An approach to the management of children with problematic severe asthma
Keywords:
Severe asthma, problematic asthma, steroids, children, allergy, multidisciplinary, managementAbstract
Children with poor asthma control despite high levels of prescribed treatment are described as having problematic severe asthma. Most of these children have steroid sensitive disease which improves with adherence to daily inhaled corticosteroids and after having removed modifiable factors like poor inhalation technique, persistent adverse environmental exposures and psychosocial factors. These children are described as having “difficult-to-treat asthma” while children with persistent symptoms despite above-mentioned factors having been addressed are described as having “severe therapy-resistant asthma”. In this review, we will describe the 6-step approach to the diagnosis and management of a child with problematic severe asthma adopted by The Royal Brompton Hospital (London, UK). The role of a multidisciplinary team is crucial for identification and treatment of modifiable factors and comorbidities in order to avoid invasive examinations and useless pharmacological treatments. The current knowledge on add-on therapies will be discussed.
References
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19. de Groot EP, Duiverman EJ, Brand PL. Dysfunctional breathing in children with asthma: a rare but relevant comorbidity. Eur Respir J. 2013 May;41(5):1068-73
20. Nagakumar P, Gambir N, Sanghani N, et al. Role of a prolonged inpatient admission when evaluating children with problematic severe asthma. Eur Respir J. 2018 Jan 31;51(2). pii: 1701061
21. Santino TA, Chaves GS, Freitas DA, Fregonezi GA, Mendonça KM. Breathing exercises for adults with asthma. Cochrane Database Syst Rev. 2020 Mar 25;3:CD001277
22. Santos Pde M, D’Oliveira A Jr, Noblat Lde A, et al. Predictors of adherence to treatment in patients with severe asthma treated at a referral center in Bahia, Brazil. J Bras Pneumol 2008; 34:995–1002
23. Royal College of Physicians. Why Asthma Still Kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry Report. London, RCP, 2014. Available from: www.rcplondon.ac.uk/sites/default/files/why-asthma-still-kills-full-report.pdf
24. Bender B, Wamboldt FS, O'Connor SL, et al. Measurement of children's asthma medication adherence by self-report, mother report, canister weight, and Doser CT. Ann Allergy Asthma Immunol. 2000 Nov;85(5):416-21
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28. Chan AH, Stewart AW, Harrison J, Camargo CA Jr, Black PN, Mitchell EA. The effect of an electronic monitoring device with audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in children with asthma: a randomised controlled trial. Lancet Respir Med. 2015 Mar;3(3):210-9
29. Pertzborn MC, Prabhakaran S, Hardy A, Baker D, Robinson MA, Hendeles L. Direct Ob-served Therapy of Inhaled Corticosteroids for Asthma at School or Daycare. Pediatr Allergy Immunol Pulmonol. 2018 Dec 1;31(4):226-229
30. Gambhir N, Longman J, Nagakumar P, et al. The role of inpatient assessment of problematic severe asthma. Arch Dis Child 2016; 101[Suppl 1]: A308-9
31. Alexander DS, Geryk L, Arrindell C, et al. Are children with asthma overconfident that they are using their inhalers correctly? J Asthma. Sep 14 2015:1-6
32. Murray CS, Foden P, Sumner H, Shepley E, Custovic A, Simpson A. Preventing Severe Asthma Exacerbations in Children. A Randomized Trial of Mite-Impermeable Bedcovers. Am J Respir Crit Care Med. 2017 Jul 15;196(2):150-158
33. Kobayashi Y, Bossley C, Gupta A, et al. Passive smoking impairs histone deacetylase-2 in children with severe asthma. Chest. Feb 2014;145(2):305-312
34. Cook J, Beresford F, Fainardi V, et al. Managing the pediatric patient with refractory asth-ma: a multidisciplinary approach. J Asthma Allergy. 2017 Apr 20;10:123-130
35. Fleming L, Koo M, Bossley CJ, Nagakumar P, Bush A, Saglani S. The utility of a mul-tidomain assessment of steroid response for predicting clinical response to omalizumab. J Allergy Clin Immunol. 2016 Jul;138(1):292-4
36. Szefler SJ, Murphy K, Harper T 3rd, et al. A phase III randomized controlled trial of tiotro-pium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol. 2017 Nov;140(5):1277-1287
37. Burch J, Griffin S, McKenna C, et al. Omalizumab for the treatment of severe persistent al-lergic asthma in children aged 6–11 years: a NICE single technology appraisal. Pharmaco-economics. 2012;30(11):991–1004
38. Rodrigo GJ, Neffen H. Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents. Pediatr Allergy Immunol. 2015 Sep;26(6):551-6
39. Humbert M, Taillé C, Mala L, Le Gros V, Just J, Molimard M; STELLAIR investigators. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosin-ophil count: the STELLAIR study. Eur Respir J. 2018 May 10;51(5)
40. Braunstahl GJ, Chen CW, Maykut R, Georgiou P, Peachey G, Bruce J. The eXpeRience reg-istry: the ‘real-world’ effectiveness of omalizumab in allergic asthma. Respir Med. 2013;107(8):1141–1151
41. Bush A, Fleming L, Saglani S. Severe asthma in children. Respirology. 2017 Jul;22(5):886-897
42. Gupta A, Ikeda M, Geng B, et al. Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype. J Allergy Clin Immunol. 2019 Nov;144(5):1336-1342.e7
43. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet (2012) 380:651–9
44. Martin Alonso A, Saglani S. Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies. Front Pediatr. 2017 Jul 5;5:154.
