prospective cohort study of infants (age, <12 months) hospitalized for bronchiolitis, the nasopharyngeal airway metabolome was profiled at hospitalization. Using a clustering approach, this study identified mutually exclusive metabotypes. This study also examined their longitudinal association with the risk of developing asthma by 5 years of age. RESULTS: Of 918 infants hospitalized for bronchiolitis (median age, 3 months), this study identified 5 distinct metabotypes-characterized by their nasopharyngeal metabolome profile: A, glycerophosphocholine-high; B, amino acid-high, polyunsaturated fatty acid-low; C, amino acid-high, glycerophospholipid-low; D, glycerophospholipid-high; and E, mixed. Compared with infants with metabotype A (who clinically resembled "classic" bronchiolitis), infants with metabotype B had a significantly higher risk for developing asthma (23% vs 41%; adjusted odds ratio, 2.22; 95% CI, 1.07-4.69). The pathway analysis showed that metabotype B had enriched amino acid (eg, methionine, histidine, glutathione) and α-linolenic/linoleic acid metabolism pathways (false discovery rate, <5 × 10-14 for all). Finally, the transcriptome analysis revealed that infants with metabotype B had upregulated IFN-α and IL-6/JAK/STAT3 pathways and downregulated fatty acid metabolism pathways (false discovery rate, <0.05 for both). CONCLUSIONS: In this multicenter prospective cohort study of infants with severe bronchiolitis, the clustering analysis of metabolome data identified biologically distinct metabotypes, including a metabotype characterized by high inflammatory amino acids and low polyunsaturated fatty acids that is at significantly increased risk for developing asthma.
BACKGROUND: Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. OBJECTIVES: We sought to identify biologically distinct subgroups based on the metabolome signatures (metabotypes) in infants with severe bronchiolitis and to examine the longitudinal relationships of metabotypes with asthma development. METHODS: In a multicenter prospective cohort study of infants (age, <12 months) hospitalized for bronchiolitis, the nasopharyngeal airway metabolome was profiled at hospitalization. Using a clustering approach, this study identified mutually exclusive metabotypes. This study also examined their longitudinal association with the risk of developing asthma by 5 years of age. RESULTS: Of 918 infants hospitalized for bronchiolitis (median age, 3 months), this study identified 5 distinct metabotypes-characterized by their nasopharyngeal metabolome profile: A, glycerophosphocholine-high; B, amino acid-high, polyunsaturated fatty acid-low; C, amino acid-high, glycerophospholipid-low; D, glycerophospholipid-high; and E, mixed. Compared with infants with metabotype A (who clinically resembled "classic" bronchiolitis), infants with metabotype B had a significantly higher risk for developing asthma (23% vs 41%; adjusted odds ratio, 2.22; 95% CI, 1.07-4.69). The pathway analysis showed that metabotype B had enriched amino acid (eg, methionine, histidine, glutathione) and α-linolenic/linoleic acid metabolism pathways (false discovery rate, <5 × 10-14 for all). Finally, the transcriptome analysis revealed that infants with metabotype B had upregulated IFN-α and IL-6/JAK/STAT3 pathways and downregulated fatty acid metabolism pathways (false discovery rate, <0.05 for both). CONCLUSIONS: In this multicenter prospective cohort study of infants with severe bronchiolitis, the clustering analysis of metabolome data identified biologically distinct metabotypes, including a metabotype characterized by high inflammatory amino acids and low polyunsaturated fatty acids that is at significantly increased risk for developing asthma.
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