Yoshihiko Raita1, Carlos A Camargo2, Yury A Bochkov3, Juan C Celedón4, James E Gern5, Jonathan M Mansbach6, Eugene P Rhee7, Robert J Freishtat8, Kohei Hasegawa2. 1. Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Electronic address: yraita1@mgh.harvard.edu. 2. Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. 3. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 4. Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa. 5. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 6. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 7. Nephrology Division and Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. 8. Division of Emergency Medicine, Children's National Hospital, Washington, DC; Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC.
Abstract
BACKGROUND: Young children with rhinovirus (RV) infection-particularly bronchiolitis-are at high risk for developing childhood asthma. Emerging evidence suggests clinical heterogeneity within RV bronchiolitis. However, little is known about these biologically distinct subgroups (endotypes) and their relations with asthma risk. OBJECTIVE: We aimed to identify RV bronchiolitis endotypes and examine their longitudinal relations with asthma risk. METHODS: As part of a multicenter prospective cohort study of infants (age <12 months) hospitalized for bronchiolitis, we integrated clinical, RV species (RV-A, RV-B, and RV-C), nasopharyngeal microbiome (16S rRNA gene sequencing), cytokine, and metabolome (liquid chromatography tandem mass spectrometry) data collected at hospitalization. We then applied network and clustering approaches to identify bronchiolitis endotypes. We also examined their longitudinal association with risks of developing recurrent wheeze by age 3 years and asthma by age 5 years. RESULTS: Of 122 infants hospitalized for RV bronchiolitis (median age, 4 months), we identified 4 distinct endotypes-mainly characterized by RV species, microbiome, and type 2 cytokine (T2) response: endotype A, virusRV-CmicrobiomemixedT2low; endotype B, virusRV-AmicrobiomeHaemophilusT2low; endotype C, virusRSV/RVmicrobiomeStreptococcusT2low; and endotype D, virusRV-CmicrobiomeMoraxellaT2high. Compared with endotype A infants, endotype D infants had a significantly higher rate of recurrent wheeze (33% vs 64%; hazard ratio, 2.23; 95% CI, 1.00-4.96; P = .049) and a higher risk for developing asthma (28% vs 59%; odds ratio, 3.74: 95% CI, 1.21-12.6; P = .03). CONCLUSIONS: Integrated-omics analysis identified biologically meaningful RV bronchiolitis endotypes in infants, such as one characterized by RV-C infection, Moraxella-dominant microbiota, and high T2 cytokine response, at higher risk for developing recurrent wheeze and asthma. This study should facilitate further research toward validating our inferences.
BACKGROUND: Young children with rhinovirus (RV) infection-particularly bronchiolitis-are at high risk for developing childhood asthma. Emerging evidence suggests clinical heterogeneity within RV bronchiolitis. However, little is known about these biologically distinct subgroups (endotypes) and their relations with asthma risk. OBJECTIVE: We aimed to identify RV bronchiolitis endotypes and examine their longitudinal relations with asthma risk. METHODS: As part of a multicenter prospective cohort study of infants (age <12 months) hospitalized for bronchiolitis, we integrated clinical, RV species (RV-A, RV-B, and RV-C), nasopharyngeal microbiome (16S rRNA gene sequencing), cytokine, and metabolome (liquid chromatography tandem mass spectrometry) data collected at hospitalization. We then applied network and clustering approaches to identify bronchiolitis endotypes. We also examined their longitudinal association with risks of developing recurrent wheeze by age 3 years and asthma by age 5 years. RESULTS: Of 122 infants hospitalized for RV bronchiolitis (median age, 4 months), we identified 4 distinct endotypes-mainly characterized by RV species, microbiome, and type 2 cytokine (T2) response: endotype A, virusRV-CmicrobiomemixedT2low; endotype B, virusRV-AmicrobiomeHaemophilusT2low; endotype C, virusRSV/RVmicrobiomeStreptococcusT2low; and endotype D, virusRV-CmicrobiomeMoraxellaT2high. Compared with endotype A infants, endotype D infants had a significantly higher rate of recurrent wheeze (33% vs 64%; hazard ratio, 2.23; 95% CI, 1.00-4.96; P = .049) and a higher risk for developing asthma (28% vs 59%; odds ratio, 3.74: 95% CI, 1.21-12.6; P = .03). CONCLUSIONS: Integrated-omics analysis identified biologically meaningful RV bronchiolitis endotypes in infants, such as one characterized by RV-C infection, Moraxella-dominant microbiota, and high T2 cytokine response, at higher risk for developing recurrent wheeze and asthma. This study should facilitate further research toward validating our inferences.
