Advertisement

Management of Medication Side Effects and Complications

  • Louise Selby
  • Louise J. FlemingEmail author
Chapter

Abstract

There are a broad range of options for the pharmacological management of asthma, starting with short-acting β2 agonists and systemic or inhaled corticosteroids (ICS). Other options for the management of asthma, and in particular severe pediatric asthma, include long-acting β2 agonists, leukotriene receptor antagonists, long-acting muscarinic antagonists, and – more recently – the so-called biologicals. In this chapter we review the potential side effects and adverse events associated with these medications, risk factors associated with such events, appropriate testing, and considerations for the management of complications that may arise from the use of these medications in children.

Keywords

Short-acting beta-2 agonists (SABAs) Inhaled corticosteroids (ICS) Hypothalamic-pituitary-adrenal (HPA) axis Synacthen test Ciclesonide Steroid alert cards Adrenal suppression Growth velocity Bone mineral density Leukotriene receptor antagonists (LTRAs) Long-acting beta-2 agonists (LABAs) Long-acting muscarinic antagonists (LAMAs) Immunomodulators 

Notes

Funding Sources

LF is an Asthma UK Senior Clinical Fellow (AUK-SCF-2017-399) and PI in the Asthma UK Centre for Applied Research.

Financial and Competing Interests’ Disclosure

LS has no conflicts of interest.

LF has received honoraria to speak at sponsored meetings from Novartis, Boehringer-Ingelheim and Astra Zeneca and for expert consultation from Novartis, Sanofi, GSK, Respiri UK and Boehringer-Ingelheim.

