Recent advances in the treatment of childhood asthma: a clinical pharmacology perspective

References

• Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet. 2020;396(10258):1204–1222.
   Google Scholar
• Wirl C, Puklova V. Prevalence of asthma and allergies in children. WHO Fact Sheet. 2007. [cited 2022 Aug 5]. Available from: https://www.euro.who.int/__data/assets/pdf_file/0012/96996/3.1.pdf
   Google Scholar
• Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches Nat Med. 2012 May 4;18(5):716–725.
   Google Scholar
• Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999 Sep;160(3):1001–1008.
   Google Scholar
• Diamant Z, Vijverberg S, Alving K, et al. Toward clinically applicable biomarkers for asthma: an EAACI position paper. Allergy. 2019 Oct;74(10):1835–1851.
   Google Scholar
• Hudey SN, Ledford DK, Cardet JC. Mechanisms of non-type 2 asthma. Curr Opin Immunol. 2020 Oct;66:123–128.
   Google Scholar
• Papi A, Brightling C, Pedersen SE, et al. Asthma. Lancet. 2018 Feb 24;391(10122):783–800.
   Google Scholar
• Hammad H, Lambrecht BN. The basic immunology of asthma Cell. 2021Mar18;184(6):1469–1485.
   Google Scholar
• Dunican EM, Elicker BM, Gierada DS, et al. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018 Mar 1;128(3):997–1009.
   Google Scholar
• Banno A, Reddy AT, Lakshmi SP, et al. Bidirectional interaction of airway epithelial remodeling and inflammation in asthma. Clin Sci (Lond). 2020 May 15;134(9):1063–1079.
   Google Scholar
• Fleming L, Tsartsali L, Wilson N, et al. Sputum inflammatory phenotypes are not stable in children with asthma. Thorax. 2012 Aug;67(8):675–681.
   Google Scholar
• Schoettler N, Strek ME. Recent advances in severe asthma: from phenotypes to personalized medicine. Chest. 2020 Mar;157(3):516–528.
   Google Scholar
• Reddel HK, Bacharier LB, Bateman ED, et al. Global initiative for asthma strategy 2021: executive summary and rationale for key changes. Am J Respir Crit Care Med. 2022 Jan 1;205(1):17–35.
   Google Scholar
• (MD) B. National asthma education and prevention program, third expert panel on the diagnosis and management of asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007.
   Google Scholar
• Johnson M. The β-adrenoceptor. Am J Respir Crit Care Med. 1998;158(supplement_2):S146–S153.
   Google Scholar
• Robert F, Lemanske J. Beta agonists in asthma: benefits and risks. UpToDate2022.
   Google Scholar
• Roux E, Molimard M, Savineau JP, et al. Muscarinic stimulation of airway smooth muscle cells. Gen Pharmacol. 1998 Sep;31(3):349–356.
   Google Scholar
• Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents Respir Res. 2010 Oct 29;11(1):149.
   Google Scholar
• PJ B. Inhaled Corticosteroids Pharmaceuticals (Basel). 2010 Mar 8;3(3):514–540.
   Google Scholar
• Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011 May;163(1):29–43.
   Google Scholar
• Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013 Nov;132(5):1033–1044.
   Google Scholar
• Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol. 1996 Jul;98(1):1–13
   Google Scholar
• Drazen JM. Pharmacology of leukotriene receptor antagonists and 5-lipoxygenase inhibitors in the management of asthma. Pharmacotherapy. 1997 Jan-Feb;17(1 Pt 2):22s–30s.
   Google Scholar
• Rachelefsky G. Childhood asthma and allergic rhinitis: the role of leukotrienes. J Pediatr. 1997 Sep;131(3):348–355.
   Google Scholar
• Thomson NC, Chaudhuri R. Omalizumab: clinical use for the management of asthma. Clin Med Insights Circ Respir Pulm Med. 2012;6:27–40.
   Google Scholar
• Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009 Sep 1;180(5):388–395.
   Google Scholar
• Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat Med. 2013 Aug;19(8):977–979.
   Google Scholar
• Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells–how did we miss them? Nat Rev Immunol. 2013 Feb;13(2):75–87.
   Google Scholar
• Smith SG, Chen R, Kjarsgaard M, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016 Jan;137(1):75–86.e8.
