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Defining pediatric asthma: phenotypes to endotypes and beyond

Pediatric Research volume 90, pages 45–51 (2021)Cite this article

Abstract

Asthma is the most common chronic pediatric lung disease that has traditionally been defined as a syndrome of airway inflammation characterized by clinical symptoms of cough and wheeze. Highlighting the complex and heterogeneous nature of asthma, this review summarizes recent advances in asthma classification that are based on pathobiology, and thereby directly addresses limitations of existent definitions of asthma. By reviewing and contrasting clinical and mechanistic features of adult and childhood asthma, the review summarizes key biomarkers that distinguish childhood asthma subtypes. While atopy and its severity are important features of childhood asthma, there is evidence to support the existence of a childhood asthma endotype distinct from the atopic endotype. Although biomarkers of non-atopic asthma are an area of future research, we summarize a clinical approach that includes existing measures of airway-specific and systemic measures of atopy, co-existing morbidities, and disease severity and control, in the definition of childhood asthma, to empower health care providers to better characterize asthma disease burden in children. Identification of biomarkers of non-atopic asthma and the contribution of genetics and epigenetics to pediatric asthma burden remains a research need, which can potentially allow delivery of precision medicine to pediatric asthma.

Impact

  • This review highlights asthma as a complex and heterogeneous disease and discusses recent advances in the understanding of the pathobiology of asthma to demonstrate the need for a more nuanced definitions of asthma.

  • We review current knowledge of asthma phenotypes and endotypes and put forth an approach to endotyping asthma that may be useful for defining asthma for clinical care as well as for future research studies in the realm of personalized medicine for asthma.

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Fig. 1: Approach for defining asthma for children.

References

  1. Hopkin, J. M. The diagnosis of asthma, a clinical syndrome. Thorax 67, 660–662 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  2. Wenzel, S. E. Complex phenotypes in asthma: current definitions. Pulm. Pharm. Ther. 26, 710–715 (2013).

    CAS  Article  Google Scholar 

  3. Wenzel, S. E. Emergence of biomolecular pathways to define novel asthma phenotypes. Type-2 immunity and beyond. Am. J. Respir. Cell. Mol. Biol. 55, 1–4 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Busse, W. W. et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N. Engl. J. Med. 364, 1005–1015 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Ortega, H. G. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371, 1198–1207 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  6. Chung, K. F. et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 43, 343–373 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. Hunt, J. If it smells like a duck, it might be an asthma subphenotype. Am. J. Respir. Crit. Care Med. 175, 975–976 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  8. Rackemann, F. M. A working classification of asthma. Am. J. Med. 3, 601–606 (1947).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. Expert Panel Report 3. Guidelines for the Diagnosis and Management of Asthma (National Institute of Health, National Heart, Lung, and Blood Institute, 2007).

  10. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: www.ginasthma.org.

  11. Castro-Rodriguez, J. A., Holberg, C. J., Wright, A. L. & Martinez, F. D. A clinical index to define risk of asthma in young children with recurrent wheezing. Am. J. Respir. Crit. Care Med. 162, 1403–1406 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. Guilbert, T. W. et al. The prevention of early asthma in kids study: design, rationale and methods for the Childhood Asthma Research and Education Network. Control Clin. Trials 25, 286–310 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  13. Amin, P. et al. Optimum predictors of childhood asthma: persistent wheeze or the Asthma Predictive Index? J. Allergy Clin. Immunol. Pract. 2, 709–715 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  14. Bousquet, J. et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J. Allergy Clin. Immunol. 126, 926–938 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  15. Bell, M. C. & Busse, W. W. Severe asthma: an expanding and mounting clinical challenge. J. Allergy Clin. Immunol. Pract. 1, 110–121 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  16. Van Wonderen, K. E. et al. Different definitions in childhood asthma: how dependable is the dependent variable? Eur. Respir. J. 36, 48–56 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  17. Barsky, E. E., Giancola, L. M., Baxi, S. N. & Gaffin, J. M. A practical approach to severe asthma in children. Ann. Am. Thorac. Soc. 15, 399–408 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  18. Rastogi, D. & Liu, A. in Difficult to Treat Asthma: Clinical Essentials (eds Khurana, S. & Holguin, F.) (Humana Press, 2020).

