Severe bronchiolitis profiling as the first step towards prevention of asthma
Main Article Content
Keywords
Asthma, Bronchiolitis, Child, Virus, Wheezing
Abstract
Bronchiolitis is the most common respiratory infection leading to hospitalization and constitutes a significant healthcare burden. The two main viral agents causing bronchiolitis, respiratory syncytial virus (RSV) and rhinovirus (RV), have distinct cytopathic, immune response, and clinical characteristics. Different approaches have been suggested for subtyping bronchiolitis based on viral etiology, atopic status, transcriptome profiles in blood, airway metabolome, lipidomic data, and airway microbiota. The highest risk of asthma at school age has been in a subgroup of bronchiolitis characterized by older age, high prevalence of RV infection, previous breathing problems, and/or eczema. Regarding solely viral etiology, RV-bronchiolitis in infancy has been linked to a nearly three times higher risk of developing asthma than RSV-bronchiolitis. Although treatment with betamimetics and systemic corticosteroids has been found ineffective in bronchiolitis overall, it can be beneficial for infants with severe RV bronchiolitis. Thus, there is a need to develop a more individualized therapeutic approach for bronchiolitis and follow-up strategies for infants at higher risk of asthma in the future perspective.
References
2. Mahant S, Parkin PC, Thavam T, Imsirovic H, Tuna M, Knight B, et al. Rates in bronchiolitis hospitalization, intensive care unit use, mortality, and costs from 2004 to 2018. JAMA Pediatr. 2022;176(3):270–9. 10.1001/jamapediatrics.2021.5177
3. Régnier SA, Huels J. Association between respiratory syncytial virus hospitalizations in infants and respiratory sequelae: Systematic review and meta-analysis. Pediatr Infect Dis J. 2013;32(8):820–6. 10.1097/INF.0b013e31829061e8
4. Makrinioti H, Hasegawa K, Lakoumentas J, Xepapadaki P, Tsolia M, Castro-Rodriguez JA, et al. The role of respiratory syncytial virus-and rhinovirus-induced bronchiolitis in recurrent wheeze and asthma—A systematic review and meta--analysis. Pediatr Allergy Immunol. 2022;33(3):e13741. 10.1111/pai.13741
5. Sander B, Finkelstein Y, Lu H, Nagamuthu C, Graves E, Ramsay LC, et al. Healthcare cost attributable to bronchiolitis: A population-based cohort study. PLoS One. 2021;16(12):e0260809. 10.1371/journal.pone.0260809
6. Díez-Gandía E, Gómez-Álvarez C, López-Lacort M, Muñoz-Quiles C, Úbeda-Sansano I, Díez-Domingo J, et al. The impact of childhood RSV infection on children’s and parents’ quality of life: A prospective multicenter study in Spain. BMC Infect Dis. 2021;21(1):924. 10.1186/s12879-021-06629-z
7. Mansbach JM, Clark S, Teach SJ, Gern JE, Piedra PA, Sullivan AF, et al. Children hospitalized with rhinovirus bronchiolitis have asthma-like characteristics. J Pediatr. 2016;172:202–4.e1. 10.1016/j.jpeds.2016.01.041
8. Haddadin Z, Rankin DA, Lipworth L, Suh M, McHenry R, Blozinski A, et al. Respiratory virus surveillance in infants across different clinical settings. J Pediatr. 2021;234:164–71.e2. 10.1016/j.jpeds.2021.03.036
9. Mansbach JM, Piedra PA, Teach SJ, Sullivan AF, Forgey T, Clark S, et al. Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med. 2012;166(8):700–6. 10.1001/archpediatrics.2011.1669
