Redefining the Role of Bronchoscopy in the Workup of Severe Uncontrolled Asthma in the Era of Biologics

Abstract

BackgroundSevere uncontrolled asthma (SUA) is frequently treated with biologic therapy if a T2 phenotype is found. Bronchoscopy is not routinely recommended in these patients unless a specific indication to rule out comorbidities is present.Research QuestionIs routine bronchoscopy safe and useful in phenotyping and endotyping patients with SUA before the indication of a biologic therapy?Study Design and MethodsProspective study of consecutive patients with SUA who were referred to a specialized asthma clinic to assess the indication of a biologic therapy. Patients were clinically phenotyped as T2-allergic, T2-eosinophilic, and non-T2. All patients underwent bronchoscopy, and systematic data collection of endoscopic findings, microbiology of bronchial aspirate, and presence of eosinophils in bronchial biopsy were recorded and compared between asthma phenotypes. Cluster analysis was performed accordingly.ResultsOne hundred patients were recruited and classified as T2-allergic (28%), T2-eosinophilic (64%), and non-T2 (8%). On bronchoscopy, signs of gastroesophageal reflux disease were detected in 21%, vocal cord dysfunction in 5%, and tracheal abnormalities in 3%. Bronchial aspirate culture isolated bacteria in 27% of patients and fungi in 14%. Three clusters were identified: nonspecific, upper airway, and infection, the latter being less frequently associated with submucosal eosinophilia. Eosinophils were detected in 91% of bronchial biopsies. Despite a correlation to blood eosinophils, five patients with T2-phenotypes showed no eosinophils in bronchial biopsy, and three patients with non-T2 showed eosinophils in bronchial biopsy. Only one patient had moderate bleeding.InterpretationRoutine bronchoscopy in SUA eligible for biologic therapy is a safe procedure that can help to better phenotype and personalize asthma management. Severe uncontrolled asthma (SUA) is frequently treated with biologic therapy if a T2 phenotype is found. Bronchoscopy is not routinely recommended in these patients unless a specific indication to rule out comorbidities is present. Is routine bronchoscopy safe and useful in phenotyping and endotyping patients with SUA before the indication of a biologic therapy? Prospective study of consecutive patients with SUA who were referred to a specialized asthma clinic to assess the indication of a biologic therapy. Patients were clinically phenotyped as T2-allergic, T2-eosinophilic, and non-T2. All patients underwent bronchoscopy, and systematic data collection of endoscopic findings, microbiology of bronchial aspirate, and presence of eosinophils in bronchial biopsy were recorded and compared between asthma phenotypes. Cluster analysis was performed accordingly. One hundred patients were recruited and classified as T2-allergic (28%), T2-eosinophilic (64%), and non-T2 (8%). On bronchoscopy, signs of gastroesophageal reflux disease were detected in 21%, vocal cord dysfunction in 5%, and tracheal abnormalities in 3%. Bronchial aspirate culture isolated bacteria in 27% of patients and fungi in 14%. Three clusters were identified: nonspecific, upper airway, and infection, the latter being less frequently associated with submucosal eosinophilia. Eosinophils were detected in 91% of bronchial biopsies. Despite a correlation to blood eosinophils, five patients with T2-phenotypes showed no eosinophils in bronchial biopsy, and three patients with non-T2 showed eosinophils in bronchial biopsy. Only one patient had moderate bleeding. Routine bronchoscopy in SUA eligible for biologic therapy is a safe procedure that can help to better phenotype and personalize asthma management. Take-home PointsStudy Question: Does routine bronchoscopy help to phenotype patients with severe uncontrolled asthma potentially eligible for biologic therapy?Results: Routine bronchoscopy clusters patients with severe uncontrolled asthma and identifies treatable traits that are not accurately detected otherwise, such as tissue eosinophilia, upper airway disease, or infection.Interpretation: Routine bronchoscopy in patients with severe uncontrolled asthma is a safe procedure that can help to better phenotype and personalize asthma management. Study Question: Does routine bronchoscopy help to phenotype patients with severe uncontrolled asthma potentially eligible for biologic therapy? Results: Routine bronchoscopy clusters patients with severe uncontrolled asthma and identifies treatable traits that are not accurately detected otherwise, such as tissue eosinophilia, upper airway disease, or infection. Interpretation: Routine bronchoscopy in patients with severe uncontrolled asthma is a safe procedure that can help to better phenotype and personalize asthma management. Despite adherence to medium-to-high-dose inhaled corticosteroids and long-acting bronchodilators, approximately 3% to 7% of the population with asthma had severe uncontrolled asthma (SUA).1Hekking P.W. Wener R.R. Amelink M. Zwinderman A.H. Bouvy M.L. Bel E.H. The prevalence of severe refractory asthma.J Allergy Clin Immunol. 