Severe Asthma in Children

  • Bradley E. Chipps
  • Neil G. Parikh
  • Sheena K. Maharaj
Pediatric Allergy and Immunology (W Dolen, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric Allergy and Immunology

Abstract

Purpose of Review

The aim of this study is to characterize, diagnose, evaluate, and treat severe childhood asthma.

Recent Findings

Understanding the occurrence of the physiologic and clinical presentations of childhood severe asthma, the treatment and response may be predicted by biomarkers, but the patient’s response is highly variable.

Summary

The onset of severe asthma occurs early and is primarily predicted by severity of viral infection and coexistence of the atopic state.

Keywords

Severe asthma Childhood asthma Biomarkers Biologic therapy Pharmacologic therapy 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Chipps reports personal fees from AstraZeneca, Boehringer Ingelheim, Circassia, Genentech Novartis, and Teva. Drs. Parikh and Maharaj declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of Particular Interest, Published Recently, Have Been Highlighted as: • Of Importance •• Of Major Importance

  1. 1.
    Fitzpatrick AM, Teague WG, Meyers DA, 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 Immunol. 2011;127:382–9.CrossRefPubMedGoogle Scholar
  2. 2.
    • Denlinger LC, Phillips BR, Ramratnam S, et al. Inflammatory and Cormorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med. 2017;195(3):302–9. Expanded understanding of predictors of children who are exacerbation prone. PubMedGoogle Scholar
  3. 3.
    Chipps BE, Zeiger RS, Borish L, et al. Key findings and clinical implications from the Epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. J Allergy Clin Immunol. 2012;130:332–42.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Fleming L, Murray C, Bansal AT, et al. The burden of severe asthma in childhood and adolescence: results from the Paediatric U-BIOPRED cohorts. Eur Respir J. 2015;46:1322–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Pongracic JA, Krouse RZ, Babineau DC, et al. Distinguishing characteristics of difficult-to-control asthma in Inner-City children and adolescents. J Allergy Clin Immunol. 2016;138:1030–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Sheehan WJ, Phipatanakul W. Difficult to control asthma: epidemiology and its link with environmental factors. Curr Opin Allergy Clin Immunol. 2015;15(5):397–401.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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;136:312–22.e7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Fitzpatrick AM. Severe asthma in children: lessons learned and future directions. J Allergy Clin Immunol Pract. 2016;4:11–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Henderson J, Granell R, Heron J, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax. 2008;63:974–80.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    • Tai A, Tran H, Roberts M, et al. Outcomes of childhood asthma to the age of 50 years. J Allergy Clin Immunol. 2014;133:1572–8. Longest follow-up of any Asthma Cohort giving insight into the predictors of persistent asthma. CrossRefPubMedGoogle Scholar
  11. 11.
    Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349(15):1414–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Taussig LM, Wright AL, Holberg CJ, et al. Tucson Children’s respiratory study: 1980 to present. J Allergy Clin Immunol. 2003;111:661–75.CrossRefPubMedGoogle Scholar
  13. 13.
    Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl Med. 2016;375(9):871–8.CrossRefGoogle Scholar
  14. 14.
    •• McGeachie MJ, Zhou YX, Sternberg AL, et al. Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med. 2016;374(19):1842–52. A very insightful analysis of trajectories of lung function that may predict COPD. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Covar RA, Spahn JD, Murphy JR, et al. Progression of asthma measured by lung function in the childhood asthma management Program. Am J Respir Crit Care Med. 2004;170:234–41.CrossRefPubMedGoogle Scholar
  16. 16.
    Pruteanu A, Chauhan B, Zhang L, Prietsch S, Ducharme F. Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. Evidence-Based Child Health: A Cochrane Review Journal. 2014;9(4):931–1046.CrossRefGoogle Scholar
  17. 17.
    Zeiger R, Mauger D, Bacharier L, Guilbert T, Martinez F, Lemanske R, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;356(21):1990–2001.CrossRefGoogle Scholar
  18. 18.
    Global strategy for asthma management and prevention 2015.Google Scholar
  19. 19.
    Bisgaard H, Le Roux P, Bjamer D, Dymek A, Vermeulen J, Hultquist C. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006;130(6):1733–43.CrossRefPubMedGoogle Scholar
  20. 20.
    • Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database of Systemic Reviews 2013:12. Supportive data that ICS/LABA fixed and reliever therapy is effective although not currently FDA approved. Google Scholar
  21. 21.
    Turner S, Richardson K, Murray C, Thomas M, Hillyer E, Burden A, et al. Long-acting β-agonist in combination or separate inhaler as step up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. J Allergy Clin Immunol Pract. 2017;5(1):99–106.CrossRefPubMedGoogle Scholar
