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2021 Brazilian Thoracic Association recommendations for the management of severe asthma

ABSTRACT

Advances in the understanding that severe asthma is a complex and heterogeneous disease and in the knowledge of the pathophysiology of asthma, with the identification of different phenotypes and endotypes, have allowed new approaches for the diagnosis and characterization of the disease and have resulted in relevant changes in pharmacological management. In this context, the definition of severe asthma has been established, being differentiated from difficult-to-control asthma. These recommendations address this topic and review advances in phenotyping, use of biomarkers, and new treatments for severe asthma. Emphasis is given to topics regarding personalized management of the patient and selection of biologicals, as well as the importance of evaluating the response to treatment. These recommendations apply to adults and children with severe asthma and are targeted at physicians involved in asthma treatment. A panel of 17 Brazilian pulmonologists was invited to review recent evidence on the diagnosis and management of severe asthma, adapting it to the Brazilian reality. Each of the experts was responsible for reviewing a topic or question relevant to the topic. In a second phase, four experts discussed and structured the texts produced, and, in the last phase, all experts reviewed and approved the present manuscript and its recommendations.

Keywords:
Asthma/therapy; Asthma/drug therapy; Asthma/prevention & control; Antibodies, monoclonal, humanized

RESUMO

Os avanços no entendimento de que a asma grave é uma doença complexa e heterogênea, e os progressos que ocorreram no conhecimento de sua fisiopatologia, com a identificação de diferentes fenótipos e endotipos, permitiram novas abordagens para seu diagnóstico e caracterização, bem como resultaram em mudanças consideráveis em seu manejo farmacológico. Nesse contexto, se estabelece a definição de asma grave, diferenciando-a da asma de difícil controle. As presentes recomendações abordam esse tópico e revisam os avanços referentes a fenotipagem, uso de biomarcadores e novos tratamentos para asma grave. Ênfase é dada para tópicos voltados para a seleção personalizada do paciente e do imunobiológico, bem como para a importância da avaliação da resposta ao tratamento. Estas recomendações se aplicam a adultos e crianças com asma grave e destinam-se a médicos envolvidos no tratamento da doença. Um painel de 17 pneumologistas brasileiros foi convidado a revisar as evidências recentes referentes ao diagnóstico e manejo da asma grave, adaptadas à realidade brasileira. A cada um dos especialistas coube revisar um tópico ou questão relevante em relação ao tema. Em uma segunda fase, quatro especialistas discutiram e estruturaram os textos elaborados, e, na última fase, todos revisaram e aprovaram o presente manuscrito e suas recomendações.

Descritores:
Asma/terapia; Asma/tratamento farmacológico; Asma/prevenção & controle; Anticorpos monoclonais humanizados

INTRODUCTION

Advances in the understanding of the pathophysiology and heterogeneity of severe asthma have led to new approaches to diagnosis and characterization of severe asthma, as well as to new effective drugs for asthma control. These are promising times for the management of severe asthma, which, despite being an uncommon presentation of asthma, has a major impact on the health care system and on patients’ quality of life.

Increasing knowledge of cellular, molecular, and genetic mechanisms involved in the pathophysiology of asthma has led to advances in the characterization of phenotypes and endotypes, as well as in the personalized management of asthma.11 Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?. Physiol Rev. 2020;100(3):983-1017. https://doi.org/10.1152/physrev.00023.2019
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Given the heterogeneity and complexity of severe asthma, case identification requires specialist follow-up, preferably at a referral center. Systematized approach and follow-up are needed in order to confirm the diagnosis; gather evidence of treatment adherence; ensure correct inhaler use; investigate and control comorbidities; and optimize pharmacological and nonpharmacological interventions.22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
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3 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
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-44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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Previous estimates of disease prevalence and cost have been based on older definitions that are no longer current used,55 Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126(5):926-938. https://doi.org/10.1016/j.jaci.2010.07.019
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resulting in overestimated prevalence. More recently, a study conducted in the Netherlands and using the American Thoracic Society/European Respiratory Society (ATS/ERS) definition of severe asthma,33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
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3.7% of asthma patients were estimated to have severe asthma.66 Hekking PW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135(4):896-902. https://doi.org/10.1016/j.jaci.2014.08.042
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In a database analysis conducted in the United Kingdom in 2018, < 1% of asthma patients were estimated to have uncontrolled severe eosinophilic asthma.77 Kerkhof M, Tran TN, Soriano JB, Golam S, Gibson D, Hillyer EV, et al. Healthcare resource use and costs of severe, uncontrolled eosinophilic asthma in the UK general population. Thorax. 2018;73(2):116-124. https://doi.org/10.1136/thoraxjnl-2017-210531
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Patients with severe asthma have increased morbidity and mortality,88 Chipps BE, Zeiger RS, Borish L, Wenzel SE, Yegin A, Hayden ML, et al. Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol. 2012;130(2):332-42.e10. https://doi.org/10.1016/j.jaci.2012.04.014
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a greater number (and increasingly severe) of comorbidities,99 Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C, et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry. Thorax. 2016;71(4):339-346. https://doi.org/10.1136/thoraxjnl-2015-207630
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and more frequent health care utilization for asthma.1010 O'Neill S, Sweeney J, Patterson CC, Menzies-Gow A, Niven R, Mansur AH, et al. The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Registry. Thorax. 2015;70(4):376-378. https://doi.org/10.1136/thoraxjnl-2013-204114
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Severe asthma has been shown to result in very high costs to families and to the Brazilian Unified Health Care System.1111 Stirbulov R, Lopes da Silva N, Maia SC, Carvalho-Netto E, Angelini L. Cost of severe asthma in Brazil-systematic review. J Asthma. 2016;53(10):1063-1070. https://doi.org/10.3109/02770903.2016.1171338
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An intervention implemented at an asthma referral center in Brazil and involving the provision of free medication was found to be effective in improving disease control and reducing associated costs.1212 Cruz AA, Souza-Machado A, Franco R, Souza-Machado C, Ponte EV, Moura Santos P, et al. The impact of a program for control of asthma in a low-income setting. World Allergy Organ J. 2010;3(4):167-174. https://doi.org/10.1097/WOX.0b013e3181dc3383
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In a study analyzing a database from the Brazilian private health care system between 2010 and 2015, the mean cost per hospitalization for asthma was shown to be $8,655.00 (in U.S. dollars).1313 Nascimento OA, Paloni E, dos Santos FM, Viana K, Oliveira Silva D, Saturnino LTM, et al. Cost of asthma exacerbations on the private healthcare system in Brazil (abstract). Am J Resp Crit Care Med. 2018;197:A4850. Available from: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A4850
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Therefore, the cost of not providing access to experienced specialists at referral centers or personalized treatment alternatives for specific asthma phenotypes can be very high.

The present recommendations provide physicians with guidance on the management of severe asthma in adults, adolescents, and children ≥ 6 years of age. A total of 17 pulmonologists from referral centers for severe asthma in Brazil were invited to review the current knowledge of severe asthma and develop these recommendations adapted for Brazil. An expert panel examined major advances in topics such as the definition of severe asthma, phenotyping, biomarkers, and new treatments for severe asthma. On the basis of current evidence and international guidelines, each panel member was assigned a topic for review. Harmonization was performed in two phases. In the first phase, 4 panel members discussed and structured all texts. In the second phase, all panel members reviewed, discussed, and revised the recommendations until a consensus was reached.

DEFINITION OF SEVERE ASTHMA

Severe asthma is a subset of difficult-to-control asthma (DCA). DCA is asthma that remains uncontrolled despite step IV or V treatment22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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or that requires step IV or V treatment because of the concomitant presence of one or more factors affecting disease control. Potentially modifiable or controllable factors are responsible for the difficulty in achieving and maintaining disease control.

This document defines as having severe asthma the patient with asthma confirmed by an objective method, with good adherence to treatment, and who, despite the elimination or minimization of factors associated with lack of disease control, requires high doses of inhaled corticosteroids (IC; (budesonide ≥ 1600 μg or equivalent) associated with a second controller drug (long-acting beta2 bronchodilator - LABAs and/or long-acting antimuscarinic - LAMAs and/or antileukotrienes) or oral corticosteroids (OC) ≥ 50% of the days of previous year, to maintain control of the disease or that it still remains uncontrolled, due to the intrinsic severity of the asthma.33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
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DIAGNOSTIC INVESTIGATION OF DCA AND SEVERE ASTHMA IN ADULTS

Confirmation of asthma diagnosis

The diagnostic investigation of DCA and severe asthma begins with an objective confirmation of the diagnosis because, given the complexity of diagnosing asthma, misdiagnosis is common and results in inappropriate management.1515 Aaron SD, Vandemheen KL, FitzGerald JM, Ainslie M, Gupta S, Lemière C, et al. Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma. JAMA. 2017;317(3):269-279. https://doi.org/10.1001/jama.2016.19627
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Asthma is characterized by respiratory symptoms, variable airflow limitation, and airway hyperresponsiveness.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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An FEV1/FVC ratio below the lower limit of normal constitutes evidence of obstructive lung disease on spirometry. Airflow obstruction reversibility is evidenced by an acute (10-15 min) FEV1 response to a short-acting inhaled bronchodilator (albuterol, 200-400 µg). A significant bronchodilator response is defined as a ≥ 12% and ≥ 200 mL increase in FEV1 from baseline1616 Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-968. https://doi.org/10.1183/09031936.05.00035205
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or a ≥ 7% and ≥ 200 mL increase in FEV1 over the reference values.1717 Pereira CAC. Espirometria. J Pneumol. 2002;28(Suppl 3):S1-S82. https://doi.org/10.1023/A:1021836204655
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Airflow obstruction reversibility is also demonstrated by comparing baseline lung function and lung function parameters after 4 weeks of treatment with corticosteroids or by comparing lung function parameters between visits during periods of clinical stability.1818 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2020 [cited 2020 Mar 1]. Global Strategy for Asthma Management and Prevention (2020 update). [Adobe Acrobat document, 211p.]. Available from: https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_final_wms.pdf
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,1919 Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391(10122):783-800. https://doi.org/10.1016/S0140-6736(17)33311-1
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Daily PEF variability > 20% can also be helpful in confirming the diagnosis of asthma.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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Changes in bronchodilator response are also evidenced by an increase in FVC, a ≥ 350 mL increase being considered significant.1717 Pereira CAC. Espirometria. J Pneumol. 2002;28(Suppl 3):S1-S82. https://doi.org/10.1023/A:1021836204655
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This most commonly occurs in the presence of severe obstruction as a consequence of hyperinflation, air trapping, or both.2020 Quanjer PH, Ruppel GL, Langhammer A, Krishna A, Mertens F, Johannessen A, et al. Bronchodilator Response in FVC Is Larger and More Relevant Than in FEV1 in Severe Airflow Obstruction. Chest. 2017;151(5):1088-1098. https://doi.org/10.1016/j.chest.2016.12.017
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The absence of bronchodilator response on spirometry does not exclude a diagnosis of asthma, particularly in severe asthma, which can present with airway remodeling, increased airflow obstruction, and reduced FEV1.2121 Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, et al. Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J Appl Physiol (1985). 2008;104(2):394-403. https://doi.org/10.1152/japplphysiol.00329.2007
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In such cases, when spirometry fails to characterize asthma, other diagnostic methods can be used. Spirometry can be repeated after appropriate washout from bronchodilators2222 Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200(8):e70-e88. https://doi.org/10.1164/rccm.201908-1590ST
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during the onset of symptoms, or after a course of systemic corticosteroids showing a > 10% change in FEV1.2323 Phipatanakul W, Mauger DT, Sorkness RL, Gaffin JM, Holguin F, Woodruff PG, et al. Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma [published correction appears in Am J Respir Crit Care Med. 2018 Apr 1;197(7):970-971]. Am J Respir Crit Care Med. 2017;195(11):1439-1448. https://doi.org/10.1164/rccm.201607-1453OC
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Another diagnostic option is methacholine challenge testing.2424 Coates AL, Wanger J, Cockcroft DW, Culver BH; Bronchoprovocation Testing Task Force: Kai-Håkon Carlsen, Diamant Z, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017;49(5):1601526. https://doi.org/10.1183/13993003.01526-2016
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Corticosteroid treatment reduces bronchial hyperresponsiveness (BHR); therefore, negative challenge testing in patients treated with corticosteroids does not exclude a diagnosis of asthma.2424 Coates AL, Wanger J, Cockcroft DW, Culver BH; Bronchoprovocation Testing Task Force: Kai-Håkon Carlsen, Diamant Z, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017;49(5):1601526. https://doi.org/10.1183/13993003.01526-2016
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,2525 Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000;161(1):309-329. https://doi.org/10.1164/ajrccm.161.1.ats11-99
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In addition, corticosteroid treatment can be gradually tapered in clinically stable patients with negative challenge testing, a 2- to 4-week follow-up period being followed by another functional assessment.

In patients with severe asthma, lung function can be assessed with plethysmography by measuring lung volumes,33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
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,44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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adding parameters that express airflow obstruction such as lung hyperinflation and air trapping. Plethysmography can also be used in order to demonstrate airflow obstruction reversibility by showing significant reductions in RV and specific airway resistance after bronchodilator administration.2626 Newton MF, O'Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest. 2002;121(4):1042-1050. https://doi.org/10.1378/chest.121.4.1042
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Although small airway changes can be present in patients with asthma regardless of asthma severity, they are more common in those with disease that is more severe.2727 Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study [published correction appears in Lancet Respir Med. 2019 Sep;7(9):e28]. Lancet Respir Med. 2019;7(5):402-416. https://doi.org/10.1016/S2213-2600(19)30049-9
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Tests such as impulse oscillometry, nitrogen washout, plethysmography, spirometry, or any combination of the four can contribute to the identification of small airway dysfunction. FEF 25-75% and CVF reduction have been found to be the physiological parameters that best reflect small and medium airflow obstruction.2727 Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study [published correction appears in Lancet Respir Med. 2019 Sep;7(9):e28]. Lancet Respir Med. 2019;7(5):402-416. https://doi.org/10.1016/S2213-2600(19)30049-9
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Small airway dysfunction must be carefully evaluated in patients with severe asthma because it can increase the difficulty in achieving disease control.

In the diagnostic investigation of severe asthma, HRCT is recommended44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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for making a differential diagnosis and investigating respiratory comorbidities. In addition, HRCT can help characterize small airway involvement, air trapping, airway narrowing, bronchial wall thickening, and mucus plugging, all of which are associated with increased asthma severity.2828 Fitzpatrick AM, Moore WC. Severe Asthma Phenotypes - How Should They Guide Evaluation and Treatment?. J Allergy Clin Immunol Pract. 2017;5(4):901-908. https://doi.org/10.1016/j.jaip.2017.05.015
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Dynamic HRCT (including neck imaging) can be used in order to evaluate vocal cord dysfunction and excessive central airway collapse (tracheobronchomalacia, dynamic airway collapse, or both).2929 Low K, Lau KK, Holmes P, Crossett M, Vallance N, Phyland D, et al. Abnormal vocal cord function in difficult-to-treat asthma. Am J Respir Crit Care Med. 2011;184(1):50-56. https://doi.org/10.1164/rccm.201010-1604OC
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Assessment of treatment adherence and inhaler technique

Treatment adherence is associated with patient level of education, beliefs, and access to medication and health care.3030 Dal-Fabbro AL. Book Review: Adherence to long-term therapies: Evidence for action. Cad Saude Publica. 2005;21(4) https://doi.org/10.1590/S0102-311X2005000400037. https://doi.org/10.1590/S0102-311X2005000400037
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There is no relationship between poor adherence to asthma controller medications and the severity of asthma.3131 Blake KV. Improving adherence to asthma medications: current knowledge and future perspectives [published correction appears in Curr Opin Pulm Med. 2017 Jul;23(4):376]. Curr Opin Pulm Med. 2017;23(1):62-70. https://doi.org/10.1097/MCP.0000000000000334
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In patients with DCA, adherence to inhaled controller medications is approximately 50%,3232 Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2009;180(9):817-822. https://doi.org/10.1164/rccm.200902-0166OC
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,3333 Boulet LP, Vervloet D, Magar Y, Foster JM. Adherence: the goal to control asthma. Clin Chest Med. 2012;33(3):405-417. https://doi.org/10.1016/j.ccm.2012.06.002
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even in specialized severe asthma centers.3434 Heaney LG, Horne R. Non-adherence in difficult asthma: time to take it seriously. Thorax. 2012;67(3):268-270. https://doi.org/10.1136/thoraxjnl-2011-200257
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Assessing treatment adherence in clinical practice is challenging because the instruments that are currently available still need improvement.3535 Senna G, Caminati M, Lockey RF. Allergen immunotherapy adherence in the real world: how bad is it and how can it be improved? Curr Treat Options Allergy. 2015; 2:39-53. https://doi.org/10.1007/s40521-014-0037-6 https://doi.org/10.1007/s40521-014-0037-6
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Adherence to treatment with the ICS+LABA combination is > 80% in less than half of severe asthma patients before and after initiation of treatment with biologicals.3636 Caminati M, Vianello A, Andretta M, Menti AM, Tognella S, Degli Esposti L, et al. Low adherence to inhaled corticosteroids/long-acting ß2-agonists and biologic treatment in severe asthmatics. ERJ Open Res. 2020;6(2):00017-2020. https://doi.org/10.1183/23120541.00017-2020
https://doi.org/10.1183/23120541.00017-2...

37 Lee J, Tay TR, Radhakrishna N, Hore-Lacy F, Mackay A, Hoy R, et al. Nonadherence in the era of severe asthma biologics and thermoplasty. Eur Respir J. 2018;51(4):1701836. https://doi.org/10.1183/13993003.01836-2017
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38 Allen DJ, Holmes LJ, Hince KA, Daly R, Ustabashi C, Tavernier G. Nonadherence with inhaled preventer therapy in severe asthmatic patients on long-term omalizumab. Eur Respir J. 2018;52(2):1801025. https://doi.org/10.1183/13993003.01025-2018
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-3939 Jeffery MM, Shah ND, Karaca-Mandic P, Ross JS, Rank MA. Trends in Omalizumab Utilization for Asthma: Evidence of Suboptimal Patient Selection. J Allergy Clin Immunol Pract. 2018;6(5):1568-1577.e4. https://doi.org/10.1016/j.jaip.2017.07.034
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In addition, adherence to maintenance treatment should be constantly evaluated3636 Caminati M, Vianello A, Andretta M, Menti AM, Tognella S, Degli Esposti L, et al. Low adherence to inhaled corticosteroids/long-acting ß2-agonists and biologic treatment in severe asthmatics. ERJ Open Res. 2020;6(2):00017-2020. https://doi.org/10.1183/23120541.00017-2020
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,4040 Costello RW, Cushen B. Looking back to go forward: adherence to inhaled therapy before biologic therapy in severe asthma. Eur Respir J. 2020;55(5):2000954. https://doi.org/10.1183/13993003.00954-2020
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because patients with good adherence to ICS respond better to treatment with biologicals.4040 Costello RW, Cushen B. Looking back to go forward: adherence to inhaled therapy before biologic therapy in severe asthma. Eur Respir J. 2020;55(5):2000954. https://doi.org/10.1183/13993003.00954-2020
https://doi.org/10.1183/13993003.00954-2...
,4141 d'Ancona G, Kavanagh J, Roxas C, Green L, Fernandes M, Thomson L, et al. Adherence to corticosteroids and clinical outcomes in mepolizumab therapy for severe asthma. Eur Respir J. 2020;55(5):1902259. https://doi.org/10.1183/13993003.02259-2019
https://doi.org/10.1183/13993003.02259-2...