45. Koolen BB, Pijnenburg MW, Brackel HJ, et al. Comparing Global Initiative for Asthma (GINA) criteria with the Childhood Asthma Control Test (C-ACT) and Asthma Control Test (ACT). Eur Respir J. 2011 Sep;38(3):561-6
46. Fleming L, Murray C, Bansal AT, et al. The burden of severe asthma in childhood and ado-lescence: results from the paediatric U-BIOPRED cohorts. Eur Respir J. 2015 Nov;46(5):1322-33
47. Raat H, Bueving HJ, de Jongste JC, Grol MH, Juniper EF, van der Wouden JC. Responsive-ness, longitudinal- and cross-sectional construct validity of the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) in Dutch children with asthma. Qual Life Res. 2005 Feb;14(1):265-72
48. Dodig S, Richter D, Zrinski-Topić R. Inflammatory markers in childhood asthma. Clin Chem Lab Med 2011;49:587-99
49. Cabral AL, Vollmer WM, Barbirotto RM, Martins MA. Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to-severe asthma: a prospective, 5-month study. Ann Allergy Asthma Immunol 2009;103:206-11
50. Waibel V, Ulmer H, Horak E. Assessing asthma control: symptom scores, GINA levels of asthma control, lung function, and exhaled nitric oxide. Pediatr Pulmonol 2012;47:113-118
51. Heffler E, Carpagnano GE, Favero E, et al. Fractional Exhaled Nitric Oxide (FENO) in the management of asthma: a position paper of the Italian Respiratory Society (SIP/IRS) and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). Multidiscip Respir Med. 2020 Feb 19;15(1):36
52. Kwda A, Gldc P, Baui B, et al. Effect of long term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma. BMC Pediatr. 2019 Nov 5;19(1):411
53. Zollner EW, Lombard CJ, Galal U, Hough S, Irusen EM, Weinberg E. Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children. Pediatrics. 2012;130:e1512.
54. Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab. 2000;85(2):652–7
55. Bush A, Saglani S, Fleming L. Severe asthma: looking beyond the amount of medication. Lancet Respir Med. 2017 Nov;5(11):844-846
2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Available from: https://ginasthma.org/gina-reports/. Accessed March 1st 2020
3. Bush A, Hedlin G, Carlsen KH, de Benedictis F, Lodrup-Carlsen K, Wilson N. Severe childhood asthma: a common international approach? Lancet. 2008; 372: 1019-21
4. Hedlin G, Bush A, Carlsen KL, et al. Problematic severe asthma in children, not one problem but many: a GA(2) LEN initiative. Eur Respir J 2010; 36: 196–201
5. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014 Feb;43(2):343-73
6. Gustafsson PM, Watson L, Davis KJ, Rabe KF. Poor asthma control in children: evidence from epidemiological surveys and implications for clinical practice. Int J Clin Pract. 2006 Mar;60(3):321-34
7. Fuhlbrigge AL, Kelly HW. Inhaled corticosteroids in children: effects on bone mineral den-sity and growth. Lancet Respir Med. 2014 Jun;2(6):487-96
8. Tai A, Tran H, Roberts M, Clarke N, Wilson J, Robertson CF. The association between childhood asthma and adult chronic obstructive pulmonary disease. Thorax. 2014 Sep;69(9):805-10
9. Bracken M, Fleming L, Hall P, et al. The importance of nurse-led home visits in the assess-ment of children with problematic asthma. Arch Dis Child. 2009;94(10):780–4, Klok T, Kaptein AA, Duiverman EJ, Brand PL. Long-term adherence to inhaled corticosteroids in children with asthma: Observational study. Respir Med. 2015 Sep;109(9):1114-9
10. Bender B, Milgrom H, Apter A. Adherence intervention research: what have we learned and what do we do next? J Allergy Clin Immunol 2003; 112: 489–494
11. Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosino-philia and remodeling without T(H) 2 cytokines. J Allergy Clin Immunol 2012; 129(4):974-82
12. Fitzpatrick AM. Severe Asthma in Children: Lessons Learned and Future Directions. The journal of allergy and clinical immunology. In practice. Jan-Feb 2016;4(1):11-19
