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Figure.  Between-Virus Differences in the Proportion of Patients Who Remained Recurrent Wheeze–Free Over 36 Months According to Immunoglobulin E(IgE) Sensitization Status in Infancy
Between-Virus Differences in the Proportion of Patients Who Remained Recurrent Wheeze–Free Over 36 Months According to Immunoglobulin E(IgE) Sensitization Status in Infancy

A, Kaplan-Meier curve in the overall analytic cohort (n = 716). Compared with infants with respiratory syncytial virus (RSV)–only bronchiolitis, the risk of developing recurrent wheeze by age 3 years was not significantly different in those with rhinovirus A or rhinovirus B infection (both log-rank P > .10). In contrast, the risk was significantly higher in infants with rhinovirus C bronchiolitis (log-rank P = .006). B, Kaplan-Meier curve among the positive IgE sensitization strata (n = 138). Similar to the analysis in the overall cohort, compared with infants with RSV-only bronchiolitis, the risk of developing recurrent wheeze was significantly higher only in those with rhinovirus C infection (log-rank P = .01). C, Kaplan-Meier curve in the negative IgE sensitization strata (n = 578). The risk of developing recurrent wheeze did not differ between the virus groups (log-rank P > .05). Corresponding hazard ratios are presented in Table 2.

Table 1.  Baseline Characteristics and Clinical Presentation of 716 Infants Hospitalized for Bronchiolitis by Virus Groupa
Baseline Characteristics and Clinical Presentation of 716 Infants Hospitalized for Bronchiolitis by Virus Groupa
Table 2.  Associations of Respiratory Viruses With Risks of Developing Recurrent Wheeze by Age 3 Years According to IgE Sensitization Status at the Enrollment
Associations of Respiratory Viruses With Risks of Developing Recurrent Wheeze by Age 3 Years According to IgE Sensitization Status at the Enrollment
Table 3.  Associations of Respiratory Viruses With Risks of Developing Recurrent Wheeze, With or Without Asthma at Age 4 Years According to IgE Sensitization at the Enrollment
Associations of Respiratory Viruses With Risks of Developing Recurrent Wheeze, With or Without Asthma at Age 4 Years According to IgE Sensitization at the Enrollment
1.
Hasegawa  K, Tsugawa  Y, Brown  DF, Mansbach  JM, Camargo  CA  Jr.  Trends in bronchiolitis hospitalizations in the United States, 2000-2009.  Pediatrics. 2013;132(1):28-36. doi:10.1542/peds.2012-3877PubMedGoogle ScholarCrossref
2.
Bacharier  LB, Cohen  R, Schweiger  T,  et al.  Determinants of asthma after severe respiratory syncytial virus bronchiolitis.  J Allergy Clin Immunol. 2012;130(1):91-100.e3. doi:10.1016/j.jaci.2012.02.010PubMedGoogle ScholarCrossref
3.
Mikalsen  IB, Halvorsen  T, Øymar  K.  The outcome after severe bronchiolitis is related to gender and virus.  Pediatr Allergy Immunol. 2012;23(4):391-398. doi:10.1111/j.1399-3038.2012.01283.xPubMedGoogle ScholarCrossref
4.
Sigurs  N, Aljassim  F, Kjellman  B,  et al.  Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life.  Thorax. 2010;65(12):1045-1052. doi:10.1136/thx.2009.121582PubMedGoogle ScholarCrossref
5.
Castro  M, Schweiger  T, Yin-DeClue  H,  et al.  Cytokine response after severe respiratory syncytial virus bronchiolitis in early life.  J Allergy Clin Immunol. 2008;122(4):726-733.e3. doi:10.1016/j.jaci.2008.07.010PubMedGoogle ScholarCrossref
6.
Kotaniemi-Syrjänen  A, Vainionpää  R, Reijonen  TM, Waris  M, Korhonen  K, Korppi  M.  Rhinovirus-induced wheezing in infancy—the first sign of childhood asthma?  J Allergy Clin Immunol. 2003;111(1):66-71. doi:10.1067/mai.2003.33PubMedGoogle ScholarCrossref
7.
Reijonen  TM, Kotaniemi-Syrjänen  A, Korhonen  K, Korppi  M.  Predictors of asthma three years after hospital admission for wheezing in infancy.  Pediatrics. 2000;106(6):1406-1412. doi:10.1542/peds.106.6.1406PubMedGoogle ScholarCrossref
8.
Balekian  DS, Linnemann  RW, Hasegawa  K, Thadhani  R, Camargo  CA  Jr.  Cohort study of severe bronchiolitis during infancy and risk of asthma by age 5 years.  J Allergy Clin Immunol Pract. 2017;5(1):92-96. doi:10.1016/j.jaip.2016.07.004PubMedGoogle ScholarCrossref
9.
Hasegawa  K, Mansbach  JM, Camargo  CA  Jr.  Infectious pathogens and bronchiolitis outcomes.  Expert Rev Anti Infect Ther. 2014;12(7):817-828. doi:10.1586/14787210.2014.906901PubMedGoogle ScholarCrossref
10.
Kusel  MM, de Klerk  NH, Kebadze  T,  et al.  Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.  J Allergy Clin Immunol. 2007;119(5):1105-1110. doi:10.1016/j.jaci.2006.12.669PubMedGoogle ScholarCrossref
11.
Lemanske  RF  Jr, Jackson  DJ, Gangnon  RE,  et al.  Rhinovirus illnesses during infancy predict subsequent childhood wheezing.  J Allergy Clin Immunol. 2005;116(3):571-577. doi:10.1016/j.jaci.2005.06.024PubMedGoogle ScholarCrossref
12.
Midulla  F, Nicolai  A, Ferrara  M,  et al.  Recurrent wheezing 36 months after bronchiolitis is associated with rhinovirus infections and blood eosinophilia.  Acta Paediatr. 2014;103(10):1094-1099. doi:10.1111/apa.12720PubMedGoogle ScholarCrossref
13.
van der Gugten  AC, van der Zalm  MM, Uiterwaal  CS, Wilbrink  B, Rossen  JW, van der Ent  CK.  Human rhinovirus and wheezing: short and long-term associations in children.  Pediatr Infect Dis J. 2013;32(8):827-833.PubMedGoogle Scholar
14.
Liu  L, Pan  Y, Zhu  Y,  et al.  Association between rhinovirus wheezing illness and the development of childhood asthma: a meta-analysis.  BMJ Open. 2017;7(4):e013034. doi:10.1136/bmjopen-2016-013034PubMedGoogle ScholarCrossref
15.
Kusel  MM, Kebadze  T, Johnston  SL, Holt  PG, Sly  PD.  Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.  Eur Respir J. 2012;39(4):876-882. doi:10.1183/09031936.00193310PubMedGoogle ScholarCrossref
16.
Jackson  DJ, Gangnon  RE, Evans  MD,  et al.  Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.  Am J Respir Crit Care Med. 2008;178(7):667-672. doi:10.1164/rccm.200802-309OCPubMedGoogle ScholarCrossref
17.
Rubner  FJ, Jackson  DJ, Evans  MD,  et al.  Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence.  J Allergy Clin Immunol. 2017;139(2):501-507. doi:10.1016/j.jaci.2016.03.049PubMedGoogle ScholarCrossref
18.
Calışkan  M, Bochkov  YA, Kreiner-Møller  E,  et al.  Rhinovirus wheezing illness and genetic risk of childhood-onset asthma.  N Engl J Med. 2013;368(15):1398-1407. doi:10.1056/NEJMoa1211592PubMedGoogle ScholarCrossref
19.
Backman  K, Ollikainen  H, Piippo-Savolainen  E, Nuolivirta  K, Korppi  M.  Asthma and lung function in adulthood after a viral wheezing episode in early childhood.  Clin Exp Allergy. 2018;48(2):138-146. doi:10.1111/cea.13062PubMedGoogle ScholarCrossref
20.
Bochkov  YA, Gern  JE.  Rhinoviruses and their receptors: implications for allergic disease.  Curr Allergy Asthma Rep. 2016;16(4):30. doi:10.1007/s11882-016-0608-7PubMedGoogle ScholarCrossref
21.
Lee  WM, Lemanske  RF  Jr, Evans  MD,  et al.  Human rhinovirus species and season of infection determine illness severity.  Am J Respir Crit Care Med. 2012;186(9):886-891. doi:10.1164/rccm.201202-0330OCPubMedGoogle ScholarCrossref
22.
Linder  JE, Kraft  DC, Mohamed  Y,  et al.  Human rhinovirus C: age, season, and lower respiratory illness over the past 3 decades.  J Allergy Clin Immunol. 2013;131(1):69-77.e1, 6. doi:10.1016/j.jaci.2012.09.033PubMedGoogle ScholarCrossref
23.
Turunen  R, Jartti  T, Bochkov  YA, Gern  JE, Vuorinen  T.  Rhinovirus species and clinical characteristics in the first wheezing episode in children.  J Med Virol. 2016;88(12):2059-2068. doi:10.1002/jmv.24587PubMedGoogle ScholarCrossref
24.
Martin  EK, Kuypers  J, Chu  HY,  et al.  Molecular epidemiology of human rhinovirus infections in the pediatric emergency department.  J Clin Virol. 2015;62:25-31. doi:10.1016/j.jcv.2014.11.006PubMedGoogle ScholarCrossref
25.
