Managing Chronic Cough Due to Asthma and NAEB in Adults and Adolescents

CHEST Guideline and Expert Panel Report
Published:January 20, 2020DOI:https://doi.org/10.1016/j.chest.2019.12.021

      Background

      Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB.

      Methods

      We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents > 12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology.

      Results

      Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism.

      Conclusions

      This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research.

      Key Words

      Abbreviations:

      Feno ( fractional exhaled nitric oxide), NAEB ( non-asthmatic eosinophilic bronchitis), RCT ( randomized controlled trial)
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      References

        • Global Initiative for Asthma (GINA)
        Global strategy for asthma management and prevention. 2018.
        http://www.ginasthma.org
        Date accessed: February 20, 2018
        • Brightling C.E.
        • Ward R.
        • Goh K.L.
        • Wardlaw A.J.
        • Pavord I.D.
        Eosinophilic bronchitis is an important cause of chronic cough.
        Am J Respir Crit Care Med. 1999; 160: 406-410
        • Carney I.K.
        • Gibson P.G.
        • Murree-Allen K.
        • Saltos N.
        • Olson L.G.
        • Hensley M.J.
        A systematic evaluation of mechanisms in chronic cough.
        Am J Respir Crit Care Med. 1997; 156: 211-216
        • Ayik S.O.
        • Basoglu O.K.
        • Erdinc M.
        • Bor S.
        • Veral A.
        • Bilgen C.
        Eosinophilic bronchitis as a cause of chronic cough.
        Respir Med. 2003; 97: 695-701
        • Irwin R.S.
        • Curley F.J.
        • French C.L.
        Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy.
        Am Rev Respir Dis. 1990; 141: 640-647
        • McGarvey L.P.
        • Heaney L.G.
        • Lawson J.T.
        • et al.
        Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol.
        Thorax. 1998; 53: 738-743
        • Lai K.
        • Chen R.
        • Lin J.
        • et al.
        A prospective, multicenter survey on causes of chronic cough in China.
        Chest. 2013; 143: 613-620
        • Corrao W.M.
        • Braman S.S.
        • Irwin R.S.
        Chronic cough as the sole presenting manifestation of bronchial asthma.
        N Engl J Med. 1979; 300: 633-637
        • Chung K.F.
        • Wenzel S.E.
        • Brozek J.L.
        • et al.
        International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
        Eur Respir J. 2014; 43: 343-373
        • Gibson P.G.
        • Dolovich J.
        • Denburg J.
        • Ramsdale E.H.
        • Hargreave F.E.
        Chronic cough:eosinophilic bronchitis without asthma.
        Lancet. 1989; 1: 1346-1348
        • Lemiere C.
        • Efthimiadis A.
        • Hargreave F.E.
        Occupational eosinophilic bronchitis without asthma: an unknown occupational airway disease.
        J Allergy Clin Immunol. 1997; 100: 852-853
        • Brightling C.E.
        • Symon F.A.
        • Birring S.S.
        • Bradding P.
        • Wardlaw A.J.
        • Pavord I.D.
        Comparison of airway immunopathology of eosinophilic bronchitis and asthma.
        Thorax. 2003; 58: 528-532
        • Gibson P.G.
        • Zlatic K.
        • Scott J.
        • Sewell W.
        • Woolley K.
        • Saltos N.
        Chronic cough resembles asthma with IL-5 and granulocyte-macrophage colony-stimulating factor gene expression in bronchoalveolar cells.
        J Allergy Clin Immunol. 1998; 101: 320-326
        • Brightling C.E.
        • Bradding P.
        • Symon F.A.
        • Holgate S.T.
        • Wardlaw A.J.
        • Pavord I.D.
        Mast-cell infiltration of airway smooth muscle in asthma.