References

  1. 1.
    GINA. Pocket guide for asthma management and prevention for adults and children older than 5 years https://ginasthma.org/2018-pocket-guide-for-asthma-management-and-prevention/: Global Initiative for Asthma; 2018.
  2. 2.
    Ebmeier S, Thayabaran D, Braithwaite I, Benamara C, Weatherall M, Beasley R. Trends in international asthma mortality: analysis of data from the WHO mortality database from 46 countries (1993-2012). Lancet. 2017;390(10098):935–45.CrossRefGoogle Scholar
  3. 3.
    Davis DJ, Dattel BJ, Ballard PL, Roberts JM. Beta-adrenergic receptors and cyclic adenosine monophosphate generation in human fetal lung. Pediatr Res. 1987;21(2):142–7.CrossRefGoogle Scholar
  4. 4.
    Montgomery GL, Tepper RS. Changes in airway reactivity with age in normal infants and young children. Am Rev Respir Dis. 1990;142(6 Pt 1):1372–6.CrossRefGoogle Scholar
  5. 5.
    Henderson AJ, Young S, Stick SM, Landau LI, LeSouef PN. Effect of salbutamol on histamine induced bronchoconstriction in healthy infants. Thorax. 1993;48(4):317–23.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Prendiville A, Green S, Silverman M. Airway responsiveness in wheezy infants: evidence for functional beta adrenergic receptors. Thorax. 1987;42(2):100–4.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Nadel JA, Barnes PJ. Autonomic regulation of the airways. Annu Rev Med. 1984;35:451–67.CrossRefGoogle Scholar
  8. 8.
    Goldstein AB, Castile RG, Davis SD, Filbrun DA, Flucke RL, McCoy KS, et al. Bronchodilator responsiveness in normal infants and young children. Am J Respir Crit Care Med. 2001;164(3):447–54.CrossRefGoogle Scholar
  9. 9.
    Sharif Z, Al-Alawi M. Beware of beta! A case of salbutamol-induced lactic acidosis in severe asthma. BMJ Case Rep. 2018;2018.Google Scholar
  10. 10.
    Haffner CA, Kendall MJ. Metabolic effects of beta 2-agonists. J Clin Pharm Ther. 1992;17(3):155–64.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bremner P, Siebers R, Crane J, Beasley R, Burgess C. Partial vs full beta-receptor agonism. A clinical study of inhaled albuterol and fenoterol. Chest. 1996;109(4):957–62.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bonnelykke K, Jespersen JJ, Bisgaard H. Age dependent systemic exposure to inhaled salbutamol. Br J Clin Pharmacol. 2007;64(2):241–4.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Abramson MJ, Walters J, Walters EH. Adverse effects of beta-agonists: are they clinically relevant? Am J Respir Med. 2003;2(4):287–97.CrossRefGoogle Scholar
  14. 14.
    Barnes PJ. Distribution of receptor targets in the lung. Proc Am Thorac Soc. 2004;1(4):345–51.CrossRefGoogle Scholar
  15. 15.
    Johnston SL, Edwards MR. Mechanisms of adverse effects of {beta}-agonists in asthma. Thorax. 2009;64(9):739–41.CrossRefGoogle Scholar
  16. 16.
    Edwards MR, Haas J, Panettieri RA Jr, Johnson M, Johnston SL. Corticosteroids and beta2 agonists differentially regulate rhinovirus-induced interleukin-6 via distinct Cis-acting elements. J Biol Chem. 2007;282(21):15366–75.CrossRefGoogle Scholar
  17. 17.
    Turner S, Francis B, Vijverberg S, Pino-Yanes M, Maitland-van der Zee AH, Basu K, et al. Childhood asthma exacerbations and the Arg16 beta2-receptor polymorphism: a meta-analysis stratified by treatment. J Allergy Clin Immunol. 2016;138(1):107–13. e5CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Caratti G, Matthews L, Poolman T, Kershaw S, Baxter M, Ray D. Glucocorticoid receptor function in health and disease. Clin Endocrinol. 2015;83(4):441–8.CrossRefGoogle Scholar
  19. 19.
    Contoli M, Pauletti A, Rossi MR, Spanevello A, Casolari P, Marcellini A, et al. Long-term effects of inhaled corticosteroids on sputum bacterial and viral loads in COPD. Eur Respir J. 2017;50(4).Google Scholar
  20. 20.
    Green BJ, Wiriyachaiporn S, Grainge C, Rogers GB, Kehagia V, Lau L, et al. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One. 2014;9(6):e100645.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir Med. 2006;100(8):1307–17.CrossRefGoogle Scholar