Piralla  A, Rovida  F, Campanini  G,  et al.  Clinical severity and molecular typing of human rhinovirus C strains during a fall outbreak affecting hospitalized patients.  J Clin Virol. 2009;45(4):311-317. doi:10.1016/j.jcv.2009.04.016PubMedGoogle ScholarCrossref
26.
Bashir  H, Grindle  K, Vrtis  R,  et al.  Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens.  J Allergy Clin Immunol. 2018;141(2):822-824.e9. doi:10.1016/j.jaci.2017.09.027PubMedGoogle ScholarCrossref
27.
Esquivel  A, Busse  WW, Calatroni  A,  et al.  Effects of omalizumab on rhinovirus infections, illnesses, and exacerbations of asthma.  Am J Respir Crit Care Med. 2017;196(8):985-992. doi:10.1164/rccm.201701-0120OCPubMedGoogle ScholarCrossref
28.
Bizzintino  J, Lee  WM, Laing  IA,  et al.  Association between human rhinovirus C and severity of acute asthma in children.  Eur Respir J. 2011;37(5):1037-1042. doi:10.1183/09031936.00092410PubMedGoogle ScholarCrossref
29.
Fawkner-Corbett  DW, Khoo  SK, Duarte  CM,  et al.  Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil.  J Med Virol. 2016;88(1):58-63. doi:10.1002/jmv.24300PubMedGoogle ScholarCrossref
30.
Cox  DW, Bizzintino  J, Ferrari  G,  et al.  Human rhinovirus species C infection in young children with acute wheeze is associated with increased acute respiratory hospital admissions.  Am J Respir Crit Care Med. 2013;188(11):1358-1364. doi:10.1164/rccm.201303-0498OCPubMedGoogle ScholarCrossref
31.
Stewart  CJ, Mansbach  JM, Wong  MC,  et al.  Associations of nasopharyngeal metabolome and microbiome with severity among infants with bronchiolitis: a multiomic analysis.  Am J Respir Crit Care Med. 2017;196(7):882-891. doi:10.1164/rccm.201701-0071OCPubMedGoogle ScholarCrossref
32.
Hasegawa  K, Mansbach  JM, Ajami  NJ,  et al; the MARC-35 Investigators.  Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis.  Eur Respir J. 2016;48(5):1329-1339. doi:10.1183/13993003.00152-2016PubMedGoogle ScholarCrossref
33.
Hasegawa  K, Mansbach  JM, Ajami  NJ,  et al.  Serum cathelicidin, nasopharyngeal microbiota, and disease severity among infants hospitalized with bronchiolitis.  J Allergy Clin Immunol. 2017;139(4):1383-1386.e6. doi:10.1016/j.jaci.2016.09.037PubMedGoogle ScholarCrossref
34.
Emergency Medicine Network. Emergency Medicine Network. http://www.emnet-usa.org/. Accessed August 15, 2018.
35.
Ralston  SL, Lieberthal  AS, Meissner  HC,  et al; American Academy of Pediatrics.  Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis.  Pediatrics. 2014;134(5):e1474-e1502. doi:10.1542/peds.2014-2742PubMedGoogle ScholarCrossref
36.
Hasegawa  K, Jartti  T, Mansbach  JM,  et al.  Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: multicenter cohort studies in the United States and Finland.  J Infect Dis. 2015;211(10):1550-1559. doi:10.1093/infdis/jiu658PubMedGoogle ScholarCrossref
37.
Mansbach  JM, Piedra  PA, Teach  SJ,  et al; MARC-30 Investigators.  Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis.  Arch Pediatr Adolesc Med. 2012;166(8):700-706. doi:10.1001/archpediatrics.2011.1669PubMedGoogle ScholarCrossref
38.
Beckham  JD, Cadena  A, Lin  J,  et al.  Respiratory viral infections in patients with chronic, obstructive pulmonary disease.  J Infect. 2005;50(4):322-330. doi:10.1016/j.jinf.2004.07.011PubMedGoogle ScholarCrossref
39.
Lu  X, Holloway  B, Dare  RK,  et al.  Real-time reverse transcription-PCR assay for comprehensive detection of human rhinoviruses.  J Clin Microbiol. 2008;46(2):533-539. doi:10.1128/JCM.01739-07PubMedGoogle ScholarCrossref
40.
Bochkov  YA, Grindle  K, Vang  F, Evans  MD, Gern  JE.  Improved molecular typing assay for rhinovirus species A, B, and C.  J Clin Microbiol. 2014;52(7):2461-2471. doi:10.1128/JCM.00075-14PubMedGoogle ScholarCrossref
41.
Hasegawa  K, Piedra  PA, Bauer  CS,  et al; MARC-35 Investigators.  Nasopharyngeal CCL5 in infants with severe bronchiolitis and risk of recurrent wheezing: a multi-center prospective cohort study.  Clin Exp Allergy. 2018;48(8):1063-1067. doi:10.1111/cea.13166PubMedGoogle ScholarCrossref
42.
US Department of Health and Human Services.  National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma (NIH Publication 08-4051). Bethesda, MD: National Institutes of Health; 2007.
43.
National Institutes of Health. Infant specific-IgE, rhinovirus-C bronchiolitis, and incident asthma in MARC-35. http://grantome.com/grant/NIH/R01-AI114552-04. Accessed August 15, 2018.
44.
Martinez  FD, Wright  AL, Taussig  LM, Holberg  CJ, Halonen  M, Morgan  WJ; the Group Health Medical Associates.  Asthma and wheezing in the first six years of life.  N Engl J Med. 1995;332(3):133-138. doi:10.1056/NEJM199501193320301PubMedGoogle ScholarCrossref
45.
Stein  RT, Martinez  FD.  Asthma phenotypes in childhood: lessons from an epidemiological approach.  Paediatr Respir Rev. 2004;5(2):155-161. doi:10.1016/j.prrv.2004.01.007PubMedGoogle ScholarCrossref
46.
Camargo  CA  Jr, Ingham  T, Wickens  K,  et al; New Zealand Asthma and Allergy Cohort Study Group.  Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.  Pediatrics. 2011;127(1):e180-e187. doi:10.1542/peds.2010-0442PubMedGoogle ScholarCrossref
47.
Nakagome  K, Bochkov  YA, Ashraf  S,  et al.  Effects of rhinovirus species on viral replication and cytokine production.  J Allergy Clin Immunol. 2014;134(2):332-341. doi:10.1016/j.jaci.2014.01.029PubMedGoogle ScholarCrossref
48.
Jackson  DJ, Makrinioti  H, Rana  BM,  et al.  IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo.  Am J Respir Crit Care Med. 2014;190(12):1373-1382. doi:10.1164/rccm.201406-1039OCPubMedGoogle ScholarCrossref
49.
Saglani  S, Lui  S, Ullmann  N,  et al.  IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma.  J Allergy Clin Immunol. 2013;132(3):676-685.e13. doi:10.1016/j.jaci.2013.04.012PubMedGoogle ScholarCrossref
50.
Beale  J, Jayaraman  A, Jackson  DJ,  et al.  Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation.  Sci Transl Med. 2014;6(256):256ra134. doi:10.1126/scitranslmed.3009124PubMedGoogle ScholarCrossref
51.
Durrani  SR, Montville  DJ, Pratt  AS,  et al.  Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children.  J Allergy Clin Immunol. 2012;130(2):489-495. doi:10.1016/j.jaci.2012.05.023PubMedGoogle ScholarCrossref
52.
Gern  JE.  The ABCs of rhinoviruses, wheezing, and asthma.  J Virol. 2010;84(15):7418-7426. doi:10.1128/JVI.02290-09PubMedGoogle ScholarCrossref
53.
Bønnelykke  K, Sleiman  P, Nielsen  K,  et al.  A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.  Nat Genet. 2014;46(1):51-55. doi:10.1038/ng.2830PubMedGoogle ScholarCrossref
54.
Bochkov  YA, Watters  K, Ashraf  S,  et al.  Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication.  Proc Natl Acad Sci U S A. 2015;112(17):5485-5490. doi:10.1073/pnas.1421178112PubMedGoogle ScholarCrossref
55.
Bønnelykke  K, Coleman  AT, Evans  MD,  et al.  Cadherin-related family member 3 genetics and rhinovirus C respiratory illnesses.  Am J Respir Crit Care Med. 2018;197(5):589-594. doi:10.1164/rccm.201705-1021OCPubMedGoogle ScholarCrossref
56.
Edwards  MR, Walton  RP, Jackson  DJ,  et al; EAACI Anti-infectives in Asthma and Asthma Exacerbations Task Force.  The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations.  Allergy. 2018;73(1):50-63. doi:10.1111/all.13257PubMedGoogle ScholarCrossref
57.
Teach  SJ, Gill  MA, Togias  A,  et al.  Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations.  J Allergy Clin Immunol. 2015;136(6):1476-1485. doi:10.1016/j.jaci.2015.09.008PubMedGoogle ScholarCrossref
58.
Castro-Rodríguez  JA, Holberg  CJ, Wright  AL, Martinez  FD.  A clinical index to define risk of asthma in young children with recurrent wheezing.  Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403-1406. doi:10.1164/ajrccm.162.4.9912111PubMedGoogle ScholarCrossref
Original Investigation
April 1, 2019