Inhaler technique is as important as treatment adherence, being one of the major causes of poorly controlled asthma.3434 Heaney LG, Horne R. Non-adherence in difficult asthma: time to take it seriously. Thorax. 2012;67(3):268-270. https://doi.org/10.1136/thoraxjnl-2011-200257
https://doi.org/10.1136/thoraxjnl-2011-2...
A systematic evaluation of all inhaler technique steps is essential because of the association between some of the steps and poorly controlled asthma.4242 Price DB, Román-Rodríguez M, McQueen RB, Bosnic-Anticevich S, Carter V, Gruffydd-Jones K, et al. Inhaler Errors in the CRITIKAL Study: Type, Frequency, and Association with Asthma Outcomes. J Allergy Clin Immunol Pract. 2017;5(4):1071-1081.e9. https://doi.org/10.1016/j.jaip.2017.01.004
https://doi.org/10.1016/j.jaip.2017.01.0...

Correct inhaler use requires ongoing training. Despite educational interventions, inhaler technique errors are common even in patients with severe asthma.4343 Sulaiman I, Greene G, MacHale E, Seheult J, Mokoka M, D'Arcy S, et al. A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma. Eur Respir J. 2018;51(1):1701126. https://doi.org/10.1183/13993003.01126-2017
https://doi.org/10.1183/13993003.01126-2...
In a study in which treatment adherence and inhaler technique were simultaneously and objectively evaluated in patients with moderate-to-severe asthma, 27% achieved asthma control after improving their inhaler technique.4343 Sulaiman I, Greene G, MacHale E, Seheult J, Mokoka M, D'Arcy S, et al. A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma. Eur Respir J. 2018;51(1):1701126. https://doi.org/10.1183/13993003.01126-2017
https://doi.org/10.1183/13993003.01126-2...

Investigation of exposures that can worsen asthma control

Achieving and maintaining asthma control can be difficult because of exposures such as allergens, irritants, environmental pollution, smoking, occupational agents, and/or drugs. Because these exposures lead to poor asthma control, they should be addressed in all asthma patients, especially those with DCA.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
https://ginasthma.org/wp-content/uploads...

Household exposure

Mites, cats, dogs, cockroaches, rodents, and fungi are the urban and domestic allergens that are most commonly associated with difficulty in controlling asthma.4444 Sheehan WJ, Phipatanakul W. Difficult-to-control asthma: epidemiology and its link with environmental factors. Curr Opin Allergy Clin Immunol. 2015;15(5):397-401. https://doi.org/10.1097/ACI.0000000000000195
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,4545 Le Cann P, Paulus H, Glorennec P, Le Bot B, Frain S, Gangneux JP. Home Environmental Interventions for the Prevention or Control of Allergic and Respiratory Diseases: What Really Works. J Allergy Clin Immunol Pract. 2017;5(1):66-79. https://doi.org/10.1016/j.jaip.2016.07.011
https://doi.org/10.1016/j.jaip.2016.07.0...
Although only a few population-based studies have examined the prevalence of atopy in Brazil, evidence suggests that sensitization to aeroallergens varies across regions and types of study.4646 Weinmayr G, Weiland SK, Björkstén B, Brunekreef B, Büchele G, Cookson WO, et al. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med. 2007;176(6):565-574. https://doi.org/10.1164/rccm.200607-994OC
https://doi.org/10.1164/rccm.200607-994O...
,4747 Naspitz CK, Solé D, Jacob CA, Sarinho E, Soares FJ, Dantas V, et al. Sensitization to inhalant and food allergens in Brazilian atopic children by in vitro total and specific IgE assay. Allergy Project-PROAL [Article in Portuguese]. J Pediatr (Rio J). 2004;80(3):203-210. https://doi.org/10.2223/1184
https://doi.org/10.2223/1184...

Studies examining the efficacy of measures to prevent exposure to house dust in controlling asthma4848 Schuers M, Chapron A, Guihard H, Bouchez T, Darmon D. Impact of non-drug therapies on asthma control: A systematic review of the literature. Eur J Gen Pract. 2019;25(2):65-76. https://doi.org/10.1080/13814788.2019.1574742
https://doi.org/10.1080/13814788.2019.15...
,4949 Zuiani C, Custovic A. Update on House Dust Mite Allergen Avoidance Measures for Asthma. Curr Allergy Asthma Rep. 2020;20(9):50. https://doi.org/10.1007/s11882-020-00948-y
https://doi.org/10.1007/s11882-020-00948...
have yielded controversial results. There is no consensus among guidelines regarding the usefulness of such measures in accordance with a study carried out in 2020.4949 Zuiani C, Custovic A. Update on House Dust Mite Allergen Avoidance Measures for Asthma. Curr Allergy Asthma Rep. 2020;20(9):50. https://doi.org/10.1007/s11882-020-00948-y
https://doi.org/10.1007/s11882-020-00948...

Environmental exposure

There is an association between air pollution and asthma exacerbation.5050 Tanaka H, Nakatani E, Fukutomi Y, Sekiya K, Kaneda H, Iikura M, et al. Identification of patterns of factors preceding severe or life-threatening asthma exacerbations in a nationwide study. Allergy. 2018;73(5):1110-1118. https://doi.org/10.1111/all.13374
https://doi.org/10.1111/all.13374...
,5151 Perez L, Declercq C, Iñiguez C, Aguilera I, Badaloni C, Ballester F, et al. Chronic burden of near-roadway traffic pollution in 10 European cities (APHEKOM network). Eur Respir J. 2013;42(3):594-605. https://doi.org/10.1183/09031936.00031112
https://doi.org/10.1183/09031936.0003111...
Air pollutants associated with worsening asthma control include fine particulate matter (PM2.5), ozone, nitrogen dioxide, and carbon monoxide. In 2015, ozone and PM2.5 accounted for 8-20% and 4-9%, respectively, of asthma ER visits worldwide.5252 Anenberg SC, Henze DK, Tinney V, Kinney PL, Raich W, Fann N, et al. Estimates of the Global Burden of Ambient [Formula: see text], Ozone, and [Formula: see text] on Asthma Incidence and Emergency Room Visits. Environ Health Perspect. 2018;126(10):107004. https://doi.org/10.1289/EHP3766
https://doi.org/10.1289/EHP3766...
Special attention should be given to exposure to PM2.5 from biomass burning, because it is associated with increased ER visits and hospitalizations for asthma.5353 Borchers Arriagada N, Horsley JA, Palmer AJ, Morgan GG, Tham R, Johnston FH. Association between fire smoke fine particulate matter and asthma-related outcomes: Systematic review and meta-analysis. Environ Res. 2019;179(Pt A):108777. https://doi.org/10.1016/j.envres.2019.108777
https://doi.org/10.1016/j.envres.2019.10...
In a study conducted in Brazil, there was a 50% increase in hospital admissions for asthma during the sugarcane burning season.5454 Arbex MA, Martins LC, de Oliveira RC, Pereira LA, Arbex FF, Cançado JE, et al. Air pollution from biomass burning and asthma hospital admissions in a sugar cane plantation area in Brazil. J Epidemiol Community Health. 2007;61(5):395-400. https://doi.org/10.1136/jech.2005.044743
https://doi.org/10.1136/jech.2005.044743...

Exposure to smoking

Active and passive smoking are associated with increased exacerbations, hospitalizations, and lung function impairment, but smoking cessation or reduction is an independent, modifiable factor for asthma control.5555 Comhair SA, Gaston BM, Ricci KS, Hammel J, Dweik RA, Teague WG, et al. Detrimental effects of environmental tobacco smoke in relation to asthma severity. PLoS One. 2011;6(5):e18574. https://doi.org/10.1371/journal.pone.0018574
https://doi.org/10.1371/journal.pone.001...
Therefore, it is important to evaluate patient smoking status at each visit in order to achieve smoking cessation.

Asthma patients who use illicit drugs are more likely to require intensive care or experience severe exacerbations, especially when illicit drug use is associated with poor adherence to asthma controller medications.5656 Moghaddas F, Smith C, Pilcher D, O'Hehir R, Hew M, Dabscheck E. Need for intensive care in patients admitted for asthma: Red flags from the social history. Respirology. 2016;21(7):1251-1254. https://doi.org/10.1111/resp.12831
https://doi.org/10.1111/resp.12831...

Work-related exposure

Workplace exposures have major clinical implications for severe asthma. Work-related asthma (WRA) includes occupational asthma (OA) and work-exacerbated asthma (WEA), which is also known as work-aggravated asthma.

OA is defined by the presence of asthma symptoms and reversible airflow obstruction, BHR, or a combination of the two as a result of workplace exposures rather than exposures outside the workplace. It can be caused by sensitizers or irritants.5757 Chan-Yeung M, Malo JL. Occupational asthma. N Engl J Med. 1995;333(2):107-112. https://doi.org/10.1056/NEJM199507133330207
https://doi.org/10.1056/NEJM199507133330...
,5858 Mapp CE, Boschetto P, Maestrelli P, Fabbri LM. Occupational asthma. Am J Respir Crit Care Med. 2005;172(3):280-305. https://doi.org/10.1164/rccm.200311-1575SO
https://doi.org/10.1164/rccm.200311-1575...
WEA is defined as preexisting asthma worsened by workplace conditions.5959 Henneberger PK, Redlich CA, Callahan DB, Harber P, Lemière C, Martin J, et al. An official american thoracic society statement: work-exacerbated asthma. Am J Respir Crit Care Med. 2011;184(3):368-378. https://doi.org/10.1164/rccm.812011ST
https://doi.org/10.1164/rccm.812011ST...

OA and WEA are primarily triggered by inhaled fumes, gases, dust, and smoke.6060 Blanc PD, Annesi-Maesano I, Balmes JR, Cummings KJ, Fishwick D, Miedinger D, et al. The Occupational Burden of Nonmalignant Respiratory Diseases. An Official American Thoracic Society and European Respiratory Society Statement. Am J Respir Crit Care Med. 2019;199(11):1312-1334. https://doi.org/10.1164/rccm.201904-0717ST
https://doi.org/10.1164/rccm.201904-0717...
Workers such as bakers, agricultural workers, metalworkers, carpenters, and workers exposed to latex are at an increased occupational risk, and these workplace exposures should be carefully investigated and excluded as a cause of poorly controlled asthma.6161 Karjalainen A, Kurppa K, Martikainen R, Karjalainen J, Klaukka T. Exploration of asthma risk by occupation--extended analysis of an incidence study of the Finnish population. Scand J Work Environ Health. 2002;28(1):49-57. https://doi.org/10.5271/sjweh.646
https://doi.org/10.5271/sjweh.646...

The estimated incidence and prevalence of OA and WEA vary depending on the study population and workplace exposure. In an analysis of 9 studies, the estimated incidence of OA was 16%.6060 Blanc PD, Annesi-Maesano I, Balmes JR, Cummings KJ, Fishwick D, Miedinger D, et al. The Occupational Burden of Nonmalignant Respiratory Diseases. An Official American Thoracic Society and European Respiratory Society Statement. Am J Respir Crit Care Med. 2019;199(11):1312-1334. https://doi.org/10.1164/rccm.201904-0717ST
https://doi.org/10.1164/rccm.201904-0717...
However, there is little information on the impact of occupational exposure on severe asthma.6262 Vandenplas O, Godet J, Hurdubaea L, Rifflart C, Suojalehto H, Walusiak-Skorupa J, et al. Severe Occupational Asthma: Insights From a Multicenter European Cohort. J Allergy Clin Immunol Pract. 2019;7(7):2309-2318.e4. https://doi.org/10.1016/j.jaip.2019.03.017
https://doi.org/10.1016/j.jaip.2019.03.0...

In a European cohort of patients with OA (N = 997), the prevalence of severe asthma was 16.2%. Asthma severity was correlated with persistent exposure to the causative agent, asthma duration, education level, early-onset asthma, and sputum production.6262 Vandenplas O, Godet J, Hurdubaea L, Rifflart C, Suojalehto H, Walusiak-Skorupa J, et al. Severe Occupational Asthma: Insights From a Multicenter European Cohort. J Allergy Clin Immunol Pract. 2019;7(7):2309-2318.e4. https://doi.org/10.1016/j.jaip.2019.03.017
https://doi.org/10.1016/j.jaip.2019.03.0...

In severe asthma patients suspected of having poorly controlled asthma because of workplace exposures, a diagnostic flow chart6363 Jares EJ, Baena-Cagnani CE, Gómez RM. Diagnosis of occupational asthma: an update. Curr Allergy Asthma Rep. 2012;12(3):221-231. https://doi.org/10.1007/s11882-012-0259-2
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should be used for diagnostic confirmation. Once the diagnosis is confirmed, patients should be removed from exposure.6363 Jares EJ, Baena-Cagnani CE, Gómez RM. Diagnosis of occupational asthma: an update. Curr Allergy Asthma Rep. 2012;12(3):221-231. https://doi.org/10.1007/s11882-012-0259-2
https://doi.org/10.1007/s11882-012-0259-...

Identification and management of comorbidities

Identification and management of comorbidities potentially affecting asthma control is part of the multidisciplinary approach to DCA and severe asthma because comorbidities are associated with worse outcomes.6464 Clark VL, Gibson PG, Genn G, Hiles SA, Pavord ID, McDonald VM. Multidimensional assessment of severe asthma: A systematic review and meta-analysis. Respirology. 2017;22(7):1262-1275. https://doi.org/10.1111/resp.13134
https://doi.org/10.1111/resp.13134...
,6565 Rogliani P, Sforza M, Calzetta L. The impact of comorbidities on severe asthma. Curr Opin Pulm Med. 2020;26(1):47-55. https://doi.org/10.1097/MCP.0000000000000640
https://doi.org/10.1097/MCP.000000000000...
Comorbidities are, for the most part, treatable, and appropriate comorbidity management can reduce the dose and required number of asthma controller medications, contributing to improving asthma control and patient quality of life, as well as reducing asthma exacerbations.

The prevalence of comorbidities in patients with severe asthma is high (ranging from 51% to 95%).6666 Heaney LG, Conway E, Kelly C, Johnston BT, English C, Stevenson M, et al. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax. 2003;58(7):561-566. https://doi.org/10.1136/thorax.58.7.561
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,6767 Robinson DS, Campbell DA, Durham SR, Pfeffer J, Barnes PJ, Chung KF, et al. Systematic assessment of difficult-to-treat asthma. Eur Respir J. 2003;22(3):478-483. https://doi.org/10.1183/09031936.03.00017003
https://doi.org/10.1183/09031936.03.0001...
In a study conducted in Brazil, all of the patients with severe asthma reported having at least one comorbidity, and approximately 70% reported having at least three. The most common comorbidities were rhinitis, gastroesophageal reflux disease (GERD), and hypertension.6868 Marques Mello L, Viana KP, Moraes Dos Santos F, Saturnino LTM, Kormann ML, Lazaridis E, et al. Severe asthma and eligibility for biologics in a Brazilian cohort. J Asthma. 2021;58(7):958-966. https://doi.org/10.1080/02770903.2020.1748049
https://doi.org/10.1080/02770903.2020.17...

Upper airway comorbidities

Allergic rhinitis and chronic rhinosinusitis with or without nasal polyps

The prevalence of allergic rhinitis is 80% in patients with asthma.6969 Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63 Suppl 86:8-160. https://doi.org/10.1111/j.1398-9995.2007.01620.x
https://doi.org/10.1111/j.1398-9995.2007...
In Brazil, the prevalence of allergic rhinitis in patients with severe asthma ranges from 72% to 96.5%.6868 Marques Mello L, Viana KP, Moraes Dos Santos F, Saturnino LTM, Kormann ML, Lazaridis E, et al. Severe asthma and eligibility for biologics in a Brazilian cohort. J Asthma. 2021;58(7):958-966. https://doi.org/10.1080/02770903.2020.1748049
https://doi.org/10.1080/02770903.2020.17...
,7070 de Carvalho-Pinto RM, Cukier A, Angelini L, Antonangelo L, Mauad T, Dolhnikoff M, et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respir Med. 2012;106(1):47-56. https://doi.org/10.1016/j.rmed.2011.08.013
https://doi.org/10.1016/j.rmed.2011.08.0...
A diagnosis of allergic rhinitis is made on the basis of patient clinical history and a nasal symptom questionnaire, as well as a positive aeroallergen-specific IgE screen, a positive skin prick test for aeroallergens, or both. Nearly half of patients with severe asthma have chronic rhinosinusitis with or without nasal polyps.7171 Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315-323. https://doi.org/10.1164/rccm.200906-0896OC
https://doi.org/10.1164/rccm.200906-0896...
,7272 Tay TR, Hew M. Comorbid "treatable traits" in difficult asthma: Current evidence and clinical evaluation. Allergy. 2018;73(7):1369-1382. https://doi.org/10.1111/all.13370
https://doi.org/10.1111/all.13370...
A diagnosis of chronic rhinosinusitis is made on the basis of patient clinical history, a nasal symptom questionnaire, sinus CT, and nasofibroscopy.

Studies have shown that appropriate management of allergic rhinitis and rhinosinusitis with or without nasal polyps has a positive impact on asthma control.7373 Tiotiu A, Plavec D, Novakova S, Mihaicuta S, Novakova P, Labor M, et al. Current opinions for the management of asthma associated with ear, nose and throat comorbidities. Eur Respir Rev. 2018;27(150):180056. https://doi.org/10.1183/16000617.0056-2018
https://doi.org/10.1183/16000617.0056-20...

74 Head K, Chong LY, Piromchai P, Hopkins C, Philpott C, Schilder AG, et al. Systemic and topical antibiotics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016;4:CD011994. https://doi.org/10.1002/14651858.CD011994.pub2
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-7575 Smith KA, Pulsipher A, Gabrielsen DA, Alt JA. Biologics in Chronic Rhinosinusitis: An Update and Thoughts for Future Directions. Am J Rhinol Allergy. 2018;32(5):412-423. https://doi.org/10.1177/1945892418787132
https://doi.org/10.1177/1945892418787132...

Obstructive sleep apnea

In adults, obstructive sleep apnea (OSA) is most prevalent in patients with severe asthma and is an independent risk factor for poor asthma control,7676 Teodorescu M, Polomis DA, Hall SV, Teodorescu MC, Gangnon RE, Peterson AG, et al. Association of obstructive sleep apnea risk with asthma control in adults. Chest. 2010;138(3):543-550. https://doi.org/10.1378/chest.09-3066
https://doi.org/10.1378/chest.09-3066...
being associated with more severe exacerbations7777 Wang Y, Liu K, Hu K, Yang J, Li Z, Nie M, et al. Impact of obstructive sleep apnea on severe asthma exacerbations. Sleep Med. 2016;26:1-5. https://doi.org/10.1016/j.sleep.2016.06.013
https://doi.org/10.1016/j.sleep.2016.06....
and accelerated decline in lung function.7878 Wang TY, Lo YL, Lin SM, Huang CD, Chung FT, Lin HC, et al. Obstructive sleep apnoea accelerates FEV1 decline in asthmatic patients. BMC Pulm Med. 2017;17(1):55. https://doi.org/10.1186/s12890-017-0398-2
https://doi.org/10.1186/s12890-017-0398-...

A diagnosis of OSA is made on the basis of nighttime and daytime symptoms, as well as abnormal polysomnographic findings. Asthma control, quality of life, and lung function were found to improve after initiation of CPAP therapy in asthma patients with moderate-to-severe OSA.7979 Serrano-Pariente J, Plaza V, Soriano JB, Mayos M, López-Viña A, Picado C, et al. Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea. Allergy. 2017;72(5):802-812. https://doi.org/10.1111/all.13070
https://doi.org/10.1111/all.13070...

Vocal cord dysfunction

Vocal cord dysfunction (VCD) is defined as abnormal adduction of the vocal cords resulting in airflow obstruction. The prevalence of VCD in patients with DCA is as high as 32%.8080 Tay TR, Radhakrishna N, Hore-Lacy F, Smith C, Hoy R, Dabscheck E, et al. Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life. Respirology. 2016;21(8):1384-1390. https://doi.org/10.1111/resp.12838
https://doi.org/10.1111/resp.12838...
The most common symptoms are inspiratory dyspnea, wheezing and/or stridor in the neck, dysphonia, and hoarseness.8181 Yelken K, Yilmaz A, Guven M, Eyibilen A, Aladag I. Paradoxical vocal fold motion dysfunction in asthma patients. Respirology. 2009;14(5):729-733. https://doi.org/10.1111/j.1440-1843.2009.01568.x
https://doi.org/10.1111/j.1440-1843.2009...
Common triggering factors include emotional stress, airway irritants, sudden changes in temperature, infections, and physical exercise.