   Google Scholar
• Yanagibashi T, Satoh M, Nagai Y, et al. Allergic diseases: from bench to clinic - Contribution of the discovery of interleukin-5. Cytokine. 2017 Oct;98:59–70.
   Google Scholar
• Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015 Jan;16(1):45–56.
   Google Scholar
• Fala L. Nucala (Mepolizumab): first IL-5 antagonist monoclonal antibody FDA approved for maintenance treatment of patients with severe asthma. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):106–110.
   Google Scholar
• Pelaia C, Calabrese C, Vatrella A, et al. Benralizumab: from the basic mechanism of action to the potential use in the biological therapy of severe eosinophilic asthma. Biomed Res Int. 2018;2018:4839230.
   Google Scholar
• Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033–1039.
   Google Scholar
• Howarth PH, Bradding P, Montefort S, et al. Mucosal inflammation and asthma. Am J Respir Crit Care Med. 1994 Nov;150(5 Pt 2):S18–22.
   Google Scholar
• Gleich GJ. Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol. 2000 Apr;105(4):651–663.
   Google Scholar
• McBrien CN, Menzies-Gow A. The biology of eosinophils and their role in asthma. Front Med (Lausanne). 2017;4:93.
   Google Scholar
• Rossjohn J, McKinstry WJ, Woodcock JM, et al. Structure of the activation domain of the GM-CSF/IL-3/IL-5 receptor common beta-chain bound to an antagonist. Blood. 2000 Apr 15;95(8):2491–2498.
   Google Scholar
• Murphy JM, Young IG. IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitam Horm. 2006;74:1–30.
   Google Scholar
• Ishino T, Pasut G, Scibek J, et al. Kinetic interaction analysis of human interleukin 5 receptor alpha mutants reveals a unique binding topology and charge distribution for cytokine recognition. J Biol Chem. 2004 Mar 5;279(10):9547–9556.
   Google Scholar
• Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010 Jun;125(6):1344–1353.e2.
   Google Scholar
• Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J Biol Chem. 2002 Jul 26;277(30):26733–26740.
   Google Scholar
• Shinkawa T, Nakamura K, Yamane N, et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem. 2003 Jan 31;278(5):3466–3473.
   Google Scholar
• Sehmi R, Lim HF, Mukherjee M, et al. Benralizumab attenuates airway eosinophilia in prednisone-dependent asthma. J Allergy Clin Immunol. 2018 Apr;141(4):1529–1532.e8.
   Google Scholar
• Hillas G, Fouka E, Papaioannou AI. Antibodies targeting the interleukin-5 signaling pathway used as add-on therapy for patients with severe eosinophilic asthma: a review of the mechanism of action, efficacy, and safety of the subcutaneously administered agents, mepolizumab and benralizumab. Expert Rev Respir Med. 2020 Apr;14(4):353–365.
   Google Scholar
• Del Rosso JQ. MONOCLONAL ANTIBODY THERAPIES for atopic dermatitis: where are we now in the spectrum of disease management? J Clin Aesthet Dermatol. 2019 Feb;12(2):39–41.
   Google Scholar
• Thibodeaux Q, Smith MP, Ly K, et al. A review of dupilumab in the treatment of atopic diseases. Hum Vaccin Immunother. 2019;15(9):2129–2139.
   Google Scholar
• Harb H, Chatila TA. Mechanisms of dupilumab. Clin Exp Allergy. 2020 Jan;50(1):5–14.
   Google Scholar
• Menzies-Gow A, Colice G, Griffiths JM, et al. NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020 Oct 13;21(1):266.
   Google Scholar
• Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017 Sep 7;377(10):936–946.
   Google Scholar
• Alvaro-Lozano M, Akdis CA, Akdis M, et al. EAACI allergen immunotherapy user’s guide. Pediatr Allergy Immunol. 2020 May;31 Suppl 25(Suppl25):1–101.
   Google Scholar
• Agache I, Lau S, Akdis CA, et al. EAACI guidelines on allergen immunotherapy: house dust mite-driven allergic asthma. Allergy. 2019 May;74(5):855–873.
   Google Scholar
• Di Bona D, Frisenda F, Albanesi M, et al. Efficacy and safety of allergen immunotherapy in patients with allergy to molds: a systematic review. Clin Exp Allergy. 2018 Nov;48(11):1391–1401.
   Google Scholar
• Peter S, Creticos M. Subcutaneous immunotherapy (SCIT) for allergic disease: indications and efficacy. UpToDate2022.