10. Kenmoe S, Kengne-Nde C, Ebogo-Belobo JT, Mbaga DS, Fatawou Modiyinji A, Njouom R. Systematic review and meta-analysis of the prevalence of common respiratory viruses in children < 2 years with bronchiolitis in the pre-COVID-19 pandemic era. PLoS One. 2020;15(11):e0242302. 10.1371/journal.pone.0242302
11. Smyth RL, Openshaw PJ. Bronchiolitis. Lancet. 2006; 368(9532): 312–22. 10.1016/S0140-6736(06)69077-6
12. Hall CB, Weinberg GA, Blumkin AK, Edwards KM, Staat MA, Schultz AF, et al. Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics. 2013;132(2):e341–8. 10.1542/peds.2013-0303
13. Wrotek A, Czajkowska M, Jackowska T. Seasonality of respiratory syncytial virus hospitalization. Adv Exp Med Biol. 2020;1279:93–100. 10.1007/5584_2020_503
14. Sirimi N, Miligkos M, Koutouzi F, Petridou E, Siahanidou T, Michos A. Respiratory syncytial virus activity and climate parameters during a 12-year period. J Med Virol. 2016;88(6):931–7. 10.1002/jmv.24430
15. Hasegawa K, Goto T, Hirayama A, Laham FR, Mansbach JM, Piedra PA, et al. Respiratory virus epidemiology among US infants with severe bronchiolitis: Analysis of 2 multicenter, multiyear cohort studies. Pediatr Infect Dis J. 2019;38(8):e180–e3. 10.1097/INF.0000000000002279
16. Grochowska M, Ambrożej D, Wachnik A, Demkow U, Podsiadły E, Feleszko W. The impact of the COVID-19 pandemic lockdown on pediatric infections—A single-center retrospective study. Microorganisms. 2022;10(1):178. 10.3390/microorganisms10010178
17. Haapanen M, Renko M, Artama M, Kuitunen I. The impact of the lockdown and the re-opening of schools and day cares on the epidemiology of SARS-CoV-2 and other respiratory infections in children—A nationwide register study in Finland. EClinicalMedicine. 2021;34:100807. 10.1016/j.eclinm.2021.100807
18. Maglione M, Pascarella A, Botti C, Ricci G, Morelli F, Camelia F, et al. Changing epidemiology of acute viral respiratory infections in hospitalized children: The post-lockdown effect. Children (Basel). 2022;9(8):1242. 10.3390/children9081242
19. Berdah L, Romain AS, Rivière S, Schnuriger A, Perrier M, Carbajal R, et al. Retrospective observational study of the influence of the COVID-19 outbreak on infants’ hospitalisation for acute bronchiolitis. BMJ Open. 2022;12(10):e059626. 10.1136/bmjopen-2021-059626
20. van Summeren J, Meijer A, Aspelund G, Casalegno JS, Erna G, Hoang U, et al. Low levels of respiratory syncytial virus activity in Europe during the 2020/21 season: What can we expect in the coming summer and autumn/winter? Euro Surveill. 2021;26(29):2100639. 10.2807/1560-7917.ES.2021.26.29.2100639
21. Brisca G, Mariani M, Buratti S, Ferretti M, Pirlo D, Buffoni I, et al. How has the SARS-CoV-2 pandemic changed the epidemiology and management of acute bronchiolitis? Pediatr Pulmonol. 2023. 10.1002/ppul.26315
22. Billard MN, Bont LJ. Quantifying the RSV immunity debt following COVID-19: A public health matter. Lancet Infect Dis. 2023;23(1):3–5. 10.1016/S1473-3099(22)00544-8
23. Guedj R, Lorrot M, Lecarpentier T, Leger PL, Corvol H, Carbajal R. Infant bronchiolitis dramatically reduced during the second French COVID-19 outbreak. Acta Paediatr. 2021;110(4):1297–9. 10.1111/apa.15780
24. Movva N, Suh M, Reichert H, Hintze B, Sendak MP, Wolf Z, et al. Respiratory syncytial virus during the COVID-19 pandemic compared to historic levels: A retrospective cohort study of a health system. J Infect Dis. 2022;226(Suppl 2):S175–S183. 10.1093/infdis/jiac220
