Overcoming the Bronchiolitis Blues: Embracing Global Collaboration and Disease HeterogeneityJonathan M. Mansbach, MD, MPH, a Kohei Hasegawa, MD, MPHb

Although bronchiolitis is 1 of the most common conditions in infancy, no medicine has been proven to be consistently beneficial. As a result, the primary objective of frontline providers in primary care and emergency medicine is to triage infants to the appropriate level of care (ie, home, hospital ward, or intensive care) for their hydration and respiratory needs.1

However, prospectively validated risk-stratification tools for infants with bronchiolitis do not exist for frontline providers. Freire et al, 2 as part of the Pediatric Emergency Research Networks, addressed this knowledge gap by analyzing data that were collected from 38 emergency departments across the globe to develop a bronchiolitis risk score. In the resulting article, 2 the authors report that the usual suspects (ie, being ≤2 months of age; having apnea; oxygen saturation of <90%; signs of increased work of breathing [including nasal flaring, grunting, and retractions]; and dehydration and/or poor feeding) were all predictive of escalated care, which is defined as hospitalization with a high-flow nasal cannula, noninvasive or invasive ventilation, or intensive care admission.

Although many clinicians feel comfortable triaging infants with bronchiolitis at either end of the severity spectrum (ie, well or critically ill), their comfort wanes when triaging moderately ill infants whose outcomes are less certain. For example, using

Freire et al’s2 scoring system, a 1-month-old who is not feeding well, is dehydrated, and has a room-air oxygen saturation of <90% in the emergency department triage has 8 risk points and is predicted to have a ∼50% chance of needing escalated care. Clinicians at hospitals without ready access to advanced infant respiratory support measures would need to decide if they should provide hydration and observe the infant for further signs of respiratory distress or recommend immediate transfer to a tertiary- or quaternary-care center, possibly hundreds of miles away. These difficult decisions may become somewhat easier after the authors refine their score during their proposed prospective validation study.

Beyond refining the predictors in the risk score, another critical issue is variability in the outcome (escalated care). The use of different respiratory support methods varies within and between countries, 3, 4 and there is no accepted measure that can be used to confirm which subset of infants truly needs escalated care. Indeed, without some objective means of understanding the outcome, low oxygen saturations may become a self-fulfilling prophecy of an overly valued measure of severity, leading to overtreatment.5

As researchers develop risk scores and evaluate new respiratory support methods, 6, 7 there needs to be a simultaneous push to identify bronchiolitis subgroups by improving our understanding of the underlying

aDepartment of Medicine, Boston Children’s Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts; and bDepartment of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

DOI: https:// doi. org/ 10. 1542/ peds. 2018- 1982

Accepted for publication Jun 25, 2018

Address correspondence to Jonathan M. Mansbach, MD, MPH, Department of Medicine, Boston Children’s Hospital, 300 Longwood Ave, 9 S. 9157, Boston, MA 02115. E-mail: jonathan.mansbach@childrens.harvard.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by the National Institutes of Health (grant R01AI108588). Funded by the National Institutes of Health (NIH).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

To cite: Mansbach JM and Hasegawa K. Over-coming the Bronchiolitis Blues: Embracing Global Collaboration and Disease Heterogeneity. Pedi­atrics. 2018;142(3):e20181982

NIH

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pathobiology. Without this groundwork, clinicians will continue to treat and researchers will continue to analyze children with bronchiolitis as 1 homogeneous group despite data suggesting that bronchiolitis is heterogeneous.8 Indeed, when the underlying pathobiology of a condition is not accounted for in otherwise rigorous studies, there is an increased chance of obfuscating true associations between exposure and outcome. During the proposed validation study, the authors would ideally create a biorepository to eventually incorporate biologically based identifiers (eg, specific viruses, 9 microbiome patterns, 10 and host responses11, 12) that would be used to improve disease classification and the relevance of the risk score for infants with each identifier.

For example, recent data support clinical, bacterial, and mechanistic differences between respiratory syncytial virus (RSV) and rhinovirus, the 2 viruses that cause 85% of the cases of bronchiolitis requiring hospitalization. Compared with children with RSV bronchiolitis,

children with rhinovirus bronchiolitis have a shorter hospital length of stay9, 13 and are significantly more likely to be treated with systemic corticosteroids when hospitalized14 and with inhaled corticosteroids the year after hospitalization.15 Furthermore, RSV-only and rhinovirus-only infections are associated with different bacteria in the nasopharyngeal airway at hospitalization.16 And differences in bacterial dominance in the nasopharynx at hospitalization are associated with a higher risk of intensive care use.10 There are also results revealing mechanistic differences between RSV-only and rhinovirus-only infections, including distinct microRNA expression profiles17 and completely separate metabolic pathways.18 Although replication is needed, these differences reveal that the one-size-fits-all approach to caring for and analyzing infants with bronchiolitis may be limited.