Association of Rhinovirus C Bronchiolitis and Immunoglobulin E Sensitization During Infancy With Development of Recurrent Wheeze

Author Affiliations
  • 1Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Departments of Pediatrics and Medicine, University of Wisconsin School of Medicine and Public Health, Madison
  • 4Department of Molecular Virology and Microbiology and Pediatrics, Baylor College of Medicine, Houston, Texas
  • 5Division of Allergy and Immunology, Phoenix Children's Hospital, Phoenix, Arizona
  • 6Division of Emergency Medicine and Department of Pediatrics, Children’s National Health System, Washington, DC
  • 7Division of Hospital Medicine, Children's Hospital of Los Angeles, Los Angeles, California
JAMA Pediatr. 2019;173(6):544-552. doi:10.1001/jamapediatrics.2019.0384
Key Points

Question  Is severe bronchiolitis by different rhinovirus species during infancy associated with distinct risks of developing recurrent wheeze?

Findings  In this cohort study of 716 infants who were hospitalized for bronchiolitis, compared with respiratory syncytial virus infection, rhinovirus C infection was associated with a higher risk of developing recurrent wheeze by age 3 years. Furthermore, infants with rhinovirus C infection and IgE sensitization (to food or aeroallergen) in infancy had 3-fold higher risks of recurrent wheeze while those without sensitization had no significant differences.

Meaning  The study identifies infants at higher risk of developing recurrent wheeze and informs strategies to develop targeted preventive therapies.

Abstract

Importance  Rhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities.

Objective  To examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze.

Design, Setting, and Participants  This multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014).

Exposures  Major causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C).

Main Outcomes and Measures  Development of recurrent wheeze (as defined in national asthma guidelines) by age 3 years.

Results  This analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction< .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1).

Conclusions and Relevance  This multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.

Introduction

Bronchiolitis is the leading cause of hospitalizations in US infants, accounting for 130 000 hospitalizations annually.1 In addition to the substantial acute morbidity, cohort studies have also demonstrated that 30% to 40% of infants hospitalized for bronchiolitis (severe bronchiolitis) subsequently develop recurrent wheeze and childhood asthma.2-8 Among various causative pathogens, rhinovirus is the second most common pathogen following respiratory syncytial virus (RSV) and it contributes to 20% to 40% of severe bronchiolitis.9 Epidemiological studies have reported that rhinovirus infection in early life, particularly with allergic sensitization, is associated with a higher risk of developing recurrent wheeze10-14 and childhood asthma.14-19

The recent advent of sequencing technologies has led to the identification of approximately 170 rhinovirus genotypes that are classified into 3 species (rhinovirus A, B, and C).20 Studies have demonstrated that rhinovirus C is associated with a higher severity of acute respiratory infection21-26 and asthma exacerbation.26-29 Additionally, a single-center study of 197 Australian children reported that children with atopic diseases with rhinovirus C wheezing illness had a higher risk of future respiratory hospitalizations.30 However, to our knowledge, no longitudinal study has investigated the association of rhinovirus C infection with allergic sensitization in infants, let alone infants with bronchiolitis, with subsequent respiratory morbidities.