Laryngoscopy is the gold standard for confirming a diagnosis of VCD8282 Perkins PJ, Morris MJ. Vocal cord dysfunction induced by methacholine challenge testing. Chest. 2002;122(6):1988-1993. https://doi.org/10.1378/chest.122.6.1988
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,8383 Lee J, Denton E, Hoy R, Tay TR, Bondarenko J, Hore-Lacy F, et al. Paradoxical Vocal Fold Motion in Difficult Asthma Is Associated with Dysfunctional Breathing and Preserved Lung Function. J Allergy Clin Immunol Pract. 2020;8(7):2256-2262. https://doi.org/10.1016/j.jaip.2020.02.037
https://doi.org/10.1016/j.jaip.2020.02.0...
and must be performed during an attack, demonstrating abnormal adduction of the vocal cords during inspiration. Flattening of the inspiratory loop on the flow-volume curve on spirometry is suggestive of VCD.8484 Forrest LA, Husein T, Husein O. Paradoxical vocal cord motion: classification and treatment. Laryngoscope. 2012;122(4):844-853. https://doi.org/10.1002/lary.23176
https://doi.org/10.1002/lary.23176...
Dynamic CT of the neck,2929 Low K, Lau KK, Holmes P, Crossett M, Vallance N, Phyland D, et al. Abnormal vocal cord function in difficult-to-treat asthma. Am J Respir Crit Care Med. 2011;184(1):50-56. https://doi.org/10.1164/rccm.201010-1604OC
https://doi.org/10.1164/rccm.201010-1604...
questionnaires,8585 Traister RS, Fajt ML, Landsittel D, Petrov AA. A novel scoring system to distinguish vocal cord dysfunction from asthma. J Allergy Clin Immunol Pract. 2014;2(1):65-69. https://doi.org/10.1016/j.jaip.2013.09.002
https://doi.org/10.1016/j.jaip.2013.09.0...
,8686 Fowler SJ, Thurston A, Chesworth B, Cheng V, Constantinou P, Vyas A, et al. VCDQ--a Questionnaire for symptom monitoring in vocal cord dysfunction. Clin Exp Allergy. 2015;45(9):1406-1411. https://doi.org/10.1111/cea.12550
https://doi.org/10.1111/cea.12550...
and laryngoscopy during exercise can help to identify cases of VCD.8787 Tervonen H, Niskanen MM, Sovijärvi AR, Hakulinen AS, Vilkman EA, Aaltonen LM. Fiberoptic videolaryngoscopy during bicycle ergometry: a diagnostic tool for exercise-induced vocal cord dysfunction. Laryngoscope. 2009;119(9):1776-1780. https://doi.org/10.1002/lary.20558
https://doi.org/10.1002/lary.20558...

There is no specific treatment for VCD. Treatment options include speech therapy (respiratory training and voice therapy), psychotherapy, and elimination of triggering factors.7272 Tay TR, Hew M. Comorbid "treatable traits" in difficult asthma: Current evidence and clinical evaluation. Allergy. 2018;73(7):1369-1382. https://doi.org/10.1111/all.13370
https://doi.org/10.1111/all.13370...

Other comorbidities

Dysfunctional breathing

The pathophysiology of dysfunctional breathing is poorly understood,7272 Tay TR, Hew M. Comorbid "treatable traits" in difficult asthma: Current evidence and clinical evaluation. Allergy. 2018;73(7):1369-1382. https://doi.org/10.1111/all.13370
https://doi.org/10.1111/all.13370...
and dysfunctional breathing symptoms can be confused with asthma symptoms. Dysfunctional breathing coexists with DCA and is underdiagnosed.8888 Radhakrishna N, Tay TR, Hore-Lacy F, Stirling R, Hoy R, Dabscheck E, et al. Validated questionnaires heighten detection of difficult asthma comorbidities. J Asthma. 2017;54(3):294-299. https://doi.org/10.1080/02770903.2016.1212369
https://doi.org/10.1080/02770903.2016.12...
On the basis of the Nijmegen Questionnaire,8989 van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen Questionnaire in recognition of the hyperventilation syndrome. J Psychosom Res. 1985;29(2):199-206. https://doi.org/10.1016/0022-3999(85)90042-X
https://doi.org/10.1016/0022-3999(85)900...
the prevalence of dysfunctional breathing in patients with DCA ranges from 30% to 64%.8080 Tay TR, Radhakrishna N, Hore-Lacy F, Smith C, Hoy R, Dabscheck E, et al. Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life. Respirology. 2016;21(8):1384-1390. https://doi.org/10.1111/resp.12838
https://doi.org/10.1111/resp.12838...
,9090 Stanton AE, Vaughn P, Carter R, Bucknall CE. An observational investigation of dysfunctional breathing and breathing control therapy in a problem asthma clinic. J Asthma. 2008;45(9):758-765. https://doi.org/10.1080/02770900802252093
https://doi.org/10.1080/0277090080225209...

Dysfunctional breathing involves abnormal breathing patterns9191 Thomas M, McKinley RK, Freeman E, Foy C, Price D. The prevalence of dysfunctional breathing in adults in the community with and without asthma. Prim Care Respir J. 2005;14(2):78-82. https://doi.org/10.1016/j.pcrj.2004.10.007
https://doi.org/10.1016/j.pcrj.2004.10.0...
described and classified elsewhere,9292 Barker N, Everard ML. Getting to grips with 'dysfunctional breathing'. Paediatr Respir Rev. 2015;16(1):53-61. https://doi.org/10.1016/j.prrv.2014.10.001
https://doi.org/10.1016/j.prrv.2014.10.0...
,9393 Boulding R, Stacey R, Niven R, Fowler SJ. Dysfunctional breathing: a review of the literature and proposal for classification. Eur Respir Rev. 2016;25(141):287-294. https://doi.org/10.1183/16000617.0088-2015
https://doi.org/10.1183/16000617.0088-20...
a disordered breathing pattern being a major component of dysfunctional breathing. The most well-known forms of dysfunctional breathing are hyperventilation syndrome and idiopathic hyperventilation.9494 Vidotto LS, Carvalho CRF, Harvey A, Jones M. Dysfunctional breathing: what do we know?. J Bras Pneumol. 2019;45(1):e20170347. https://doi.org/10.1590/1806-3713/e20170347
https://doi.org/10.1590/1806-3713/e20170...

In asthma patients, dysfunctional breathing is associated with an increase in ER visits and unscheduled visits, as well as with activity limitations and impaired physical and mental health.9595 Ritz T, Bobb C, Edwards M, Steptoe A. The structure of symptom report in asthma: a reevaluation. J Psychosom Res. 2001;51(5):639-645. https://doi.org/10.1016/S0022-3999(01)00271-9
https://doi.org/10.1016/S0022-3999(01)00...
,9696 Ritz T, Rosenfield D, Meuret AE, Bobb C, Steptoe A. Hyperventilation symptoms are linked to a lower perceived health in asthma patients. Ann Behav Med. 2008;35(1):97-104. https://doi.org/10.1007/s12160-007-9014-7
https://doi.org/10.1007/s12160-007-9014-...
Dysfunctional breathing can coexist with other comorbidities, is common in patients with anxiety disorders such as panic disorder9797 Meuret AE, Ritz T. Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies. Int J Psychophysiol. 2010;78(1):68-79. https://doi.org/10.1016/j.ijpsycho.2010.05.006
https://doi.org/10.1016/j.ijpsycho.2010....
and in those with VCD,8383 Lee J, Denton E, Hoy R, Tay TR, Bondarenko J, Hore-Lacy F, et al. Paradoxical Vocal Fold Motion in Difficult Asthma Is Associated with Dysfunctional Breathing and Preserved Lung Function. J Allergy Clin Immunol Pract. 2020;8(7):2256-2262. https://doi.org/10.1016/j.jaip.2020.02.037
https://doi.org/10.1016/j.jaip.2020.02.0...
,9898 Low K, Ruane L, Uddin N, Finlay P, Lau KK, Hamza K, et al. Abnormal vocal cord movement in patients with and without airway obstruction and asthma symptoms. Clin Exp Allergy. 2017;47(2):200-207. https://doi.org/10.1111/cea.12828
https://doi.org/10.1111/cea.12828...
and is independently associated with worsening of quality of life and asthma control.8080 Tay TR, Radhakrishna N, Hore-Lacy F, Smith C, Hoy R, Dabscheck E, et al. Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life. Respirology. 2016;21(8):1384-1390. https://doi.org/10.1111/resp.12838
https://doi.org/10.1111/resp.12838...

Few studies have examined the treatment of dysfunctional breathing.9494 Vidotto LS, Carvalho CRF, Harvey A, Jones M. Dysfunctional breathing: what do we know?. J Bras Pneumol. 2019;45(1):e20170347. https://doi.org/10.1590/1806-3713/e20170347
https://doi.org/10.1590/1806-3713/e20170...
In patients with DCA, breathing exercises have been found to improve the Nijmegen Questionnaire score and asthma control, as well as reducing the frequency of exacerbations.9999 Tay TR, Lee J, Radhakrishna N, Hore-Lacy F, Stirling R, Hoy R, et al. A Structured Approach to Specialist-referred Difficult Asthma Patients Improves Control of Comorbidities and Enhances Asthma Outcomes. J Allergy Clin Immunol Pract. 2017;5(4):956-964.e3. https://doi.org/10.1016/j.jaip.2016.12.030
https://doi.org/10.1016/j.jaip.2016.12.0...

Anxiety and depression

Patients with severe asthma are more likely to experience symptoms of anxiety and depression than are those with asthma that is less severe.100100 Yonas MA, Marsland AL, Emeremni CA, Moore CG, Holguin F, Wenzel S. Depressive symptomatology, quality of life and disease control among individuals with well-characterized severe asthma. J Asthma. 2013;50(8):884-890. https://doi.org/10.3109/02770903.2013.810750
https://doi.org/10.3109/02770903.2013.81...
Although the prevalence of anxiety and depression symptoms in patients with severe asthma has been reported to be 38% and 25%, respectively,101101 McDonald VM, Hiles SA, Godbout K, Harvey ES, Marks GB, Hew M, et al. Treatable traits can be identified in a severe asthma registry and predict future exacerbations. Respirology. 2019;24(1):37-47. https://doi.org/10.1111/resp.13389
https://doi.org/10.1111/resp.13389...
anxiety and depression have been overlooked in the evaluation of DCA and severe asthma.6464 Clark VL, Gibson PG, Genn G, Hiles SA, Pavord ID, McDonald VM. Multidimensional assessment of severe asthma: A systematic review and meta-analysis. Respirology. 2017;22(7):1262-1275. https://doi.org/10.1111/resp.13134
https://doi.org/10.1111/resp.13134...
Anxiety and depression symptoms are associated with difficulty in controlling asthma,102102 Robinson D, Campbell D, Durham S, Pfeffer J, Barnes P, Chung K, et al. Systematic assessment of difficult-to-treat asthma. Eur Respir J. 2003;22(3):478-483. https://doi.org/10.1183/09031936.03.00017003
https://doi.org/10.1183/09031936.03.0001...
increased use of health services,103103 Wang G, Zhou T, Wang L, Wang L, Fu JJ, Zhang HP, et al. Relationship between current psychological symptoms and future risk of asthma outcomes: a 12-month prospective cohort study. J Asthma. 2011;48(10):1041-1050. https://doi.org/10.3109/02770903.2011.631238
https://doi.org/10.3109/02770903.2011.63...
near-fatal asthma attacks, and increased mortality.104104 Heaney LG, Conway E, Kelly C, Gamble J. Prevalence of psychiatric morbidity in a difficult asthma population: relationship to asthma outcome. Respir Med. 2005;99(9):1152-1159. https://doi.org/10.1016/j.rmed.2005.02.013
https://doi.org/10.1016/j.rmed.2005.02.0...
These unfavorable outcomes might be related to poor adherence to the prescribed medication regimen, irregular medical follow-up care, and inappropriate asthma management practices.105105 Nishimura K, Hajiro T, Oga T, Tsukino M, Sato S, Ikeda A. A comparison of two simple measures to evaluate the health status of asthmatics: the Asthma Bother Profile and the Airways Questionnaire 20. J Asthma. 2004;41(2):141-146. https://doi.org/10.1081/JAS-120026070
https://doi.org/10.1081/JAS-120026070...

In a real-life study,106106 Robinson R, Barber K, Jones G, Blakey J, Burhan H. Exploring the relationship between generalised anxiety/depression scales and asthma-specific quality of life/control questionnaires in a specialist asthma clinic. J Asthma. 2021;58(7):912-920. https://doi.org/10.1080/02770903.2020.1744640
https://doi.org/10.1080/02770903.2020.17...
asthma control and quality of life questionnaires were found to correlate well with anxiety and depression scales. Therefore, patients with uncontrolled asthma and low quality of life should be screened for symptoms of anxiety and depression106106 Robinson R, Barber K, Jones G, Blakey J, Burhan H. Exploring the relationship between generalised anxiety/depression scales and asthma-specific quality of life/control questionnaires in a specialist asthma clinic. J Asthma. 2021;58(7):912-920. https://doi.org/10.1080/02770903.2020.1744640
https://doi.org/10.1080/02770903.2020.17...
and referred for follow-up in specialized centers.

GERD

GERD is a common comorbidity in patients with severe asthma.6868 Marques Mello L, Viana KP, Moraes Dos Santos F, Saturnino LTM, Kormann ML, Lazaridis E, et al. Severe asthma and eligibility for biologics in a Brazilian cohort. J Asthma. 2021;58(7):958-966. https://doi.org/10.1080/02770903.2020.1748049
https://doi.org/10.1080/02770903.2020.17...
,107107 Field SK, Underwood M, Brant R, Cowie RL. Prevalence of gastroesophageal reflux symptoms in asthma. Chest. 1996;109(2):316-322. https://doi.org/10.1378/chest.109.2.316
https://doi.org/10.1378/chest.109.2.316...

108 Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med. 2000;162(1):34-39. https://doi.org/10.1164/ajrccm.162.1.9907072
https://doi.org/10.1164/ajrccm.162.1.990...
-109109 Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119(2):405-413. https://doi.org/10.1016/j.jaci.2006.11.639
https://doi.org/10.1016/j.jaci.2006.11.6...
A diagnosis of GERD is made on the basis of clinical symptoms, upper gastrointestinal endoscopy, and 24-h esophageal pH monitoring, with or without esophageal manometry and pH-impedance testing. Patients with DCA and symptoms of GERD should undergo treatment, which consists of lifestyle changes, pharmacological interventions, and, in some cases, surgery.110110 Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev. 2003;(2):CD001496. https://doi.org/10.1002/14651858.CD001496
https://doi.org/10.1002/14651858.CD00149...

Obesity

Evidence from cross-sectional studies suggests that obese individuals are at an increased risk for asthma.111111 Souza ECC, Pizzichini MMM, Dias M, Cunha MJ, Matte DL, Karloh M, et al. Body mass index, asthma, and respiratory symptoms: a population-based study. J Bras Pneumol. 2019;46(1):e20190006. https://doi.org/10.1590/1806-3713/e20190006
https://doi.org/10.1590/1806-3713/e20190...
,112112 Azizpour Y, Delpisheh A, Montazeri Z, Sayehmiri K, Darabi B. Effect of childhood BMI on asthma: a systematic review and meta-analysis of case-control studies. BMC Pediatr. 2018;18(1):143. https://doi.org/10.1186/s12887-018-1093-z
https://doi.org/10.1186/s12887-018-1093-...
Obese asthma patients have disease that is more severe, poorly controlled asthma, reduced quality of life, and increased ER visits and hospitalizations.113113 Baffi CW, Winnica DE, Holguin F. Asthma and obesity: mechanisms and clinical implications. Asthma Res Pract. 2015;1:1. https://doi.org/10.1186/s40733-015-0001-7
https://doi.org/10.1186/s40733-015-0001-...

114 Barros LL, Souza-Machado A, Corrêa LB, Santos JS, Cruz C, Leite M, et al. Obesity and poor asthma control in patients with severe asthma. J Asthma. 2011;48(2):171-176. https://doi.org/10.3109/02770903.2011.554940
https://doi.org/10.3109/02770903.2011.55...
-115115 Vortmann M, Eisner MD. BMI and health status among adults with asthma. Obesity (Silver Spring). 2008;16(1):146-152. https://doi.org/10.1038/oby.2007.7
https://doi.org/10.1038/oby.2007.7...
This might be due to several factors, including the type of inflammation, obesity-related comorbidities (OSA and GERD), and factors related to respiratory mechanics.

There is evidence that obesity increases the production of proinflammatory mediators in asthma, which are associated with visceral fat and can lead to increased BHR and bronchospasm.116116 Arteaga-Solis E, Zee T, Emala CW, Vinson C, Wess J, Karsenty G. Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma [published correction appears in Cell Metab. 2013 Mar 5;17(3):463-4]. Cell Metab. 2013;17(1):35-48. https://doi.org/10.1016/j.cmet.2012.12.004
https://doi.org/10.1016/j.cmet.2012.12.0...
,117117 Scott HA, Gibson PG, Garg ML, Wood LG. Airway inflammation is augmented by obesity and fatty acids in asthma. Eur Respir J. 2011;38(3):594-602. https://doi.org/10.1183/09031936.00139810
https://doi.org/10.1183/09031936.0013981...
Cross-sectional studies have suggested that obese asthma patients have predominantly neutrophilic airway inflammation.117117 Scott HA, Gibson PG, Garg ML, Wood LG. Airway inflammation is augmented by obesity and fatty acids in asthma. Eur Respir J. 2011;38(3):594-602. https://doi.org/10.1183/09031936.00139810
https://doi.org/10.1183/09031936.0013981...
,118118 van Veen IH, Ten Brinke A, Sterk PJ, Rabe KF, Bel EH. Airway inflammation in obese and nonobese patients with difficult-to-treat asthma. Allergy. 2008;63(5):570-574. https://doi.org/10.1111/j.1398-9995.2007.01597.x
https://doi.org/10.1111/j.1398-9995.2007...
This inflammatory pattern is predominantly seen in obese women with asthma, constituting the “asthma-obesity” phenotype.7171 Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315-323. https://doi.org/10.1164/rccm.200906-0896OC
https://doi.org/10.1164/rccm.200906-0896...

Weight loss should be included in the treatment plan for obese patients with severe asthma.119119 Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database Syst Rev. 2012;(7):CD009339. https://doi.org/10.1002/14651858.CD009339.pub2
https://doi.org/10.1002/14651858.CD00933...
,120120 Okoniewski W, Lu KD, Forno E. Weight Loss for Children and Adults with Obesity and Asthma. A Systematic Review of Randomized Controlled Trials. Ann Am Thorac Soc. 2019;16(5):613-625. https://doi.org/10.1513/AnnalsATS.201810-651SR
https://doi.org/10.1513/AnnalsATS.201810...
Weight loss can improve asthma control and lung function (FVC), as well as reducing the need for medications, without affecting inflammatory markers or markers of bronchial responsiveness.120120 Okoniewski W, Lu KD, Forno E. Weight Loss for Children and Adults with Obesity and Asthma. A Systematic Review of Randomized Controlled Trials. Ann Am Thorac Soc. 2019;16(5):613-625. https://doi.org/10.1513/AnnalsATS.201810-651SR
https://doi.org/10.1513/AnnalsATS.201810...
,121121 Dias-Júnior SA, Reis M, de Carvalho-Pinto RM, Stelmach R, Halpern A, Cukier A. Effects of weight loss on asthma control in obese patients with severe asthma. Eur Respir J. 2014;43(5):1368-1377. https://doi.org/10.1183/09031936.00053413
https://doi.org/10.1183/09031936.0005341...
Obese asthma patients who were enrolled in a weight loss and physical activity program and who lost 5-10% of their body weight were found to have improved asthma control and quality of life.122122 Freitas PD, Ferreira PG, Silva AG, Stelmach R, Carvalho-Pinto RM, Fernandes FL, et al. The Role of Exercise in a Weight-Loss Program on Clinical Control in Obese Adults with Asthma. A Randomized Controlled Trial. Am J Respir Crit Care Med. 2017;195(1):32-42. https://doi.org/10.1164/rccm.201603-0446OC
https://doi.org/10.1164/rccm.201603-0446...
Bariatric surgery also results in improved asthma control, quality of life, and lung function.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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,123123 Boulet LP, Turcotte H, Martin J, Poirier P. Effect of bariatric surgery on airway response and lung function in obese subjects with asthma. Respir Med. 2012;106(5):651-660. https://doi.org/10.1016/j.rmed.2011.12.012
https://doi.org/10.1016/j.rmed.2011.12.0...