25. Jartti T, Smits HH, Bønnelykke K, Bircan O, Elenius V, Konradsen JR, et al. Bronchiolitis needs a revisit: Distinguishing between virus entities and their treatments. Allergy. 2019;74(1):40–52. 10.1111/all.13624
26. Rubner FJ, Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, et al. Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence. J Allergy Clin Immunol. 2017;139(2):501–7. 10.1016/j.jaci.2016.03.049
27. Lukkarinen M, Koistinen A, Turunen R, Lehtinen P, Vuorinen T, Jartti T. Rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age. J Allergy Clin Immunol. 2017;140(4):988–95. 10.1016/j.jaci.2016.12.991
28. Bergroth E, Aakula M, Elenius V, Remes S, Piippo-Savolainen E, Korppi M, et al. Rhinovirus type in severe bronchiolitis and the development of asthma. J Allergy Clin Immunol Pract. 2020;8(2):588–95.e4. 10.1016/j.jaip.2019.08.043
29. Meissner HC. Viral bronchiolitis in children. N Engl J Med. 2016;374(1):62–72. 10.1056/NEJMra1413456
30. Jackson DJ, Gern JE. Rhinovirus infections and their roles in asthma: Etiology and exacerbations. J Allergy Clin Immunol Pract. 2022;10(3):673–81. 10.1016/j.jaip.2022.01.006
31. Tacon CE, Wiehler S, Holden NS, Newton R, Proud D, Leigh R. Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-{kappa}B. Am J Respir Cell Mol Biol. 2010;43(2):201–9. 10.1165/rcmb.2009-0216OC
32. Skevaki CL, Psarras S, Volonaki E, Pratsinis H, Spyridaki IS, Gaga M, et al. Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features. Clin Transl Allergy. 2012;2(1):14. 10.1186/2045-7022-2-14
33. XuChen X, Weinstock J, Arroyo M, Salka K, Chorvinsky E, Abutaleb K, et al. Airway remodeling factors during-early-life rhinovirus infection and the effect of premature birth. Front Pediatr. 2021;9:610478. 10.3389/fped.2021.610478
34. Ruiz S, Calvo C, Pozo F, Casas I, García-García ML. Lung function, allergic sensitization and asthma in school-aged children after viral-coinfection bronchiolitis. Sci Rep. 2022;12(1):7552. 10.1038/s41598-022-11356-9
35. Everman JL, Sajuthi S, Saef B, Rios C, Stoner AM, Numata M, et al. Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations. J Allergy Clin Immunol. 2019;144(4):962-71. 10.1016/j.jaci.2019.01.052
36. Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Mercader JM, Belgrave D, 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):51–5. 10.1038/ng.2830
37. Calışkan M, Bochkov YA, Kreiner-Møller E, Bønnelykke K, Stein MM, Du G, et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med. 2013;368(15):1398–407. 10.1056/NEJMoa1211592
38. Jartti T, Kuusipalo H, Vuorinen T, Söderlund-Venermo M, Allander T, Waris M, et al. Allergic sensitization is associated with rhinovirus-, but not other virus-, induced wheezing in children. Pediatr Allergy Immunol. 2010;21(7):1008–14. 10.1111/j.1399-3038.2010.01059.x
39. Pelletier JH, Au AK, Fuhrman D, Clark RSB, Horvat C. Trends in bronchiolitis ICU admissions and ventilation practices: 2010–2019. Pediatrics. 2021;147(6):e2020039115. 10.1542/peds.2020-039115
40. Mammas IN, Drysdale SB, Rath B, Theodoridou M, Papaioannou G, Papatheodoropoulou A, et al. Update on current views and advances on RSV infection (Review). Int J Mol Med. 2020;46(2):509–20. 10.3892/ijmm.2020.4641
41. Stevens TP, Sinkin RA, Hall CB, Maniscalco WM, McConnochie KM. Respiratory syncytial virus and premature infants born at 32 weeks’ gestation or earlier: hospitalization and economic implications of prophylaxis. Arch Pediatr Adolesc Med. 2000;154(1):55–61.