   Google Scholar
• Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010 Aug;4(8):Cd001186.
   Google Scholar
• Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol. 2010 Nov;126(5):942–949.
   Google Scholar
• Valovirta E, Berstad AK, de Blic J, et al. Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis. Clin Ther. 2011 Oct;33(10):1537–1546.
   Google Scholar
• James C, Bernstein DI. Allergen immunotherapy: an updated review of safety. Curr Opin Allergy Clin Immunol. 2017 Feb;17(1):55–59.
   Google Scholar
• Buels KS, Fryer AD. Muscarinic receptor antagonists: effects on pulmonary function. Handb Exp Pharmacol. 2012;208:317–341.
   Google Scholar
• Kim LHY, Saleh C, Whalen-Browne A, et al. Triple vs dual inhaler therapy and asthma outcomes in moderate to severe asthma: a systematic review and meta-analysis. Jama. 2021 Jun 22;325(24):2466–2479.
   Google Scholar
• Virchow JC, Kuna P, Paggiaro P, et al. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet. 2019 Nov 9;394(10210):1737–1749.
   Google Scholar
• Canonica GW, Colombo GL, Bruno GM, et al. Shadow cost of oral corticosteroids-related adverse events: a pharmacoeconomic evaluation applied to real-life data from the severe asthma network in Italy (SANI) registry. World Allergy Organ J. 2019;12(1):100007.
   Google Scholar
• Waljee AK, Rogers MA, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. Bmj. 2017 Apr;12(357):j1415.
   Google Scholar
• Lefebvre P, Duh MS, Lafeuille MH, et al. Acute and chronic systemic corticosteroid-related complications in patients with severe asthma. J Allergy Clin Immunol. 2015 Dec;136(6):1488–1495.
   Google Scholar
• Anderson WC 3rd, Szefler SJ. Cost-effectiveness and comparative effectiveness of biologic therapy for asthma: to biologic or not to biologic? Ann Allergy Asthma Immunol. 2019 Apr;122(4):367–372.
   Google Scholar
• Green RH, Brightling CE, Woltmann G, et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002 Oct;57(10):875–879.
   Google Scholar
• Louis R, Schleich F, Barnes PJ. Corticosteroids: still at the frontline in asthma treatment? Clin Chest Med. 2012 Sep;33(3):531–541.
   Google Scholar
• Petsky HL, Cates CJ, Kew KM, et al. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax. 2018 Dec;73(12):1110–1119.
   Google Scholar
• Choi BS. Eosinophils and childhood asthma Clin Exp Pediatr. 2021 Feb;64(2): 60–67.
   Google Scholar
• Li J, Panganiban R, Kho AT, et al. Circulating microRNAs and treatment response in childhood asthma. Am J Respir Crit Care Med. 2020 Jul 1;202(1):65–72.
   Google Scholar
• Slob EMA, Richards LB, Vijverberg SJH, et al. Genome-wide association studies of exacerbations in children using long-acting beta2-agonists. Pediatr Allergy Immunol. 2021 Aug;32(6):1197–1207.
   Google Scholar
• Turner S, Francis B, Vijverberg S, et al. Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: a meta-analysis stratified by treatment. J Allergy Clin Immunol. 2016 Jul;138(1):107–113.e5.
   Google Scholar
• Ruffles T, Jones CJ, Palmer C, et al. 2021Aug Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents, Eur Respir J;58:2004107.
   Google Scholar
• Peters SP, Bleecker ER, Kunselman SJ, et al. Predictors of response to tiotropium versus salmeterol in asthmatic adults. J Allergy Clin Immunol. 2013 Nov;132(5):1068–1074.e1.
   Google Scholar
• Casale TB, Bateman ED, Vandewalker M, et al. Tiotropium respimat add-on is efficacious in symptomatic asthma, independent of T2 phenotype. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):923–935.e9.
   Google Scholar
• Cheng WC, Wu BR, Liao WC, et al. Clinical predictors of the effectiveness of tiotropium in adults with symptomatic asthma: a real-life study. J Thorac Dis. 2018 Jun;10(6):3661–3669.
   Google Scholar
• Lazarus SC, Krishnan JA, King TS, et al. Mometasone or tiotropium in mild asthma with a low sputum eosinophil level. N Engl J Med.2019 May 23;380(21):2009–2019.