To address this knowledge gap, we conducted a multicenter prospective cohort study of racially/ethnically diverse infants with severe bronchiolitis to examine the association of infection by specific respiratory viruses (including rhinovirus species) with the development of recurrent wheeze. Specifically, we hypothesized that, compared with infants with RSV-only bronchiolitis, those with rhinovirus C bronchiolitis, particularly with early allergic sensitization, have a higher risk of developing recurrent wheezing.

Methods
Study Design, Setting, and Participants

This is a preplanned analysis of data from an ongoing, multicenter prospective cohort study of infants (<12 months) hospitalized for bronchiolitis. This study, called the 35th Multicenter Airway Research Collaboration (MARC-35),31-33 is coordinated by the Emergency Medicine Network,34 which is a collaboration of 245 participating hospitals.

Using a standardized protocol,31-33 the investigators at 17 sites across 14 US states (eTable 1 in the Supplement) enrolled infants hospitalized with an attending physician diagnosis of bronchiolitis during 3 consecutive bronchiolitis seasons from November 1, 2011, to April 30, 2014. Bronchiolitis was defined by the American Academy of Pediatrics guidelines as acute respiratory illness with some combination of rhinitis, cough, tachypnea, wheezing, crackles, and retractions.35 We excluded infants who were transferred to a participating hospital more than 24 hours after the original hospitalization or those with known heart-lung disease, immunodeficiency, immunosuppression, or a gestational age younger than 32 weeks. All patients were treated at the discretion of the treating physician. Of 1016 infants initially enrolled into the MARC-35 cohort, 921 (91%) completed the run-in procedures (ie, contact at both 1 week after hospital discharge and 3 weeks after hospitalization) and comprised the longitudinal cohort. The institutional review board at each participating hospital approved the study. Written informed consent was obtained from the parent or guardian.

Data Collection

Investigators conducted a structured interview that assessed patients’ demographic characteristics, family, medical, and environmental history, and details of the bronchiolitis course. After the index hospitalization for bronchiolitis (and run-in procedures), interviewers began interviewing parents/legal guardians by telephone at 6-month intervals in addition to medical record review by trained physicians. All data were reviewed at the Emergency Medicine Network Coordinating Center at Massachusetts General Hospital (Boston, Massachusetts), and site investigators were queried about missing data and discrepancies identified by manual data checks.

Nasopharyngeal aspirate samples were collected by trained site investigators using the standardized protocol that was used in a previous multicenter cohort study of children with bronchiolitis.36,37 All sites used the same collection equipment (Medline Industries) and collected the samples within 24 hours of hospitalization. The nasopharyngeal sample was added to virus transport medium and stored at −80 °C.

Primary Exposure

The primary exposure was the infecting virus, with a focus on the 2 most common causative viruses of bronchiolitis: RSV and rhinovirus (A, B, and C species). Nasopharyngeal samples were first tested for 17 respiratory viruses (including RSV and rhinovirus) by using real-time polymerase chain reaction (PCR) assays.36-38 Specifically, complementary DNA was generated using gene-specific primers for rhinovirus and singleplex real-time PCR was used. The details of the rhinovirus primers and probes have been described elsewhere.39 Next, to identify the rhinovirus species (A, B, and C), rhinovirus-positive samples were genotyped by using molecular typing assay using partial sequencing.40

IgE Measurement

Serum-specific IgE (sIgE) was measured at enrollment using 2 different assays (ImmunoCAP sIgE and ImmunoCAP ISAC; ThermoFisher Scientific) at the Phadia Immunology Reference Laboratory as previously described.41 The sIgE allergen assays conducted were milk, egg white, peanut, cashew nut, and walnut; a positive test result was defined as 0.35 kU/L. The ImmunoCAP ISAC microarray immunoassay measures IgE antibodies to 112 components from 51 allergen sources, including foods and aeroallergens. A positive result was defined as 0.30 ISU-E or more (I; ISU-E provides an indication of IgE levels and is standardized to ImmunoCAP sIgE units. IgE sensitization was defined by having 1 or more positive values for serum allergen-specific IgE at the index hospitalization).

Outcome Measures

The outcome measure of interest was development of recurrent wheeze by age 3 years. Recurrent wheeze was defined in the 2007 National Institutes of Health (NIH) asthma guidelines as having at least 2 corticosteroid-requiring exacerbations in 6 months or having at least 4 wheezing episodes in 1 year that last at least 1 day and affect sleep.42

Statistical Analyses

First, we categorized patients into 4 groups: RSV-only (reference) and 3 rhinovirus species (A, B, and C) infection groups, excluding 5 infants with coinfection of multiple rhinovirus species. We examined the between-group differences in the patient characteristics and clinical presentation by using Kruskal-Wallis, χ2, and Fisher exact tests as appropriate. Next, to examine the association of viruses with the risk of outcome, we modeled the time to event (ie, the development of recurrent wheeze) by fitting Cox proportional hazards models. Patients who did not have an outcome were censored at their last follow-up interview or at the time of withdrawal during the 36-month follow-up period. In the multivariable model, we adjusted for 7 patient-level potential confounders (age, sex, race/ethnicity, parental history of asthma, household siblings, IgE sensitization, and bronchiolitis severity defined by the use of mechanical ventilation [continuous positive airway pressure and/or intubation] during the index hospitalization) and accounted for between-hospital differences by including the sites as random effects. We chose these covariates on the basis of a priori knowledge and clinical plausibility.9 By using age strata, the evaluation of scaled Schoenfeld residuals was not statistically significant in the model. Additionally, based on an a priori–defined hypothesis,43 we also tested for interactions between virology and IgE sensitization and stratified the analysis by IgE sensitization status.

We conducted several sensitivity analyses. First, we performed a subgroup analysis that excluded 101 infants with RSV/rhinovirus coinfection. Second, to address the potential heterogeneity of recurrent wheeze,44,45 we also fit the models with stratifying the recurrent wheeze outcome (by age 3 years) by asthma status at age 4 years. Asthma was defined using a commonly used epidemiologic definition46: physician-diagnosis of asthma, with either asthma medication use (eg, albuterol inhaler or inhaled corticosteroids) or asthma-associated symptoms (eg, wheezing or nocturnal cough) in the preceding year. Lastly, we repeated the primary analysis, excluding the subset of children who did not have recurrent wheeze but who developed asthma. Analysis used R, version 3.4 (R Foundation). All P values were 2-tailed, with P < .05 considered statistically significant.

