Refractory Asthma: Importance of Bronchoscopy to Identify Phenotypes and Direct Therapy

doi:10.1378/chest.11-0741

Chest

Volume 141, Issue 3, March 2012, Pages 599-606

https://doi.org/10.1378/chest.11-0741 Get rights and content

Background

The pathophysiology of refractory asthma is not well understood; thus, treatment modalities are not targeted to specific phenotypes but rather to a broad-based treatment approach. The objective of this study was to develop refractory asthma phenotypes based on bronchoscopic evaluation and to develop from this information specific, directed, personalized therapy.

Methods

Fifty-eight patients with difficult-to-treat (refractory) asthma were characterized by the use of fiber-optic bronchoscopy with visual scoring systems of the upper and lower airways as well as with BAL, endobronchial biopsy, and brush. Response to changes in therapy was evaluated by changes in the Asthma Control Test and pulmonary function.

Results

Five mutually exclusive phenotypes were formulated based on bronchoscopic evaluation: gastroesophageal reflux, subacute bacterial infection, tissue eosinophilia, combination, and nonspecific. Specific directed therapy yielded a significant improvement in the Asthma Control Test and pulmonary function for the entire group as well as for each defined subgroup except for the nonspecific group. Of interest, visual scoring of the supraglottic abnormalities identified 34 of 35 patients with gastroesophageal reflux and may give a better insight into asthmatic problems associated with chronic proximal reflux than standard testing.

Conclusions

Bronchoscopic evaluation of the upper and lower airways can provide important information toward characterizing refractory asthma so as to better individualize therapeutic options and improve asthma control and lung function in patients with difficult-to-treat asthma.

Section snippets

Patient Population

National Jewish Institutional Review Board approval (HS2477) was obtained to use these prospective clinical data for publication. Patients aged ≥ 18 years were assessed by history, physical examination, routine laboratory studies, Asthma Control Test (ACT),⁹ and spirometry. Prospective inclusion criteria were a 12% improvement in FEV₁ postbronchodilator or positive provocative concentration of methacholine to produce a 20% fall in FEV₁ of ≤ 6 mg/mL. Refractory asthma was defined by American

Results

Demographic characteristics are shown in Table 1. Forty-five patients (78%) met the FEV₁ reversibility criterion of > 12%, with the remaining 13 meeting the provocative concentration of methacholine to produce a 20% fall in FEV₁ criteria of < 6 mg/mL. Prior to bronchoscopy and phenotyping, the 20 initial patients treated with intensified asthma therapy showed no improvement in ACT or lung function (Fig 1).

Discussion

The purpose of this study was to evaluate the effectiveness of bronchoscopic analysis in managing patients with refractory asthma. In spite of standard asthma therapy, up to 50% of patients are still not well controlled or can be refractory to treatment.² From this evaluation, four different phenotypes were identified that, even with decreased standard asthma therapies, demonstrated improvement in lung function and asthma control using specific directed interventions (Figs 2A, 2B, e-Tables 4-6

Acknowledgments

Author contributions: Dr Martin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Good: contributed to the study design, data collection, analyses, and manuscript writing.

Ms Kolakowski: contributed to the study design, data collection, analyses, and manuscript writing.

Dr Groshong: contributed to the data collection, analyses, and manuscript writing.

Dr Murphy: contributed to the study design, data

References (31)

SE Wenzel
Asthma: defining of the persistent adult phenotypes
Lancet
(2006)
M Schatz et al.
Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists
J Allergy Clin Immunol
(2006)
AB Thompson et al.
The bronchitis index. A semiquantitative visual scale for the assessment of airways inflammation
Chest
(1993)
DL Hahn et al.
Serologic markers for Chlamydia pneumoniae in asthma
Ann Allergy Asthma Immunol
(2000)
JS Seggev et al.
Isotype-specific antibody responses to acute Mycoplasma pneumoniae infection
Ann Allergy Asthma Immunol
(1996)
PG Woodruff et al.
Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma
J Allergy Clin Immunol
(2001)
National Asthma Education and Prevention Program (National Heart Lung and Blood Institute) Third Expert Panel on the Management of Asthma
National Center for Biotechnology Information
Expert Panel Report 3 Guidelines for the Diagnosis and Management of Asthmas
(2007)
ED Bateman et al.
Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study
Am J Respir Crit Care Med
(2004)
DM Mannino et al.
Surveillance for asthma—United States, 1980-1999
MMWR Surveill Summ
(2002)
National Heart, Lung, and Blood Institute
Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases
(2002)

American Thoracic Society

Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions

Am J Respir Crit Care Med

(2000)

S Wenzel

Severe asthma in adults

Am J Respir Crit Care Med

(2005)

WC Moore et al.

Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program

Am J Respir Crit Care Med

(2010)

K Kenn et al.

Vocal cord dysfunction: what do we know?

Eur Respir J

(2011)

PC Belafsky et al.