        N Engl J Med. 2002; 346: 1699-1705
        • Siddiqui S.
        • Mistry V.
        • Doe C.
        • et al.
        Airway hyperresponsiveness is dissociated from airway wall structural remodeling.
        J Allergy Clin Immunol. 2008; 122 (41.e1-e3): 335-341
        • Hancox R.J.
        • Leigh R.
        • Kelly M.M.
        • Hargreave F.E.
        Eosinophilic bronchitis.
        Lancet. 2001; 358: 1104
        • Berry M.A.
        • Hargadon B.
        • McKenna S.
        • et al.
        Observational study of the natural history of eosinophilic bronchitis.
        Clin Exp Allergy. 2005; 35: 598-601
        • Lai K.
        • Liu B.
        • Xu D.
        • et al.
        Will nonasthmatic eosinophilic bronchitis develop chronic airway obstruction?: a prospective, observational study.
        Chest. 2015; 148: 887-894
        • Park S.W.
        • Lee Y.M.
        • Jang A.S.
        • et al.
        Development of chronic airway obstruction in patients with eosinophilic bronchitis: a prospective follow-up study.
        Chest. 2004; 125: 1998-2004
        • Matsumoto H.
        • Niimi A.
        • Takemura M.
        • et al.
        Prognosis of cough variant asthma:a retrospective analysis.
        J Asthma. 2006; 43: 131-135
        • Dicpinigaitis P.V.
        Chronic cough due to asthma: ACCP evidence-based clinical practice guidelines.
        Chest. 2006; 129: 75S-79S
        • Brightling C.E.
        Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines.
        Chest. 2006; 129: 116S-121S
        • FitzGerald J.M.
        • Lemiere C.
        • Lougheed M.D.
        • et al.
        Recognition and management of severe asthma: a Canadian Thoracic Society position statement.
        Can J Respiratory Critical Care Sleep Med. 2017; 1: 199-221
        • British Thoracic Society/Scottish Intercollegiate Guidelines Network
        British guideline on the management of asthma. 2016.
        https://www.brit-thoracic.org.uk
        Date accessed: December 15, 2018
        • Lewis S.Z.
        • Diekemper R.
        • Ornelas J.
        • Casey K.R.
        Methodologies for the development of CHEST guidelines and expert panel reports.
        Chest. 2014; 146: 182-192
        • Lewis S.Z.
        • Diekemper R.L.
        • French C.T.
        • et al.
        Methodologies for the Development of the Management of Cough: CHEST Guideline and Expert Panel Report.
        Chest. 2014; 146: 1395-1402
        • Higgins J.P.T.
        • Green Se
        Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. 2011.
        http://handbook-5-1.cochrane.org/
        Date accessed: December 15, 2018
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
        • Huang X.
        • Lin J.
        • Demner-Fushman D.
        Evaluation of PICO as a knowledge representation for clinical questions.
        AMIA Annu Symp Proc. 2006; : 359-363
        • Higgins J.P.
        • Altman D.G.
        • Gotzsche P.C.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Diekemper R.L.
        • Ireland B.K.
        • Merz L.R.
        Development of the Documentation and Appraisal Review Tool for systematic reviews.
        World J Meta-Anal. 2015; 3: 142-150
        • Chaudhuri R.
        • McMahon A.D.
        • Thomson L.J.
        • et al.
        Effect of inhaled corticosteroids on symptom severity and sputum mediator levels in chronic persistent cough.
        J Allergy Clin Immunol. 2004; 113: 1063-1070
        • Takemura M.
        • Niimi A.
        • Matsumoto H.
        • et al.
        Clinical, physiological and anti-inflammatory effect of montelukast in patients with cough variant asthma.
        Respiration. 2012; 83: 308-315
        • Tamaoki J.
        • Yokohori N.
        • Tagaya E.
        • et al.