124 Dixon AE, Pratley RE, Forgione PM, Kaminsky DA, Whittaker-Leclair LA, Griffes LA, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol. 2011;128(3):508-15.e152. https://doi.org/10.1016/j.jaci.2011.06.009
https://doi.org/10.1016/j.jaci.2011.06.0...
-125125 Upala S, Thavaraputta S, Sanguankeo A. Improvement in pulmonary function in asthmatic patients after bariatric surgery: a systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15(5):794-803. https://doi.org/10.1016/j.soard.2018.12.018
https://doi.org/10.1016/j.soard.2018.12....

Figure 1 shows a flow chart for the management of DCA in adults.

Figure 1
Flow chart of severe asthma diagnosis and phenotyping. ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; VCD: vocal cord dysfunction; GERD: gastroesophageal reflux disease; OSA: obstructive sleep apnea; ABPA: allergic bronchopulmonary aspergillosis; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; OCS: oral corticosteroid; EosIS: eosinophils in induced sputum; EosPB: eosinophils in peripheral blood; FeNO: fractional exhaled nitric oxide.

BIOMARKERS

Biomarkers can help to identify different phenotypes and endotypes, as well as predicting the response to severe asthma treatment.126126 Diamant Z, Vijverberg S, Alving K, Bakirtas A, Bjermer L, Custovic A, et al. Toward clinically applicable biomarkers for asthma: An EAACI position paper. Allergy. 2019;74(10):1835-1851. https://doi.org/10.1111/all.13806
https://doi.org/10.1111/all.13806...
The most widely used biomarkers of type 2 (T2)-high inflammation are IgE, eosinophils in induced sputum (EosIS), eosinophils in peripheral blood (EosPB), and fractional exhaled nitric oxide (FeNO).127127 Tiotiu A. Biomarkers in asthma: state of the art. Asthma Res Pract. 2018;4:10. https://doi.org/10.1186/s40733-018-0047-4
https://doi.org/10.1186/s40733-018-0047-...

IgE

IgE plays an important role in the pathogenesis of allergic asthma. Exposure to exogenous allergens triggers an inflammatory cascade with interleukins (IL-4, IL-5, and IL-13), as well as activation of different cells. IL-4 and IL-13 stimulate B lymphocytes to produce IgE.128128 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65. https://doi.org/10.1038/nri3786
https://doi.org/10.1038/nri3786...

The allergic asthma phenotype is confirmed by clinical history and an immediate hypersensitivity response (a positive skin prick test), a positive specific serum IgE response to at least one aeroallergen, or a combination of the two. Age can affect IgE levels, and nonatopic patients can present with elevated IgE levels.129129 Narendra D, Blixt J, Hanania NA. Immunological biomarkers in severe asthma. Semin Immunol. 2019;46:101332. https://doi.org/10.1016/j.smim.2019.101332
https://doi.org/10.1016/j.smim.2019.1013...
Diagnosis of the allergic asthma phenotype does not depend on total serum IgE; serum IgE, although, total serum IgE is used in order to calculate the dose of anti-IgE for the treatment of patients with severe asthma.

EosIS and EosPB

Induced sputum (IS) is a noninvasive method that allows quantification of airway inflammatory cells130130 Fitzpatrick AM. Biomarkers of asthma and allergic airway diseases. Ann Allergy Asthma Immunol. 2015;115(5):335-340. https://doi.org/10.1016/j.anai.2015.09.003
https://doi.org/10.1016/j.anai.2015.09.0...
,131131 Medrek SK, Parulekar AD, Hanania NA. Predictive Biomarkers for Asthma Therapy. Curr Allergy Asthma Rep. 2017;17(10):69. https://doi.org/10.1007/s11882-017-0739-5
https://doi.org/10.1007/s11882-017-0739-...
and, consequently, identification of different phenotypes, although the cutoff point to characterize T2-high eosinophilic inflammation in asthma varies across studies (≥ 2% or ≥ 3%).44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
https://ginasthma.org/wp-content/uploads...
,132132 Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013;13:11. https://doi.org/10.1186/1471-2466-13-11
https://doi.org/10.1186/1471-2466-13-11...

In a study analyzing a database from the Belgian Severe Asthma Registry,132132 Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013;13:11. https://doi.org/10.1186/1471-2466-13-11
https://doi.org/10.1186/1471-2466-13-11...
55% and 21% of the patients, respectively, were found to have eosinophilic and nonesosinophilic asthma. In Brazil, the prevalence of inflammatory phenotypes in patients with severe asthma varies across cohorts, the eosinophilic phenotype having predominated in one study7070 de Carvalho-Pinto RM, Cukier A, Angelini L, Antonangelo L, Mauad T, Dolhnikoff M, et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respir Med. 2012;106(1):47-56. https://doi.org/10.1016/j.rmed.2011.08.013
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and the noneosinophilic phenotype having predominated in another one.133133 de Farias CF, Amorim MM, Dracoulakis M, Caetano LB, Santoro IL, Fernandes AL. Nasal lavage, blood or sputum: Which is best for phenotyping asthma?. Respirology. 2017;22(4):671-677. https://doi.org/10.1111/resp.12958
https://doi.org/10.1111/resp.12958...

An increased percentage of EosIS (≥ 2% or ≥ 3%) is a predictor of response to ICS and OCS,134134 Cowan DC, Taylor DR, Peterson LE, Cowan JO, Palmay R, Williamson A, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol. 2015;135(4):877-883.e1. https://doi.org/10.1016/j.jaci.2014.10.026
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as well as of uncontrolled asthma and an increased risk of exacerbations.135135 Pizzichini MMM, Rocha CC, de Souza Tavares MG, Steidle LJM, Maureci da Silva R, Dal Pizzol F, et al. How does the GINA definition of control correlate with quality of life and sputum cellularity?. ERJ Open Res. 2019;5(1):00146-2018. https://doi.org/10.1183/23120541.00146-2018
https://doi.org/10.1183/23120541.00146-2...
The use of a therapeutic approach to maintain the percentage of EosIS below 3% has been reported to reduce the risk of exacerbations in comparison with standard management.136136 Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax. 2012;67(3):199-208. https://doi.org/10.1136/thx.2010.135574
https://doi.org/10.1136/thx.2010.135574...

137 Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715-1721. https://doi.org/10.1016/S0140-6736(02)11679-5
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-138138 Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemière C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483-494. https://doi.org/10.1183/09031936.06.00137704
https://doi.org/10.1183/09031936.06.0013...

Difficulties in implementing IS in clinical practice have led to a search for surrogate markers,131131 Medrek SK, Parulekar AD, Hanania NA. Predictive Biomarkers for Asthma Therapy. Curr Allergy Asthma Rep. 2017;17(10):69. https://doi.org/10.1007/s11882-017-0739-5
https://doi.org/10.1007/s11882-017-0739-...
EosPB therefore being proposed as a simpler, cheaper, and more widely available option. Although EosPB counts partially correlate with EosIS counts,139139 Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70(2):115-120. https://doi.org/10.1136/thoraxjnl-2014-205634
https://doi.org/10.1136/thoraxjnl-2014-2...
eosinophilia in blood is also associated with increased severity and an increased risk of asthma exacerbation.140140 Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med. 2015;3(11):849-858. https://doi.org/10.1016/S2213-2600(15)00367-7
https://doi.org/10.1016/S2213-2600(15)00...
There is also evidence that an elevated EosPB count is associated with a better response to ICS.141141 Silva JN, Rocha A, de Souza IA, Athanazio R, Ponte EV. Does peripheral blood eosinophil count predict lung function improvement in adult subjects with asthma? Ann Allergy Asthma Immunol. 2021;S1081-1206(21)00413-0. https://doi.org/10.1016/j.anai.2021.05.024
https://doi.org/10.1016/j.anai.2021.05.0...

Caution is needed when interpreting EosPB counts because eosinophilia in blood can be caused by different diseases,142142 Gibson PG. Variability of blood eosinophils as a biomarker in asthma and COPD. Respirology. 2018;23(1):12-13. https://doi.org/10.1111/resp.13200
https://doi.org/10.1111/resp.13200...
can vary over time,143143 Lugogo NL, Kreindler JL, Martin UJ, Cook B, Hirsch I, Trudo FJ. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Ann Allergy Asthma Immunol. 2020;125(2):171-176. https://doi.org/10.1016/j.anai.2020.04.011
https://doi.org/10.1016/j.anai.2020.04.0...
and can decrease with the use of a corticosteroid, especially OCS.144144 Spector SL, Tan RA. Is a single blood eosinophil count a reliable marker for "eosinophilic asthma?". J Asthma. 2012;49(8):807-810. https://doi.org/10.3109/02770903.2012.713428
https://doi.org/10.3109/02770903.2012.71...
In Brazil, a controlled study of individuals without asthma showed that major factors associated with increased EosPB were atopy, allergic rhinitis, and smoking.145145 Kwon N, Pizzichini E, Bansal AT, Albers FC, Barnes N, Rile JH, et al. Factors that affect blood eosinophil counts in a non-asthmatic population: Post hoc analysis of data from Brazil. World Allergy Organ J. 2020;13(5):100119. https://doi.org/10.1016/j.waojou.2020.100119
https://doi.org/10.1016/j.waojou.2020.10...
Therefore, EosPB counts must be interpreted in the context of medical conditions and factors that can potentially influence EosPB levels.

For patients with severe asthma, the GINA suggests an EosPB count of ≥ 150 cells/µL as a cutoff point for detection of T2-high inflammation. Given the variability of EosPB counts, they should be performed at least three times and with the lowest possible dose of OCS.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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FeNO

FeNO is a noninvasive measurement of airway inflammation. An elevated FeNO is a marker of eosinophilic inflammation.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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Although elevated FeNO and EosPB commonly occur concomitantly, these biomarkers represent different aspects of T2-high inflammation.146146 Menzies-Gow A, Mansur AH, Brightling CE. Clinical utility of fractional exhaled nitric oxide in severe asthma management. Eur Respir J. 2020;55(3):1901633. https://doi.org/10.1183/13993003.01633-2019
https://doi.org/10.1183/13993003.01633-2...
An elevated FeNO correlates with increased lung function impairment147147 Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602-615. https://doi.org/10.1164/rccm.9120-11ST
https://doi.org/10.1164/rccm.9120-11ST...
and more severe exacerbations.148148 Mansur AH, Srivastava S, Sahal A. Disconnect of type 2 biomarkers in severe asthma; dominated by FeNO as a predictor of exacerbations and periostin as predictor of reduced lung function. Respir Med. 2018;143:31-38. https://doi.org/10.1016/j.rmed.2018.08.005
https://doi.org/10.1016/j.rmed.2018.08.0...
,149149 Price DB, Bosnic-Anticevich S, Pavord ID, Roche N, Halpin DMG, Bjermer L, et al. Association of elevated fractional exhaled nitric oxide concentration and blood eosinophil count with severe asthma exacerbations. Clin Transl Allergy. 2019;9:41. https://doi.org/10.1186/s13601-019-0282-7
https://doi.org/10.1186/s13601-019-0282-...

FeNO cutoff points vary across studies. Some guidelines state that, in adults, FeNO < 25 ppb is normal, FeNO > 50 ppb is high, and FeNO values of 25-50 ppb should be interpreted in association with clinical factors at the time of evaluation.147147 Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602-615. https://doi.org/10.1164/rccm.9120-11ST
https://doi.org/10.1164/rccm.9120-11ST...
,150150 Heffler E, Carpagnano GE, Favero E, Guida G, Maniscalco M, Motta A, 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;15(1):36. https://doi.org/10.4081/mrm.2020.36
https://doi.org/10.4081/mrm.2020.36...
,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...
However, according to the GINA, FeNO ≥ 20 ppb characterizes T2-high inflammation.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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In addition to the wide variability of FeNO cutoff points, FeNO can increase or decrease as a result of factors such as use of ICS, OCS, or a combination of the two, as well as nonadherence to treatment.152152 Cloutier MM, Dixon AE, Krishnan JA, Lemanske RF Jr, Pace W, Schatz M. Managing Asthma in Adolescents and Adults: 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program. JAMA. 2020;324(22):2301-2317. https://doi.org/10.1001/jama.2020.21974
https://doi.org/10.1001/jama.2020.21974...

PHENOTYPING

Severe asthma is a complex heterogeneous disease with several different pathophysiological mechanisms and phenotypes, the identification of which can lead to successful targeted therapy.11 Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?. Physiol Rev. 2020;100(3):983-1017. https://doi.org/10.1152/physrev.00023.2019
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A phenotype is defined as the observable characteristics of an organism that result from the interaction of its genotype with the environment.

Phenotyping based on the cellularity of the inflammatory response has resulted in the recognition of two major asthma phenotypes, namely, eosinophilic asthma and noneosinophilic asthma. Noneosinophilic asthma is associated with neutrophilic or paucigranulocytic inflammation.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...
Eosinophilic asthma is the more common phenotype, being found in most (70%) of the patients without previous treatment for asthma (i.e., treatment-naïve patients)153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...

154 Lee VS, Pizzichini MMM, Marques LJ, Ferreira SC, Pizzichini E. Airway inflammation in steroid-naïve asthmatics: characteristics of induced sputum. J Bras Pneumol. 2003;29(4):188-195. https://doi.org/10.1590/S0102-35862003000400005. https://doi.org/10.1590/S0102-35862003000400005
https://doi.org/10.1590/S0102-3586200300...
-155155 Louis R, Sele J, Henket M, et al. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy. 2002;57(10):907-912. https://doi.org/10.1034/j.1398-9995.2002.23608.x
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and in half of those undergoing treatment with corticosteroids.132132 Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013;13:11. https://doi.org/10.1186/1471-2466-13-11
https://doi.org/10.1186/1471-2466-13-11...
,156156 Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment. Thorax. 2002;57(2):178-182. https://doi.org/10.1136/thorax.57.2.178
https://doi.org/10.1136/thorax.57.2.178...

Severe asthma can also be classified by molecular phenotype (endotype), which is related to identification of a specific pathophysiological pathway for a given phenotype. The characteristics of a clinically useful endotype are as follows: a plausible molecular mechanism; longitudinal stability; correlation with relevant clinical outcomes; association with a biomarker that characterizes this pathophysiological pathway and that can be measured in practice; and response to targeted therapy.11 Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?. Physiol Rev. 2020;100(3):983-1017. https://doi.org/10.1152/physrev.00023.2019
https://doi.org/10.1152/physrev.00023.20...

T2-high asthma is the best characterized endotype, resulting from the interaction between innate and adaptive immunity.157157 Busse WW, Kraft M, Rabe KF, Deniz Y, Rowe PJ, Ruddy M, et al. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation. Eur Respir J. 2021;58(2):2003393. https://doi.org/10.1183/13993003.03393-2020
https://doi.org/10.1183/13993003.03393-2...
The T2-high endotype was initially designated Th2-high in recognition of the central role that Th2 lymphocytes play in the adaptive inflammatory response, with production of IL-4, IL-5, and IL-13 (Figure 2). However, the Th2-high asthma endotype was later designated T2-high asthma after evidence that innate immunity also plays an important role in this inflammatory pathway, with group 2 innate lymphoid cells (ILC2) producing large quantities of IL-5 and IL-13.158158 Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019;50(4):975-991. https://doi.org/10.1016/j.immuni.2019.03.018
https://doi.org/10.1016/j.immuni.2019.03...
,159159 Peters MC, Wenzel SE. Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma. Lancet. 2020;395(10221):371-383. https://doi.org/10.1016/S0140-6736(19)33005-3
https://doi.org/10.1016/S0140-6736(19)33...

Figure 2
Inflammatory mechanisms of T2-high asthma phenotype. The figure schematically represents the main cells and cytokines involved in the adaptive and innate inflammatory response of the T2-high phenotype in severe asthma. In genetically susceptible individuals, inhalation of allergens (adaptive immunity), smoke, bacteria, and viruses (innate immunity) initiates and perpetuates the T2-high inflammatory cascade. TSLP: thymic stromal lymphopoietin; TCR: T-cell receptor; MHC2: major histocompatibility complex class 2; GATA3: transcription factor encoded by the GATA3 gene; ILC2: group 2 innate lymphoid cells; PGD2: prostaglandin D2; ECP: eosinophil cationic protein; MBP: major basic protein; EPO: eosinophil peroxidase.

The T2-high inflammatory response is mediated by Th2 lymphocytes and ILC2, as well as by IgE-producing B lymphocytes, eosinophils, mast cells, and basophils.128128 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65. https://doi.org/10.1038/nri3786
https://doi.org/10.1038/nri3786...
,158158 Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019;50(4):975-991. https://doi.org/10.1016/j.immuni.2019.03.018
https://doi.org/10.1016/j.immuni.2019.03...
Whether the innate or adaptive immune response will predominate in the inflammatory response of asthma depends on the phenotype (i.e., allergic or nonallergic asthma).160160 Porsbjerg CM, Sverrild A, Lloyd CM, Menzies-Gow AN, Bel EH. Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics. Eur Respir J. 2020;56(5):2000260. https://doi.org/10.1183/13993003.00260-2020
https://doi.org/10.1183/13993003.00260-2...

IL-4 is essential for the maturation of naïve lymphocytes into Th2 lymphocytes and for the switch of B lymphocytes to IgE-producing B lymphocytes. IgE binds to high-affinity receptors on basophils and mast cells, promoting their degranulation and thus releasing several proinflammatory mediators.161161 Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205-217. https://doi.org/10.1038/nri2273
https://doi.org/10.1038/nri2273...
IL-5 is responsible for the recruitment, maturation, activation, and survival of eosinophils, which secrete several proinflammatory cytokines and chemokines.128128 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65. https://doi.org/10.1038/nri3786
https://doi.org/10.1038/nri3786...
IL-13 promotes fibrosis and smooth muscle remodeling and, together with IL-4, regulates IgE production and induces goblet cell hyperplasia, with increased mucus production. Mast cells produce prostaglandin D2, which binds to its receptor on Th2 lymphocytes, leading to the release of IL-5 and IL-9, which increase mucus production.128128 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65. https://doi.org/10.1038/nri3786
https://doi.org/10.1038/nri3786...
,160160 Porsbjerg CM, Sverrild A, Lloyd CM, Menzies-Gow AN, Bel EH. Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics. Eur Respir J. 2020;56(5):2000260. https://doi.org/10.1183/13993003.00260-2020
https://doi.org/10.1183/13993003.00260-2...
,162162 Hall S, Agrawal DK. Key mediators in the immunopathogenesis of allergic asthma. Int Immunopharmacol. 2014;23(1):316-329. https://doi.org/10.1016/j.intimp.2014.05.034
https://doi.org/10.1016/j.intimp.2014.05...
IL-4 and IL-13 also induce the expression of adhesion molecules in vascular endothelial cells, thus promoting the transmigration of eosinophils from the bloodstream to the airway tissue, which results in accumulation of eosinophils in the bronchial mucosa.163163 Doran E, Cai F, Holweg CTJ, Wong K, Brumm J, Arron JR. Interleukin-13 in Asthma and Other Eosinophilic Disorders. Front Med (Lausanne). 2017;4:139. https://doi.org/10.3389/fmed.2017.00139
https://doi.org/10.3389/fmed.2017.00139...