Results
Patient Characteristics

Of 921 infants in the longitudinal cohort, 716 (78%) had RSV-only or rhinovirus bronchiolitis and were eligible for this analysis. Among the analytic cohort, the median age was 2.9 months (interquartile range, 1.6-3.8 months), 430 (60%) were male; 321 (45%) were non-Hispanic white, 163 (23%) were non-Hispanic black, 204 (28%) were Hispanic, and 28 (4%) were other. Additionally, 138 (19%) had IgE sensitization at the enrollment (of whom 128 [93%] had IgE sensitization to food) and 107 (15%) underwent intensive care during the index hospitalization. Overall, 231 children (32%) developed recurrent wheeze by age 3 years. Of the 716 infants in the analytic cohort, 541 (76%) had bronchiolitis with RSV only (the reference group), 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection; 101 (14%) had RSV/rhinovirus coinfection. Table 1 and eTable 2 in the Supplement summarize the patient characteristics and clinical course of bronchiolitis. While most variables did not differ between the 4 virus groups, we noted significant differences in age, day care use, and having household siblings (Table 1).

Infants With Rhinovirus C Infection and Risk of Developing Recurrent Wheeze

The Kaplan-Meier curves for the recurrent wheeze outcome are shown in the Figure. Overall, the multivariable Cox proportional hazards model demonstrated that, compared with infants with RSV-only infection, the risk of developing recurrent wheeze was not significantly different in those with rhinovirus A or B infection. In contrast, infants with rhinovirus C had a significantly higher risk of recurrent wheeze (adjusted hazard ratio [HR], 1.58; 95% CI, 1.08-2.32; Table 2 and Figure, A). In the sensitivity analysis excluding 101 infants with coinfection, the significant association persisted (adjusted HR, 3.76; 95% CI, 2.40-5.90; eTable 3 in the Supplement) while in the analysis excluding those with rhinovirus-only infection, there was no significant association (eTable 4 in the Supplement).

Differences in Virus-Recurrent Wheeze Association by IgE Sensitization Status During Infancy

Further, there was a significant interaction between virus groups and IgE sensitization during infancy on the risk of recurrent wheeze (P for interaction< .01), suggesting that the magnitude of virus-outcome association differed by IgE sensitization status. Indeed, among infants who had IgE sensitization at enrollment, the magnitude of the association between rhinovirus C infection and outcomes was larger, with a corresponding adjusted HR of 3.03 (95% CI, 1.20-7.61; Table 2 and Figure, B). In contrast, among infants who did not have IgE sensitization at enrollment, there was no significant difference in the risk of recurrent wheeze between the virus groups (Table 2 and Figure, C).

Persistence of Significant Association Among Children With Recurrent Wheeze Who Developed Asthma

To address potential heterogeneity of recurrent wheeze, we further stratified the outcome by subsequent asthma status and found that rhinovirus C infection was significantly associated with a higher risk of recurrent wheeze that resulted in asthma at age 4 years (Table 3). For example, among infants who had IgE sensitization, the rhinovirus C infection group had a higher risk (adjusted HR, 4.06; 95% CI, 1.17-14.1). In contrast, there was no significant association between the virus and risks of developing recurrent wheeze that did not result in asthma. In the sensitivity analysis that excluded children without recurrent wheeze but who developed asthma, the results did not materially change (eTable 5 in the Supplement).

Discussion

In this prospective multicenter cohort of 716 infants with severe bronchiolitis, we found that the risk of developing recurrent wheeze differed by the causative virus of the bronchiolitis. Specifically, compared with infants with RSV-only infection, those with rhinovirus C infection had a higher risk of recurrent wheeze. We also found that the association remained significant only in infants who had IgE sensitization during infancy. For example, infants with rhinovirus C infection and IgE sensitization had a 3-fold increased risk of recurrent wheeze while those without IgE sensitization had no significant differences. Furthermore, the data also suggest that the observed findings are driven by the associations with a subtype of recurrent wheeze, recurrent wheeze with subsequent development of asthma. To our knowledge, this is the first study that has investigated the longitudinal association of rhinovirus C bronchiolitis in infancy with the risk of chronic respiratory morbidities in later childhood.

Although RSV is the most common pathogen associated with bronchiolitis and has been effectively used to define bronchiolitis cohorts,46 emerging evidence suggests that rhinovirus infection during early life has strong associations with the development of chronic respiratory morbidities, such as recurrent wheeze10-14 and childhood asthma.14-19 Additionally, several epidemiological studies have also reported interrelations of rhinovirus infection and allergic sensitization with the risk of chronic outcomes. For example, in the Childhood Origins of Asthma cohort of 259 predominantly white children at high risk of asthma, children with rhinovirus infection and IgE sensitization to aeroallergens at age 1 year had an increased risk of asthma at ages 6 and 13 years.16,17 Likewise, in an Australian cohort of 198 white children at high risk for allergic diseases, those with rhinovirus infection during infancy and a positive skin prick test result to food or aeroallergen by age 2 years had a higher risk of recurrent wheeze at age 5 years10; those with rhinovirus infection during infancy and a positive skin prick test result only after age 2 years had an increased risk of asthma at age 10 years.15 These findings are consistent with our observations in a larger, racially/ethnically diverse sample of US children. Moreover, the larger cohort provided the opportunity to examine the potentially different role of rhinovirus species.

Since the identification of rhinovirus C in 2006,20 studies have reported that this specific species is associated with a higher severity of acute respiratory infection21-26 and asthma exacerbation.26-29 Yet, little has been known about the role of rhinovirus C infection during early life on the development of chronic respiratory morbidities. Within the sparse literature, in a single-center study of 197 Australian children (mean age, 3 years) who presented to the emergency department with an acute wheezing episode, children with rhinovirus C infection had an increased risk of future respiratory hospitalizations compared with those with other viruses.30 Our multicenter study corroborates these earlier reports and extends them by demonstrating the longitudinal associations between rhinovirus C infection during infancy in conjunction with early IgE sensitization and the risk of chronic respiratory morbidities.

The mechanisms underlying the observed associations between rhinovirus C bronchiolitis, IgE sensitization, and the development of recurrent wheeze warrant clarification. First, it is possible that there is a causal relationship (ie, severe rhinovirus C infection modulates host immune response and damages the airways during early infancy, which is a crucial period of lung development).9 Indeed, studies have shown that acute rhinovirus respiratory infection induces various cellular factors regulating airway inflammation, repair, and remodeling,20 and that rhinovirus-C infection, in particular, leads to increased proinflammatory cytokine and chemokine production (eg, interleukin [IL] 6, chemokine ligand 8, and chemokine ligand 10) and higher cytotoxicity compared with rhinovirus B infection.47 Additionally, rhinovirus infection and allergen exposures increase airway epithelial cell production of IL-25 and IL-33, promoting type 2 airway inflammation and remodeling.48-50 Second, severe rhinovirus infection could simply be an early marker of impaired antiviral response (eg, diminished types I and III interferon production) in the setting of an abnormal host response (eg, an enhanced expression of a high-affinity IgE receptor and cross-linking).51 Third, the results may reflect the “2-hit hypothesis”52 (ie, that genetic predisposition to asthma in conjunction with severe respiratory infection in early life leads to recurrent wheeze and childhood asthma). Indeed, recent studies have shown that cadherin-related family member 3 (CDHR3) gene, an asthma susceptibility gene,53 encodes a protein that mediates the binding and entry of rhinovirus C54 and that its genetic variant increases the cell surface expression of CDHR3 protein in the airway epithelium,54 thereby leading to enhanced rhinovirus C binding, replication, and airway injury.55 Finally, these mechanisms are not mutually exclusive. Notwithstanding the complexity, identifying the association of rhinovirus C bronchiolitis and IgE sensitization during infancy with the development of recurrent wheeze (and asthma) is an important finding. Our data, in conjunction with the earlier studies, provide an evidence base for the early identification of children at high risk for chronic respiratory morbidities as well as the development of targeted prevention strategies (eg, anti-IgE therapy, vaccines, and antiviral agents).27,56,57