        Comparable effect of a leukotriene receptor antagonist and long-acting beta2-adrenergic agonist in cough variant asthma.
        Allergy Asthma Proc. 2010; 31: e78-e84
        • Aaronson D.W.
        Evaluation of cetirizine in patients with allergic rhinitis and perennial asthma.
        Ann Allergy Asthma Immunol. 1996; 76: 440-446
        • Rafferty P.
        • Jackson L.
        • Smith R.
        • Holgate S.T.
        Terfenadine, a potent histamine H1-receptor antagonist in the treatment of grass pollen sensitive asthma.
        Br J Clin Pharmacol. 1990; 30: 229-235
        • Bao W.
        • Chen Q.
        • Lin Y.
        • et al.
        Efficacy of procaterol combined with inhaled budesonide for treatment of cough-variant asthma.
        Respirology. 2013; 18: 53-61
        • Irwin R.S.
        • French C.T.
        • Smyrnios N.A.
        • Curley F.J.
        Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.
        Arch Intern Med. 1997; 157: 1981-1987
        • Bergmann K.C.
        • Bauer C.P.
        • Overlack A.
        A placebo-controlled, blind comparison of nedocromil sodium and beclomethasone dipropionate in bronchial asthma.
        Curr Med Res Opin. 1989; 11: 533-542
        • Connolly K.C.
        • Peake M.D.
        • Halpin D.M.G.
        • Golightly L.
        • Turbitt M.L.
        Challenging current asthma treatment guidelines: improved control of asthma symptoms with nebulised budesonide in patients with severe asthma receiving continuous oral steroids.
        Dis Manag Health Outcomes. 2000; 7: 217-225
        • Di Franco A.
        • Dente F.L.
        • Giannini D.
        • et al.
        Effects of inhaled corticosteroids on cough threshold in patients with bronchial asthma.
        Pulm Pharmacol Ther. 2001; 14: 35-40
        • Malo J.L.
        • Cartier A.
        • Cote J.
        • et al.
        Influence of inhaled steroids on recovery from occupational asthma after cessation of exposure: an 18-month double-blind crossover study.
        Am J Respir Crit Care Med. 1996; 153: 953-960
        • Dicpinigaitis P.V.
        • Dobkin J.B.
        • Reichel J.
        Antitussive effect of the leukotriene receptor antagonist zafirlukast in subjects with cough-variant asthma.
        J Asthma. 2002; 39: 291-297
        • Spector S.L.
        • Tan R.A.
        Effectiveness of montelukast in the treatment of cough variant asthma.
        Ann Allergy Asthma Immunol. 2004; 93: 232-236
        • Bianco S.
        • Del Bono N.
        • Grassi V.
        • Orefice U.
        Effectiveness of nedocromil sodium versus placebo as additions to routine asthma maintenance therapy: a multicentre, double-blind, group comparative trial.
        Respiration. 1989; 56: 204-211
        • Bone M.F.
        • Kubik M.M.
        • Keaney N.P.
        • et al.
        Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids: a double blind, placebo controlled study.
        Thorax. 1989; 44: 654-659
        • Blumenthal M.N.
        • Selcow J.
        • Spector S.
        • Zeiger R.S.
        • Mellon M.
        A multicenter evaluation of the clinical benefits of cromolyn sodium aerosol by metered-dose inhaler in the treatment of asthma.
        J Allergy Clin Immunol. 1988; 81: 681-687
        • Callaghan B.
        • Teo N.C.
        • Clancy L.
        Effects of the addition of nedocromil sodium to maintenance bronchodilator therapy in the management of chronic asthma.
        Chest. 1992; 101: 787-792
        • Cherniack R.M.
        • Wasserman S.I.
        • Ramsdell J.W.
        • et al.
        A double-blind multicenter group comparative study of the efficacy and safety of nedocromil sodium in the management of asthma. North American Tilade Study Group.
        Chest. 1990; 97: 1299-1306
        • Clancy L.
        • Keogan S.
        Treatment of nocturnal asthma with nedocromil sodium.