Damage to the airway epithelium-the interface between the external and internal environments-leads to increased expression and release of IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), all of which stimulate ILC2 to produce IL-4 and IL-13 (Figure 2). Epithelial cell-derived cytokines, also known as alarmins, play an important mediating role in the inflammatory response to a variety of external stimuli, including allergens, viruses, bacteria, smoke, and pollutants.128128 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65. https://doi.org/10.1038/nri3786
https://doi.org/10.1038/nri3786...
,158158 Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019;50(4):975-991. https://doi.org/10.1016/j.immuni.2019.03.018
https://doi.org/10.1016/j.immuni.2019.03...
,160160 Porsbjerg CM, Sverrild A, Lloyd CM, Menzies-Gow AN, Bel EH. Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics. Eur Respir J. 2020;56(5):2000260. https://doi.org/10.1183/13993003.00260-2020
https://doi.org/10.1183/13993003.00260-2...
,164164 McGregor MC, Krings JG, Nair P, Castro M. Role of Biologics in Asthma. Am J Respir Crit Care Med. 2019;199(4):433-445. https://doi.org/10.1164/rccm.201810-1944CI
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,165165 van Rijt L, von Richthofen H, van Ree R. Type 2 innate lymphoid cells: at the cross-roads in allergic asthma. Semin Immunopathol. 2016;38(4):483-496. https://doi.org/10.1007/s00281-016-0556-2
https://doi.org/10.1007/s00281-016-0556-...
At the same time, inadequate epithelial repair occurs, resulting in airway remodeling. In turn, airway remodeling leads to an increase in proinflammatory mediators, resulting in more inflammation and epithelial damage (Figure 2).157157 Busse WW, Kraft M, Rabe KF, Deniz Y, Rowe PJ, Ruddy M, et al. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation. Eur Respir J. 2021;58(2):2003393. https://doi.org/10.1183/13993003.03393-2020
https://doi.org/10.1183/13993003.03393-2...

The T2-high endotype is characterized by increased expression of IL-4, IL-5, and IL-13; airway and blood eosinophilia; airway epithelial dysfunction; and IgE production in the allergic phenotype.11 Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?. Physiol Rev. 2020;100(3):983-1017. https://doi.org/10.1152/physrev.00023.2019
https://doi.org/10.1152/physrev.00023.20...
,158158 Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019;50(4):975-991. https://doi.org/10.1016/j.immuni.2019.03.018
https://doi.org/10.1016/j.immuni.2019.03...
This results in BHR, airflow obstruction, and exacerbations. The T2-high endotype is characterized by elevated biomarkers such as EosIS, EosPB, and FeNO.157157 Busse WW, Kraft M, Rabe KF, Deniz Y, Rowe PJ, Ruddy M, et al. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation. Eur Respir J. 2021;58(2):2003393. https://doi.org/10.1183/13993003.03393-2020
https://doi.org/10.1183/13993003.03393-2...
It accounts for 50-75% of severe asthma cases.166166 Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma [published correction appears in Am J Respir Crit Care Med. 2009 Oct 15;180(8):796]. Am J Respir Crit Care Med. 2009;180(5):388-395. https://doi.org/10.1164/rccm.200903-0392OC
https://doi.org/10.1164/rccm.200903-0392...
,167167 Jackson DJ, Busby J, Pfeffer PE, Menzies-Gow A, Brown T, Gore R, et al. Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era. Thorax. 2021;76(3):220-227. https://doi.org/10.1136/thoraxjnl-2020-215168
https://doi.org/10.1136/thoraxjnl-2020-2...

Although the T2-low endotype has yet to be completely defined, it is characterized by the absence of a T2-high inflammatory response. The pathophysiology of T2-low asthma has yet to be fully understood and is possibly associated with the activation of innate and acquired immune responses. The T2-low endotype includes neutrophilic asthma and paucigranulocytic asthma.168168 Hinks TSC, Levine SJ, Brusselle GG. Treatment options in type-2 low asthma. Eur Respir J. 2021;57(1):2000528. https://doi.org/10.1183/13993003.00528-2020
https://doi.org/10.1183/13993003.00528-2...
In patients with T2-low asthma, the gene-external trigger interaction can result in the production of alarmins (IL-33 and TSLP), which stimulate Th17 lymphocytes to produce IL-6, IL-8, and IL-17, all of which playing an important role in the attraction and stimulation of neutrophils. In addition, activation of Th1 lymphocytes can occur, stimulating neutrophilic inflammation via the production of TNF-α and INF-γ.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...

Severe allergic eosinophilic asthma

Patients with allergic eosinophilic asthma have atopy, variable airflow obstruction, and bronchodilator response. They also have good response to ICS and present with eosinophilic inflammation associated with elevated total serum IgE levels and/or FeNO (≥ 20 ppb).11 Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?. Physiol Rev. 2020;100(3):983-1017. https://doi.org/10.1152/physrev.00023.2019
https://doi.org/10.1152/physrev.00023.20...
,153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...
Patients with severe allergic eosinophilic asthma present with frequent exacerbations and do not always respond well to high-dose ICS alone or in combination with OCS, incomplete airflow reversibility occurring in some cases.

A confirmed diagnosis of severe allergic eosinophilic asthma requires an objective measure of atopy (skin prick testing and/or allergen-specific IgE in peripheral blood) and an increase in EosIS (≥ 2-3%) and/or EosPB (≥ 150 cells/µL).44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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From a pathophysiological standpoint, airway inflammation in T2-high allergic asthma begins with repeated exposure of epithelial cells to inhaled allergens; in genetically susceptible individuals, this triggers an inflammatory response that is predominantly mediated by Th2 lymphocytes, IgE-producing B lymphocytes, eosinophils, mast cells, and basophils.128128 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65. https://doi.org/10.1038/nri3786
https://doi.org/10.1038/nri3786...
In this inflammatory pathway, dendritic cells present inhaled antigens to naïve T lymphocytes, which, in turn, switch to Th2 lymphocytes and starts producing IgE IL-4, IL-5, and IL-13. IL-4 stimulates the switch of B lymphocytes (Figure 2), which begin to produce IgE. IgE binds to high-affinity receptors on mast cells and basophils, which release inflammatory mediators (leukotrienes, prostaglandin, and histamine).169169 Brusselle G, Bracke K. Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11 Suppl 5:S322-S328. https://doi.org/10.1513/AnnalsATS.201403-118AW
https://doi.org/10.1513/AnnalsATS.201403...

Severe nonallergic eosinophilic asthma

Patients with nonallergic eosinophilic asthma usually have late-onset asthma associated with eosinophilic inflammation but not with atopy. This phenotype predominates in females and in asthma patients with chronic rhinosinusitis, with or without nasal polyposis, and/or obesity. In addition, these patients tend to have more severe airflow limitation, frequent exacerbations, and poorer response to corticosteroids.11 Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?. Physiol Rev. 2020;100(3):983-1017. https://doi.org/10.1152/physrev.00023.2019
https://doi.org/10.1152/physrev.00023.20...
,153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...
,158158 Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019;50(4):975-991. https://doi.org/10.1016/j.immuni.2019.03.018
https://doi.org/10.1016/j.immuni.2019.03...
The severe nonallergic eosinophilic asthma phenotype is confirmed by an increase in the percentage of EosIS (≥ 2-3%) and/or EosPB (≥ 150 cells/μL) in the absence of parameters for atopy.

In severe nonallergic eosinophilic asthma, ILC2 plays an important role (Figure 2). Nonallergic triggers, such as environmental or occupational pollutants, irritants, or microbes, stimulate airway epithelial cells to produce alarmins (TSLP, IL-33, and IL-25) which, by activating ILC2, stimulate the production of IL-5 and IL-13 that induce eosinophilic inflammation.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...
,169169 Brusselle G, Bracke K. Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11 Suppl 5:S322-S328. https://doi.org/10.1513/AnnalsATS.201403-118AW
https://doi.org/10.1513/AnnalsATS.201403...

Severe noneosinophilic asthma

The T2-low endotype includes a heterogeneous group of asthma patients. In general, these patients present with highly symptomatic, late-onset disease, no atopy, and poor response to corticosteroids. This endotype is often associated with obesity.

The prevalence of severe noneosinophilic asthma phenotypes (neutrophilic or paucigranulocytic) varies between 30% and 50%.167167 Jackson DJ, Busby J, Pfeffer PE, Menzies-Gow A, Brown T, Gore R, et al. Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era. Thorax. 2021;76(3):220-227. https://doi.org/10.1136/thoraxjnl-2020-215168
https://doi.org/10.1136/thoraxjnl-2020-2...
,170170 Schleich F, Brusselle G, Louis R, Vandenplas O, Michils A, Pilette C, et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir Med. 2014;108(12):1723-1732. https://doi.org/10.1016/j.rmed.2014.10.007
https://doi.org/10.1016/j.rmed.2014.10.0...
The absence of T2 inflammatory characteristics may be due to several factors unrelated to the asthma endotype. Therefore, it is recommended that the diagnosis of severe noneosinophilic asthma be made only after excluding situations that may interfere with eosinophilia, such as the effect of corticosteroid treatment,137137 Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715-1721. https://doi.org/10.1016/S0140-6736(02)11679-5
https://doi.org/10.1016/S0140-6736(02)11...
,138138 Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemière C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483-494. https://doi.org/10.1183/09031936.06.00137704
https://doi.org/10.1183/09031936.06.0013...
,171171 Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65(5):384-390. https://doi.org/10.1136/thx.2009.126722
https://doi.org/10.1136/thx.2009.126722...
recent infections,172172 Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol. 1995;95(4):843-852. https://doi.org/10.1016/S0091-6749(95)70128-1
https://doi.org/10.1016/S0091-6749(95)70...
,173173 Pizzichini MM, Pizzichini E, Efthimiadis A, Chauhan AJ, Johnston SL, Hussack P, et al. Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. Am J Respir Crit Care Med. 1998;158(4):1178-1184. https://doi.org/10.1164/ajrccm.158.4.9712082
https://doi.org/10.1164/ajrccm.158.4.971...
and exposure to occupational irritants or pollutants.174174 Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax. 2002;57(7):643-648. https://doi.org/10.1136/thorax.57.7.643
https://doi.org/10.1136/thorax.57.7.643...
,175175 Sze E, Bhalla A, Nair P. Mechanisms and therapeutic strategies for non-T2 asthma. Allergy. 2020;75(2):311-325. https://doi.org/10.1111/all.13985
https://doi.org/10.1111/all.13985...

Neutrophilic asthma

Neutrophilic asthma, whose pathophysiology is poorly understood, also involves innate and adaptive immunities. The diagnosis of neutrophilic asthma is confirmed by IS cell count confirming the absence of eosinophilia and the presence of neutrophilia (≥ 40-70%) more than once.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...
,176176 Carr TF, Zeki AA, Kraft M. Eosinophilic and Noneosinophilic Asthma. Am J Respir Crit Care Med. 2018;197(1):22-37. https://doi.org/10.1164/rccm.201611-2232PP
https://doi.org/10.1164/rccm.201611-2232...
Neutrophilic IS is commonly associated with frequent respiratory infections, smoking, exposure to environmental or occupational pollutants, and, in some cases, chronic treatment with corticosteroids.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...
In individuals with neutrophilic asthma, the gene-external trigger interaction results in the production of alarmins (IL-33 and TSLP), stimulating Th17 lymphocytes to produce IL-6, IL-8, and IL-17, which play an important role in neutrophil attraction and stimulation. In addition, Th1 lymphocyte activation may occur, which also promotes neutrophilic inflammation via TNF-α and INF-γ production.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...

The differential diagnosis of neutrophilic asthma includes persistent bacterial airway infections, nontuberculous mycobacteriosis, cystic fibrosis, primary ciliary dyskinesia, bronchiectasis, primary immunodeficiency, smoking, and COPD.168168 Hinks TSC, Levine SJ, Brusselle GG. Treatment options in type-2 low asthma. Eur Respir J. 2021;57(1):2000528. https://doi.org/10.1183/13993003.00528-2020
https://doi.org/10.1183/13993003.00528-2...

Paucigranulocytic asthma

Paucigranulocytic asthma is uncommon. Diagnosis is made by the absence of eosinophilia and neutrophilia in IS. This pattern does not exclude airway inflammation, since this phenotype is accompanied by smooth muscle hypertrophy, remodeling, goblet cell hyperplasia, and BHR.153153 Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017;377(10):965-976. https://doi.org/10.1056/NEJMra1608969
https://doi.org/10.1056/NEJMra1608969...

PHARMACOLOGICAL TREATMENT OF SEVERE ASTHMA IN ADULTS

In recent years, important changes have taken place in the management of severe asthma in parallel with a better understanding of the pathophysiology and phenotyping of the disease. Current recommendations22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
https://ginasthma.org/wp-content/uploads...
,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...
for the treatment of severe asthma include high doses of ICS+LABA as the preferred treatment. In patients with uncontrolled asthma, LAMA and/or biologicals can be associated.

LAMA

LAMAs are long-acting bronchodilators that inhibit muscarinic acetylcholine receptors located in the airways. Consequently, they cause relaxation, decreased bronchial muscle tone, and decreased mucus secretion.177177 Cazzola M, Rogliani P, Matera MG. The latest on the role of LAMAs in asthma. J Allergy Clin Immunol. 2020;146(6):1288-1291. https://doi.org/10.1016/j.jaci.2020.06.014
https://doi.org/10.1016/j.jaci.2020.06.0...
Several LAMAs (tiotropium, aclidinium, glycopyrronium, and umeclidinium bromides) are available or under study for the treatment of asthma.

Tiotropium bromide

At present, tiotropium bromide is the only LAMA approved for use in Brazil for the treatment of asthma. Evidence for tiotropium prescription as an additional treatment for uncontrolled, moderate-to-severe asthma (steps IV and V) are based on randomized controlled trials (RCTs) in adults and adolescents,178178 Kerstjens HA, Disse B, Schröder-Babo W, Bantje TA, Gahlemann M, Sigmund R, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2):308-314. https://doi.org/10.1016/j.jaci.2011.04.039
https://doi.org/10.1016/j.jaci.2011.04.0...

179 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):1198-1207. https://doi.org/10.1056/NEJMoa1208606
https://doi.org/10.1056/NEJMoa1208606...
-180180 Hamelmann E, Bernstein JA, Vandewalker M, Moroni-Zentgraf P, Verri D, Unseld A, et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur Respir J. 2017;49(1):1601100. https://doi.org/10.1183/13993003.01100-2016
https://doi.org/10.1183/13993003.01100-2...
as well as in children.181181 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):1277-1287. https://doi.org/10.1016/j.jaci.2017.01.014
https://doi.org/10.1016/j.jaci.2017.01.0...
In adults with severe uncontrolled asthma, the addition of tiotropium significantly increased lung function and decreased exacerbations.182182 Halpin DMG, Hamelmann EH, Frith PA, Moroni-Zentgraf PM, van Hecke B, Unseld A, et al. Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis. Pulm Ther. 2020;6(1):131-140. https://doi.org/10.1007/s41030-020-00113-w
https://doi.org/10.1007/s41030-020-00113...
This effect was similarly reported in two other studies in adolescents178178 Kerstjens HA, Disse B, Schröder-Babo W, Bantje TA, Gahlemann M, Sigmund R, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2):308-314. https://doi.org/10.1016/j.jaci.2011.04.039
https://doi.org/10.1016/j.jaci.2011.04.0...
and children179179 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):1198-1207. https://doi.org/10.1056/NEJMoa1208606
https://doi.org/10.1056/NEJMoa1208606...
with severe asthma. In adults, these results were independent of baseline characteristics,183183 Casale TB, Aalbers R, Bleecker ER, Meltzer EO, Zaremba-Pechmann L, de la Hoz A, et al. Tiotropium Respimat(r) add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics. Respir Med. 2019;158:97-109. https://doi.org/10.1016/j.rmed.2019.09.014
https://doi.org/10.1016/j.rmed.2019.09.0...
eosinophil counts, and serum IgE levels.184184 Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, et al. Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype. J Allergy Clin Immunol Pract. 2018;6(3):923-935.e9. https://doi.org/10.1016/j.jaip.2017.08.037
https://doi.org/10.1016/j.jaip.2017.08.0...

Tiotropium is approved for the treatment of asthma of patients older than 6 years of age at a dose of 5 µg/day. This medication is recommended as an additional medication for patients with uncontrolled asthma who are already receiving moderate or high doses of ICS+LABA (steps IV or V).22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
https://ginasthma.org/wp-content/uploads...
Tiotropium has been shown to be a safe drug when added to other medications in asthma treatment.178178 Kerstjens HA, Disse B, Schröder-Babo W, Bantje TA, Gahlemann M, Sigmund R, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2):308-314. https://doi.org/10.1016/j.jaci.2011.04.039
https://doi.org/10.1016/j.jaci.2011.04.0...

Other LAMAs

Evidence from RCTs suggests that other combinations of ICS+LABA or ultra LABA (indacaterol and vilanterol)+LAMA (umeclidinium and glycopyrronium) may be treatment options for severe asthma.185185 Kerstjens HAM, Maspero J, Chapman KR, van Zyl-Smit RN, Hosoe M, Tanase AM, et al. Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study. Lancet Respir Med. 2020;8(10):1000-1012. https://doi.org/10.1016/S2213-2600(20)30190-9
https://doi.org/10.1016/S2213-2600(20)30...

186 Lee LA, Bailes Z, Barnes N, Boulet LP, Edwards D, Fowler A, et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial [published correction appears in Lancet Respir Med. 2021 Jan 4;:]. Lancet Respir Med. 2021;9(1):69-84. https://doi.org/10.1016/S2213-2600(20)30389-1
https://doi.org/10.1016/S2213-2600(20)30...
-187187 Virchow JC, Kuna P, Paggiaro P, Papi A, Singh D, Corre S, 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;394(10210):1737-1749. https://doi.org/10.1016/S0140-6736(19)32215-9
https://doi.org/10.1016/S0140-6736(19)32...

Biologicals

In Brazil, four biologicals are approved for use in the treatment of severe asthma (omalizumab, mepolizumab, benralizumab, and dupilumab). Given the heterogeneity and complexity of severe asthma and assuming that the selected agent should target a particular phenotype/endotype (Chart 1), this approach requires experience. In addition, treatment with biologicals depends on differences in the local health care system, reimbursement policies, and accessibility; therefore, specialists should be responsible for this management.

Chart 1
Endotypes, phenotypes, and biomarkers.

Omalizumab

Omalizumab is a humanized anti-IgE monoclonal antibody that acts as an inhibitor of free IgE binding to its high-affinity receptor on the membrane of mast cells and basophils. By means of this mechanism of action, IgE cannot act on effector cells, blocking degranulation and the consequent release of inflammatory mediators. It also promotes downregulation188188 Domingo C. Omalizumab for severe asthma: efficacy beyond the atopic patient?. Drugs. 2014;74(5):521-533. https://doi.org/10.1007/s40265-014-0203-y
https://doi.org/10.1007/s40265-014-0203-...
of these membrane receptors, making them less numerous. Omalizumab does not alter IgE production, but it blocks free circulating IgE, forming immune complexes that will be eliminated by the reticuloendothelial system.189189 Pelaia C, Calabrese C, Terracciano R, de Blasio F, Vatrella A, Pelaia G. Omalizumab, the first available antibody for biological treatment of severe asthma: more than a decade of real-life effectiveness. Ther Adv Respir Dis. 2018;12:1753466618810192. https://doi.org/10.1177/1753466618810192
https://doi.org/10.1177/1753466618810192...
It is indicated for the treatment of severe allergic asthma (step V).22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
https://ginasthma.org/wp-content/uploads...
,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...