13. Bossley CJ, Fleming L, Ullmann N, et al. Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach. The Journal of allergy and clinical immunology. 2016;138(2):413-20 e6
14. Ullmann N, Bossley CJ, Fleming L, et al. Blood eosinophil counts rarely reflect airway eo-sinophilia in children with severe asthma. Allergy 2013;68(3):402-6
15. Szefler SJ, Casale TB, Haselkorn T, Yoo B, Ortiz B, Kattan M, Busse WW. Treatment Ben-efit with Omalizumab in Children by Indicators of Asthma Severity. J Allergy Clin Immunol Pract. 2020 Apr 13. pii: S2213-2198(20)30332-9
16. Peters MC, McGrath KW, Hawkins GA, et al. Plasma interleukin-6 concentrations, metabol-ic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. 2016 Jul;4(7):574-584
17. Lang JE, Holbrook JT, Mougey EB, et al. Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype. Ann Am Thorac Soc. 2015 Jun;12(6):878-85
18. Holbrook JT, Wise RA, Gold BD, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA. 2012;307:373–381
19. de Groot EP, Duiverman EJ, Brand PL. Dysfunctional breathing in children with asthma: a rare but relevant comorbidity. Eur Respir J. 2013 May;41(5):1068-73
20. Nagakumar P, Gambir N, Sanghani N, et al. Role of a prolonged inpatient admission when evaluating children with problematic severe asthma. Eur Respir J. 2018 Jan 31;51(2). pii: 1701061
21. Santino TA, Chaves GS, Freitas DA, Fregonezi GA, Mendonça KM. Breathing exercises for adults with asthma. Cochrane Database Syst Rev. 2020 Mar 25;3:CD001277
22. Santos Pde M, D’Oliveira A Jr, Noblat Lde A, et al. Predictors of adherence to treatment in patients with severe asthma treated at a referral center in Bahia, Brazil. J Bras Pneumol 2008; 34:995–1002
23. Royal College of Physicians. Why Asthma Still Kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry Report. London, RCP, 2014. Available from: www.rcplondon.ac.uk/sites/default/files/why-asthma-still-kills-full-report.pdf
24. Bender B, Wamboldt FS, O'Connor SL, et al. Measurement of children's asthma medication adherence by self-report, mother report, canister weight, and Doser CT. Ann Allergy Asthma Immunol. 2000 Nov;85(5):416-21
25. Jochmann A, Artusio L, Jamalzadeh A, et al. Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children. Eur Respir J. 2017 Dec 21;50(6). pii: 1700910
26. Children’s asthma action plan. Available from: https://www.asthma.org.uk/advice/child/manage/action-plan/. Accessed April 23rd 2020
27. Morton RW, Elphick HE, Rigby AS, et al. STAAR: a randomised controlled trial of elec-tronic adherence monitoring with reminder alarms and feedback to improve clinical out-comes for children with asthma. Thorax. 2017 Apr;72(4):347-354
28. Chan AH, Stewart AW, Harrison J, Camargo CA Jr, Black PN, Mitchell EA. The effect of an electronic monitoring device with audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in children with asthma: a randomised controlled trial. Lancet Respir Med. 2015 Mar;3(3):210-9
29. Pertzborn MC, Prabhakaran S, Hardy A, Baker D, Robinson MA, Hendeles L. Direct Ob-served Therapy of Inhaled Corticosteroids for Asthma at School or Daycare. Pediatr Allergy Immunol Pulmonol. 2018 Dec 1;31(4):226-229
30. Gambhir N, Longman J, Nagakumar P, et al. The role of inpatient assessment of problematic severe asthma. Arch Dis Child 2016; 101[Suppl 1]: A308-9
31. Alexander DS, Geryk L, Arrindell C, et al. Are children with asthma overconfident that they are using their inhalers correctly? J Asthma. Sep 14 2015:1-6
32. Murray CS, Foden P, Sumner H, Shepley E, Custovic A, Simpson A. Preventing Severe Asthma Exacerbations in Children. A Randomized Trial of Mite-Impermeable Bedcovers. Am J Respir Crit Care Med. 2017 Jul 15;196(2):150-158
33. Kobayashi Y, Bossley C, Gupta A, et al. Passive smoking impairs histone deacetylase-2 in children with severe asthma. Chest. Feb 2014;145(2):305-312
34. Cook J, Beresford F, Fainardi V, et al. Managing the pediatric patient with refractory asth-ma: a multidisciplinary approach. J Asthma Allergy. 2017 Apr 20;10:123-130