  19. Gibson, P. G. & Simpson, J. L. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 64, 728–735 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Postma, D. S. & Rabe, K. F. The asthma-COPD overlap syndrome. N. Engl. J. Med. 373, 1241–1249 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. Holgate, S. T. Pathogenesis of asthma. Clin. Exp. Allergy 38, 872–897 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Holgate, S. T. et al. Asthma. Nat. Rev. Dis. Prim. 1, 15025 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  23. Moore, W. C. et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J. Allergy Clin. Immunol. 119, 405–413 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  24. Moore, W. C. et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 181, 315–323 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  25. Lotvall, J. et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol. 127, 355–360 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  26. Teague, W. G. et al. Baseline features of the Severe Asthma Research Program (SARP III) Cohort: differences with age. J. Allergy Clin. Immunol. Pract. 6, 545–554.e4 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  27. Fitzpatrick, A. M. et al. Individualized therapy for persistent asthma in young children. J. Allergy Clin. Immunol. 138, 1608–1618.e12 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  28. Pongracic, J. A. et al. Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents. J. Allergy Clin. Immunol. 138, 1030–1041 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  29. Zoratti, E. M. et al. Asthma phenotypes in inner-city children. J. Allergy Clin. Immunol. 138, 1016–1029 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  30. Reddy, M. B., Liu, A. H., Robinson, J. L. & Klinnert, M. D. Recurrent wheeze phenotypes in poor urban preschool-age children. J. Allergy Clin. Immunol. Pract. (2018).

  31. Brown, K. R. et al. Endotypes of difficult-to-control asthma in inner-city African American children. PLoS ONE 12, e0180778 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Liu, A. H. et al. Pathways through which asthma risk factors contribute to asthma severity in inner-city children. J. Allergy Clin. Immunol. 138, 1042–1050 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  33. Just, J. et al. Two novel, severe asthma phenotypes identified during childhood using a clustering approach. Eur. Resp. J. 40, 55–60 (2012).

    Article  Google Scholar 

  34. Panico, L., Stuart, B., Bartley, M. & Kelly, Y. Asthma trajectories in early childhood: identifying modifiable factors. PLoS ONE 9, e111922 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. Su, M. W. et al. Childhood asthma clusters reveal neutrophil-predominant phenotype with distinct gene expression. Allergy 73, 2024–2032 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Deliu, M. et al. Features of asthma which provide meaningful insights for understanding the disease heterogeneity. Clin. Exp. Allergy 48, 39–47 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. Teach, S. J. et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J. Allergy Clin. Immunol. 136, 1476–1485 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Qian, Z. et al. Respiratory responses to diverse indoor combustion air pollution sources. Indoor Air 17, 135–142 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. Patel, M. M. et al. Traffic-related particulate matter and acute respiratory symptoms among New York City area adolescents. Environ. Health Perspect. 118, 1338–1343 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  40. Sarnat, S. E. et al. Air pollution and acute respiratory response in a panel of asthmatic children along the U.S.-Mexico border. Environ. Health Perspect. 120, 437–444 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. Kanchongkittiphon, W. et al. Indoor environmental exposures and exacerbation of asthma: an update to the 2000 review by the Institute of Medicine. Environ. Health Perspect. 123, 6–20 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  42. Dick, S. et al. Associations between environmental exposures and asthma control and exacerbations in young children: a systematic review. BMJ Open 4, e003827 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  43. Brandt, E. B. et al. Diesel exhaust particle induction of IL-17A contributes to severe asthma. J. Allergy Clin. Immmunol. 132, 1194–1204 (2013).