2015; 135: 896-902Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar In the last decade, there has been increasing awareness of the importance of phenotypes and endotypes of asthma, especially related to low and high T2 inflammation, that guides the new therapeutic advances for patients with severe asthma. However, there is still a lack of reliable surrogate markers of T2 inflammation; blood eosinophil count (BEC), fractional exhaled nitric oxide (Feno), and IgE are the most common biomarkers used. Evidence suggests that the eosinophilic phenotype of severe asthma is more prevalent than previously identified and is phenotypically distinct, addressing issues of phenotype heterogeneity and phenotype instability, concluding that identification of treatable traits across phenotypes should improve therapeutic precision.2Heaney L.G. Perez de Llano L. Al-Ahmad M. et al.Eosinophilic and noneosinophilic asthma: an expert consensus framework to characterize phenotypes in a global real-life severe asthma cohort.Chest. 2021; 160: 814-830Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar In keeping with this concept, recent evidence suggests that eosinophil variability is associated with poorer clinical outcomes, which may explain the poor correlation between blood and tissue eosinophils.3Toledo-Pons N. van Boven J.F.M. Muncunill J. et al.Impact of blood eosinophil variability in asthma: a real-life population study.Ann Am Thorac Soc. 2022; 19: 407-414Crossref PubMed Scopus (9) Google Scholar The need to identify more precisely a T2-high phenotype led to proposing induced sputum as a clinical tool to address the treatment of severe asthma. However, the European Respiratory Society/American Thoracic Society guideline on severe asthma suggests using BEC rather than sputum eosinophils because the latter is only performed in specialized centers because of its complexity.4Holguin F. Cardet J.C. Chung K.F. et al.Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline.Eur Respir J. 2020; 551900588Crossref PubMed Scopus (351) Google Scholar Conversely, multiple confounding factors and comorbidities may cause symptom deterioration affecting the control of asthma and should be evaluated in the assessment of severe asthma. For instance, the co-existence of gastroesophageal reflux disease (GERD) or the role of infections, for example, have been previously documented5Kiljander T.O. Laitinen J.O. The prevalence of gastroesophageal reflux disease in adult asthmatics.Chest. 2004; 126: 1490-1494Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,6Mastronarde J.G. Anthonisen N.R. Castro M. et al.Efficacy of esomeprazole for treatment of poorly controlled asthma.N Engl J Med. 2009; 360: 1487-1499Crossref PubMed Scopus (335) Google Scholar as causes of poor symptomatic control, but their precise prevalence is unknown. Furthermore, various studies have shown that the airway microbiome in patients with asthma differs from that of healthy people,7Marri P.R. Stern D.A. Wright A.L. Billheimer D. Martinez F.D. Asthma-associated differences in microbial composition of induced sputum.J Allergy Clin Immunol. 2013; 131: 346-352Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar,8Huang Y.J. Boushey H.A. The microbiome in asthma.J Allergy Clin Immunol. 2015; 135: 25-30Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar and that potentially pathogenic bacteria are more commonly found in patients with asthma than in healthy subjects.9Hilty M. Burke C. Pedro H. et al.Disordered microbial communities in asthmatic airways.PLoS One. 2010; 5e8578Crossref PubMed Scopus (1289) Google Scholar Bronchoscopy has been used over the last century for the investigation of asthma and studying the pathogenesis of the disease10Jarjour N.N. Peters S.P. Djukanović R. Calhoun W.J. Investigative use of bronchoscopy in asthma.Am J Respir Crit Care Med. 1998; 157: 692-697Crossref PubMed Scopus (66) Google Scholar; however, its use in the routine evaluation of SUA is controversial, especially in those with FEV1 < 60% predicted.11Workshop summary and guidelines: investigative use of bronchoscopy, lavage, and bronchial biopsies in asthma and other airway diseases.J Allergy Clin Immunol. 1991; 88: 808-814Abstract Full Text PDF PubMed Scopus (186) Google Scholar According to the Spanish guideline for the management of asthma (2021)12Plaza V. Alobid I. Alvarez C. et al.Spanish Asthma Management Guidelines (GEMA) VERSION 5.1. Highlights and Controversies.Arch Bronconeumol (Engl Ed). 