  22. 22.
    Wolthers OD. Extra-fine particle inhaled corticosteroids, pharma-cokinetics and systemic activity in children with asthma. Pediatr Allergy Immunol. 2016;27(1):13–21.CrossRefGoogle Scholar
  23. 23.
    Derendorf H, Nave R, Drollmann A, Cerasoli F, Wurst W. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J. 2006;28(5):1042–50.CrossRefGoogle Scholar
  24. 24.
    Heffler E, Madeira LNG, Ferrando M, Puggioni F, Racca F, Malvezzi L, et al. Inhaled corticosteroids safety and adverse effects in patients with asthma. J Allergy Clin Immunol Pract. 2018;6(3):776–81.CrossRefGoogle Scholar
  25. 25.
    Bayman E, Drake AJ. Adrenal suppression with glucocorticoid therapy: still a problem after all these years? Arch Dis Child. 2017;102(4):338–9.CrossRefGoogle Scholar
  26. 26.
    Broersen LH, Pereira AM, Jorgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6):2171–80.CrossRefGoogle Scholar
  27. 27.
    Dunlop KA, Carson DJ, Steen HJ, McGovern V, McNaboe J, Shields MD. Monitoring growth in asthmatic children treated with high dose inhaled glucocorticoids does not predict adrenal suppression. Arch Dis Child. 2004;89(8):713–6.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Goldbloom EB, Mokashi A, Cummings EA, Abish S, Benseler SM, Huynh HQ, et al. Symptomatic adrenal suppression among children in Canada. Arch Dis Child. 2017;102(4):338–9.CrossRefGoogle Scholar
  29. 29.
    Jochmann A, Artusio L, Jamalzadeh A, Nagakumar P, Delgado-Eckert E, Saglani S, et al. Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children. Eur Respir J. 2017;50(6).Google Scholar
  30. 30.
    Tsartsali L, Papadopoulos M, Lagona E, Papadimitriou A, Kanaka-Gantenbein C, Louizou E, et al. Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids. Neuroimmunomodulation. 2012;19(2):88–95.CrossRefGoogle Scholar
  31. 31.
    Hawcutt DB, Francis B, Carr DF, Jorgensen AL, Yin P, Wallin N, et al. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study. Lancet Respir Med. 2018;6(6):442–50.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chabre O, Goichot B, Zenaty D, Bertherat J. Group 1. Epidemiology of primary and secondary adrenal insufficiency: Prevalence and incidence, acute adrenal insufficiency, long-term morbidity and mortality. Ann Endocrinol (Paris). 2017;78(6):490–4.CrossRefGoogle Scholar
  33. 33.
    Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2014;4(2):739–69.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Paton J, Jardine E, McNeill E, Beaton S, Galloway P, Young D, et al. Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone. Arch Dis Child. 2006;91(10):808–13.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335(16):1206–12.CrossRefGoogle Scholar
  36. 36.
    Mellis CM, Phelan PD. Asthma deaths in children--a continuing problem. Thorax. 1977;32(1):29–34.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Shenoy SD, Swift PG, Cody D. Growth impairment and adrenal suppression on low-dose inhaled beclomethasone. J Paediatr Child Health. 2006;42(3):143–4.CrossRefGoogle Scholar
  38. 38.
    Sim D, Griffiths A, Armstrong D, Clarke C, Rodda C, Freezer N. Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma. Eur Respir J. 2003;21(4):633–6.CrossRefGoogle Scholar
  39. 39.
    Priftis KN, Papadimitriou A, Gatsopoulou E, Yiallouros PK, Fretzayas A, Nicolaidou P. The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children. Eur Respir J. 2006;27(2):316–20.CrossRefGoogle Scholar
  40. 40.
    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.PubMedGoogle Scholar
  41. 41.
    Blair J, Lancaster G, Titman A, Peak M, Newlands P, Collingwood C, et al. Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma. Clin Endocrinol. 2014;80(3):376–83.CrossRefGoogle Scholar
  42. 42.