42. Do LAH, Pellet J, van Doorn HR, Tran AT, Nguyen BH, Tran TTL, et al. Host transcription profile in nasal epithelium and whole blood of hospitalized children under 2 years of age with respiratory syncytial virus infection. J Infect Dis. 2017;217(1):134–46. 10.1093/infdis/jix519
43. Mejias A, Dimo B, Suarez NM, Garcia C, Suarez-Arrabal MC, Jartti T, et al. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLoS Med. 2013;10(11):e1001549. 10.1371/journal.pmed.1001549
44. Heinonen S, Jartti T, Garcia C, Oliva S, Smitherman C, Anguiano E, et al. Rhinovirus detection in symptomatic and asymptomatic children: Value of host transcriptome analysis. Am J Respir Crit Care Med. 2016;193(7):772–82. 10.1164/rccm.201504-0749OC
45. Jansen RR, Wieringa J, Koekkoek SM, Visser CE, Pajkrt D, Molenkamp R, et al. Frequent detection of respiratory viruses without symptoms: Toward defining clinically relevant cutoff values. J Clin Microbiol. 2011;49(7):2631–6. 10.1128/JCM.02094-10
46. Rhedin S, Lindstrand A, Rotzén-Östlund M, Tolfvenstam T, Ohrmalm L, Rinder MR, et al. Clinical utility of PCR for common viruses in acute respiratory illness. Pediatrics. 2014;133(3):e538–45. 10.1542/peds.2013-3042
47. van Benten I, Koopman L, Niesters B, Hop W, van Middelkoop B, de Waal L, et al. Predominance of rhinovirus in the nose of symptomatic and asymptomatic infants. Pediatr Allergy Immunol. 2003;14(5):363–70. 10.1034/j.1399-3038.2003.00064.x
48. van den Bergh MR, Biesbroek G, Rossen JW, de Steenhuijsen Piters WA, Bosch AA, van Gils EJ, et al. Associations between pathogens in the upper respiratory tract of young children: Interplay between viruses and bacteria. PLoS One. 2012;7(10):e47711. 10.1371/journal.pone.0047711
49. de Steenhuijsen Piters WA, Heinonen S, Hasrat R, Bunsow E, Smith B, Suarez-Arrabal MC, et al. Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am J Respir Crit Care Med. 2016;194(9):1104–15. 10.1164/rccm.201602-0220OC
50. van den Kieboom CH, Ahout IM, Zomer A, Brand KH, de Groot R, Ferwerda G, et al. Nasopharyngeal gene expression, a novel approach to study the course of respiratory syncytial virus infection. Eur Respir J. 2015;45(3):718–25. 10.1183/09031936.00085614
51. Fujiogi M, Raita Y, Pérez-Losada M, Freishtat RJ, Celedón JC, Mansbach JM, et al. Integrated relationship of nasopharyngeal airway host response and microbiome associates with bronchiolitis severity. Nat Commun. 2022;13(1):4970. 10.1038/s41467-022-32323-y
52. Rodriguez-Fernandez R, Tapia LI, Yang CF, Torres JP, Chavez-Bueno S, Garcia C, et al. Respiratory syncytial virus genotypes, host immune profiles, and disease severity in young children hospitalized with bronchiolitis. J Infect Dis. 2017;217(1):24–34. 10.1093/infdis/jix543
53. Fujiogi M, Camargo CA, Jr., Raita Y, Bochkov YA, Gern JE, Mansbach JM, et al. Association of rhinovirus species with nasopharyngeal metabolome in bronchiolitis infants: A multicenter study. Allergy. 2020;75(9):2379–83. 10.1111/all.14326
54. Brealey JC, Chappell KJ, Galbraith S, Fantino E, Gaydon J, Tozer S, et al. Streptococcus pneumoniae colonization of the nasopharynx is associated with increased severity during respiratory syncytial virus infection in young children. Respirology. 2018;23(2):220–7. 10.1111/resp.13179
55. Zhu Z, Camargo CA, Jr., Raita Y, Fujiogi M, Liang L, Rhee EP, et al. Metabolome subtyping of severe bronchiolitis in infancy and risk of childhood asthma. J Allergy Clin Immunol. 2022;149(1):102–12. 10.1016/j.jaci.2021.05.036