   Google Scholar
• Szefler SJ, Vogelberg C, Bernstein JA, et al. Tiotropium is efficacious in 6- to 17-Year-Olds with asthma, independent of T2 phenotype. J Allergy Clin Immunol Pract. 2019 Sep-Oct;7(7):2286–2295.e4.
   Google Scholar
• Shah SP, Grunwell J, Shih J, et al. Exploring the utility of noninvasive type 2 inflammatory markers for prediction of severe asthma exacerbations in children and adolescents. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2624–2633.e2.
   Google Scholar
• Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013 Apr 15;187(8):804–811.
   Google Scholar
• Casale TB, Chipps BE, Rosén K, et al. Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma. Allergy. 2018 Feb;73(2):490–497.
   Google Scholar
• Brusselle G, Michils A, Louis R, et al. “Real-life” effectiveness of omalizumab in patients with severe persistent allergic asthma: the PERSIST study. Respir Med. 2009 Nov;103(11):1633–1642.
   Google Scholar
• Brusselle G, Germinaro M, Weiss S, et al. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther. 2017;43:39–45.
   Google Scholar
• Bleecker ER, Wechsler ME, FitzGerald JM, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018;52(4):4.
   Google Scholar
• FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018;6(1):51–64.
   Google Scholar
• Albers FC, Licskai C, Chanez P, et al. Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma. Respir Med. 2019;159:105806.
   Google Scholar
• Wechsler M, McDonald M, Garin M.C. Reslizumab high-responder and super-responder asthma patients. Am J Respir Crit Care Med. 2018:197.
   Google Scholar
• Jackson DJ, Humbert M, Hirsch I, et al. Ability of serum IgE concentration to predict exacerbation risk and benralizumab efficacy for patients with severe eosinophilic asthma. Adv Ther. 2020 Feb;37(2):718–729.
   Google Scholar
• Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–2496.
   Google Scholar
• Lombardi C, Bagnasco D, Passalacqua G. Biological agents for severe asthma: the evolution of the at-home self-injection approach. Curr Opin Allergy Clin Immunol. 2020 Aug;20(4):421–427.
   Google Scholar
• Makhecha S, Jamalzadeh A, Irving S, et al. Paediatric severe asthma biologics service: from hospital to home. Arch Dis Child. 2021 Sep;106(9):900–902.
   Google Scholar
• Bonini M, Usmani OS. Novel methods for device and adherence monitoring in asthma. Curr Opin Pulm Med. 2018 Jan;24(1):63–69.
   Google Scholar
• Huss K, Winkelstein ML, Crosbie K, et al. ’Backpack adventures in asthma’: interactive multimedia computer game piques childrens’ interest in asthma. J Allergy Clin Immunol. 2001;107(2):239.
   Google Scholar
• McPherson A, Forster D, Glazebrook C, et al. The asthma files: evaluation of a multimedia package for children’s asthma education. Paediatr Nurs. 2002 Mar;14(2):32–35.
   Google Scholar
• Shames RS, Sharek P, Mayer M, et al. Effectiveness of a multicomponent self-management program in at-risk, school-aged children with asthma. Ann Allergy Asthma Immunol. 2004 Jun;92(6):611–618.
   Google Scholar
• McPherson AC, Glazebrook C, Forster D, et al. A randomized, controlled trial of an interactive educational computer package for children with asthma. Pediatrics. 2006 Apr;117(4):1046–1054.
   Google Scholar
• Vrijens B, Dima AL, Van Ganse E, et al. What we mean when we talk about adherence in respiratory medicine. J Allergy Clin Immunol Pract. 2016 Sep-Oct;4(5):802–812.
   Google Scholar
• Burgess SW, Sly PD, Devadason SG. Providing feedback on adherence increases use of preventive medication by asthmatic children. J Asthma. 2010 Mar;47(2):198–201.
   Google Scholar
• Lee JR, Leo S, Liao S, et al. Electronic adherence monitoring devices for children with asthma: a systematic review and meta-analysis of randomised controlled trials. Int J Nurs Stud. 2021 Oct;122:104037.
   Google Scholar
• Lammers N, van Hoesel MHT, Kamphuis M, et al. Assessing exercise-Induced bronchoconstriction in children; the need for testing. Front Pediatr. 2019;7:157.