        Thorax. 1994; 49: 1225-1227
        • Fairfax A.J.
        • Allbeson M.
        A double-blind group comparative trial of nedocromil sodium and placebo in the management of bronchial asthma.
        J Int Med Res. 1988; 16: 216-224
        • Fink J.N.
        • Forman S.
        • Silvers W.S.
        • Soifer M.M.
        • Tashkin D.P.
        • Wilson A.F.
        A double-blind study of the efficacy of nedocromil sodium in the management of asthma in patients using high doses of bronchodilators.
        J Allergy Clin Immunol. 1994; 94: 473-481
        • Fyans P.G.
        • Chatterjee P.C.
        • Chatterjee S.S.
        A trial comparing nedocromil sodium (Tilade) and placebo in the management of bronchial asthma.
        Clin Allergy. 1986; 16: 505-511
        • Fyans P.G.
        • Chatterjee P.C.
        • Chatterjee S.S.
        Effects of adding nedocromil sodium (Tilade) to the routine therapy of patients with bronchial asthma.
        Clin Exp Allergy. 1989; 19: 521-538
        • Lal S.
        • Malhotra S.
        • Gribben D.
        • Hodder D.
        Nedocromil sodium: a new drug for the management of bronchial asthma.
        Thorax. 1984; 39: 809-812
        • Mann J.S.
        • Clement P.
        • Sheridan A.Q.
        • Soryal I.
        • Fairfax A.J.
        • Holgate S.T.
        Inhaled lodoxamide tromethamine in the treatment of perennial asthma:a double-blind placebo-controlled study.
        J Allergy Clin Immunol. 1985; 76: 83-90
        • Petty T.L.
        • Rollins D.R.
        • Christopher K.
        • Good J.T.
        • Oakley R.
        Cromolyn sodium is effective in adult chronic asthmatics.
        Am Rev Respir Dis. 1989; 139: 694-701
        • Rebuck A.S.
        • Kesten S.
        • Boulet L.P.
        • et al.
        A 3-month evaluation of the efficacy of nedocromil sodium in asthma: a randomized, double-blind, placebo-controlled trial of nedocromil sodium conducted by a Canadian multicenter study group.
        J Allergy Clin Immunol. 1990; 85: 612-617
        • Schwartz H.J.
        • Blumenthal M.
        • Brady R.
        • et al.
        A comparative study of the clinical efficacy of nedocromil sodium and placebo. How does cromolyn sodium compare as an active control treatment?.
        Chest. 1996; 109: 945-952
        • van As A.
        • Chick T.W.
        • Bodman S.F.
        • et al.
        A group comparative study of the safety and efficacy of nedocromil sodium (Tilade) in reversible airways disease: a preliminary report.
        Eur J Respir Dis Suppl. 1986; 147: 143-148
        • Wells A.
        • Drennan C.
        • Holst P.
        • Jones D.
        • Rea H.
        • Thornley P.
        Comparison of nedocromil sodium at two dosage frequencies with placebo in the management of chronic asthma.
        Respir Med. 1992; 86: 311-316
        • Etter R.L.
        • Jackson R.H.
        • Raymer W.J.
        Effects of theophylline-alcohol with potassium iodide in asthmatic patients.
        Ann Allergy. 1969; 27: 70-78
        • Fairfax A.J.
        • Clarke R.
        • Chatterjee S.S.
        • et al.
        Controlled-release theophylline in the treatment of nocturnal asthma.
        J Int Med Res. 1990; 18: 273-281
        • Hedman J.
        • Seideman P.
        • Albertioni F.
        • Stenius-Aarniala B.
        Controlled trial of methotrexate in patients with severe chronic asthma.
        Eur J Clin Pharmacol. 1996; 49: 347-349
        • Nierop G.
        • Gijzel W.P.
        • Bel E.H.
        • Zwinderman A.H.
        • Dijkman J.H.
        Auranofin in the treatment of steroid dependent asthma: a double blind study.
        Thorax. 1992; 47: 349-354
        • Pavord I.
        • Hall I.
        • Wahedna I.
        • Cooper S.
        • Tattersfield A.
