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Review

Severe pediatric asthma endotypes: current limits and future perspectives

, , , , , , & show all
Pages 675-690 | Received 21 Apr 2023, Accepted 29 Aug 2023, Published online: 05 Sep 2023

References

  • Ferrante G, La Grutta S. The burden of pediatric asthma. Front Pediatr. 2018;6:186. doi: 10.3389/fped.2018.00186
  • Fleming L, Heaney L. Severe asthma-perspectives from adult and pediatric pulmonology. Front Pediatr. 2019;7:389. doi: 10.3389/fped.2019.00389
  • Global Initiative for Asthma. Global strategy for asthma management and prevention. GINA main report. 2022. Available from: https://ginasthma.org/reports/
  • Gaillard EA, Kuehni CE, Turner S, et al. European respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years. Eur Respir J. 2021;58:2004173. doi: 10.1183/13993003.04173-2020
  • Bush A. This child’s asthma appears to be severe: but where actually is the severe problem? Acta Med Acad. 2020;49(2):103–116. doi: 10.5644/ama2006-124.290
  • Andrenacci B, Ferrante G, Roberto G, et al. Challenges in uncontrolled asthma in pediatrics: important considerations for the clinician. Expert Rev Clin Immunol. 2022;18(8):807–821. doi: 10.1080/1744666X.2022.2093187
  • Licari A, Manti S, Castagnoli R, et al. Targeted therapy for severe asthma in children and adolescents: current and future perspectives. Paediatr Drugs. 2019;21(4):215–237. doi: 10.1007/s40272-019-00345-7
  • Conrad LA, Cabana MD, Rastogi D. Defining pediatric asthma: phenotypes to endotypes and beyond. Pediatr Res. 2021;90(1):45–51. doi: 10.1038/s41390-020-01231-6
  • Rackemann FM. A working classification of asthma. Am j med. 1947;3(5):601–606. doi: 10.1016/0002-9343(47)90204-0
  • Fitzpatrick AM. Severe asthma in children: lessons learned and future directions. J Allergy Clin Immunol Pract. 2016;4(1):11–19. quiz 20-1. doi: 10.1016/j.jaip.2015.10.008
  • Teague WG, Phillips BR, Fahy JV, et al. Baseline features of the severe asthma research Program (SARP III) cohort: differences with age. J Allergy Clin Immunol Pract. 2018;6(2):545–554.e4. doi: 10.1016/j.jaip.2017.05.032
  • Shaw DE, Sousa AR, Fowler SJ, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46(5):1308–1321. doi: 10.1183/13993003.00779-2015
  • Fitzpatrick AM, Teague WG. Progressive airflow limitation is a feature of children with severe asthma. J Allergy Clin Immunol. 2011;127(1):282–284. doi: 10.1016/j.jaci.2010.10.036
  • Bigler J, Boedigheimer M, Schofield JPR, et al. A severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts. Am J Respir Crit Care Med. 2017;195(10):1311–1320. doi: 10.1164/rccm.201604-0866OC
  • Fitzpatrick AM, Higgins M, Holguin F, et al. The molecular phenotype of severe asthma in children. J Allergy Clin Immunol. 2010;125(4):851–857.e18. doi: 10.1016/j.jaci.2010.01.048
  • Mthembu N, Ikwegbue P, Brombacher F, et al. Respiratory Viral and bacterial factors that influence early childhood asthma. Front Allergy. 2021;2:692841. doi: 10.3389/falgy.2021.692841
  • Sabogal Piñeros YS, Bal SM, Dijkhuis A, et al. Eosinophils capture viruses, a capacity that is defective in asthma. Allergy. 2019;74(10):1898–1909. doi: 10.1111/all.13802
  • Fainardi V, Esposito S, Chetta A, et al. Asthma phenotypes and endotypes in childhood. Minerva Med. 2022;113(1):94–105. doi: 10.23736/S0026-4806.21.07332-8
  • Davis KU, Sheats MK. The role of neutrophils in the pathophysiology of asthma in humans and horses. Inflammation. 2021;44(2):450–465. doi: 10.1007/s10753-020-01362-2
  • Andersson CK, Adams A, Nagakumar P, et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J Allergy Clin Immunol. 2017;139(6):1819–1829.e11. doi: 10.1016/j.jaci.2016.09.022
  • Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129:974–82.e13.
  • Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107–1119. doi: 10.1016/S0140-6736(08)61452-X
  • Irvin C, Zafar I, Good J, et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol. 2014;134(5):1175–1186.e7. doi: 10.1016/j.jaci.2014.05.038
  • Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol. 2010;10:838–848. doi: 10.1038/nri2870
  • Green BJ, Wiriyachaiporn S, Grainge C, et al. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One. 2014;9(6):e100645. doi: 10.1371/journal.pone.0100645
  • Simpson JL, Powell H, Boyle MJ, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148–155. doi: 10.1164/rccm.200707-1134OC
  • Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322–329. doi: 10.1136/thoraxjnl-2012-202698
  • Shah R, Bunyavanich S. The airway microbiome and pediatric asthma. Curr Opin Pediatr. 2021 Dec 1;33(6):639–647. doi: 10.1097/MOP.0000000000001054
  • Elliot JG, Noble PB, Mauad T, et al. Inflammation-dependent and independent airway remodelling in asthma. Respirology. 2018;23(12):1138–1145. doi: 10.1111/resp.13360
  • Baraldo S, Turato G, Bazzan E, et al. Noneosinophilic asthma in children: relation with airway remodelling. Eur Respir J. 2011;38(3):575–583. doi: 10.1183/09031936.00168210
  • Martin Alonso A, Saglani S. Mechanisms mediating pediatric severe asthma and potential novel therapies. Front Pediatr. 2017;5:154. doi: 10.3389/fped.2017.00154
  • Fang L, Sun Q, Roth M. Immunologic and non-immunologic mechanisms leading to airway remodeling in asthma. Int J Mol Sci. 2020;21(3):757. doi: 10.3390/ijms21030757
  • Gon Y, Hashimoto S. Role of airway epithelial barrier dysfunction in pathogenesis of asthma. Allergol Int. 2018;67(1):12–17. doi: 10.1016/j.alit.2017.08.011
  • Diamant Z, Vijverberg S, Alving K, et al. Toward clinically applicable biomarkers for asthma: an EAACI position paper. Allergy. 2019;74(10):1835–1851. doi: 10.1111/all.13806
  • Hagendorens MM, Ebo DG, Schuerwegh AJ, et al. Differences in circulating dendritic cell subtypes in cord blood and peripheral blood of healthy and allergic children. Clin Exp Allergy. 2003;33(5):633–639. doi: 10.1046/j.1365-2222.2003.01649.x
  • Maggi L, Montaini G, Mazzoni A, et al. Human circulating group 2 innate lymphoid cells can express CD154 and promote IgE production. J Allergy Clin Immunol. 2017 Mar;139(3):964–976.e4. doi: 10.1016/j.jaci.2016.06.032
  • Hartl D, Tirouvanziam R, Laval J, et al. Innate immunity of the lung: from basic mechanisms to translational medicine. J Innate Immun. 2018;10(5–6):487–501. doi: 10.1159/000487057
  • Puttur F, Gregory LG, Lloyd CM. Airway macrophages as the guardians of tissue repair in the lung. Immunol Cell Biol. 2019;97(3):246–257. doi: 10.1111/imcb.12235
  • Fricker M, Qin L, Sánchez-Ovando S, et al. An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype. Allergy. 2022 Apr;77(4):1204–1215. doi: 10.1111/all.15087
  • Maggi E, Parronchi P, Azzarone BG, et al. A pathogenic integrated view explaining the different endotypes of asthma and allergic disorders. Allergy. 2022 Nov;77(11):3267–3292. doi: 10.1111/all.15445
  • Ozdemir C, Kucuksezer UC, Akdis M, et al. The concepts of asthma endotypes and phenotypes to guide current and novel treatment strategies. Expert Rev Respir Med. 2018 Sep;12(9):733–743. doi: 10.1080/17476348.2018.1505507
  • Benito-Villalvilla C, Soria I, Subiza JL, et al. Novel vaccines targeting dendritic cells by coupling allergoids to mannan. Allergo J Int. 2018;27(8):256–262. doi: 10.1007/s40629-018-0069-8
  • Celebi Sozener Z, Ozdel Ozturk B, Cerci P, et al. Epithelial barrier hypothesis: effect of the external exposome on the microbiome and epithelial barriers in allergic disease. Allergy. 2022 May;77(5):1418–1449. doi: 10.1111/all.15240
  • Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol. 2021 Nov;21(11):739–751. doi: 10.1038/s41577-021-00538-7