    di Iorgi N, Napoli F, Allegri A, Secco A, Calandra E, Calcagno A, et al. The accuracy of the glucagon test compared to the insulin tolerance test in the diagnosis of adrenal insufficiency in young children with growth hormone deficiency. J Clin Endocrinol Metab. 2010;95(5):2132–9.CrossRefGoogle Scholar
  43. 43.
    Obrynba KS, Hoffman RP, Repaske DR, Anglin K, Kamboj MK. No central adrenal insufficiency found in patients with Prader-Willi syndrome with an overnight metyrapone test. J Pediatr Endocrinol Metab. 2018;31(7):809–14.CrossRefGoogle Scholar
  44. 44.
    British Thoracic Society; Scottish Intercollegiate Guideline Network. British guideline on the management of asthma: a national clinical guideline. Revised 2019. https://www.sign.ac.uk/assets/sign158.pdf. Accessed October 2019.
  45. 45.
    Bossley CJ, Fleming L, Gupta A, Regamey N, Frith J, Oates T, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129(4):974–82. e13CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Zollner EW, Lombard CJ, Galal U, Hough FS, Irusen EM, Weinberg E. Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children. Pediatrics. 2012;130(6):e1512–9.CrossRefGoogle Scholar
  47. 47.
    Crowley S. Inhaled glucocorticoids and adrenal function: an update. Paediatr Respir Rev. 2003;4(2):153–61.CrossRefGoogle Scholar
  48. 48.
    Harrison BD, Rees LH, Cayton RM, Nabarro JD. Recovery of hypothalamo-pituitary-adrenal function in asthmatics whose oral steroids have been stopped or reduced. Clin Endocrinol. 1982;17(2):109–18.CrossRefGoogle Scholar
  49. 49.
    Priftis KN, Papadimitriou A, Anthracopoulos MB, Gatsopoulou E, Fretzayas A, Nicolaidou P, et al. Adrenal function improves in asthmatic children on inhaled steroids: a longitudinal study. Neuroimmunomodulation. 2006;13(1):56–62.CrossRefGoogle Scholar
  50. 50.
    Priftis KN, Papadimitriou A, Nicolaidou P, Chrousos GP. The hypothalamic-pituitary-adrenal axis in asthmatic children. Trends Endocrinol Metab. 2008;19(1):32–8.CrossRefGoogle Scholar
  51. 51.
    Wolfgram PM, Allen DB. Factors influencing growth effects of inhaled corticosteroids in children. J Allergy Clin Immunol. 2015;136(6):1711–2. e2CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Allen DB. Inhaled corticosteroids and growth: still an issue after all these years. J Pediatr. 2015;166(2):463–9.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Zhang L, Pruteanu AI, Prietsch SO, Chauhan BF, Ducharme FM. Cochrane in context: inhaled corticosteroids in children with persistent asthma: effects on growth and dose-response effects on growth. Evid Based Child Health. 2014;9(4):1047–51.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985–97.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Guilbert TW, Mauger DT, Allen DB, Zeiger RS, Lemanske RF Jr, Szefler SJ, et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. J Allergy Clin Immunol. 2011;128(5):956–63 e1–7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med. 2009;360(4):339–53.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kelly HW, Strunk RC, Donithan M, Bloomberg GR, McWilliams BC, Szefler S, et al. Growth and bone density in children with mild-moderate asthma: a cross-sectional study in children entering the childhood asthma management program (CAMP). J Pediatr. 2003;142(3):286–91.CrossRefGoogle Scholar
  58. 58.
    Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med. 2012;367(10):904–12.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018;61(1):7–16.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Fuhlbrigge AL, Kelly HW. Inhaled corticosteroids in children: effects on bone mineral density and growth. Lancet Respir Med. 2014;2(6):487–96.CrossRefGoogle Scholar
  61. 61.
    Kapadia CR, Nebesio TD, Myers SE, Willi S, Miller BS, Allen DB, et al. Endocrine effects of inhaled corticosteroids in children. JAMA Pediatr. 2016;170(2):163–70.CrossRefGoogle Scholar
  62. 62.
    Sidoroff VH, Ylinen MK, Kroger LM, Kroger HP, Korppi MO. Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood wheezing. Pediatr Pulmonol. 2015;50(1):1–7.CrossRefGoogle Scholar
  63. 63.