  22. 22.
    Kerstjens H, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367:1198–207.CrossRefPubMedGoogle Scholar
  23. 23.
    Hamelmann E, Bateman E, Vogelberg C, Szefler S, Vandewalker M, Moroni-Zentgraf P, et al. Tiotropium add on therapy in adolescents with moderate asthma: a 1 year randomized controlled trial. J Allergy Clin Immunol. 2016;138(2):441–50.CrossRefPubMedGoogle Scholar
  24. 24.
    Vogelberg C, Engel M, Moroni-Zentgraf P, Leonaviciute-Klimantaviciene M, Sigmund R, Downie J, et al. Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: a randomized dose-ranging study. Respir Med. 2014;108:1268–76.CrossRefPubMedGoogle Scholar
  25. 25.
    • Vogelberg C, Moroni-Zentgraf P, Leonaviciute-Klimantaviciene M, Sigmund R, Hamelmann E, Engel M, et al. A randomized dose-ranging study of tiotropium Respimat in children with symptomatic asthma despite inhaled corticosteroid. Respiratory Research 2015:16(20). Data to support the new indication for Tiotropium from 6 years old. Google Scholar
  26. 26.
    Keeney G, Gray M, Morrison A, Leavas M, Kessler E, Hill G, et al. Dexamethaose for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014;133(3):493–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cronin JJ, McCoy S, Kennedey U, An Fhaili SN, Wakai A, Hayden J, et al. Randomized trial of single dose oral dexamethasone versus multidose prednisolone for acute exacerbations of asthma in children who attend the emergency department. Ann Emerg Med. 2016;67(5):593–601.CrossRefPubMedGoogle Scholar
  28. 28.
    Buchvald F, Bisgaard H. FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr. Am J Respir Crit Care Med. 2001;163(3 Pt 1):699–704.CrossRefPubMedGoogle Scholar
  29. 29.
    Alving K, Malinovschi A. Basic aspects of exhaled nitric oxide. Eur Respir Mon. 2010;48:1–31.Google Scholar
  30. 30.
    Covar RA, Szefler SJ, Martin RJ, Sundstrom DA, Silkoff PE, Murphy J, Young DA, Spahn JD. Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma. J Pediar. 2003;142:469–75.CrossRefGoogle Scholar
  31. 31.
    Dweik RA, Sorkness RL, Wenzel S, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma.Google Scholar
  32. 32.
    Vahlkvist S, Sinding M, Skamstrup K, Bisgaard H. Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure. J Allergy Clin Immunol. 2006;117:1272–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Petsky HL, Cates CJ, Lasserson TJ, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax. 2012;67:199–208.CrossRefPubMedGoogle Scholar
  34. 34.
    Robroeks CM, van Berkel JJ, Jobsis Q, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013;42:98–106.CrossRefPubMedGoogle Scholar
  35. 35.
    Van der Schee MP, Palmay R, Cowan JO, Taylor DR. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp Allergy. 2013;42(11):1217–25.CrossRefGoogle Scholar
  36. 36.
    Nadif R, Siroux V, Oryszczyn MP, Ravault C, Pison C, et al. Epidemiological study on the genetics and environment of asthma (EGEA). Heterogeneity of asthma according to blood inflammatory patterns. Thorax. 2009;64(5):374–80.CrossRefPubMedGoogle Scholar
  37. 37.
    Fahy J. Eosinophilic and neutrophilic inflammation in asthma; insights from clinical studies. Porc Am Thorac Soc. 2009;6:256–9.CrossRefGoogle Scholar
  38. 38.
    Ulrik CS. Peripheral eosinophilc counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp Allergy. 1995;25(9):820–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Farooqui N, Khan BQ, Wan JY, Lieberman P. Blood eosinophils as markers of inflammation in asthma. Ann Allergy Asthma Immunol. 2009;103(Suppl3):A56–7.Google Scholar
  40. 40.
    van Veen IH, ten Brinke A, Gauw SA, Sterk PJ, Rabe KF, Bel EH. Consistency of sputum eosinophilia in difficult-to-treat asthma: a 5-year follow-up study. J Allergy Clin Immunol. 2009;123:615–7. 7.e1-2 CrossRefGoogle Scholar
  41. 41.
    •• Schleich FN, Chevremont A, Paulus V, Henket M, Manise M, et al. Improtance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J. 2014;44:97–108. Important analysis of predictors of Asthma exacerbations. CrossRefPubMedGoogle Scholar
  42. 42.
    Saglani S, Lloyd CM. Eosinophils in the pathogenesis of pediatric severe asthma. Curr Opin Allergy Clin Immunol. 2014;14(2):143–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108:184–90.CrossRefPubMedGoogle Scholar
  44. 44.
    Uchida M, Shiraishi H, Ohta S, Arima K, Taniguchi K, Suzuki S, et al. Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2012;46:677–86.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, et al. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A. 2010;107:14170–5.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130:647–54.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Takayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Imunol. 2006;118:98–104.CrossRefGoogle Scholar
  48. 48.
    Corren J, Lemanske RF, Hanania NA, Korenblat PE, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088–98.CrossRefPubMedGoogle Scholar
  49. 49.