Efficacy and effectiveness

Pivotal studies on omalizumab were carried out when the understanding of severe asthma differed from the current one. The most important study that comes close to the concepts used today is that by Humbert et al.190190 Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309-316. https://doi.org/10.1111/j.1398-9995.2004.00772.x
https://doi.org/10.1111/j.1398-9995.2004...
In this scenario, adding omalizumab to the combination of high-dose ICS+LABA reduced exacerbations by 26% and improved quality of life. However, a real-life study191191 Humbert M, Taillé 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):1702523. https://doi.org/10.1183/13993003.02523-2017
https://doi.org/10.1183/13993003.02523-2...
showed that the inclusion of omalizumab for the treatment of severe asthma caused a 50-60% reduction in the exacerbation rate and a 50% reduction in the OCS dose.

A systematic review192192 Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559. https://doi.org/10.1002/14651858.CD003559.pub4
https://doi.org/10.1002/14651858.CD00355...
that included 25 RCTs involving patients with moderate-to-severe allergic asthma showed that omalizumab, when compared with placebo, reduced exacerbations and hospitalizations and allowed a small reduction in the ICS dose. Another review193193 MacDonald KM, Kavati A, Ortiz B, Alhossan A, Lee CS, Abraham I. Short- and long-term real-world effectiveness of omalizumab in severe allergic asthma: systematic review of 42 studies published 2008-2018. Expert Rev Clin Immunol. 2019;15(5):553-569. https://doi.org/10.1080/1744666X.2019.1574571
https://doi.org/10.1080/1744666X.2019.15...
that included 42 real-life studies in adults and children with asthma showed that the addition of omalizumab in the treatment improved asthma control, reduced ER visits and hospitalizations, as well as the dose of ICS (mean reduction of 32% in the ICS dose). On average, 83% of patients were able to reduce or eliminate the use of OCS.

Predictors of response

Response to treatment with omalizumab has no predictor or single outcome, although patients with high EosPB and FeNO levels tend to have a better response.194194 Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, 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;187(8):804-811. https://doi.org/10.1164/rccm.201208-1414OC
https://doi.org/10.1164/rccm.201208-1414...
The GINA suggests that EosPB ≥ 260 cells/µL and/or FeNO ≥ 20 ppb can be used as predictors of good response.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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This document, in line with those by the ATS/ERS,33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
https://doi.org/10.1183/09031936.0020201...
the British Thoracic Society,195195 Healthcare Improvement Scotland [homepage on the Internet]. Edinburgh: Scottish Intercollegiate Guidelines Network [cited 2019 Mar 01]. British guideline on the management of asthma. Available from: https://www.sign.ac.uk/sign-158-british-guideline-on-themanagement-of-asthma.html
https://www.sign.ac.uk/sign-158-british-...
and The National Institute for Health and Care Excellence,196196 National Institute for Health and Care Excellence [homepage on the Internet]. London: the Institute; c2017 [cited 2019 May 01]. Asthma: diagnosis, monitoring and chronic asthma management. [Adobe Acrobat document, 39p.]. Available from: https://www.nice.org.uk/guidance/ng80/resources/asthma-diagnosismonitoring-and-chronicasthma-management-pdf-1837687975621
https://www.nice.org.uk/guidance/ng80/re...
questions the use of these biomarkers to assess the response to omalizumab, because the abovementioned cutoff points were derived from a retrospective analysis194194 Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, 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;187(8):804-811. https://doi.org/10.1164/rccm.201208-1414OC
https://doi.org/10.1164/rccm.201208-1414...
and are in disagreement with the results of a real-life study,191191 Humbert M, Taillé 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):1702523. https://doi.org/10.1183/13993003.02523-2017
https://doi.org/10.1183/13993003.02523-2...
which found no differences in the effect of omalizumab in patients with severe eosinophilic or noneosinophilic asthma. Therefore, the use of these cutoff values could limit the use of omalizumab to a group of patients who would eventually benefit from this treatment.

Indication

Omalizumab is recommended for patients with severe allergic asthma ≥ 6 years of age. The dose varies depending on patient weight (20-150 kg) and total serum IgE (30-1,500 IU/mL) and is administered subcutaneously every 2 or 4 weeks (Chart 2). However, the baseline IgE level does not characterize atopy and does not predict the response to treatment.197197 Bousquet J, Wenzel S, Holgate S, Lumry W, Freeman P, Fox H. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest. 2004;125(4):1378-1386. https://doi.org/10.1378/chest.125.4.1378
https://doi.org/10.1378/chest.125.4.1378...
In addition, after starting treatment, that level should not be used as an indicator of response.198198 Korn S, Haasler I, Fliedner F, Becher G, Strohner P, Staatz A, et al. Monitoring free serum IgE in severe asthma patients treated with omalizumab. Respir Med. 2012;106(11):1494-1500. https://doi.org/10.1016/j.rmed.2012.07.010
https://doi.org/10.1016/j.rmed.2012.07.0...
It is recommended that the efficacy of omalizumab be evaluated based on clinical outcomes at least 16 weeks after treatment onset.199199 Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2(5):525-36.e1. https://doi.org/10.1016/j.jaip.2014.03.010
https://doi.org/10.1016/j.jaip.2014.03.0...

Chart 2
Biologicals for T2-high severe asthma endotype.

Safety

The most common adverse effects are local reactions. Anaphylaxis can occur in up to 0.2% of patients within the first 2 h of its administration, both in the first and in subsequent applications.200200 Baker DL, Nakamura GR, Lowman HB, Fischer SK. Evaluation of IgE Antibodies to Omalizumab (Xolair(r)) and Their Potential Correlation to Anaphylaxis. AAPS J. 2016;18(1):115-123. https://doi.org/10.1208/s12248-015-9821-x
https://doi.org/10.1208/s12248-015-9821-...
For this reason, it is recommended that the patient be monitored in an environment equipped for the treatment of this complication. The possibility of cardiac and cerebrovascular events should also be monitored.201201 Iribarren C, Rahmaoui A, Long AA, Szefler SJ, Bradley MS, Carrigan G, et al. Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma. J Allergy Clin Immunol. 2017;139(5):1489-1495.e5. https://doi.org/10.1016/j.jaci.2016.07.038
https://doi.org/10.1016/j.jaci.2016.07.0...

Mepolizumab

Mepolizumab is a fully humanized IgG1/k monoclonal antibody with high affinity for the IL-5 ligand, which inhibits IL-5 from binding with its alpha receptor epitope, blocking its activity and, consequently, the eosinophilic inflammatory response.202202 Smith DA, Minthorn EA, Beerahee M. Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Clin Pharmacokinet. 2011;50(4):215-227. https://doi.org/10.2165/11584340-000000000-00000
https://doi.org/10.2165/11584340-0000000...

Efficacy and effectiveness

RCTs have demonstrated that adding mepolizumab to the treatment of patients with severe eosinophilic asthma and frequent exacerbations reduced EosPB and exacerbations.203203 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):651-659. https://doi.org/10.1016/S0140-6736(12)60988-X
https://doi.org/10.1016/S0140-6736(12)60...

204 Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma [published correction appears in N Engl J Med. 2015 Apr 30;372(18):1777]. N Engl J Med. 2014;371(13):1198-1207. https://doi.org/10.1056/NEJMoa1403290
https://doi.org/10.1056/NEJMoa1403290...

205 Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5(5):390-400. https://doi.org/10.1016/S2213-2600(17)30125-X
https://doi.org/10.1016/S2213-2600(17)30...
-206206 Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197. https://doi.org/10.1056/NEJMoa1403291
https://doi.org/10.1056/NEJMoa1403291...
In patients with severe asthma and OCS-dependent, the median OCS dose reduction, in comparison with placebo, was 50%.206206 Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197. https://doi.org/10.1056/NEJMoa1403291
https://doi.org/10.1056/NEJMoa1403291...
These benefits persisted for up to 4.5 years.207207 Khurana S, Brusselle GG, Bel EH, FitzGerald JM, Masoli M, Korn S, et al. Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study. Clin Ther. 2019;41(10):2041-2056.e5. https://doi.org/10.1016/j.clinthera.2019.07.007
https://doi.org/10.1016/j.clinthera.2019...

The effectiveness and safety of mepolizumab have also been proven in real-life studies.207207 Khurana S, Brusselle GG, Bel EH, FitzGerald JM, Masoli M, Korn S, et al. Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study. Clin Ther. 2019;41(10):2041-2056.e5. https://doi.org/10.1016/j.clinthera.2019.07.007
https://doi.org/10.1016/j.clinthera.2019...

208 Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L, et al. Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma. Chest. 2020;158(2):491-500. https://doi.org/10.1016/j.chest.2020.03.042
https://doi.org/10.1016/j.chest.2020.03....
-209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
A British study including 99 patients with EosPB ≥ 300 cells/μL has demonstrated a 54% reduction in exacerbations. The use of mepolizumab reduced OCS doses in corticosteroid-dependent asthma patients, and the use of OCS could be discontinued in 57% of patients. Approximately 73% of patients were classified as responders and 28% as super-responders. Patients with nasal polyposis, better asthma control-determined by the Asthma Control Questionnaire with six questions (ACQ-6)-low BMI, and using OCS have shown to have the best treatment response.208208 Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L, et al. Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma. Chest. 2020;158(2):491-500. https://doi.org/10.1016/j.chest.2020.03.042
https://doi.org/10.1016/j.chest.2020.03....

In a study,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
the inclusion of mepolizumab in the treatment of patients with severe eosinophilic asthma (N = 309) showed that 86% were responders (reduction in symptoms and in exacerbations, as well as improvement in quality of life and lung function). After 12 months of treatment, 24% of the patients were considered super-responders (ACQ-5 < 1.0, no exacerbations, and OCS free).

Predictors of response

The main predictors of response to mepolizumab are EosPB ≥ 150 cells/µL,210210 Albers FC, Licskai C, Chanez P, Bratton DJ, Bradford ES, Yancey SW, 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. https://doi.org/10.1016/j.rmed.2019.105806
https://doi.org/10.1016/j.rmed.2019.1058...
,211211 Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4(7):549-556. https://doi.org/10.1016/S2213-2600(16)30031-5
https://doi.org/10.1016/S2213-2600(16)30...
presence of exacerbations in the previous year,203203 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):651-659. https://doi.org/10.1016/S0140-6736(12)60988-X
https://doi.org/10.1016/S0140-6736(12)60...
adult-onset asthma,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
and presence of nasal polyposis.212212 Howarth P, Chupp G, Nelsen LM, Bradford ES, Bratton DJ, Smith SG, et al. Severe eosinophilic asthma with nasal polyposis: A phenotype for improved sinonasal and asthma outcomes with mepolizumab therapy. J Allergy Clin Immunol. 2020;145(6):1713-1715. https://doi.org/10.1016/j.jaci.2020.02.002
https://doi.org/10.1016/j.jaci.2020.02.0...

Indication

Mepolizumab is recommended for patients with severe eosinophilic asthma (≥ 150 cells/μL) ≥ 6 years of age. In 6-to 11-year-old patients, the dose is 40 mg, and in those > 12 years of age or who weighs > 40 kg, the dose is 100 mg, subcutaneously, every 4 weeks (Chart 2). It is recommended that its efficacy be evaluated based on clinical outcomes at least 12 weeks after treatment onset.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...

Safety

The major adverse events are bronchial infections, irritation at the site of application, and headache. Anaphylaxis is rare.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...
,213213 Agache I, Beltran J, Akdis C, Akdis M, Canelo-Aybar C, Canonica GW, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020;75(5):1023-1042. https://doi.org/10.1111/all.14221
https://doi.org/10.1111/all.14221...

Benralizumab

Benralizumab is a monoclonal antibody that binds to the alpha chain of the IL-5 receptor, which blocks the effect of IL-5 on eosinophils, causing their apoptosis through cell-mediated cytotoxicity.214214 Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, 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;125(6):1344-1353.e2. https://doi.org/10.1016/j.jaci.2010.04.004
https://doi.org/10.1016/j.jaci.2010.04.0...
Benralizumab also significantly reduces eosinophils in the airways, bone marrow, blood, and IS.215215 Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia [published correction appears in J Allergy Clin Immunol. 2014 Apr;133(4):1232]. J Allergy Clin Immunol. 2013;132(5):1086-1096.e5. https://doi.org/10.1016/j.jaci.2013.05.020
https://doi.org/10.1016/j.jaci.2013.05.0...

Efficacy and effectiveness

The efficacy of benralizumab has been proven in several RCTs216216 FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141. https://doi.org/10.1016/S0140-6736(16)31322-8
https://doi.org/10.1016/S0140-6736(16)31...

217 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 ß2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127. https://doi.org/10.1016/S0140-6736(16)31324-1
https://doi.org/10.1016/S0140-6736(16)31...

218 Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. https://doi.org/10.1056/NEJMoa1703501
https://doi.org/10.1056/NEJMoa1703501...
-219219 Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial [published correction appears in Lancet Respir Med. 2019 Jan;7(1):e1]. Lancet Respir Med. 2019;7(1):46-59. https://doi.org/10.1016/S2213-2600(18)30406-5
https://doi.org/10.1016/S2213-2600(18)30...
and in two systematic reviews.220220 Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9(9):CD010834. https://doi.org/10.1002/14651858.CD010834.pub3
https://doi.org/10.1002/14651858.CD01083...
,221221 Tian BP, Zhang GS, Lou J, Zhou HB, Cui W. Efficacy and safety of benralizumab for eosinophilic asthma: A systematic review and meta-analysis of randomized controlled trials. J Asthma. 2018;55(9):956-965. https://doi.org/10.1080/02770903.2017.1379534
https://doi.org/10.1080/02770903.2017.13...
Although phase III studies included patients with moderate-to-severe asthma,216216 FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141. https://doi.org/10.1016/S0140-6736(16)31322-8
https://doi.org/10.1016/S0140-6736(16)31...
,217217 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 ß2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127. https://doi.org/10.1016/S0140-6736(16)31324-1
https://doi.org/10.1016/S0140-6736(16)31...
a reanalysis of these studies evaluating only patients with severe asthma (according to the ATS/ERS criteria)33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
https://doi.org/10.1183/09031936.0020201...
showed that the inclusion of benralizumab in the treatment of patients with EosPB ≥ 300 cells/μL reduced exacerbations and increased FEV1.222222 Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018;52(4):1800936. https://doi.org/10.1183/13993003.00936-2018
https://doi.org/10.1183/13993003.00936-2...
In OCS-dependent patients with severe asthma, the median dose reduction was 50% when compared with placebo.223223 FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, Metcalfe P, 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. https://doi.org/10.1016/S2213-2600(17)30344-2
https://doi.org/10.1016/S2213-2600(17)30...

Real-life studies have confirmed the effectiveness of benralizumab in the management of severe asthma.224224 Bagnasco D, Brussino L, Bonavia M, Calzolari E, Caminati M, Caruso C, et al. Efficacy of Benralizumab in severe asthma in real life and focus on nasal polyposis. Respir Med. 2020;171:106080. https://doi.org/10.1016/j.rmed.2020.106080
https://doi.org/10.1016/j.rmed.2020.1060...
,225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....
A British study including 130 patients with severe asthma and EosPB ≥ 400 cells/μL has demonstrated a 72.8% reduction in exacerbations. In 51% of corticosteroid-dependent patients the use of OCS could be discontinued. Patients were classified as responders (86%) and super-responders (39%), these responses being associated with higher EosPB and less severe disease (better FEV1, better asthma control, better quality of life, and lower dose of OCS).225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....

Predictors of response

The best predictors of response to treatment with benralizumab are chronic use of OCS, nasal polyposis, pre-bronchodilator FEV1 < 65% of the predicted value, and late-onset asthma.222222 Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018;52(4):1800936. https://doi.org/10.1183/13993003.00936-2018
https://doi.org/10.1183/13993003.00936-2...

Indication

Benralizumab is recommended for patients with severe eosinophilic asthma ≥ 18 years of age.22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
https://ginasthma.org/wp-content/uploads...
,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...
It is administered subcutaneously at a dose of 30 mg. The first three applications are made every 4 weeks and, from the fourth application on, every 8 weeks (Chart 2). The first assessment of the response to treatment should be made at least after 12 weeks.1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
https://ginasthma.org/wp-content/uploads...
,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...

Safety

The most common adverse events are nasopharyngitis, bronchial infections, reactions at the site of application, and headache. Anaphylaxis is rare.219219 Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial [published correction appears in Lancet Respir Med. 2019 Jan;7(1):e1]. Lancet Respir Med. 2019;7(1):46-59. https://doi.org/10.1016/S2213-2600(18)30406-5
https://doi.org/10.1016/S2213-2600(18)30...
,226226 Cushen B, Menzies-Gow A. Benralizumab: an updated treatment of eosinophilic asthma. Expert Rev Respir Med. 2020;14(5):435-444. https://doi.org/10.1080/17476348.2020.1739526
https://doi.org/10.1080/17476348.2020.17...

Dupilumab

Dupilumab is a human monoclonal antibody of the IgG4 class that binds to the alpha subunit of the IL-4 receptor, blocking common signaling for IL-4 and IL-13,227227 Macdonald LE, Karow M, Stevens S, Auerbach W, Poueymirou WT, Yasenchak J, et al. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl Acad Sci U S A. 2014;111(14):5147-5152. https://doi.org/10.1073/pnas.1323896111
https://doi.org/10.1073/pnas.1323896111...
which are important mediators in T2 inflammation.

Efficacy and effectiveness

Initial studies with dupilumab in patients with uncontrolled, moderate-to-severe asthma showed a reduction in exacerbations, improvement in lung function, and asthma control.228228 Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-2466. https://doi.org/10.1056/NEJMoa1304048
https://doi.org/10.1056/NEJMoa1304048...
,229229 Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. https://doi.org/10.1016/S0140-6736(16)30307-5
https://doi.org/10.1016/S0140-6736(16)30...
The efficacy of dupilumab has been proven in a phase III RCT230230 Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378(26):2486-2496. https://doi.org/10.1056/NEJMoa1804092
https://doi.org/10.1056/NEJMoa1804092...
with a 52-week follow-up that included asthma patients ≥ 12 years of age and uncontrolled, moderate-to-severe disease. When compared with placebo, dupilumab reduced exacerbations by up to 48%, increased FEV1 (140 mL difference in comparison with placebo), and improved symptoms and quality of life. When patients were stratified by EosPB, those with a level of ≥ 300 cells/µL had a more significant reduction in exacerbations (67%) and a greater increase in FEV1 (difference in relation to placebo of 240 mL). Dupilumab also reduced inflammatory markers (FeNO, IgE, and periostin).

Another RCT231231 Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-2485. https://doi.org/10.1056/NEJMoa1804093
https://doi.org/10.1056/NEJMoa1804093...
including corticosteroid-dependent patients with severe asthma has demonstrated that dupilumab was effective in reducing the OCS dose (−70% vs. −42% when compared with placebo). In addition, the treatment reduced severe exacerbations by 59%, increased FEV1 by 220 mL, improved asthma control, and reduced FeNO. In that study,231231 Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-2485. https://doi.org/10.1056/NEJMoa1804093
https://doi.org/10.1056/NEJMoa1804093...
the favorable effects were independent of the baseline levels of EosPB and FeNO. The beneficial effects of dupilumab have also been confirmed in a real-life study.232232 Dupin C, Belhadi D, Guilleminault L, Gamez AS, Berger P, De Blay F, et al. Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort. Clin Exp Allergy. 2020;50(7):789-798. https://doi.org/10.1111/cea.13614
https://doi.org/10.1111/cea.13614...

Predictors of response

The major predictors of response to treatment with dupilumab are high EosPB levels and FeNO ≥ 25 ppb.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
https://ginasthma.org/wp-content/uploads...

Indication

In Brazil, dupilumab is recommended for patients ≥ 12 years of age and uncontrolled, severe eosinophilic asthma (elevated EosPB and/or FeNO). It is also recommended for patients on continuous use of OCS, regardless of baseline levels of EosPB and FeNO. The recommended initial dose is 400 mg subcutaneously, followed by 200 mg every 2 weeks. In corticosteroid-dependent patients and/or with comorbidities (atopic dermatitis, nasal polyposis, or eosinophilic esophagitis), an initial dose of 600 mg is recommended, followed by doses of 300 mg every 2 weeks (Chart 2).