   Google Scholar
• McQuaid EL, Kopel SJ, Nassau JH. Behavioral adjustment in children with asthma: a meta-analysis. J Dev Behav Pediatr. 2001 Dec;22(6):430–439.
   Google Scholar
• van der Kamp MR, Klaver EC, Thio BJ, et al. WEARCON: wearable home monitoring in children with asthma reveals a strong association with hospital based assessment of asthma control. BMC Med Inform Decis Mak. 2020 Aug 14;20(1):192.
   Google Scholar
• Carew C, Cox DW. Laps or lengths? The effects of different exercise programs on asthma control in children. J Asthma. 2018 Aug;55(8):877–881.
   Google Scholar
• Abdelbasset WK, Alsubaie SF, Tantawy SA, et al. Evaluating pulmonary function, aerobic capacity, and pediatric quality of life following a 10-week aerobic exercise training in school-aged asthmatics: a randomized controlled trial. Patient Prefer Adherence. 2018;12:1015–1023.
   Google Scholar
• Lu KD, Forno E. Exercise and lifestyle changes in pediatric asthma. Curr Opin Pulm Med. 2020 Jan;26(1):103–111.
   Google Scholar
• Malden S, Gillespie J, Hughes A, et al. Obesity in young children and its relationship with diagnosis of asthma, vitamin D deficiency, iron deficiency, specific allergies and flat-footedness: a systematic review and meta-analysis. Obes Rev. 2021 Mar;22(3):e13129.
   Google Scholar
• Wang M, Liu M, Wang C, et al. Association between vitamin D status and asthma control: a meta-analysis of randomized trials. Respir Med. 2019 Apr;150:85–94.
   Google Scholar
• Forno E, Bacharier LB, Phipatanakul W, et al. Effect of Vitamin D3 supplementation on severe asthma exacerbations in children with asthma and low Vitamin D levels: the VDKA randomized clinical trial. Jama. 2020 Aug 25;324(8):752–760.
   Google Scholar
• Simpson JL, Scott R, Boyle MJ, et al. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006 Jan;11(1):54–61.
   Google Scholar
• Zhou Y, Jackson D, Bacharier LB, et al. The upper-airway microbiota and loss of asthma control among asthmatic children. Nat Commun. 2019 Dec 16;10(1):5714.
   Google Scholar
• Abdel-Aziz MI, Neerincx AH, Vijverberg SJ, et al. Omics for the future in asthma. Semin Immunopathol. 2020 Feb;42(1):111–126.
   Google Scholar
• Abdel-Aziz MI, Brinkman P, Vijverberg SJH, et al. Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months. J Allergy Clin Immunol. 2021 Jan;147(1):123–134.
   Google Scholar
• Macfarlane S, Macfarlane GT. Regulation of short-chain fatty acid production. Proc Nutr Soc. 2003 Feb;62(1):67–72.
   Google Scholar
• Frati F, Salvatori C, Incorvaia C, et al. The Role of the Microbiome in Asthma: the Gut⁻Lung Axis. Int J Mol Sci. 2018 Dec 30;20(1):123.
   Google Scholar
• Ghimire JJ, Jat KR, Sankar J, et al. Azithromycin for poorly controlled asthma in children: a randomized controlled trial. Chest. 2022 Jun;161(6):1456–1464.
   Google Scholar
• Piacentini GL, Peroni DG, Bodini A, et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc. 2007 Mar-Apr;28(2):194–198.
   Google Scholar
• Neerincx AH, Vijverberg SJH, Bos LDJ, et al. Breathomics from exhaled volatile organic compounds in pediatric asthma. Pediatr Pulmonol. 2017 Dec;52(12):1616–1627.
   Google Scholar
• Schleich FN, Zanella D, Stefanuto PH, et al. Exhaled volatile organic compounds are able to discriminate between neutrophilic and eosinophilic asthma. Am J Respir Crit Care Med. 2019 Aug 15;200(4):444–453.
   Google Scholar
• Robroeks CM, van Berkel JJ, Jöbsis Q, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013 Jul;42(1):98–106.
   Google Scholar
• 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 Nov;46(5):1322–1333.
   Google Scholar
• 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 Mar-Apr;6(2):545–554.e4.
   Google Scholar
• Abdel-Aziz MI, Neerincx AH, Vijverberg SJH, et al. A system pharmacology multi-omics approach toward uncontrolled pediatric asthma. J Pers Med. 2021 May 28;11(6):484.
   Google Scholar