Limitations

Our study has potential limitations. First, the study did not have information from “healthy controls.” However, the objective was to investigate the role of respiratory virus infection in early infancy on the development of recurrent wheeze among infants with severe bronchiolitis, of whom 30% to 40% will develop asthma.2-8 Second, this analysis examined the association of different respiratory viruses with the risk of recurrent wheeze rather than incident asthma at older age. However, the presence of recurrent wheeze carries a 5.5-fold increased risk of developing asthma by age 6 years.58 Additionally, our data also demonstrated significant associations between rhinovirus C infection and recurrent wheeze with the subsequent development of asthma. Regardless, to better address this important question, the study participants are currently being followed up longitudinally up to age 6 years and older. Third, as with any observational study, causal inferences could be confounded by unmeasured factors, such as cocirculating viruses and practice patterns within hospitals or regions. Yet, the observed association between bronchiolitis viruses and recurrent wheeze remained significant after accounting for between-hospital differences using mixed-effects models. Lastly, even with our racially/ethnically and geographically diverse US sample, we must generalize the inferences cautiously beyond infants with severe bronchiolitis. Still, the data remain highly relevant for 130 000 hospitalized US children each year.1 A further understanding of hospitalized infants at the highest risk (eg, those with rhinovirus C bronchiolitis and early IgE sensitization) could better delineate the mechanism linking early respiratory virus infections to asthma in larger populations of children.

Conclusions

In this prospective multicenter cohort of 716 infants with severe bronchiolitis, we found significant between-virus differences in the risk of developing recurrent wheeze by age 3 years. Infants with rhinovirus C infection, particularly with IgE sensitization during infancy, had the highest risk. Additionally, the data also suggest that the findings were driven by the associations with recurrent wheeze that resulted in asthma at age 4 years. Our data facilitate further investigations into the mechanisms underlying the association between distinct respiratory viruses, host immunity, and respiratory health in children. Furthermore, the study identifies infants at higher risk of developing recurrent wheeze and asthma and informs strategies to develop targeted preventive therapies.

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Article Information

Accepted for Publication: December 19, 2018.

Corresponding Author: Kohei Hasegawa, MD, MPH, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St, Ste 920, Boston, MA 02114-1101 (khasegawa1@partners.org).

Published Online: April 1, 2019. doi:10.1001/jamapediatrics.2019.0384

Author Contributions: Dr Hasegawa had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Hasegawa, Mansbach, Camargo.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hasegawa, Mansbach.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Hasegawa.

Obtained funding: Hasegawa, Camargo.

Administrative, technical, or material support: Mansbach, Gern, Piedra, Wu, Sullivan, Camargo.

Supervision: Bauer, Camargo.

Other - Viral typing: Gern.

Conflict of Interest Disclosures: Dr Hasegawa reported grants from the National Institutes of Health [NIH], Novartis, and Teva. Drs Mansbach, Bochkov, Bauer, Wu, Piedra, and Camargo reported grants from NIH. Dr Gern reported personal fees and stock options from Meissa Vaccines; personal fees from Regeneron, MedImmune, and PREP BIopharm Inc; and has a patent to Rhinovirus production pending. Dr Teach reported grants from NIH/National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, grants from National Institute of Child Health and Human Development, and Patient-Centered Outcomes Research and received royalties for service as a section editor from Uptodate Inc. No other disclosures were reported.

Funding/Support: This study was supported by grants U01 AI-087881, R01 AI-114552, R01 AI-108588, R01 AI-134940, R21 HL-129909, UG3 OD-023253, and UH3 OD-023253 from the NIH.

Role of the Funder/Sponsor: The funding organizations were not involved in the collection, management, or analysis of the data; preparation or approval of the manuscript; or decision to submit the manuscript for publication.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Additional Contributions: We thank the MARC-35 study hospitals and research personnel for their ongoing dedication to bronchiolitis and asthma research (eTable 1 in the Supplement). We also thank Courtney Tierney, MPH, Massachusetts General Hospital, and Alkis Togias, MD, National Institute of Allergy and Infectious Diseases, for their helpful contributions. No individuals were compensated for their contributions.