56. Fujiogi M, Zhu Z, Raita Y, Ooka T, Celedon JC, Freishtat R, et al. Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: A multicentre prospective study. Thorax. 2022;7(11):1059–69. 10.1136/thorax-2022-219016
57. Raita Y, Camargo CA, Jr., Bochkov YA, Celedón JC, Gern JE, Mansbach JM, et al. Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma. J Allergy Clin Immunol. 2021;147(6):2108–17. 10.1016/j.jaci.2020.11.002
58. Raita Y, Pérez-Losada M, Freishtat RJ, Harmon B, Mansbach JM, Piedra PA, et al. Integrated omics endotyping of infants with respiratory syncytial virus bronchiolitis and risk of childhood asthma. Nat Commun. 2021;12(1):3601. 10.1038/s41467-021-23859-6
59. Zhu Z, Camargo CA, Jr., Raita Y, Freishtat RJ, Fujiogi M, Hahn A, et al. Nasopharyngeal airway dual-transcriptome of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. J Allergy Clin Immunol. 2022;150(4):806–16. 10.1016/j.jaci.2022.04.017
60. Fujiogi M, Dumas O, Hasegawa K, Jartti T, Camargo CA. Identifying and predicting severe bronchiolitis profiles at high risk for developing asthma: Analysis of three prospective cohorts. EClinicalMedicine. 2022;43:101257. 10.1016/j.eclinm.2021.101257
61. Takeyama A, Hashimoto K, Sato M, Sato T, Tomita Y, Maeda R, et al. Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years. Eur J Pediatr. 2014;173(7):959–66. 10.1007/s00431-014-2277-7
62. Korppi M, Kotaniemi-Syrjänen A, Waris M, Vainionpää R, Reijonen TM. Rhinovirus-associated wheezing in infancy: Comparison with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis J. 2004;23(11):995–9. 10.1097/01.inf.0000143642.72480.53
63. Arroyo M, Salka K, Perez GF, Rodríguez-Martínez CE, Castro-Rodriguez JA, Gutierrez MJ, et al. Phenotypical sub-setting of the first episode of severe viral respiratory infection based on clinical assessment and underlying airway disease: A pilot study. Front Pediatr. 2020;8:121. 10.3389/fped.2020.00121
64. Khuri-Bulos N, Lawrence L, Piya B, Wang L, Fonnesbeck C, Faouri S, et al. Severe outcomes associated with respiratory viruses in newborns and infants: A prospective viral surveillance study in Jordan. BMJ Open. 2018;8(5):e021898. 10.1136/bmjopen-2018-021898
65. Hasegawa K, Mansbach JM, Bochkov YA, Gern JE, Piedra PA, Bauer CS, et al. Association of rhinovirus C bronchiolitis and immunoglobulin E sensitization during infancy with development of recurrent wheeze. JAMA Pediatr. 2019;173(6):544–52. 10.1001/jamapediatrics.2019.0384
66. García-García ML, Calvo C, Moreira A, Cañas JA, Pozo F, Sastre B, et al. Thymic stromal lymphopoietin, IL-33, and periostin in hospitalized infants with viral bronchiolitis. Medicine (Baltimore). 2017;96(18):e6787. 10.1097/MD.0000000000006787
67. Jartti T, Aakula M, Mansbach JM, Piedra PA, Bergroth E, Koponen P, et al. Hospital length-of-stay is associated with rhinovirus etiology of bronchiolitis. Pediatr Infect Dis J. 2014;33(8):829–34. 10.1097/INF.0000000000000313
68. Jartti T, Lehtinen P, Vanto T, Hartiala J, Vuorinen T, Mäkelä MJ, et al. Evaluation of the efficacy of prednisolone in early wheezing induced by rhinovirus or respiratory syncytial virus. Pediatr Infect Dis J. 2006;25(6):482–8. 10.1097/01.inf.0000215226.69696.0c
69. Hasegawa K, Mansbach JM, Ajami NJ, Espinola JA, Henke DM, Petrosino JF, et al. Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis. Eur Respir J. 2016;48(5):1329–39. 10.1183/13993003.00152-2016