    Roux C, Kolta S, Desfougeres JL, Minini P, Bidat E. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma. Pediatrics. 2003;111(6 Pt 1):e706–13.CrossRefGoogle Scholar
  64. 64.
    Maglione M, Poeta M, Santamaria F. New drugs for pediatric asthma. Front Pediatr. 2018;6:432.CrossRefGoogle Scholar
  65. 65.
    Mallol J, Aguirre V, Gallardo A, Cortez E, Sanchez C, Riquelme C, et al. Effect of once-daily generic ciclesonide on exhaled nitric oxide in atopic children with persistent asthma. Allergol Immunopathol (Madr). 2016;44(2):106–12.CrossRefGoogle Scholar
  66. 66.
    Agertoft L, Pedersen S. Lower-leg growth rates in children with asthma during treatment with ciclesonide and fluticasone propionate. Pediatr Allergy Immunol. 2010;21(1 Pt 2):e199–205.CrossRefGoogle Scholar
  67. 67.
    Niimi A. Cough, asthma, and cysteinyl-leukotrienes. Pulm Pharmacol Ther. 2013;26(5):514–9.CrossRefGoogle Scholar
  68. 68.
    Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: a systematic review. Pediatr Pulmonol. 2018;53:1670.CrossRefGoogle Scholar
  69. 69.
    Keskin O, Arik Yilmaz E, Motzkus C, Sackesen C, Lilly CM, Kalayci O. The effect of montelukast on early-life wheezing: a randomized, double-blinded placebo-controlled study. Pediatr Allergy Immunol. 2018;29(1):50–7.CrossRefGoogle Scholar
  70. 70.
    Nwokoro C, Pandya H, Turner S, Eldridge S, Griffiths CJ, Vulliamy T, et al. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial. Lancet Respir Med. 2014;2(10):796–803.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Ernst P, Ernst G. Neuropsychiatric adverse effects of montelukast in children. Eur Respir J. 2017;50(2).Google Scholar
  72. 72.
    Haarman MG, van Hunsel F, de Vries TW. Adverse drug reactions of montelukast in children and adults. Pharmacol Res Perspect. 2017;5(5).Google Scholar
  73. 73.
    Ali MM, O'Brien CE, Cleves MA, Martin BC. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case-control study. Pharmacoepidemiol Drug Saf. 2015;24(4):435–45.CrossRefGoogle Scholar
  74. 74.
    Glockler-Lauf SD, Finkelstein Y, Zhu J, Feldman LY, To T. Montelukast and neuropsychiatric events in children with asthma: a nested case-control study. J Pediatr. 2019;209:176.CrossRefGoogle Scholar
  75. 75.
    Schumock GT, Stayner LT, Valuck RJ, Joo MJ, Gibbons RD, Lee TA. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol. 2012;130(2):368–75.CrossRefGoogle Scholar
  76. 76.
    Cereza G, Garcia Dolade N, Laporte JR. Nightmares induced by montelukast in children and adults. Eur Respir J. 2012;40(6):1574–5.CrossRefGoogle Scholar
  77. 77.
    Matera MG, Rinaldi B, Calzetta L, Cazzola M. Assessing the viability of long-acting beta2-agonists in paediatric asthma patients: a pharmacokinetic/pharmacodynamic perspective. Expert Opin Drug Metab Toxicol. 2017;13(2):129–36.CrossRefGoogle Scholar
  78. 78.
    U.S. Food and Drug Administration. Joint Meeting of the Pulmonary Drugs Advisory Committee Drug Safety and Risk Management Advisory Committee and the Pediatric Advisory Committee. Day Two. Rockville, Maryland 22 Dec 2008. (Available in the USFDA Wayback Machine).Google Scholar
  79. 79.
    Weatherall M, Wijesinghe M, Perrin K, Harwood M, Beasley R. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy. Thorax. 2010;65(1):39–43.CrossRefGoogle Scholar
  80. 80.
    Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, Prazma CM, et al. Serious asthma events with fluticasone plus Salmeterol versus fluticasone alone. N Engl J Med. 2016;374(19):1822–30.CrossRefGoogle Scholar
  81. 81.
    Stempel DA, Szefler SJ, Pedersen S, Zeiger RS, Yeakey AM, Lee LA, et al. Safety of adding Salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016;375(9):840–9.CrossRefGoogle Scholar
  82. 82.
    Martin Alonso A, Saglani S. Mechanisms mediating pediatric severe asthma and potential novel therapies. Front Pediatr. 2017;5:154.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kerstjens HA, O'Byrne PM. Tiotropium for the treatment of asthma: a drug safety evaluation. Expert Opin Drug Saf. 2016;15(8):1115–24.CrossRefGoogle Scholar