        Effect of 443c81, an inhaled micro-opioid receptor agonist in asthma.
        Clin Exp Allergy. 1994; 24: 144-148
        • Kita T.
        • Fujimura M.
        • Ogawa H.
        • et al.
        Antitussive effects of the leukotriene receptor antagonist montelukast in patients with cough variant asthma and atopic cough.
        Allergol Int. 2010; 59: 185-192
        • Boe J.
        • Thulesius O.
        Treatment of steroid dependent asthma with beclomethasone dipropionate administered by aerosol.
        Curr Ther Res Clin Exp. 1975; 17: 460-466
        • Boyd G.
        • Abdallah S.
        • Clark R.
        Twice or four times daily beclomethasone dipropionate in mild stable asthma?.
        Clin Allergy. 1985; 15: 383-389
        • Foresi A.
        • Morelli M.C.
        • Catena E.
        Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control.
        Chest. 2000; 117: 440-446
        • Malo J.L.
        • Cartier A.
        • Merland N.
        • et al.
        Four-times-a-day dosing frequency is better than a twice-a-day regimen in subjects requiring a high-dose inhaled steroid, budesonide, to control moderate to severe asthma.
        Am Rev Respir Dis. 1989; 140: 624-628
        • Tagaya E.
        • Kondo M.
        • Kirishi S.
        • Kawagoe M.
        • Kubota N.
        • Tamaoki J.
        Effects of regular treatment with combination of salmeterol/fluticasone propionate and salmeterol alone in cough variant asthma.
        J Asthma. 2015; 52: 512-518
        • Tukiainen H.
        • Vaara J.
        • Terho E.
        • Karttunen P.
        • Silvasti M.
        Comparison of twice-daily and four-times daily administration of beclomethasone dipropionate in patients with severe chronic bronchial asthma.
        Eur J Clin Pharmacol. 1986; 30: 319-322
        • Tukiainen P.
        • Lahdensuo A.
        Effect of inhaled budesonide on severe steroid-dependent asthma.
        Eur J Respir Dis. 1987; 70: 239-244
        • Kubavat A.H.
        • Khippal N.
        • Tak S.
        • et al.
        A randomized, comparative, multicentric clinical trial to assess the efficacy and safety of zileuton extended-release tablets with montelukast sodium tablets in patients suffering from chronic persistent asthma.
        Am J Ther. 2013; 20: 154-162
        • Dorow P.
        • Schiess W.
        The influence of ketotifen and aminophylline on the central and peripheral airways.
        Arzneimittelforschung. 1983; 33: 265-268
        • Monie R.D.
        • Smith A.P.
        • Leopold D.
        • Anderson G.
        • Davies B.H.
        • Thomas G.O.
        A double-blind clinical trial of ketotifen and disodium cromoglycate in bronchial asthma.
        Br J Dis Chest. 1982; 76: 383-389
        • Wasserman S.I.
        • Furukawa C.T.
        • Henochowicz S.I.
        • et al.
        Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol.
        J Allergy Clin Immunol. 1995; 95: 541-547
        • Abidi A.
        • Gupta S.
        • Agarwal M.
        • Bhalla H.L.
        • Saluja M.
        Evaluation of efficacy of curcumin as an add-on therapy in patients of bronchial asthma.
        J Clin Diagn Res. 2014; 8: HC19-HC24
        • Nishimura K.
        • Koyama H.
        • Ishihara K.
        • et al.
        Additive effect of oxitropium bromide in combination with inhaled corticosteroids in the treatment of elderly patients with chronic asthma.
        Allergology Int. 1999; 48: 85
        • Wolstenholme R.J.
        • Shettar S.P.
        Comparison of a combination of fenoterol with ipratropium bromide (Duovent) and salbutamol in young adults with nocturnal asthma.
        Respiration. 1989; 55: 152-157
        • Moeller M.
        • Grimmbacher S.
        • Munzel U.
        Improvement of asthma therapy by a novel formoterol multidose dry powder inhaler.