    Inoue T, Akashi K, Watanabe M, Ikeda Y, et al. Periostin as a biomarker for the diagnosis of pediatric asthma. Pediatr Allergy Immunol. 2016;27(5):521–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Anderson HM, Lemanske Jr RF, Arron JR. Holweg CT, et al. relationships among aerallergen sensitization, peripheral blood eosinophils, and periostin in pediatric asthma development. J Allergy Clin Immunol. 2016;139(3):790–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Konradsen JR, Skantz E, Nordlund B, Lidegran M, James A, Ono J, et al. Predicting asthma morbidity in children using proposed markers of Th2-type inflammation. Pediatr Allergy Immunol. 2015;26(8):772–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Brightling CE, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomized, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:692–701.CrossRefPubMedGoogle Scholar
  53. 53.
    Chupp GI, Lee CG, Jarjour N, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med. 2007;357:2016–27.CrossRefPubMedGoogle Scholar
  54. 54.
    Konradsen JR, James A, Nordlund B, et al. The citinase-like protein YKL-40: a possible biomarker of inflammation and airway in severe pediatric asthma. J Allergy Clin Immunol. 2013;132:328–35.CrossRefPubMedGoogle Scholar
  55. 55.
    Specjalaski K, Jassem E. YKL-40 protein is a marker of asthma. J Asthma. 2011;48:767–72.CrossRefGoogle Scholar
  56. 56.
    Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46:1308–21.CrossRefPubMedGoogle Scholar
  57. 57.
    Nucala [prescribing information]. Research Triangle Park, NC: GSK; 2015.Google Scholar
  58. 58.
    Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–84.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198–207.CrossRefPubMedGoogle Scholar
  60. 60.
    Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985–93.CrossRefPubMedGoogle Scholar
  61. 61.
    Bel EH, Wenzel SE, Thompson PJ, Prazma CM, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189–97.CrossRefPubMedGoogle Scholar
  62. 62.
    Ortega H, Chupp G, Bardin P, Bourdin A, Garcia G, et al. The role of mepolizumabin atopic and nonatopic severe asthma with persistent eosinophilia. Eur Respir J. 2014;44:239–41.CrossRefPubMedGoogle Scholar
  63. 63.
    Sehmi R, Smith SG, Kjarsgaard M, Radford K, Boulet LP, et al. Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy. 2016;46:793–802.CrossRefPubMedGoogle Scholar
  64. 64.
    Agrawal DK, Shao Z. Pathogenesis of allergic airway inflammation. Curr Allergy Asthma Rep. 2010;10(1):39–48.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Holgate ST. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches? J Allergy Clin Immunol. 2011;128(3):495–505.CrossRefPubMedGoogle Scholar
  66. 66.
    Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, et al. Ombalizumab in asthma: an update on recent developments. J allergy Clin Immunol Pract. 2014;2(5):525–36. e1 CrossRefPubMedGoogle Scholar
  67. 67.
    MacGlashan DW, Bochner BS, Adelman DC, Jardieu PM, Togias A, McKenzie-White J, et al. Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol. 1997;158(3):1438–45.PubMedGoogle Scholar
  68. 68.
    Holgate S, Casale T, Wenzel S, et al. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115(3):459–65.CrossRefPubMedGoogle Scholar
  69. 69.
    Milgrom H, Berger W, Nayak A, Gupta N, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108(2):e36-e.CrossRefGoogle Scholar
  70. 70.
    Berger W, Gupta N, McAlary M, Fowler-Taylor A. Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Ann Allergy Asthma Immunol. 2003;91(2):182–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Silkoff PE, Romero FA, Gupta N, Townley RG, Milgrom H. Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody. Pediatrics. 2004;113(4):e308–e12.CrossRefPubMedGoogle Scholar
  72. 72.
    Lanier B, Bridges T, Kulus M, et al. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009;124(6):1210–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. New Engl J Med. 2011;364(11):1005–15.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    • Teach SJ, Gill MA, Togias A, Sorkness CA, Arbes Jr SJ, Calatroni 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):1476–85. New study affecting value of omalizumab as pre-Fall treatment to prevent exacerbation. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Deschildre A, Marguet C, Salleron J, et al. Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur Respir J. 2013;42(5):1224–33.CrossRefPubMedGoogle Scholar
  76. 76.
    • Deschildre A, Marguet C, Langlois C, Pin I, et al. Real-life longterm omalizumab therapy in children with severe allergic asthma. Eur Respir J. 2015;46(3):856–9. Second year of study in (reference 76) showing significant decrease in exacerbation in real world observation study. CrossRefPubMedGoogle Scholar
  77. 77.
    Long A, Rahmaoui A, Rothman KJ, Guinan E, et al. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab. J Allergy Clin Immunol. 2014;134(3):560–7.e4.CrossRefPubMedGoogle Scholar
  78. 78.
    Xolair (omalizumab) pediatric postmarketing pharmacovigilance and drug utilization review. 2016. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM519868.pdf.

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Bradley E. Chipps
    • 1
  • Neil G. Parikh
    • 1
  • Sheena K. Maharaj
    • 1
  1. 1.Capital Allergy and Respiratory Disease CenterSacramentoUSA

Personalised recommendations