Safety

In clinical studies, dupilumab was well tolerated and safe, and some patients may have a transient increase in EosPB.230230 Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378(26):2486-2496. https://doi.org/10.1056/NEJMoa1804092
https://doi.org/10.1056/NEJMoa1804092...

231 Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-2485. https://doi.org/10.1056/NEJMoa1804093
https://doi.org/10.1056/NEJMoa1804093...
-232232 Dupin C, Belhadi D, Guilleminault L, Gamez AS, Berger P, De Blay F, et al. Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort. Clin Exp Allergy. 2020;50(7):789-798. https://doi.org/10.1111/cea.13614
https://doi.org/10.1111/cea.13614...
Given that patients with baseline levels of EosPB > 1,500 cells/μL were not included in phase III clinical trials, there are no safety data for the use of dupilumab in this population, and, therefore, its use in these patients is not recommended to date.233233 Wenzel SE. Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes. Am J Respir Crit Care Med. 2021;203(7):809-821. https://doi.org/10.1164/rccm.202009-3631CI
https://doi.org/10.1164/rccm.202009-3631...

Azithromycin

The intermittent (250-500 mg three times/week) and prolonged (12 months) use of azithromycin as an additional therapy in uncontrolled severe asthma has been considered an option by various guidelines.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
https://ginasthma.org/wp-content/uploads...
,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...
,234234 Smith D, Du Rand IA, Addy C, Collyns T, Hart S, Mitchelmore P, et al. British Thoracic Society guideline for the use of long-term macrolides in adults with respiratory disease. BMJ Open Respir Res. 2020;7(1):e000489. Azithromycin reduces exacerbations in other chronic neutrophilic respiratory diseases, including bronchiectasis and COPD.168168 Hinks TSC, Levine SJ, Brusselle GG. Treatment options in type-2 low asthma. Eur Respir J. 2021;57(1):2000528. https://doi.org/10.1183/13993003.00528-2020
https://doi.org/10.1183/13993003.00528-2...
However, its place in the prevention of exacerbations in severe asthma is still limited by the lack of robust scientific evidence regarding potential side effects. The use of azithromycin is off-label in asthma.22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
https://doi.org/10.1183/09031936.0020201...
,1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
https://ginasthma.org/wp-content/uploads...

Azithromycin is a macrolide antibiotic with antibacterial, antiviral, and immunomodulatory properties, the latter of which include inhibition of cytokines and chemokines, decreased expression of adhesion molecules, and increased neutrophil apoptosis.235235 Altenburg J, de Graaff CS, van der Werf TS, Boersma WG. Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms. Respiration. 2011;81(1):67-74. https://doi.org/10.1159/000320319
https://doi.org/10.1159/000320319...
However, the exact mechanism by which azithromycin is effective in preventing asthma exacerbations remains unclear.168168 Hinks TSC, Levine SJ, Brusselle GG. Treatment options in type-2 low asthma. Eur Respir J. 2021;57(1):2000528. https://doi.org/10.1183/13993003.00528-2020
https://doi.org/10.1183/13993003.00528-2...

Although initial studies were directed toward noneosinophilic asthma and presented controversial results, RCTs produced evidence of the benefit of including azithromycin in the treatment of uncontrolled asthma.236236 Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322-329. https://doi.org/10.1136/thoraxjnl-2012-202698
https://doi.org/10.1136/thoraxjnl-2012-2...
,237237 Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10095):659-668. https://doi.org/10.1016/S0140-6736(17)31281-3
https://doi.org/10.1016/S0140-6736(17)31...
In the largest of these studies,237237 Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10095):659-668. https://doi.org/10.1016/S0140-6736(17)31281-3
https://doi.org/10.1016/S0140-6736(17)31...
420 adults with uncontrolled, moderate-to-severe asthma were included. Add-on therapy with azithromicin reduced exacerbations by 40% and improved quality of life, showing similar efficacy on eosinophilic and noneosinophilic phenotypes.

Side effects of prolonged use of azithromycin include diarrhea, QT interval prolongation, hearing loss, and increased Streptococcus pneumoniae, Mycoplasma pneumoniae, and nontuberculous mycobacteria (NTM) antimicrobial resistance. Performing an electrocardiogram prior to treatment onset is recommended to rule out active NTM infection. Sputum culture for NTM screening should be performed every 6 months in cases of prolonged treatment.238238 Pereira MC, Athanazio RA, Dalcin PTR, Figueiredo MRF, Gomes M, Freitas CG, et al. Brazilian consensus on non-cystic fibrosis bronchiectasis. J Bras Pneumol. 2019;45(4):e20190122. https://doi.org/10.1590/1806-3713/e20190122
https://doi.org/10.1590/1806-3713/e20190...

HOW TO ASSESS RESPONSE TO TREATMENT WITH BIOLOGICALS IN SEVERE ASTHMA

Pivotal and real-life studies have shown that most patients with severe asthma with a T2-high profile, when properly investigated, phenotyped, and considered eligible for use of biologicals, respond well to treatment.204204 Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma [published correction appears in N Engl J Med. 2015 Apr 30;372(18):1777]. N Engl J Med. 2014;371(13):1198-1207. https://doi.org/10.1056/NEJMoa1403290
https://doi.org/10.1056/NEJMoa1403290...
,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
,218218 Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. https://doi.org/10.1056/NEJMoa1703501
https://doi.org/10.1056/NEJMoa1703501...
,225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....
,231231 Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-2485. https://doi.org/10.1056/NEJMoa1804093
https://doi.org/10.1056/NEJMoa1804093...
Patients are likely to respond to treatment in different ways, and direct comparative studies between different biologicals are unavailable. Therefore, the selection of a specific biological should be individualized according to the possible predictors of response and accessibility to the medication.

Severe asthma patients should be evaluated more frequently, especially if they are using biologicals.22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
It is important to identify the objectives of treatment clearly and establish the parameters that will be systematically evaluated at each visit.

Although studies on how to assess the response to biologicals are scarce, this topic is extremely relevant in clinical practice. In order to propose a systematic approach for evaluating the response to treatment with biologicals, the present document was based on RCTs202202 Smith DA, Minthorn EA, Beerahee M. Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Clin Pharmacokinet. 2011;50(4):215-227. https://doi.org/10.2165/11584340-000000000-00000
https://doi.org/10.2165/11584340-0000000...

203 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):651-659. https://doi.org/10.1016/S0140-6736(12)60988-X
https://doi.org/10.1016/S0140-6736(12)60...

204 Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma [published correction appears in N Engl J Med. 2015 Apr 30;372(18):1777]. N Engl J Med. 2014;371(13):1198-1207. https://doi.org/10.1056/NEJMoa1403290
https://doi.org/10.1056/NEJMoa1403290...
-205205 Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5(5):390-400. https://doi.org/10.1016/S2213-2600(17)30125-X
https://doi.org/10.1016/S2213-2600(17)30...
,215215 Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia [published correction appears in J Allergy Clin Immunol. 2014 Apr;133(4):1232]. J Allergy Clin Immunol. 2013;132(5):1086-1096.e5. https://doi.org/10.1016/j.jaci.2013.05.020
https://doi.org/10.1016/j.jaci.2013.05.0...

216 FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141. https://doi.org/10.1016/S0140-6736(16)31322-8
https://doi.org/10.1016/S0140-6736(16)31...

217 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 ß2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127. https://doi.org/10.1016/S0140-6736(16)31324-1
https://doi.org/10.1016/S0140-6736(16)31...
-218218 Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. https://doi.org/10.1056/NEJMoa1703501
https://doi.org/10.1056/NEJMoa1703501...
,228228 Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-2466. https://doi.org/10.1056/NEJMoa1304048
https://doi.org/10.1056/NEJMoa1304048...

229 Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. https://doi.org/10.1016/S0140-6736(16)30307-5
https://doi.org/10.1016/S0140-6736(16)30...
-230230 Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378(26):2486-2496. https://doi.org/10.1056/NEJMoa1804092
https://doi.org/10.1056/NEJMoa1804092...
,238238 Pereira MC, Athanazio RA, Dalcin PTR, Figueiredo MRF, Gomes M, Freitas CG, et al. Brazilian consensus on non-cystic fibrosis bronchiectasis. J Bras Pneumol. 2019;45(4):e20190122. https://doi.org/10.1590/1806-3713/e20190122
https://doi.org/10.1590/1806-3713/e20190...

239 Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma [published correction appears in N Engl J Med. 2011 Feb 10;364(6):588]. N Engl J Med. 2009;360(10):973-984. https://doi.org/10.1056/NEJMoa0808991
https://doi.org/10.1056/NEJMoa0808991...

240 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;35(5):737-748. https://doi.org/10.1007/s12325-018-0702-4
https://doi.org/10.1007/s12325-018-0702-...
-241241 Corren J, Castro M, O'Riordan T, Hanania NA, Pavord ID, Quirce S, et al. Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma. J Allergy Clin Immunol Pract. 2020;8(2):516-526. https://doi.org/10.1016/j.jaip.2019.08.050
https://doi.org/10.1016/j.jaip.2019.08.0...
and real-life studies.193193 MacDonald KM, Kavati A, Ortiz B, Alhossan A, Lee CS, Abraham I. Short- and long-term real-world effectiveness of omalizumab in severe allergic asthma: systematic review of 42 studies published 2008-2018. Expert Rev Clin Immunol. 2019;15(5):553-569. https://doi.org/10.1080/1744666X.2019.1574571
https://doi.org/10.1080/1744666X.2019.15...
,208208 Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L, et al. Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma. Chest. 2020;158(2):491-500. https://doi.org/10.1016/j.chest.2020.03.042
https://doi.org/10.1016/j.chest.2020.03....
,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
,225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....
,243243 Rubin AS, Souza-Machado A, Andradre-Lima M, Ferreira F, Honda A, Matozo TM, et al. Effect of omalizumab as add-on therapy on asthma-related quality of life in severe allergic asthma: a Brazilian study (QUALITX). J Asthma. 2012;49(3):288-293. https://doi.org/10.3109/02770903.2012.660297
https://doi.org/10.3109/02770903.2012.66...

244 Gibson PG, Reddel H, McDonald VM, Marks G, Jenkins C, Gillman A, et al. Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry. Intern Med J. 2016;46(9):1054-1062. https://doi.org/10.1111/imj.13166
https://doi.org/10.1111/imj.13166...

245 Niven RM, Saralaya D, Chaudhuri R, Masoli M, Clifton I, Mansur AH, et al. Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study). BMJ Open. 2016;6(8):e011857. https://doi.org/10.1136/bmjopen-2016-011857
https://doi.org/10.1136/bmjopen-2016-011...
-246246 Carvalho-Pinto RM, Agondi RC, Giavina-Bianchi P, Cukier A, Stelmach R. Omalizumab in patients with severe uncontrolled asthma: well-defined eligibility criteria to promote asthma control. J Bras Pneumol. 2017;43(6):487-489. https://doi.org/10.1590/s1806-37562017000000012
https://doi.org/10.1590/s1806-3756201700...
RCTs have evaluated the effect of biologicals on one or more of the following outcomes: decrease in exacerbations, OCS-sparing effect, improvement of asthma control, increase in FEV1, and improvement in quality of life.203203 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):651-659. https://doi.org/10.1016/S0140-6736(12)60988-X
https://doi.org/10.1016/S0140-6736(12)60...
,206206 Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197. https://doi.org/10.1056/NEJMoa1403291
https://doi.org/10.1056/NEJMoa1403291...
,216216 FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141. https://doi.org/10.1016/S0140-6736(16)31322-8
https://doi.org/10.1016/S0140-6736(16)31...

217 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 ß2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127. https://doi.org/10.1016/S0140-6736(16)31324-1
https://doi.org/10.1016/S0140-6736(16)31...

218 Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017;376(25):2448-2458. https://doi.org/10.1056/NEJMoa1703501
https://doi.org/10.1056/NEJMoa1703501...
-219219 Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial [published correction appears in Lancet Respir Med. 2019 Jan;7(1):e1]. Lancet Respir Med. 2019;7(1):46-59. https://doi.org/10.1016/S2213-2600(18)30406-5
https://doi.org/10.1016/S2213-2600(18)30...
,229229 Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. https://doi.org/10.1016/S0140-6736(16)30307-5
https://doi.org/10.1016/S0140-6736(16)30...

230 Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378(26):2486-2496. https://doi.org/10.1056/NEJMoa1804092
https://doi.org/10.1056/NEJMoa1804092...
-231231 Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-2485. https://doi.org/10.1056/NEJMoa1804093
https://doi.org/10.1056/NEJMoa1804093...
,239239 Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma [published correction appears in N Engl J Med. 2011 Feb 10;364(6):588]. N Engl J Med. 2009;360(10):973-984. https://doi.org/10.1056/NEJMoa0808991
https://doi.org/10.1056/NEJMoa0808991...

240 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;35(5):737-748. https://doi.org/10.1007/s12325-018-0702-4
https://doi.org/10.1007/s12325-018-0702-...

241 Corren J, Castro M, O'Riordan T, Hanania NA, Pavord ID, Quirce S, et al. Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma. J Allergy Clin Immunol Pract. 2020;8(2):516-526. https://doi.org/10.1016/j.jaip.2019.08.050
https://doi.org/10.1016/j.jaip.2019.08.0...
-242242 Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985-993. https://doi.org/10.1056/NEJMoa0805435
https://doi.org/10.1056/NEJMoa0805435...
Real-life studies with a 24-48 week follow-up using inclusion criteria similar to those of RCTs identified responders, super-responders, and nonresponders to treatment.208208 Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L, et al. Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma. Chest. 2020;158(2):491-500. https://doi.org/10.1016/j.chest.2020.03.042
https://doi.org/10.1016/j.chest.2020.03....
,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
,225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....

Responders

Responders208208 Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L, et al. Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma. Chest. 2020;158(2):491-500. https://doi.org/10.1016/j.chest.2020.03.042
https://doi.org/10.1016/j.chest.2020.03....
,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
,225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....
,247247 Mukherjee M, Forero DF, Tran S, Boulay ME, Bertrand M, Bhalla A, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J. 2020;56(4):2000117. https://doi.org/10.1183/13993003.00117-2020
https://doi.org/10.1183/13993003.00117-2...
are patients with improved asthma control (a 0.5 point decrease in ACQ) and/or a reduction in exacerbations ≥ 50% and/or in the dose of OCS ≥ 50%.

Super-responders

Super-responders208208 Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L, et al. Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma. Chest. 2020;158(2):491-500. https://doi.org/10.1016/j.chest.2020.03.042
https://doi.org/10.1016/j.chest.2020.03....
,209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
,225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....
are considered to be the patients with well-controlled asthma (ACQ < 1.5), free of exacerbations, and with a reduction in the dose of OCS ≥ 80% in corticosteroid-dependent patients.

Nonresponders

Nonresponders209209 Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A, et al. Mepolizumab effectiveness and identification of super-responders in severe asthma. Eur Respir J. 2020;55(5):1902420. https://doi.org/10.1183/13993003.02420-2019
https://doi.org/10.1183/13993003.02420-2...
,247247 Mukherjee M, Forero DF, Tran S, Boulay ME, Bertrand M, Bhalla A, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J. 2020;56(4):2000117. https://doi.org/10.1183/13993003.00117-2020
https://doi.org/10.1183/13993003.00117-2...
are patients who fail to meet at least two of the following criteria: improvement in asthma control (0.5 point decrease in ACQ), reduction in exacerbations ≥ 50%, or reduction in the dose of OCS ≥ 25% in corticosteroid-dependent patients.

Figure 3 presents a suggestion of assessment of response to management of biological treatment between 6 and 12 months.

Figure 3
Assessment of response to treatment with biologicals. ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; OCS: oral corticosteroid.

A few patients previously considered responders may, over time, have a poorer response, identified by a ≥ 25% reduction in baseline FEV1, the need to increase the dose of maintenance corticosteroids, or an increase of ≥ 0.5 point in the ACQ-5.247247 Mukherjee M, Forero DF, Tran S, Boulay ME, Bertrand M, Bhalla A, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J. 2020;56(4):2000117. https://doi.org/10.1183/13993003.00117-2020
https://doi.org/10.1183/13993003.00117-2...
Clinical worsening can result from poor compliance, incorrect inhalation technique, occupational/environmental exposures, and infections. In such cases, chest CT and bronchoscopy may be necessary to investigate alternative or concomitant diagnoses. The production of antibodies against the biological can also be the cause of loss of response to treatment.225225 Kavanagh JE, Hearn AP, Dhariwal J, d'Ancona G, Douiri A, Roxas C, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. 2021;159(2):496-506. https://doi.org/10.1016/j.chest.2020.08.2083
https://doi.org/10.1016/j.chest.2020.08....
,247247 Mukherjee M, Forero DF, Tran S, Boulay ME, Bertrand M, Bhalla A, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J. 2020;56(4):2000117. https://doi.org/10.1183/13993003.00117-2020
https://doi.org/10.1183/13993003.00117-2...
,248248 Mukherjee M, Nair P. Autoimmune Responses in Severe Asthma. Allergy Asthma Immunol Res. 2018;10(5):428-447. https://doi.org/10.4168/aair.2018.10.5.428
https://doi.org/10.4168/aair.2018.10.5.4...

In the absence or loss of response, treatment must be interrupted and the patient reassessed for the possible introduction of another biological. In cases of intermediate response, treatment can be continued for 12 months. When the response is adequate, treatment should be continued; if the response is inadequate, the use of another biological should be considered.249249 Buhl R, Humbert M, Bjermer L, Chanez P, Heaney LG, Pavord I, et al. Severe eosinophilic asthma: a roadmap to consensus. Eur Respir J. 2017;49(5):1700634. https://doi.org/10.1183/13993003.00634-2017
https://doi.org/10.1183/13993003.00634-2...

Duration of treatment is yet to be established. However, it is known that interruption of treatment in responders is followed by eosinophilia250250 Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol. 2014;133(3):921-923. https://doi.org/10.1016/j.jaci.2013.11.026
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,251251 Ortega H, Lemiere C, Llanos JP, Forshag M, Price R, Albers F, et al. Outcomes following mepolizumab treatment discontinuation: real-world experience from an open-label trial. Allergy Asthma Clin Immunol. 2019;15:37. https://doi.org/10.1186/s13223-019-0348-z
https://doi.org/10.1186/s13223-019-0348-...
and exacerbations.250250 Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol. 2014;133(3):921-923. https://doi.org/10.1016/j.jaci.2013.11.026
https://doi.org/10.1016/j.jaci.2013.11.0...

Low-dose OCS

The use of OCS is an alternative option in step V with the lowest possible dose,22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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because the regular use or repeated courses of OCS is associated with serious adverse effects, although it is effective in achieving and maintaining asthma control.252252 Ramsahai JM, Wark PA. Appropriate use of oral corticosteroids for severe asthma. Med J Aust. 2018;209(S2):S18-S21. https://doi.org/10.5694/mja18.00134
https://doi.org/10.5694/mja18.00134...
Major adverse effects are bone mass loss and increased risk of bone fracture, body weight gain, metabolic syndrome, diabetes mellitus, systemic arterial hypertension, adrenal insufficiency, and immunosuppression.33 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text] [published correction appears in Eur Respir J. 2018 Jul 27;52(1):]. Eur Respir J. 2014;43(2):343-373. https://doi.org/10.1183/09031936.00202013
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,99 Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C, et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry. Thorax. 2016;71(4):339-346. https://doi.org/10.1136/thoraxjnl-2015-207630
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,1414 Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma; c2019 [cited 2019 Mar 1]. Global Strategy for Asthma Management and Prevention (2019 update). [Adobe Acrobat document, 201p.]. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June2019-wms.pdf
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,151151 Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55(1):1900588. https://doi.org/10.1183/13993003.00588-2019
https://doi.org/10.1183/13993003.00588-2...
,253253 O'Byrne P, Fabbri LM, Pavord ID, Papi A, Petruzzelli S, Lange P. Asthma progression and mortality: the role of inhaled corticosteroids. Eur Respir J. 2019;54(1):1900491. https://doi.org/10.1183/13993003.00491-2019
https://doi.org/10.1183/13993003.00491-2...