  • Januska MN, Goldman DL, Webley W, et al. Bronchoscopy in severe childhood asthma: irresponsible or irreplaceable? Pediatr Pulmonol. 2020;55(3):795–802. doi: 10.1002/ppul.24569
  • Ullmann N, Bossley CJ, Fleming L, et al. Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. Allergy. 2013;68(3):402–406. doi: 10.1111/all.12101
  • Licari A, Castagnoli R, Brambilla I, et al. Asthma endotyping and biomarkers in childhood asthma. Pediatr Allergy Immunol Pulmonol. 2018 Jun 1;31(2):44–55. doi: 10.1089/ped.2018.0886
  • Deliu M, Belgrave D, Sperrin M, et al. Asthma phenotypes in childhood. Expert Rev Clin Immunol. 2017;13(7):705–713. doi: 10.1080/1744666X.2017.1257940
  • Mendes FC, Paciência I, Ferreira AC, et al. Development and validation of exhaled breath condensate microRnas to identify and endotype asthma in children. PLoS One. 2019;14(11):e0224983. doi: 10.1371/journal.pone.0224983
  • Matysiak J, Klupczynska A, Packi K, et al. Alterations in serum-free amino acid profiles in childhood asthma. Int J Environ Res Public Health. 2020;17(13):4758. doi: 10.3390/ijerph17134758
  • De Filippo M, Votto M, Licari A, et al. Novel therapeutic approaches targeting endotypes of severe airway disease. Expert Rev Respir Med. 2021 Oct;15(10):1303–1316. doi: 10.1080/17476348.2021.1937132
  • Kuo CS, Pavlidis S, Loza M, et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017 Feb 8;49:1602135. doi: 10.1183/13993003.02135-2016
  • Picinin IF, Camargos PA, Marguet C. Cell profile of BAL fluid in children and adolescents with and without lung disease. J Bras Pneumol. 2010;36:372–385. doi: 10.1590/S1806-37132010000300016
  • de Blic J, Midulla F, Barbato A, et al. Bronchoalveolar lavage in children. ERS task force on bronchoalveolar lavage in children. Eur Respir J. 2000;15:217–231. doi: 10.1183/09031936.00.15121700
  • Choi S, Hoffman EA, Wenzel SE, et al. Quantitative computed tomographic imaging-based clustering differentiates asthmatic subgroups with distinctive clinical phenotypes. J Allergy Clin Immunol. 2017;140:690–700.e8. doi: 10.1016/j.jaci.2016.11.053
  • Silva TKBD, Zanon M, Altmayer S, et al. High-resolution CT pulmonary findings in children with severe asthma. J Pediatr (Rio J). 2021 Jan;97(1):37–43. doi: 10.1016/j.jped.2019.10.011
  • de Blic J, Tillie-Leblond I, Emond S, et al. High-resolution computed tomography scan and airway remodeling in children with severe asthma. J Allergy Clin Immunol. 2005 Oct;116:750–754.
  • Gupta A, Sjoukes A, Richards D, et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011;184(12):1342–1349. doi: 10.1164/rccm.201107-1239OC
  • Brown SD, Baxter KM, Stephenson ST, et al. Airway TGF-β1 and oxidant stress in children with severe asthma: association with airflow limitation. J Allergy Clin Immunol. 2012;129:388-96, 396.e1–8. doi: 10.1016/j.jaci.2011.11.037
  • 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.2013.04.012
  • van Mastrigt E, Vanlaeken L, Heida F, et al. The clinical utility of reticular basement membrane thickness measurements in asthmatic children. J Asthma. 2015;52:926–930. doi: 10.3109/02770903.2015.1025409
  • Wisniewski JA, Muehling LM, Eccles JD, et al. TH signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J Allergy Clin Immunol. 2018;141(6):2048–2060.e13. doi: 10.1016/j.jaci.2017.08.020
  • Teague WG, Lawrence MG, Shirley DT, et al. Lung lavage granulocyte patterns and clinical phenotypes in children with severe, therapy-resistant asthma. J Allergy Clin Immunol Pract. 2019;7:1803–1812.e10. doi: 10.1016/j.jaip.2018.12.027
  • Pal K, Feng X, Steinke JW, et al. Leukotriene A4 hydrolase activation and leukotriene B4 production by eosinophils in severe asthma. Am J Respir Cell Mol Biol. 2019;60(4):413–419. doi: 10.1165/rcmb.2018-0175OC
  • Lezmi G, Abou-Taam R, Garcelon N, et al. Evidence for a MAIT-17-high phenotype in children with severe asthma. J Allergy Clin Immunol. 2019;144:1714–1716.e6. doi: 10.1016/j.jaci.2019.08.003