References
1.
Hasegawa  K, Tsugawa  Y, Brown  DF, Mansbach  JM, Camargo  CA  Jr.  Trends in bronchiolitis hospitalizations in the United States, 2000-2009.  Pediatrics. 2013;132(1):28-36. doi:10.1542/peds.2012-3877PubMedGoogle ScholarCrossref
2.
Bacharier  LB, Cohen  R, Schweiger  T,  et al.  Determinants of asthma after severe respiratory syncytial virus bronchiolitis.  J Allergy Clin Immunol. 2012;130(1):91-100.e3. doi:10.1016/j.jaci.2012.02.010PubMedGoogle ScholarCrossref
3.
Mikalsen  IB, Halvorsen  T, Øymar  K.  The outcome after severe bronchiolitis is related to gender and virus.  Pediatr Allergy Immunol. 2012;23(4):391-398. doi:10.1111/j.1399-3038.2012.01283.xPubMedGoogle ScholarCrossref
4.
Sigurs  N, Aljassim  F, Kjellman  B,  et al.  Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life.  Thorax. 2010;65(12):1045-1052. doi:10.1136/thx.2009.121582PubMedGoogle ScholarCrossref
5.
Castro  M, Schweiger  T, Yin-DeClue  H,  et al.  Cytokine response after severe respiratory syncytial virus bronchiolitis in early life.  J Allergy Clin Immunol. 2008;122(4):726-733.e3. doi:10.1016/j.jaci.2008.07.010PubMedGoogle ScholarCrossref
6.
Kotaniemi-Syrjänen  A, Vainionpää  R, Reijonen  TM, Waris  M, Korhonen  K, Korppi  M.  Rhinovirus-induced wheezing in infancy—the first sign of childhood asthma?  J Allergy Clin Immunol. 2003;111(1):66-71. doi:10.1067/mai.2003.33PubMedGoogle ScholarCrossref
7.
Reijonen  TM, Kotaniemi-Syrjänen  A, Korhonen  K, Korppi  M.  Predictors of asthma three years after hospital admission for wheezing in infancy.  Pediatrics. 2000;106(6):1406-1412. doi:10.1542/peds.106.6.1406PubMedGoogle ScholarCrossref
8.
Balekian  DS, Linnemann  RW, Hasegawa  K, Thadhani  R, Camargo  CA  Jr.  Cohort study of severe bronchiolitis during infancy and risk of asthma by age 5 years.  J Allergy Clin Immunol Pract. 2017;5(1):92-96. doi:10.1016/j.jaip.2016.07.004PubMedGoogle ScholarCrossref
9.
Hasegawa  K, Mansbach  JM, Camargo  CA  Jr.  Infectious pathogens and bronchiolitis outcomes.  Expert Rev Anti Infect Ther. 2014;12(7):817-828. doi:10.1586/14787210.2014.906901PubMedGoogle ScholarCrossref
10.
Kusel  MM, de Klerk  NH, Kebadze  T,  et al.  Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.  J Allergy Clin Immunol. 2007;119(5):1105-1110. doi:10.1016/j.jaci.2006.12.669PubMedGoogle ScholarCrossref
11.
Lemanske  RF  Jr, Jackson  DJ, Gangnon  RE,  et al.  Rhinovirus illnesses during infancy predict subsequent childhood wheezing.  J Allergy Clin Immunol. 2005;116(3):571-577. doi:10.1016/j.jaci.2005.06.024PubMedGoogle ScholarCrossref
12.
Midulla  F, Nicolai  A, Ferrara  M,  et al.  Recurrent wheezing 36 months after bronchiolitis is associated with rhinovirus infections and blood eosinophilia.  Acta Paediatr. 2014;103(10):1094-1099. doi:10.1111/apa.12720PubMedGoogle ScholarCrossref
13.
van der Gugten  AC, van der Zalm  MM, Uiterwaal  CS, Wilbrink  B, Rossen  JW, van der Ent  CK.  Human rhinovirus and wheezing: short and long-term associations in children.  Pediatr Infect Dis J. 2013;32(8):827-833.PubMedGoogle Scholar
14.
Liu  L, Pan  Y, Zhu  Y,  et al.  Association between rhinovirus wheezing illness and the development of childhood asthma: a meta-analysis.  BMJ Open. 2017;7(4):e013034. doi:10.1136/bmjopen-2016-013034PubMedGoogle ScholarCrossref
15.
Kusel  MM, Kebadze  T, Johnston  SL, Holt  PG, Sly  PD.  Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.  Eur Respir J. 2012;39(4):876-882. doi:10.1183/09031936.00193310PubMedGoogle ScholarCrossref
16.
Jackson  DJ, Gangnon  RE, Evans  MD,  et al.  Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.  Am J Respir Crit Care Med. 2008;178(7):667-672. doi:10.1164/rccm.200802-309OCPubMedGoogle ScholarCrossref
17.
Rubner  FJ, Jackson  DJ, Evans  MD,  et al.  Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence.  J Allergy Clin Immunol. 2017;139(2):501-507. doi:10.1016/j.jaci.2016.03.049PubMedGoogle ScholarCrossref
18.
Calışkan  M, Bochkov  YA, Kreiner-Møller  E,  et al.  Rhinovirus wheezing illness and genetic risk of childhood-onset asthma.  N Engl J Med. 2013;368(15):1398-1407. doi:10.1056/NEJMoa1211592PubMedGoogle ScholarCrossref
19.
Backman  K, Ollikainen  H, Piippo-Savolainen  E, Nuolivirta  K, Korppi  M.  Asthma and lung function in adulthood after a viral wheezing episode in early childhood.  Clin Exp Allergy. 2018;48(2):138-146. doi:10.1111/cea.13062PubMedGoogle ScholarCrossref
20.
Bochkov  YA, Gern  JE.  Rhinoviruses and their receptors: implications for allergic disease.  Curr Allergy Asthma Rep. 2016;16(4):30. doi:10.1007/s11882-016-0608-7PubMedGoogle ScholarCrossref
21.
Lee  WM, Lemanske  RF  Jr, Evans  MD,  et al.  Human rhinovirus species and season of infection determine illness severity.  Am J Respir Crit Care Med. 2012;186(9):886-891. doi:10.1164/rccm.201202-0330OCPubMedGoogle ScholarCrossref
22.
Linder  JE, Kraft  DC, Mohamed  Y,  et al.  Human rhinovirus C: age, season, and lower respiratory illness over the past 3 decades.  J Allergy Clin Immunol. 2013;131(1):69-77.e1, 6. doi:10.1016/j.jaci.2012.09.033PubMedGoogle ScholarCrossref
23.
Turunen  R, Jartti  T, Bochkov  YA, Gern  JE, Vuorinen  T.  Rhinovirus species and clinical characteristics in the first wheezing episode in children.  J Med Virol. 2016;88(12):2059-2068. doi:10.1002/jmv.24587PubMedGoogle ScholarCrossref
24.
Martin  EK, Kuypers  J, Chu  HY,  et al.  Molecular epidemiology of human rhinovirus infections in the pediatric emergency department.  J Clin Virol. 2015;62:25-31. doi:10.1016/j.jcv.2014.11.006PubMedGoogle ScholarCrossref
25.
Piralla  A, Rovida  F, Campanini  G,  et al.  Clinical severity and molecular typing of human rhinovirus C strains during a fall outbreak affecting hospitalized patients.  J Clin Virol. 2009;45(4):311-317. doi:10.1016/j.jcv.2009.04.016PubMedGoogle ScholarCrossref
26.
Bashir  H, Grindle  K, Vrtis  R,  et al.  Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens.  J Allergy Clin Immunol. 2018;141(2):822-824.e9. doi:10.1016/j.jaci.2017.09.027PubMedGoogle ScholarCrossref
27.
Esquivel  A, Busse  WW, Calatroni  A,  et al.  Effects of omalizumab on rhinovirus infections, illnesses, and exacerbations of asthma.  Am J Respir Crit Care Med. 2017;196(8):985-992. doi:10.1164/rccm.201701-0120OCPubMedGoogle ScholarCrossref
28.
Bizzintino  J, Lee  WM, Laing  IA,  et al.  Association between human rhinovirus C and severity of acute asthma in children.  Eur Respir J. 2011;37(5):1037-1042. doi:10.1183/09031936.00092410PubMedGoogle ScholarCrossref
29.
Fawkner-Corbett  DW, Khoo  SK, Duarte  CM,  et al.  Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil.  J Med Virol. 2016;88(1):58-63. doi:10.1002/jmv.24300PubMedGoogle ScholarCrossref