35. Fleming L, Koo M, Bossley CJ, Nagakumar P, Bush A, Saglani S. The utility of a mul-tidomain assessment of steroid response for predicting clinical response to omalizumab. J Allergy Clin Immunol. 2016 Jul;138(1):292-4
36. Szefler SJ, Murphy K, Harper T 3rd, et al. A phase III randomized controlled trial of tiotro-pium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol. 2017 Nov;140(5):1277-1287
37. Burch J, Griffin S, McKenna C, et al. Omalizumab for the treatment of severe persistent al-lergic asthma in children aged 6–11 years: a NICE single technology appraisal. Pharmaco-economics. 2012;30(11):991–1004
38. Rodrigo GJ, Neffen H. Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents. Pediatr Allergy Immunol. 2015 Sep;26(6):551-6
39. Humbert M, Taillé C, Mala L, Le Gros V, Just J, Molimard M; STELLAIR investigators. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosin-ophil count: the STELLAIR study. Eur Respir J. 2018 May 10;51(5)
40. Braunstahl GJ, Chen CW, Maykut R, Georgiou P, Peachey G, Bruce J. The eXpeRience reg-istry: the ‘real-world’ effectiveness of omalizumab in allergic asthma. Respir Med. 2013;107(8):1141–1151
41. Bush A, Fleming L, Saglani S. Severe asthma in children. Respirology. 2017 Jul;22(5):886-897
42. Gupta A, Ikeda M, Geng B, et al. Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype. J Allergy Clin Immunol. 2019 Nov;144(5):1336-1342.e7
43. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet (2012) 380:651–9
44. Martin Alonso A, Saglani S. Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies. Front Pediatr. 2017 Jul 5;5:154.
45. Koolen BB, Pijnenburg MW, Brackel HJ, et al. Comparing Global Initiative for Asthma (GINA) criteria with the Childhood Asthma Control Test (C-ACT) and Asthma Control Test (ACT). Eur Respir J. 2011 Sep;38(3):561-6
46. Fleming L, Murray C, Bansal AT, et al. The burden of severe asthma in childhood and ado-lescence: results from the paediatric U-BIOPRED cohorts. Eur Respir J. 2015 Nov;46(5):1322-33
47. Raat H, Bueving HJ, de Jongste JC, Grol MH, Juniper EF, van der Wouden JC. Responsive-ness, longitudinal- and cross-sectional construct validity of the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) in Dutch children with asthma. Qual Life Res. 2005 Feb;14(1):265-72
48. Dodig S, Richter D, Zrinski-Topić R. Inflammatory markers in childhood asthma. Clin Chem Lab Med 2011;49:587-99
49. Cabral AL, Vollmer WM, Barbirotto RM, Martins MA. Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to-severe asthma: a prospective, 5-month study. Ann Allergy Asthma Immunol 2009;103:206-11
50. Waibel V, Ulmer H, Horak E. Assessing asthma control: symptom scores, GINA levels of asthma control, lung function, and exhaled nitric oxide. Pediatr Pulmonol 2012;47:113-118
51. Heffler E, Carpagnano GE, Favero E, et al. Fractional Exhaled Nitric Oxide (FENO) in the management of asthma: a position paper of the Italian Respiratory Society (SIP/IRS) and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). Multidiscip Respir Med. 2020 Feb 19;15(1):36
52. Kwda A, Gldc P, Baui B, et al. Effect of long term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma. BMC Pediatr. 2019 Nov 5;19(1):411
53. Zollner EW, Lombard CJ, Galal U, Hough S, Irusen EM, Weinberg E. Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children. Pediatrics. 2012;130:e1512.
54. Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab. 2000;85(2):652–7
55. Bush A, Saglani S, Fleming L. Severe asthma: looking beyond the amount of medication. Lancet Respir Med. 2017 Nov;5(11):844-846
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Fainardi V, Saglani S. An approach to the management of children with problematic severe asthma. Acta Biomed [Internet]. 2020 Sep. 7 [cited 2024 Jul. 17];91(3):e2020055. Available from: https://mattioli1885journals.com/index.php/actabiomedica/article/view/9603