  84. 84.
    Hamelmann E, Bateman ED, Vogelberg C, Szefler SJ, 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. e8CrossRefGoogle Scholar
  85. 85.
    Szefler SJ, Murphy K, Harper T 3rd, Boner A, Laki I, Engel M, et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol. 2017;140(5):1277–87.CrossRefGoogle Scholar
  86. 86.
    Vrijlandt E, El Azzi G, Vandewalker M, Rupp N, Harper T, Graham L, et al. Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2018;6(2):127–37.CrossRefGoogle Scholar
  87. 87.
    Kerstjens HA, 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(13):1198–207.CrossRefGoogle Scholar
  88. 88.
    NICE. Omalizumab for treating severe persistent allergic asthma https://www.nice.org.uk/guidance/ta278/evidence/review-decision-may-2016-2487605869 National Institute for Health and Clinical Excellence; 2016 May 17.
  89. 89.
    Humbert M, Taille C, Mala L, Le Gros V, Just J, Molimard M, et al. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018;51(5).Google Scholar
  90. 90.
    Corren J, Kavati A, Ortiz B, Colby JA, Ruiz K, Maiese BA, et al. Efficacy and safety of omalizumab in children and adolescents with moderate-to-severe asthma: a systematic literature review. Allergy Asthma Proc. 2017;38(4):250–63.CrossRefGoogle Scholar
  91. 91.
    Odajima H, Ebisawa M, Nagakura T, Fujisawa T, Akasawa A, Ito K, et al. Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy. Allergol Int. 2015;64(4):364–70.CrossRefGoogle Scholar
  92. 92.
    Odajima H, Ebisawa M, Nagakura T, Fujisawa T, Akasawa A, Ito K, et al. Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma. Allergol Int. 2017;66(1):106–15.CrossRefGoogle Scholar
  93. 93.
    GSK. European Commission approves Nucala (mepolizumab) for the treatment of children with severe asthma https://www.gsk.com/en-gb/media/press-releases/european-commission-approves-nucala-mepolizumab-for-the-treatment-of-children-with-severe-asthma Glaxo Smith Kline; 2018.
  94. 94.
    Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.CrossRefGoogle Scholar
  95. 95.
    Shimoda T, Odajima H, Okamasa A, Kawase M, Komatsubara M, Mayer B, et al. Efficacy and safety of mepolizumab in Japanese patients with severe eosinophilic asthma. Allergol Int. 2017;66(3):445–51.CrossRefGoogle Scholar
  96. 96.
    Busse WW. Biological treatments for severe asthma: where do we stand? Curr Opin Allergy Clin Immunol. 2018;18:509.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Murphy K, Jacobs J, Bjermer L, Fahrenholz JM, Shalit Y, Garin M, et al. Long-term safety and efficacy of Reslizumab in patients with Eosinophilic asthma. J Allergy Clin Immunol Pract. 2017;5(6):1572–81. e3CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, et al. Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials. J Asthma. 2018:1–10.Google Scholar
  99. 99.
    Busse WW, Maspero JF, Rabe KF, Papi A, Wenzel SE, Ford LB, et al. Liberty asthma QUEST: phase 3 randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma. Adv Ther. 2018.Google Scholar
  100. 100.
    Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–27.CrossRefGoogle Scholar
  101. 101.
    Travers J, Rothenberg ME. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015;8(3):464–75.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Collins S, Widger J, Davis A, Massie J. Management of asthma in children with long QT syndrome. Paediatr Respir Rev. 2012;13(2):100–5.PubMedGoogle Scholar
  103. 103.
    Rosero SZ, Zareba W, Moss AJ, Robinson JL, Hajj Ali RH, Locati EH, et al. Asthma and the risk of cardiac events in the long QT syndrome. Long QT syndrome investigative group. Am J Cardiol. 1999;84(12):1406–11.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Paediatric Respiratory MedicineRoyal Brompton and Harefield NHS Foundation TrustLondonUK
  2. 2.Royal Brompton and Harefield NHS Foundation TrustLondonUK

Personalised recommendations