Authors: Carlos A Camargo; Tristram Ingham; Kristin Wickens; Ravi Thadhani; Karen M Silvers; Michael J Epton; G Ian Town; Philip K Pattemore; Janice A Espinola; Julian Crane Journal: Pediatrics Date: 2010-12-27 Impact factor: 7.124
Authors: Christian Rosas-Salazar; Meghan H Shilts; Andrey Tovchigrechko; Seth Schobel; James D Chappell; Emma K Larkin; Jyoti Shankar; Shibu Yooseph; Karen E Nelson; Rebecca A Halpin; Martin L Moore; Larry J Anderson; R Stokes Peebles; Suman R Das; Tina V Hartert Journal: J Infect Dis Date: 2016-12-15 Impact factor: 5.226
Authors: Kohei Hasegawa; Claire E Hoptay; Brennan Harmon; Juan C Celedón; Jonathan M Mansbach; Pedro A Piedra; Robert J Freishtat; Carlos A Camargo Journal: Allergy Date: 2019-02-01 Impact factor: 13.146
Authors: Hans Bisgaard; Mette Northman Hermansen; Frederik Buchvald; Lotte Loland; Liselotte Brydensholt Halkjaer; Klaus Bønnelykke; Martin Brasholt; Andreas Heltberg; Nadja Hawwa Vissing; Sannie Vester Thorsen; Malene Stage; Christian Bressen Pipper Journal: N Engl J Med Date: 2007-10-11 Impact factor: 91.245
Authors: Orianne Dumas; Kohei Hasegawa; Jonathan M Mansbach; Ashley F Sullivan; Pedro A Piedra; Carlos A Camargo Journal: J Allergy Clin Immunol Date: 2018-09-18 Impact factor: 10.793
Authors: Rachel S Kelly; Bo L Chawes; Kevin Blighe; Yamini V Virkud; Damien C Croteau-Chonka; Michael J McGeachie; Clary B Clish; Kevin Bullock; Juan C Celedón; Scott T Weiss; Jessica A Lasky-Su Journal: Chest Date: 2018-06-13 Impact factor: 9.410
Authors: Christian Quast; Elmar Pruesse; Pelin Yilmaz; Jan Gerken; Timmy Schweer; Pablo Yarza; Jörg Peplies; Frank Oliver Glöckner Journal: Nucleic Acids Res Date: 2012-11-28 Impact factor: 16.971
Authors: Lyndsey M Muehling; Peter W Heymann; Holliday Carper; Deborah D Murphy; Evan Rajadhyaksha; Joshua Kennedy; Stephen V Early; Manuel Soto-Quiros; Lydiana Avila; Lisa Workman; Thomas A E Platts-Mills; Judith A Woodfolk Journal: Clin Exp Allergy Date: 2022-06-06 Impact factor: 5.401
Authors: Yoshihiko Raita; Marcos Pérez-Losada; Robert J Freishtat; Andrea Hahn; Eduardo Castro-Nallar; Ignacio Ramos-Tapia; Nathaniel Stearrett; Yury A Bochkov; James E Gern; Jonathan M Mansbach; Zhaozhong Zhu; Carlos A Camargo; Kohei Hasegawa Journal: Eur Respir J Date: 2022-07-13 Impact factor: 33.795
Authors: Makiko Nanishi; Michimasa Fujiogi; Robert J Freishtat; Claire E Hoptay; Cindy S Bauer; Michelle D Stevenson; Carlos A Camargo; Kohei Hasegawa Journal: Allergy Date: 2022-01-17 Impact factor: 14.710
Authors: Zhaozhong Zhu; Carlos A Camargo; Yoshihiko Raita; Robert J Freishtat; Michimasa Fujiogi; Andrea Hahn; Jonathan M Mansbach; Jonathan M Spergel; Marcos Pérez-Losada; Kohei Hasegawa Journal: J Allergy Clin Immunol Date: 2022-04-26 Impact factor: 14.290