        Arzneimittelforschung. 2008; 58: 168-173
        • Morice A.H.
        • Taylor M.E.
        A randomised trial of the initiation of asthma treatment.
        Asthma Gen Pract. 1999; 7: 7-9
        • Murali P.M.
        • Rajasekaran S.
        • Krishnarajasekar O.R.
        • et al.
        Plant-based formulation for bronchial asthma: a controlled clinical trial to compare its efficacy with oral salbutamol and theophylline.
        Respiration. 2006; 73: 457-463
        • Yokoyama A.
        • Kohno N.
        • Sakai K.
        • Hirasawa Y.
        • Kondo K.
        • Hiwada K.
        Effect of pranlukast, a leukotriene receptor antagonist, in patients with severe asthma refractory to corticosteroids.
        J Asthma. 1998; 35: 57-62
        • Mullarkey M.F.
        • Lammert J.K.
        • Blumenstein B.A.
        Long-term methotrexate treatment in corticosteroid-dependent asthma.
        Ann Intern Med. 1990; 112: 577-581
        • Bao W.
        • Liu P.
        • Qiu Z.
        • et al.
        Efficacy of add-on montelukast in nonasthmatic eosinophilic bronchitis: the additive effect on airway inflammation, cough and life quality.
        Chin Med J (Engl). 2015; 128: 39-45
        • Brightling C.E.
        • Ward R.
        • Wardlaw A.J.
        • Pavord I.D.
        Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis.
        Eur Respir J. 2000; 15: 682-686
        • Cai C.
        • He M.Z.
        • Zhong S.Q.
        • et al.
        Add-on montelukast vs double-dose budesonide in nonasthmatic eosinophilic bronchitis: a pilot study.
        Respir Med. 2012; 106: 1369-1375
        • Gibson P.G.
        • Hargreave F.E.
        • Girgis-Gabardo A.
        • Morris M.
        • Denburg J.A.
        • Dolovich J.
        Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid.
        Clin Exp Allergy. 1995; 25: 127-132
        • Shioya T.
        • Satake M.
        • Kagaya M.
        • et al.
        Antitussive effects of the H1-receptor antagonist epinastine in patients with atopic cough (eosinophilic bronchitis).
        Arzneimittelforschung. 2004; 54: 207-212
        • National Institute for Health and Care Excellence (NICE)
        Asthma: diagnosis, monitoring and chronic asthma management. 2017.
        • Green R.H.
        • Brightling C.E.
        • McKenna S.
        • et al.
        Asthma exacerbations and sputum eosinophil counts:a randomised controlled trial.
        Lancet. 2002; 360: 1715-1721
        • Juniper E.
        • O'Byrne P.
        • Guyatt G.
        • Ferrie P.
        • King D.
        Development and validation of a questionnaire to measure asthma control.
        Eur Respir J. 1999; 14: 902-907
        • Nathan R.A.
        • Sorkness C.A.
        • Kosinski M.
        • et al.
        Development of the asthma control test:a survey for assessing asthma control.
        J Allergy Clin Immunol. 2004; 113: 59-65
        • Pizzichini M.M.
        • Pizzichini E.
        • Parameswaran K.
        • et al.
        Nonasthmatic chronic cough: no effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia.
        Can Respir J. 1999; 6: 323-330
        • Russell R.J.
        • Brightling C.
        Pathogenesis of asthma: implications for precision medicine.
        Clin Sci (Lond). 2017; 131: 1723-1735
        • Diver S.
        • Russell R.J.
        • Brightling C.E.
        New and emerging drug treatments for severe asthma.
        Clin Exp Allergy. 2018; 48: 241-252
        • Haldar P.
        • Brightling C.E.
        • Hargadon B.
        • et al.
        Mepolizumab and exacerbations of refractory eosinophilic asthma.
        N Engl J Med. 2009; 360: 973-984
        • Brightling C.E.
        Eosinophils, bronchitis and asthma: pathogenesis of cough and airflow obstruction.
        Pulm Pharmacol Ther. 2011; 24: 324-327