70. Kirolos A, Manti S, Blacow R, Tse G, Wilson T, Lister M, et al. A systematic review of clinical practice guidelines for the diagnosis and management of bronchiolitis. J Infect Dis. 2020;222(Suppl 7):S672–S679. 10.1093/infdis/jiz600
71. Sistema General de Seguridad Social en Salud, Guíía de práctica clíínica para la evaluacióón del riesgo y manejo inicial de la neumoníía en niñños y niññas menores de 5 añños y bronquiolitis en niñños y niññas menores de 2 añños [Internet]. 2014 [cited 2022 Sep 23]. Available from: https://medicosgeneralescolombianos.com/images/Guias_2014/GPC_42_Neumonia_y_Bronquilitis.pdf
72. Instituto Mexicano del Seguro Social, Diagnóstico y tratamiento de bronquiolitis aguda en niñas/niños y en el primer nivel de atención [Internet]. 2015 [cited 2022 Sep 23]. Available from: http://almacengpc.dynalias.org/publico/bronquiolitis%20Cenetec%202008.pdf
73. Sociedad Argentina de Pediatría, Recomendaciones para el manejo de las infecciones respiratorias agudas bajas en menores de 2 años [Internet]. 2015 [cited 2022 Sep 23]. Available from: http://www.sap.org.ar/uploads/consensos/versi-oacutenabreviada.pdf
74. Rivera-Sepulveda AV, Rebmann T, Gerard J, Charney RL. Physician compliance with bronchiolitis guidelines in pediatric emergency departments. Clin Pediatr (Phila). 2019;58(9):1008–18. 10.1177/0009922819850462
75. House SA, Marin JR, Hall M, Ralston SL. Trends over time in use of nonrecommended tests and treatments since publication of the American Academy of Pediatrics Bronchiolitis Guideline. JAMA Netw Open. 2021;4(2):e2037356. 10.1001/jamanetworkopen.2020.37356
76. Cai Z, Lin Y, Liang J. Efficacy of salbutamol in the treatment of infants with bronchiolitis: A meta-analysis of 13 studies. Medicine (Baltimore). 2020;99(4):e18657. 10.1097/MD.0000000000018657
77. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014;2014(6):CD001266. 10.1002/14651858.CD001266.pub4
78. Hurme P, Homil K, Lehtinen P, Turunen R, Vahlberg T, Vuorinen T, et al. Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode. Clin Exp Allergy. 2021;51(9):1121–32. 10.1111/cea.13960
79. Ambrożej D, Makrinioti H, Whitehouse A, Papadopoulos N, Ruszczyński M, Adamiec A, et al. Respiratory virus type to guide predictive enrichment approaches in the management of the first episode of bronchiolitis: A systematic review. Front Immunol. 2022;13:1017325. 10.3389/fimmu.2022.1017325
80. Lehtinen P, Ruohola A, Vanto T, Vuorinen T, Ruuskanen O, Jartti T. Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema. J Allergy Clin Immunol. 2007;119(3):570–5. 10.1016/j.jaci.2006.11.003
81. Jartti T, Nieminen R, Vuorinen T, Lehtinen P, Vahlberg T, Gern J, et al. Short-and long-term efficacy of prednisolone for first acute rhinovirus-induced wheezing episode. J Allergy Clin Immunol. 2015;135(3):691–8.e9. 10.1016/j.jaci.2014.07.001
82. Condella A, Mansbach JM, Hasegawa K, Dayan PS, Sullivan AF, Espinola JA, et al. Multicenter study of albuterol use among infants hospitalized with bronchiolitis. West J Emerg Med. 2018;19(3):475–83. 10.5811/westjem.2018.3.35837
83. Fujiogi M, Camargo CA, Jr., Bernot JP, Freishtat RJ, Harmon B, Mansbach JM, et al. In infants with severe bronchiolitis: Dual-transcriptomic profiling of nasopharyngeal microbiome and host response. Pediatr Res. 2020;88(2):144–6. 10.1038/s41390-019-0742-8