30.
Cox  DW, Bizzintino  J, Ferrari  G,  et al.  Human rhinovirus species C infection in young children with acute wheeze is associated with increased acute respiratory hospital admissions.  Am J Respir Crit Care Med. 2013;188(11):1358-1364. doi:10.1164/rccm.201303-0498OCPubMedGoogle ScholarCrossref
31.
Stewart  CJ, Mansbach  JM, Wong  MC,  et al.  Associations of nasopharyngeal metabolome and microbiome with severity among infants with bronchiolitis: a multiomic analysis.  Am J Respir Crit Care Med. 2017;196(7):882-891. doi:10.1164/rccm.201701-0071OCPubMedGoogle ScholarCrossref
32.
Hasegawa  K, Mansbach  JM, Ajami  NJ,  et al; the MARC-35 Investigators.  Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis.  Eur Respir J. 2016;48(5):1329-1339. doi:10.1183/13993003.00152-2016PubMedGoogle ScholarCrossref
33.
Hasegawa  K, Mansbach  JM, Ajami  NJ,  et al.  Serum cathelicidin, nasopharyngeal microbiota, and disease severity among infants hospitalized with bronchiolitis.  J Allergy Clin Immunol. 2017;139(4):1383-1386.e6. doi:10.1016/j.jaci.2016.09.037PubMedGoogle ScholarCrossref
34.
Emergency Medicine Network. Emergency Medicine Network. http://www.emnet-usa.org/. Accessed August 15, 2018.
35.
Ralston  SL, Lieberthal  AS, Meissner  HC,  et al; American Academy of Pediatrics.  Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis.  Pediatrics. 2014;134(5):e1474-e1502. doi:10.1542/peds.2014-2742PubMedGoogle ScholarCrossref
36.
Hasegawa  K, Jartti  T, Mansbach  JM,  et al.  Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: multicenter cohort studies in the United States and Finland.  J Infect Dis. 2015;211(10):1550-1559. doi:10.1093/infdis/jiu658PubMedGoogle ScholarCrossref
37.
Mansbach  JM, Piedra  PA, Teach  SJ,  et al; MARC-30 Investigators.  Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis.  Arch Pediatr Adolesc Med. 2012;166(8):700-706. doi:10.1001/archpediatrics.2011.1669PubMedGoogle ScholarCrossref
38.
Beckham  JD, Cadena  A, Lin  J,  et al.  Respiratory viral infections in patients with chronic, obstructive pulmonary disease.  J Infect. 2005;50(4):322-330. doi:10.1016/j.jinf.2004.07.011PubMedGoogle ScholarCrossref
39.
Lu  X, Holloway  B, Dare  RK,  et al.  Real-time reverse transcription-PCR assay for comprehensive detection of human rhinoviruses.  J Clin Microbiol. 2008;46(2):533-539. doi:10.1128/JCM.01739-07PubMedGoogle ScholarCrossref
40.
Bochkov  YA, Grindle  K, Vang  F, Evans  MD, Gern  JE.  Improved molecular typing assay for rhinovirus species A, B, and C.  J Clin Microbiol. 2014;52(7):2461-2471. doi:10.1128/JCM.00075-14PubMedGoogle ScholarCrossref
41.
Hasegawa  K, Piedra  PA, Bauer  CS,  et al; MARC-35 Investigators.  Nasopharyngeal CCL5 in infants with severe bronchiolitis and risk of recurrent wheezing: a multi-center prospective cohort study.  Clin Exp Allergy. 2018;48(8):1063-1067. doi:10.1111/cea.13166PubMedGoogle ScholarCrossref
42.
US Department of Health and Human Services.  National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma (NIH Publication 08-4051). Bethesda, MD: National Institutes of Health; 2007.
43.
National Institutes of Health. Infant specific-IgE, rhinovirus-C bronchiolitis, and incident asthma in MARC-35. http://grantome.com/grant/NIH/R01-AI114552-04. Accessed August 15, 2018.
44.
Martinez  FD, Wright  AL, Taussig  LM, Holberg  CJ, Halonen  M, Morgan  WJ; the Group Health Medical Associates.  Asthma and wheezing in the first six years of life.  N Engl J Med. 1995;332(3):133-138. doi:10.1056/NEJM199501193320301PubMedGoogle ScholarCrossref
45.
Stein  RT, Martinez  FD.  Asthma phenotypes in childhood: lessons from an epidemiological approach.  Paediatr Respir Rev. 2004;5(2):155-161. doi:10.1016/j.prrv.2004.01.007PubMedGoogle ScholarCrossref
46.
Camargo  CA  Jr, Ingham  T, Wickens  K,  et al; New Zealand Asthma and Allergy Cohort Study Group.  Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.  Pediatrics. 2011;127(1):e180-e187. doi:10.1542/peds.2010-0442PubMedGoogle ScholarCrossref
47.
Nakagome  K, Bochkov  YA, Ashraf  S,  et al.  Effects of rhinovirus species on viral replication and cytokine production.  J Allergy Clin Immunol. 2014;134(2):332-341. doi:10.1016/j.jaci.2014.01.029PubMedGoogle ScholarCrossref
48.
Jackson  DJ, Makrinioti  H, Rana  BM,  et al.  IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo.  Am J Respir Crit Care Med. 2014;190(12):1373-1382. doi:10.1164/rccm.201406-1039OCPubMedGoogle ScholarCrossref
49.
Saglani  S, Lui  S, Ullmann  N,  et al.  IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma.  J Allergy Clin Immunol. 2013;132(3):676-685.e13. doi:10.1016/j.jaci.2013.04.012PubMedGoogle ScholarCrossref
50.
Beale  J, Jayaraman  A, Jackson  DJ,  et al.  Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation.  Sci Transl Med. 2014;6(256):256ra134. doi:10.1126/scitranslmed.3009124PubMedGoogle ScholarCrossref
51.
Durrani  SR, Montville  DJ, Pratt  AS,  et al.  Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children.  J Allergy Clin Immunol. 2012;130(2):489-495. doi:10.1016/j.jaci.2012.05.023PubMedGoogle ScholarCrossref
52.
Gern  JE.  The ABCs of rhinoviruses, wheezing, and asthma.  J Virol. 2010;84(15):7418-7426. doi:10.1128/JVI.02290-09PubMedGoogle ScholarCrossref
53.
Bønnelykke  K, Sleiman  P, Nielsen  K,  et al.  A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.  Nat Genet. 2014;46(1):51-55. doi:10.1038/ng.2830PubMedGoogle ScholarCrossref
54.
Bochkov  YA, Watters  K, Ashraf  S,  et al.  Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication.  Proc Natl Acad Sci U S A. 2015;112(17):5485-5490. doi:10.1073/pnas.1421178112PubMedGoogle ScholarCrossref
55.
Bønnelykke  K, Coleman  AT, Evans  MD,  et al.  Cadherin-related family member 3 genetics and rhinovirus C respiratory illnesses.  Am J Respir Crit Care Med. 2018;197(5):589-594. doi:10.1164/rccm.201705-1021OCPubMedGoogle ScholarCrossref
56.
Edwards  MR, Walton  RP, Jackson  DJ,  et al; EAACI Anti-infectives in Asthma and Asthma Exacerbations Task Force.  The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations.  Allergy. 2018;73(1):50-63. doi:10.1111/all.13257PubMedGoogle ScholarCrossref
57.
Teach  SJ, Gill  MA, Togias  A,  et al.  Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations.  J Allergy Clin Immunol. 2015;136(6):1476-1485. doi:10.1016/j.jaci.2015.09.008PubMedGoogle ScholarCrossref
58.
Castro-Rodríguez  JA, Holberg  CJ, Wright  AL, Martinez  FD.  A clinical index to define risk of asthma in young children with recurrent wheezing.  Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403-1406. doi:10.1164/ajrccm.162.4.9912111PubMedGoogle ScholarCrossref
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