Indeed, to make substantial progress in the care of infants with bronchiolitis, clinicians

and researchers will first need to understand and embrace the heterogeneity of this common condition. We also need to follow the lead of Pediatric Emergency Research Networks investigators. Global collaboration should be celebrated and replicated given its clear benefits in generalizability. Developing a validated global tool to help clinicians appropriately triage infants with bronchiolitis will not only be helpful, but will also provide a counterweight to our current nihilism and learned helplessness rooted in cycles of promising initial trial results that ultimately lack demonstrable benefit.19 Embracing the heterogeneity of bronchiolitis by incorporating more biologically based identifiers into bronchiolitis studies will help providers to finally overcome the bronchiolitis blues: our collective frustration every winter with having to tell parents “nothing works.”

ABBREVIATION

RSV:  respiratory syncytial virus

REFERENCES

1. Mansbach JM, Clark S, Christopher NC, et al. Prospective multicenter study of bronchiolitis: predicting safe discharges from the emergency department. Pediatrics. 2008;121(4):680–688

2. Freire G, Kuppermann N, Zemek R, et al. Predicting escalated care in infants with bronchiolitis. Pediatrics. 2018;142(3):e20174253

3. Schuh S, Babl FE, Dalziel SR, et al; Pediatric Emergency Research Networks. Practice variation in acute bronchiolitis: a Pediatric Emergency Research Networks study. Pediatrics. 2017;140(6):e20170842

4. Pierce HC, Mansbach JM, Fisher ES, et al. Variability of intensive care management for children

with bronchiolitis. Hosp Pediatr. 2015;5(4):175–184

5. Schuh S, Freedman S, Coates A, et al. Effect of oximetry on hospitalization in bronchiolitis: a randomized clinical trial. JAMA. 2014;312(7): 712–718

6. Franklin D, Babl FE, Schlapbach LJ, et al. A randomized trial of high-flow oxygen therapy in infants with bronchiolitis. N Engl J Med. 2018;378(12):1121–1131

7. Kepreotes E, Whitehead B, Attia J, et al. High-flow warm humidified oxygen versus standard low-flow nasal cannula oxygen for moderate bronchiolitis (HFWHO RCT): an open, phase 4, randomised controlled trial. Lancet. 2017;389(10072):930–939

8. Hasegawa K, Dumas O, Hartert TV, Camargo CA Jr. Advancing our understanding of infant bronchiolitis through phenotyping and endotyping: clinical and molecular approaches. Expert Rev Respir Med. 2016;10(8):891–899

9. 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

10. Hasegawa K, Mansbach JM, Ajami NJ, et al; the MARC-35 Investigators. Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised

COMPANION PAPER: A companion to this article can be found online at www. pediatrics. org/ cgi/ doi/ 10. 1542/ peds. 2017- 4253.

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for bronchiolitis. Eur Respir J. 2016;48(5):1329–1339

11. Mansbach JM, Hasegawa K, Ajami NJ, et al. Serum LL-37 levels associated with severity of bronchiolitis and viral etiology. Clin Infect Dis. 2017;65(6): 967–975

12. Hasegawa K, Mansbach JM, Ajami NJ, et al. The relationship between nasopharyngeal CCL5 and microbiota on disease severity among infants with bronchiolitis. Allergy. 2017;72(11):1796–1800

13. Jartti T, Aakula M, Mansbach JM, et al. Hospital length-of-stay is associated with rhinovirus etiology of bronchiolitis. Pediatr Infect Dis J. 2014;33(8):829–834

14. Mansbach JM, Clark S, Teach SJ, et al. Children hospitalized with rhinovirus bronchiolitis have asthma-like characteristics. J Pediatr. 2016;172:202–204.e1

15. Bergroth E, Aakula M, Korppi M, et al. Post-bronchiolitis use of asthma medication: a prospective 1-year follow-up study. Pediatr Infect Dis J. 2016;35(4):363–368

16. Mansbach JM, Hasegawa K, Henke DM, et al. Respiratory syncytial virus and rhinovirus severe bronchiolitis are associated with distinct nasopharyngeal microbiota. J Allergy Clin Immunol. 2016;137(6):1909–1913.e4

17. Hasegawa K, Pérez-Losada M, Hoptay CE, et al. RSV vs. rhinovirus

bronchiolitis: difference in nasal airway microRNA profiles and NFκB signaling. Pediatr Res. 2018;83(3):606–614

18. Stewart CJ, Hasegawa K, Wong MC, et al. Respiratory syncytial virus and rhinovirus bronchiolitis are associated with distinct metabolic pathways. J Infect Dis. 2018;217(7):1160–1169

19. Ralston SL, Lieberthal AS, Meissner HC, et al; American Academy of Pediatrics. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis [published correction appears in Pediatrics. 2015;136(4):782]. Pediatrics. 2014;134(5). Available at: www. pediatrics. org/ cgi/ content/ full/ 134/ 5/ e1474

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Jonathan M. Mansbach and Kohei HasegawaDisease Heterogeneity

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