2022; 58: 150-158Crossref PubMed Scopus (29) Google Scholar and the Global Initiative for Asthma's (GINA) guidelines (2021),13Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention.https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdfDate accessed: August 6, 2022Google Scholar bronchoscopy plays a role in the workup of SUA, mainly focused in the study of comorbidities aggravating asthma control. We appeal for the standardization and routine use of bronchoscopy in SUA before the indication of a biologic therapy. Therefore, in the current study, we aimed to explore the utility of bronchoscopy as part of the workup of SUA in identifying prespecified clinical phenotypes and to assess the safety of the procedure among the population with SUA. Second, we aimed to prospectively evaluate the efficacy of routine bronchoscopy to exclude possible risk factors and comorbidities that could be linked to poor symptomatic control. As part of a multicenter prospective study aimed to standardize and investigate the role of bronchial biopsy in SUA patients before biological therapy, consecutive patients attending specialized asthma units from five teaching hospitals with diagnoses of SUA according to GINA guidelines13Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention.https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdfDate accessed: August 6, 2022Google Scholar underwent bronchoscopy as part of the workup for their clinical evaluation. A written protocol with inclusion criteria and procedures was previously agreed to among investigators. According to that protocol, all the included patients had a history of asthma that was poorly controlled, defined as asthma control test result < 20 or at least one severe exacerbation in the prior 12 months requiring hospitalization or emergency visit, or need for maintenance oral corticosteroids to control their symptoms12Plaza V. Alobid I. Alvarez C. et al.Spanish Asthma Management Guidelines (GEMA) VERSION 5.1. Highlights and Controversies.Arch Bronconeumol (Engl Ed). 2022; 58: 150-158Crossref PubMed Scopus (29) Google Scholar,13Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention.https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdfDate accessed: August 6, 2022Google Scholar despite confirmed good adherence to high-dose inhaled corticosteroids and long-acting beta-agonists for at least 3 months (GINA step 4 or 5).13Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention.https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdfDate accessed: August 6, 2022Google Scholar Exclusion criteria for bronchoscopy were respiratory failure of any cause, acute exacerbation of asthma within the previous 4 weeks, clotting disorders, or severe comorbidity outside the lung that could increase the risk of the procedure. The protocol was approved by the Ethics Committee of the Balearic Islands (reference IB 3906 /19) and the rest of the participant centers. All patients signed an informed consent for bronchoscopy. Patients with SUA were clinically phenotyped according to BEC, Feno, and IgE, following GINA recommendations. Briefly, they were classified as (1) T2-allergic if they had symptoms associated with allergen exposure, and increased IgE and a positive skin-prick test or specific IgE to any aero-allergen regardless of the BEC or Feno; (2) T2-eosinophilic if they were not allergic and they showed biomarkers of T2 high inflammation, such as BEC > 300 cells/μL within the last 12 months, or > 100 cells/μL if receiving oral corticosteroids, or Feno > 50 ppb; and (3) non-T2 or nonallergic, noneosinophilic if they did not show characteristics of the previous two groups. As part of the clinical workup, a blood sample was taken for routine laboratory analysis, including BEC, IgE, and radioallergosorbent test for common aero-allergens. Also, skin-prick test, forced spirometry, Feno, and CT scan of the thorax were performed. Bronchodilator reversibility test was performed using salbutamol 400 μg, whereas a change in percent predicted and absolute value of FEV1 and/ or FVC ≥ 12% and 200 mL, respectively, in a single test was considered positive.14Pellegrino R. Viegi G. Brusasco V. et al.Interpretative strategies for lung function tests.Eur Respir J. 2005; 26: 948-968Crossref PubMed Scopus (4368) Google Scholar Fiber-optic bronchoscopy was performed under conscious sedation, with pretreatment with nebulized salbutamol and ipratropium bromide 10 min before the procedure, and treatment with 40 mg methylprednisolone administered IV immediately after bronchial biopsies were performed. As per protocol, bronchoscopy was always initially introduced through the nose. Information on larynx, tracheobronchial tree, bronchial mucosa, and airway secretions were systematically collected. We considered interarytenoid thickening and larynx inflammation (glottic or infraglottic) as signs of possible laryngopharyngeal