  • Grunwell JR, Stephenson ST, Tirouvanziam R, et al. Children with neutrophil-predominant severe asthma have pro-inflammatory neutrophils with enhanced survival and impaired clearance. J Allergy Clin Immunol Pract. 2019;7:516–525.e6. doi: 10.1016/j.jaip.2018.08.024
  • Adel-Patient K, Grauso M, Abou-Taam R, et al. A comprehensive analysis of immune constituents in blood and bronchoalveolar lavage Allows identification of an immune signature of severe asthma in children. Front Immunol. 2021;12:700521. doi: 10.3389/fimmu.2021.700521
  • Eller MCN, Pierantozzi Vergani K, Saraiva-Romanholo BM, et al. Bronchial eosinophils, neutrophils, and CD8 + T cells influence asthma control and lung function in schoolchildren and adolescents with severe treatment-resistant asthma. Respir Res. 2022;23(1):335. doi: 10.1186/s12931-022-02259-4
  • Cowan DC, Cowan JO, Palmay R, et al. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65(5):384–390. doi: 10.1136/thx.2009.126722
  • O’Brien CE, Tsirilakis K, Santiago MT, et al. Heterogeneity of lower airway inflammation in children with severe-persistent asthma. Pediatr Pulmonol. 2015;50(12):1200–1204. doi: 10.1002/ppul.23165
  • Liou CJ, Huang WC. Dehydroepiandrosterone suppresses eosinophil infiltration and airway hyperresponsiveness via modulation of chemokines and Th2 cytokines in ovalbumin-sensitized mice. J Clin Immunol. 2011;31(4):656–665. doi: 10.1007/s10875-011-9529-3
  • Steinke JW, Lawrence MG, Teague WG, et al. Bronchoalveolar lavage cytokine patterns in children with severe neutrophilic and paucigranulocytic asthma. J Allergy Clin Immunol. 2021;147(2):686–693.e3. doi: 10.1016/j.jaci.2020.05.039
  • Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363(13):1211–1221. doi: 10.1056/NEJMoa0906312
  • Stolarski B, Kurowska-Stolarska M, Kewin P, et al. IL-33 exacerbates eosinophil-mediated airway inflammation. J Immunol. 2010;185(6):3472–3480. doi: 10.4049/jimmunol.1000730
  • Castanhinha S, Sherburn R, Walker S, et al. Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. J Allergy Clin Immunol. 2015;136(2):312–22.e7. doi: 10.1016/j.jaci.2015.01.016
  • Milanese M, Crimi E, Scordamaglia A, et al. On the functional consequences of bronchial basement membrane thickening. J Appl Physiol (1985). 2001;91:1035–1040. doi: 10.1152/jappl.2001.91.3.1035
  • Gliklich RE, Castro M, Leavy MB, et al. Harmonized outcome measures for use in asthma patient registries and clinical practice. J Allergy Clin Immunol. 2019;144(3):671–681.e1. doi: 10.1016/j.jaci.2019.02.025
  • Bush A. How to choose the correct drug in severe pediatric asthma. Front Pediatr. 2022;10:902168. doi: 10.3389/fped.2022.902168
  • Sun J, Li Y. Long-term, low-dose macrolide antibiotic treatment in pediatric chronic airway diseases. Pediatr Res. 2022 Apr;91(5):1036–1042. doi: 10.1038/s41390-021-01613-4
  • Gubernatorova EO, Namakanova OA, Gorshkova EA, et al. Novel anti-cytokine strategies for prevention and treatment of respiratory allergic diseases. Front Immunol. 2021 May 18;12:601842. doi: 10.3389/fimmu.2021.601842
  • Ji T, Li H. T-helper cells and their cytokines in pathogenesis and treatment of asthma. Front Immunol. 2023 Jun 12;14:1149203. doi: 10.3389/fimmu.2023.1149203
  • Saunders R, Kaul H, Berair R, et al. DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment. Sci Transl Med. 2019;11(479):eaao6451. doi: 10.1126/scitranslmed.aao6451
  • Clapp PW, Jaspers I. Electronic cigarettes: their constituents and potential links to asthma. Curr Allergy Asthma Rep. 2017;17(11):79. doi: 10.1007/s11882-017-0747-5
  • Reidel B, Radicioni G, Clapp PW, 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. 2018;197(4):492–501. doi: 10.1164/rccm.201708-1590OC
  • Castro-Rodriguez JA, Saglani S, Rodriguez-Martinez CE, et al. The relationship between inflammation and remodeling in childhood asthma: a systematic review. Pediatr Pulmonol. 2018;53(6):824. doi: 10.1002/ppul.23968

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