    CAS  Article  Google Scholar 

  44. Delfino, R. J. et al. Asthma morbidity and ambient air pollution: effect modification by residential traffic-related air pollution. Epidemiology 25, 48–57 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  45. Kheirbek, I. et al. PM2.5 and ozone health impacts and disparities in New York City: sensitivity to spatial and temporal resolution. Air Qual. Atmos. Health 6, 473–486 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. Bao, W. et al. Changes in electronic cigarette use among adults in the United States, 2014–2016. JAMA 319, 2039–2041 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  47. Martin, E. M. et al. E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke. Am. J. Physiol. Lung Cell. Mol. Physiol. 311, L135–L144 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  48. Clapp, P. W. & Jaspers, I. Electronic cigarettes: their constituents and potential links to asthma. Curr. Allergy Asthma Rep. 17, 79 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Reidel, B. et al. E-cigarette use causes a unique innate immune response in the lung, involving increased neutrophilic activation and altered mucin secretion. Am. J. Respir. Crit. Care Med. 197, 492–501 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Decuyper, I. I. et al. Exploring the diagnosis and profile of cannabis allergy. J. Allergy Clin. Immunol. Pract. 7, 983–989.e5 (2019).

  51. Chang, T. S. et al. Childhood asthma clusters and response to therapy in clinical trials. J. Allergy Clin. Immunol. 133, 363–369 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  52. Szefler, S. J. et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J. Allergy Clin. Immunol. 115, 233–242 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. Lemanske, R. F. Jr. et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N. Engl. J. Med. 362, 975–985 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Malka, J. et al. Eczema and race as combined determinants for differential response to step-up asthma therapy. J. Allergy Clin. Immunol. 134, 483–485 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  55. Sorkness, C. A. et al. Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents. J. Allergy Clin. Immunol. Pract. 1, 163–171 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  56. Teach, S. J. et al. Seasonal risk factors for asthma exacerbations among inner-city children. J. Allergy Clin. Immunol. 135, 1465–1473.e5 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  57. Price, D. et al. Predicting frequent asthma exacerbations using blood eosinophil count and other patient data routinely available in clinical practice. J. Asthma Allergy 9, 1–12 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. van der Valk, R. J. et al. Daily exhaled nitric oxide measurements and asthma exacerbations in children. Allergy 67, 265–271 (2012).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  59. van Vliet, D. et al. Prediction of asthma exacerbations in children by innovative exhaled inflammatory markers: results of a longitudinal study. PLoS ONE 10, e0119434 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. Izuhara, K. et al. Periostin: an emerging biomarker for allergic diseases. Allergy 74, 2116–2128 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  61. Inoue, Y. et al. No increase in the serum periostin level is detected in elementary school-age children with allergic diseases. Allergol. Int. 64, 289–290 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. Konradsen, J. R. et al. Predicting asthma morbidity in children using proposed markers of Th2-type inflammation. Pediatr. Allergy Immunol. 26, 772–779 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  63. Andersson, C. K. et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J. Allergy Clin. Immunol. 139, 1819–1829.e11 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Januska, M. N. et al. Bronchoscopy in severe childhood asthma: Irresponsible or irreplaceable? Pediatr. Pulmonol. 55, 795–802 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  65. Ullmann, N. et al. Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. Allergy 68, 402–406 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. Fitzpatrick, A. M. et al. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J. Allergy Clin. Immmunol. 127, 382–389 (2011).

    Article  Google Scholar 

  67. Gliklich, R. E. et al. Harmonized outcome measures for use in asthma patient registries and clinical practice. J. Allergy Clin. Immunol. 144, 671–681.e1 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  68. Nishimura, K. K. et al. Early-life air pollution and asthma risk in minority children. The GALA II and SAGE II studies. Am. J. Respir. Crit. Care Med. 188, 309–318 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  69. Thakur, N. et al. Socioeconomic status and childhood asthma in urban minority youths. The GALA II and SAGE II studies. Am. J. Respir. Crit. Care Med. 188, 1202–1209 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

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Affiliations

  1. Department of Pediatrics, Albert Einstein College of Medicine, New York, NY, USA

    Laura A. Conrad & Michael D. Cabana

  2. Department of Pediatrics and Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Deepa Rastogi

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  1. Laura A. Conrad
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L.A.C, M.D.C., and D.R. contributed to conception and design, drafting, and critical review of the manuscript. All authors approve of the submitted manuscript and are personally accountable for their contributions. D.R. and M.D.C. are supported by NIH.

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Correspondence to Deepa Rastogi.

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Conrad, L.A., Cabana, M.D. & Rastogi, D. Defining pediatric asthma: phenotypes to endotypes and beyond. Pediatr Res 90, 45–51 (2021). https://doi.org/10.1038/s41390-020-01231-6

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