254 Bleecker ER, Menzies-Gow AN, Price DB, Bourdin A, Sweet S, Martin AL, et al. Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management. Am J Respir Crit Care Med. 2020;201(3):276-293. https://doi.org/10.1164/rccm.201904-0903SO
https://doi.org/10.1164/rccm.201904-0903...
-255255 Choo XN, Pavord ID. Morbidity associated with oral corticosteroids in patients with severe asthma. Thorax. 2016;71(4):302-304. https://doi.org/10.1136/thoraxjnl-2015-208242
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These undesirable effects are dose-dependent.256256 Lefebvre P, Duh MS, Lafeuille MH, Gozalo L, Desai U, Robitaille MN, et al. Acute and chronic systemic corticosteroid-related complications in patients with severe asthma. J Allergy Clin Immunol. 2015;136(6):1488-1495. https://doi.org/10.1016/j.jaci.2015.07.046
https://doi.org/10.1016/j.jaci.2015.07.0...

Gradual reduction and cessation of maintenance OCS

Due to the adverse effects of OCS, an attempt should be made to reduce its dose in all patients. No evidence-based guidelines on the best way to reduce OCS dose is available. However, expert recommendations254254 Bleecker ER, Menzies-Gow AN, Price DB, Bourdin A, Sweet S, Martin AL, et al. Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management. Am J Respir Crit Care Med. 2020;201(3):276-293. https://doi.org/10.1164/rccm.201904-0903SO
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suggest that this should gradually be carried out up to a minimum effective dose or complete weaning of the medication has been reached. The pace and speed of dose reduction should be patient tailored, based on the history of severe exacerbations, prior treatment duration, and risk and type of adverse effects. Assessment of possible adrenal insufficiency during and after the OCS reduction process is recommended.257257 Suehs CM, Menzies-Gow A, Price D, Bleecker ER, Canonica GW, Gurnell M, et al. Expert Consensus on the Tapering of Oral Corticosteroids for the Treatment of Asthma. A Delphi Study. Am J Respir Crit Care Med. 2021;203(7):871-881. https://doi.org/10.1164/rccm.202007-2721OC
https://doi.org/10.1164/rccm.202007-2721...

NONPHARMACOLOGICAL TREATMENT

Bronchial thermoplasty

Bronchial thermoplasty is an approved nonpharmacological procedure for the treatment of uncontrolled, severe asthma patients being regularly treated.258258 Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356(13):1327-1337. https://doi.org/10.1056/NEJMoa064707
https://doi.org/10.1056/NEJMoa064707...
By means of bronchoscopy, a catheter is inserted into the airways, generating radiofrequency energy and heating the bronchial walls in a controlled manner. The mechanism of action involves reduction of smooth muscle and airway nerve endings, as well as mechanical and physiological actions resulting from these reductions. The procedure must be performed in trained centers and consists of three sessions with intervals of 21 days.259259 Torrego Fernández A. Bronchial thermoplasty in the treatment of asthma. Arch Bronconeumol. 2010;46(2):85-91. https://doi.org/10.1016/j.arbres.2008.12.005
https://doi.org/10.1016/j.arbres.2008.12...
Three RCTs258258 Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356(13):1327-1337. https://doi.org/10.1056/NEJMoa064707
https://doi.org/10.1056/NEJMoa064707...
,260260 Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176(12):1185-1191. https://doi.org/10.1164/rccm.200704-571OC
https://doi.org/10.1164/rccm.200704-571O...
,261261 Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-124. https://doi.org/10.1164/rccm.200903-0354OC
https://doi.org/10.1164/rccm.200903-0354...
have investigated the safety and efficacy of bronchial thermoplasty, demonstrating improvement in quality of life and asthma control, as well as a decrease in exacerbations, emergency visits, hospitalizations, and OCS dose. These effects have been maintained for at least 10 years, with an acceptable safety profile.262262 Chaudhuri R, Rubin A, Sumino K, Lapa E Silva JR, Niven R, Siddiqui S, et al. Safety and effectiveness of bronchial thermoplasty after 10 years in patients with persistent asthma (BT10+): a follow-up of three randomised controlled trials. Lancet Respir Med. 2021;9(5):457-466. https://doi.org/10.1016/S2213-2600(20)30408-2
https://doi.org/10.1016/S2213-2600(20)30...
Bronchial thermoplasty can be considered a treatment option for those patients with severe asthma who do not qualify for or adequately respond to treatment with biologicals.

Physical activity

The paradigm of exercise practice by patients with asthma began to change at the turn of the century with data from a systematic review263263 Ram FS, Robinson SM, Black PN. Effects of physical training in asthma: a systematic review. Br J Sports Med. 2000;34(3):162-167. https://doi.org/10.1136/bjsm.34.3.162
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that compared studies that evaluated asthma patients participating in a physical training program with a group that did not perform physical activities. The group of asthma patients who performed exercises showed a significant improvement in aerobic capacity, but not in pulmonary function parameters assessed at rest.

In the following years, experimental studies have shown a reduction in IL-4 and IL-13 (pro-inflammatory cytokines) levels, suggesting an effect of physical training on reducing airway inflammation264264 Olivo CR, Vieira RP, Arantes-Costa FM, Perini A, Martins MA, Carvalho CR. Effects of aerobic exercise on chronic allergic airway inflammation and remodeling in guinea pigs. Respir Physiol Neurobiol. 2012;182(2-3):81-87. https://doi.org/10.1016/j.resp.2012.05.004
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and a significant increase in IL-10 (anti-inflammatory cytokine) expression.265265 Silva RA, Vieira RP, Duarte AC, Lopes FD, Perini A, Mauad T, et al. Aerobic training reverses airway inflammation and remodelling in an asthma murine model. Eur Respir J. 2010;35(5):994-1002. https://doi.org/10.1183/09031936.00049509
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The reduction in the levels of EosIS and FeNO were demonstrated in a clinical trial266266 Mendes FA, Almeida FM, Cukier A, Stelmach R, Jacob-Filho W, Martins MA, et al. Effects of aerobic training on airway inflammation in asthmatic patients. Med Sci Sports Exerc. 2011;43(2):197-203. https://doi.org/10.1249/MSS.0b013e3181ed0ea3
https://doi.org/10.1249/MSS.0b013e3181ed...
that compared asthma patients who performed aerobic training with a control group, indicating that training reduced airway inflammation. However, this finding was not observed in a later study.267267 França-Pinto A, Mendes FA, de Carvalho-Pinto RM, Agondi RC, Cukier A, Stelmach R, et al. Aerobic training decreases bronchial hyperresponsiveness and systemic inflammation in patients with moderate or severe asthma: a randomised controlled trial. Thorax. 2015;70(8):732-739. https://doi.org/10.1136/thoraxjnl-2014-206070
https://doi.org/10.1136/thoraxjnl-2014-2...

A study that evaluated physical training programs for asthma patients has shown improvement in quality of life, as well as a decrease in anxiety/depression and asthma symptoms.268268 Mendes FA, Gonçalves RC, Nunes MP, Saraiva-Romanholo BM, Cukier A, Stelmach R, et al. Effects of aerobic training on psychosocial morbidity and symptoms in patients with asthma: a randomized clinical trial. Chest. 2010;138(2):331-337. https://doi.org/10.1378/chest.09-2389
https://doi.org/10.1378/chest.09-2389...
Another study showed that physical training improved asthma control and promoted weight loss and reduction of systemic and airway inflammation.122122 Freitas PD, Ferreira PG, Silva AG, Stelmach R, Carvalho-Pinto RM, Fernandes FL, et al. The Role of Exercise in a Weight-Loss Program on Clinical Control in Obese Adults with Asthma. A Randomized Controlled Trial. Am J Respir Crit Care Med. 2017;195(1):32-42. https://doi.org/10.1164/rccm.201603-0446OC
https://doi.org/10.1164/rccm.201603-0446...

A systematic review269269 Hansen ESH, Pitzner-Fabricius A, Toennesen LL, Rasmusen HK, Hostrup M, Hellsten Y, et al. Effect of aerobic exercise training on asthma in adults: a systematic review and meta-analysis. Eur Respir J. 2020;56(1):2000146. https://doi.org/10.1183/13993003.00146-2020
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including studies with adult asthma patients who underwent aerobic physical training demonstrated improvements in asthma control and pulmonary function. In obese asthma patients, physical exercise also helps with weight loss.270270 Freitas PD, Ferreira PG, da Silva A, Trecco S, Stelmach R, Cukier A, et al. The effects of exercise training in a weight loss lifestyle intervention on asthma control, quality of life and psychosocial symptoms in adult obese asthmatics: protocol of a randomized controlled trial. BMC Pulm Med. 2015;15:124. https://doi.org/10.1186/s12890-015-0111-2
https://doi.org/10.1186/s12890-015-0111-...

Interventions aimed at promoting behavioral changes to improve physical activity in physically inactive adult patients with asthma have resulted in improvements in asthma control and a decrease in exacerbations, use of rescue medication and OCS bursts, as well as an increase in the practice of physical activities.271271 Freitas PD, Passos NFP, Carvalho-Pinto RM, Martins MA, Cavalheri V, Hill K, et al. A Behavior Change Intervention Aimed at Increasing Physical Activity Improves Clinical Control in Adults With Asthma: A Randomized Controlled Trial. Chest. 2021;159(1):46-57. https://doi.org/10.1016/j.chest.2020.08.2113
https://doi.org/10.1016/j.chest.2020.08....
However, other studies have found no clinically significant improvements in asthma control with increased physical activity after interventions for behavioral change. This might indicate that clinical benefits are dependent on the magnitude of the increase in regular physical activity in asthma patients.272272 Coelho CM, Reboredo MM, Valle FM, Malaguti C, Campos LA, Nascimento LM, et al. Effects of an unsupervised pedometer-based physical activity program on daily steps of adults with moderate to severe asthma: a randomized controlled trial. J Sports Sci. 2018;36(10):1186-1193. https://doi.org/10.1080/02640414.2017.1364402
https://doi.org/10.1080/02640414.2017.13...
,273273 Ma J, Strub P, Xiao L, Lavori PW, Camargo CA Jr, Wilson SR, et al. Behavioral weight loss and physical activity intervention in obese adults with asthma. A randomized trial. Ann Am Thorac Soc. 2015;12(1):1-11. https://doi.org/10.1513/AnnalsATS.201406-271OC
https://doi.org/10.1513/AnnalsATS.201406...

Although supervised physical exercise based on structured programs might potentially improve asthma,269269 Hansen ESH, Pitzner-Fabricius A, Toennesen LL, Rasmusen HK, Hostrup M, Hellsten Y, et al. Effect of aerobic exercise training on asthma in adults: a systematic review and meta-analysis. Eur Respir J. 2020;56(1):2000146. https://doi.org/10.1183/13993003.00146-2020
https://doi.org/10.1183/13993003.00146-2...
personal preferences of patients and barriers encountered in the practice of physical activity should be taken into account.274274 Mancuso CA, Sayles W, Robbins L, Phillips EG, Ravenell K, Duffy C, et al. Barriers and facilitators to healthy physical activity in asthma patients. J Asthma. 2006;43(2):137-143. https://doi.org/10.1080/02770900500498584
https://doi.org/10.1080/0277090050049858...
These findings point to the important role of physical activity in asthma management, indicating that the implementation of nonpharmacological measures, such as the practice of physical activity, needs to be considered together with pharmacological treatment in patients with severe asthma or DCA as well. The GINA recommends that adults with asthma engage in regular physical activity.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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DIAGNOSIS AND MANAGEMENT OF SEVERE ASTHMA IN CHILDREN AND ADOLESCENTS

Diagnostic aspects

The diagnostic criteria for asthma in children are the same as those established for adults. We emphasize, however, that in the 6- to 11-year age group, there are differences in lung function parameters: FEV1/FVC ratio < 0.9; reversibility to bronchodilator use > 12% of baseline values; mean variability of PEF > 13%; and > 12% reduction in FEV1 after exercise challenge testing.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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In addition, children with severe asthma do not commonly present with significant changes in or loss of pulmonary function.275275 Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF Jr, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med. 2004;170(4):426-432. https://doi.org/10.1164/rccm.200308-1178OC
https://doi.org/10.1164/rccm.200308-1178...
Methacholine challenge testing should be restricted to cases with normal spirometry results and symptoms suggestive of asthma. A negative test result makes the diagnosis of asthma unlikely.276276 Hallstrand TS, Leuppi JD, Joos G, Hall GL, Carlsen KH, Kaminsky DA, et al. ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing. Eur Respir J. 2018;52(5):1801033. https://doi.org/10.1183/13993003.01033-2018
https://doi.org/10.1183/13993003.01033-2...

The definition of severe asthma in patients between 6 and 11 years of age does not differ from that in adolescents and adults. However, it is important to highlight that ICS doses differ in this age group, being considered as a high dose > 400 µg/day of beclomethasone dipropionate (fine particle-hydrofluoroalkane) or equivalent.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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Children suspected of having severe asthma should always be evaluated and managed by a specialist.22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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The differential diagnosis of severe asthma in this age group includes cystic fibrosis, post-infectious bronchiolitis obliterans, foreign body aspiration, primary ciliary dyskinesia, congenital immunodeficiencies, congenital heart disease, among others.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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The investigation of severe asthma in this age group includes some aspects that are worth mentioning. There is no evidence to recommend routine chest CT. In severe asthma, CT should only be performed to exclude other diseases.277277 Bush A, Saglani S. Management of severe asthma in children. Lancet. 2010;376(9743):814-825. https://doi.org/10.1016/S0140-6736(10)61054-9
https://doi.org/10.1016/S0140-6736(10)61...
Investigation of gastroesophageal reflux should only be performed in selected cases. Treatment of asymptomatic gastroesophageal reflux rarely results in clinical improvement of asthma.277277 Bush A, Saglani S. Management of severe asthma in children. Lancet. 2010;376(9743):814-825. https://doi.org/10.1016/S0140-6736(10)61054-9
https://doi.org/10.1016/S0140-6736(10)61...
The risk of exacerbations is reduced by measuring FeNO levels to guide the pharmacological treatment in children.278278 Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev. 2016;11(11):CD011439. https://doi.org/10.1002/14651858.CD011439.pub2
https://doi.org/10.1002/14651858.CD01143...
Collection of IS is not recommended for pharmacological management in children.279279 Petsky HL, Li A, Chang AB. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev. 2017;8(8):CD005603. https://doi.org/10.1002/14651858.CD005603.pub3
https://doi.org/10.1002/14651858.CD00560...

Severe asthma in children between 6 and 11 years of age should be phenotyped for a T2-high inflammatory profile using allergen sensitization testing, EosPB or EosIS (when available), and FeNO.44 Global Initiative for Asthma [homepage on the internet]. Bethesda: Global Initiative for Asthma; c2021 [cited 2021 Jun 1]. Global Strategy for Asthma Management and Prevention (2021 update). Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf
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T2-high allergic eosinophilic asthma is the predominant phenotype in children with severe asthma.280280 Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716-725. https://doi.org/10.1038/nm.2678
https://doi.org/10.1038/nm.2678...

Treatment in children between 6 and 11 years of age

High doses of ICS+LABA are recommended for the treatment of severe asthma (step V) in children between 6 and 11 years of age. Prior to phenotyping, it is recommended to associate tiotropium with ICS+LABA in order to achieve and maintain asthma control.22020 Brazilian Thoracic Association recommendations for the management of asthma. J Bras Pneumol. 2020;46(1):e20190307. https://doi.org/10.1590/1806-3713/e20190307
https://doi.org/10.1590/1806-3713/e20190...
,281281 Rodrigo GJ, Neffen H. Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic asthma: A systematic review. Pediatr Allergy Immunol. 2017;28(6):573-578. https://doi.org/10.1111/pai.12759
https://doi.org/10.1111/pai.12759...
Phenotyping is recommended in patients who do not achieve control.

In Brazil, two biologicals-omalizumab (anti-IgE) and mepolizumab (anti-IL-5)-have been approved for the treatment of asthma patients with the T2-high phenotype in this age group. The choice of the biological should be defined individually, considering biomarkers and access to treatment.

Efficacy and safety of omalizumab in children with severe asthma has been proven in an RCT282282 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):250-263. https://doi.org/10.2500/aap.2017.38.4067
https://doi.org/10.2500/aap.2017.38.4067...
and in a real-life study.283283 Deschildre A, Marguet C, Salleron J, Pin I, Rittié JL, Derelle J, et al. Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur Respir J. 2013;42(5):1224-1233. https://doi.org/10.1183/09031936.00149812
https://doi.org/10.1183/09031936.0014981...
A study in children and adolescents in Brazil showed that the inclusion of omalizumab in the treatment regimen improved asthma control and reduced hospitalizations and OCS dose.284284 Pitrez PM, de Souza RG, Roncada C, Heinzmann-Filho JP, Santos G, Pinto LA, et al. Impact of omalizumab in children from a middle-income country with severe therapy-resistant asthma: A real-life study. Pediatr Pulmonol. 2017;52(11):1408-1413. https://doi.org/10.1002/ppul.23845
https://doi.org/10.1002/ppul.23845...
Some children present with total IgE levels higher than the limits recommended in the manufacturer directions for omalizumab, contraindicating its use.285285 Bossley CJ, Saglani S, Kavanagh C, Payne DN, Wilson N, Tsartsali L, et al. Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma. Eur Respir J. 2009;34(5):1052-1059. https://doi.org/10.1183/09031936.00186508
https://doi.org/10.1183/09031936.0018650...

Efficacy and safety of mepolizumab for children between 6 and 11 years of age was demonstrated in one study.286286 Gupta A, Ikeda M, Geng B, Azmi J, Price RG, Bradford ES, et al. Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype. J Allergy Clin Immunol. 2019;144(5):1336-1342.e7. https://doi.org/10.1016/j.jaci.2019.08.005
https://doi.org/10.1016/j.jaci.2019.08.0...
The doses of biologicals in this age group are described in Chart 2.

The response to treatment with biologicals should periodically be evaluated by means of objective measures of asthma control and reductions in exacerbations/hospitalizations and in the dose of OCS. Treatment duration in patients with good clinical response and recommendations on replacing biologicals in cases of treatment failure are yet to be established.

SUMMARY OF RECOMMENDATIONS FOR THE MANAGEMENT OF SEVERE ASTHMA

  • Patients diagnosed with or suspected of having severe asthma should be referred to a specialist

  • Adherence to treatment and proper inhalation technique must be verified at all medical visits

  • Comorbidities and environmental/occupational exposures that may worsen asthma control should be investigated and, if present, eliminated or minimized

  • Patients who need treatment with high-dose ICS (budesonide ≥ 1,600 µg or equivalent) associated with LABA and/or LAMA and/or antileukotrienes and/or OCS to maintain control or those whose asthma still remains uncontrolled should be considered as patients with severe asthma, due to the intrinsic severity of the disease

  • The inclusion of tiotropium bromide in the treatment of severe asthma is recommended, preferably prior to the use of biologicals

  • Patients with a confirmed diagnosis of severe asthma and a recommendation for treatment with biologicals should be phenotyped

  • When available, IS analysis should be performed to phenotype severe asthma

  • Measuring EosPB levels should be carried out for severe asthma phenotyping when EosIS analysis is unavailable

  • Specific IgE and/or skin prick testing should be carried out for phenotyping all patients with severe asthma

  • The total serum IgE level should be used to calculate the dose of omalizumab but not for phenotyping or treatment follow-up

  • Routine use of FeNO for phenotyping or as a management strategy for severe asthma is not recommended

  • The choice of the biological should be based on the phenotype and access to the medication

  • The evaluation of response to treatment should be objective, using as parameters asthma control and reduction in exacerbations and of the dose of corticosteroids

  • The treatment of responders should be continued indefinitely

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  • Financial support:

    None.

Publication Dates

  • Publication in this collection
    15 Dec 2021
  • Date of issue
    2021

History

  • Received
    06 July 2021
  • Accepted
    05 Aug 2021
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