reflux. Vocal cord dysfunction was diagnosed when the following criteria were present: (1) adduction of vocal cords during inspiration, or both inspiration and expiration; (2) 50% closure of cords. Tracheal abnormalities included stenosis, tracheobronchomalacia, and excessive dynamic airway collapse, which were considered as a unique finding and defined as a collapse of the airway resulting in greater than 50% narrowing of the cross-sectional lumen during normal breathing. Bronchial aspirate, defined as the collection of undiluted secretions sitting in the airways, was taken for microbiological and cytologic evaluation, and a bronchial biopsy was performed for histopathologic evaluation when possible. Biopsy was not taken if the bronchoscopy showed cause of poor control or when the considered there was a risk of the procedure because of poor or bleeding. of bronchoscopy was considered if there was that of or or that forced of the procedure. Bronchoscopy were systematically evaluated by an expert who and the eosinophils in the as and 3 > 10 were as for of normal was performed for that were as or accordingly. The test, test, or test were used as analysis was performed using at with the of to identify the Cluster et analysis and clinical asthma J Respir Crit Care Med. 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H. R. in severe asthma is associated with the identification of in sputum.J PubMed Scopus Google Scholar found that of fungi from the airway of patients with asthma is common in the of and that therapy was associated with clinical On the et C. et presence of in asthmatic is not related to clinical disease 2020; PubMed Scopus Google Scholar found that approximately of their had fungi in that was not related to asthma or control or We found that patients with SUA, despite being with their asthma have treatable traits that be identified unless a specific test is and bronchoscopy can identify most of these BEC and Feno are used as biomarkers of T2 inflammation and to biological therapy in severe eosinophilic R. G. and value of blood eosinophil fractional exhaled nitric and their in severe asthma: a J Respir Crit Care Med. PubMed Scopus Google Scholar but in the use of these biomarkers have been previously et J. The of blood eosinophil count and to sputum in the of severe eosinophilic Respir J. Scholar found of both Feno and BEC in the of sputum in patients with uncontrolled asthma. Conversely, et et eosinophil count and prospective asthma disease a Respir Med. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar found that BEC more than 400 was associated with uncontrolled asthma and exacerbation In the current study, we identified eosinophils in the bronchial biopsy of a of patients with asthma with T2 but not in On the patients classified clinically as non-T2 because of low of T2 biomarkers showed eosinophils in the bronchial biopsy, one of of severe Furthermore, we found of the had only submucosal the current study was not to evaluate tissue eosinophilia, we that bronchial biopsy is a reliable and safe for identifying to assess airway eosinophilia, such as induced are and not in whereas bronchoscopy is a routine procedure in single respiratory the of bronchoscopy to identify other causes of poor control, such as vocal cord or and to microbiological from the airways, to the routine use of bronchoscopy in the evaluation of patient with severe asthma before a biologic therapy is have clinical on the current the presence of submucosal in the bronchial biopsy the clinical phenotypes used in the of three patients classified clinically as non-T2 showed tissue eosinophilia, and of the T2 patients had no tissue eosinophilia. Furthermore, among the of of T2-allergic could be as T2-eosinophilic on the presence of submucosal eosinophils in bronchial biopsies regardless of their blood eosinophils, which could the of biological therapy used. The systematic data collection and consecutive of patients with SUA in specialized asthma centers and the safety of the procedure. However, should be the population to be more frequently T2-eosinophilic, which is a common finding in respiratory and the of non-T2 asthma phenotype was which on the latter Second, bronchial biopsy was not performed in all and its was not which could to of the However, is on standardization of the of bronchial biopsy in severe asthma, and the in the various centers are to in the treatable traits were identified and according to clinical the study was not to evaluate the of on asthma control. We that routine bronchoscopy is a safe procedure in severe asthma during the workup of patients who are potentially for a biologic therapy and data that could help to better phenotype these patients and be a for asthma management. The study was by the de of of and by the asthma of

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