The validity and reliability of the reflux finding score (RFS)

Laryngoscope

(2001)

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Redefining the Role of Bronchoscopy in the Workup of Severe Uncontrolled Asthma in the Era of Biologics: A Prospective Study
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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.
Refractory neutrophilic asthma and ciliary genes
2022, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Blood, lung function, computed tomography (CT) of the chest, and bronchoscopic samples were collected from subjects ≥18 years old using previously described protocols3 (see this article’s Methods section in the Online Repository available at www.jacionline.org). BAL was analyzed for cell count/differential and positive PCR-based respiratory viruses/bacteria, categorized as SBI.3,4 Total RNA was extracted using the ZR RNA MicroPrep kit (Zymo Research, Irvine, Calif) following the manufacturer’s protocols; an RNA integrity number of ≥7 was confirmed before sample processing; and the labeled complementary DNA was hybridized via Affymetrix Human Genome U133 Plus 2.0 GeneChip arrays (Affymetrix, Santa Clara, Calif).
Refractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear.
We sought to characterize and clinically correlate gene expression differences between refractory and nonrefractory (NR) asthma to uncover molecular mechanisms driving group distinctions.
Microarray gene expression of paired airway epithelial brush and endobronchial biopsy samples was compared between 60 RA and 30 NR subjects. Subjects were hierarchically clustered to identify subgroups of RA, and biochemical and clinical traits (airway inflammatory molecules, respiratory pathogens, chest imaging) were compared between groups. Weighted gene correlation network analysis was used to identify coexpressed gene modules. Module expression scores were compared between groups using linear regression, controlling for age, sex, and body mass index.
Differential gene expression analysis showed upregulation of proneutrophilic and downregulation of ciliary function genes/pathways in RA compared to NR. A subgroup of RA with downregulated ciliary gene expression had increased levels of subclinical infections, airway neutrophilia, and eosinophilia as well as higher chest imaging mucus burden compared to other RA, the dominant differences between RA and NR. Weighted gene correlation network analysis identified gene modules related to ciliary function, which were downregulated in RA and were associated with lower pulmonary function and higher airway wall thickness/inflammation, markers of poorer asthma control.
Identification of a novel ciliary-deficient subgroup of RA suggests that diminished mucociliary clearance may underlie repeated asthma exacerbations despite adequate treatment, necessitating further exploration of function, mechanism, and therapeutics.
The Role of Comorbidities in Difficult-to-Control Asthma in Adults and Children
2022, Journal of Allergy and Clinical Immunology: In Practice
Assessment of asthma comorbidities, conditions that adversely affect the pathobiology of asthma or impair its response to therapies, is a fundamental step in the evaluation and management of patients with difficult-to-treat asthma. Identifying and effectively treating asthma comorbidities, such as obesity, obstructive sleep apnea, and chronic sinusitis with nasal polyps, may improve asthma control and reduce exacerbations. In addition, identifying comorbid T2 inflammatory conditions may help guide optimal selection of biologic therapies. Here, we describe common comorbid conditions found in adult and pediatric difficult-to-control asthma, discuss evidence for the association with asthma morbidity and treatment benefit, and provide information on how and when to assess comorbidities.
New insights in the diagnosis of chronic refractory cough
2018, Respiratory Medicine
Chronic Refractory Cough (CRC) is a common condition that significantly impairs patients' quality of life. Unfortunately, in many situations patients continue to experience CRC in spite of following published guidelines for diagnosis and treatment.
99 patients were referred to National Jewish Health (NJH), a specialty respiratory center for evaluation of CRC (cough ≥ 8 weeks duration). Study duration occurred over 18 months. Intake evaluation for all patients included history, physical examination, spirometry and fiberoptic laryngoscopy. Testing to confirm causes of CRC were performed. Specific therapy for each potential cause was provided. A visual analog cough scale measured cough response.
Ten final diagnostic categories were found in the cohort of 99 patients with CRC: Obstructive sleep apnea (apnea/hypoxia index ≥ 5), rhinosinusitis, Tracheobronchomalacia (≥65% collapse of airway with dynamic expiratory imaging), esophageal dysmotility, gastroesophageal reflux, abnormal swallowing with laryngeal penetration, asthma, COPD, bronchiectasis and paradoxical vocal cord movement. In these patients there were 42 incorrect intake diagnoses and 101 new diagnoses established. Patients with CRC have had multiple diagnoses (3.8 ± 1.6) associated with chronic cough. With directed therapy 71/76 (93%) patients had resolution or improvement in cough symptoms.
Among patients referred to a specialty respiratory center with CRC multiple concomitant diagnoses for cough were common. Certain diagnoses such as OSA and TBM have not been reported in cough guidelines but in this study are commonly associated diagnoses. Targeted therapy for each recognized diagnosis improves patient response.
Guiding principles for use of newer biologics and bronchial thermoplasty for patients with severe asthma
2017, Annals of Allergy, Asthma and Immunology
Severe asthma poses significant disease-related and economic burdens in the United States. Challenges in practice include how to define “severe asthma” for a given patient, knowing which are the right tests to perform and when, and having a better understanding of a patient's asthma phenotype. Furthermore, current guidelines do not address a clear, practical approach to treatment that is based on a patient's asthma phenotype.
To develop a consensus on the definition of severe asthma, the role of biomarkers and phenotyping severe asthma, and the use of newer biologic therapies and bronchial thermoplasty to help guide practicing clinicians.
A roundtable meeting was convened with a panel of severe asthma experts to discuss areas in practice that are not adequately addressed by current guidelines, specifically phenotype-guided treatment.
We describe a consensus on the definition of severe asthma, asthma phenotyping with the use of available biomarkers, and guiding principles for newer biologic therapies and bronchial thermoplasty.
To optimize therapy and improve outcomes such as daily symptoms, quality of life, exacerbations, and hospitalizations, a clear picture of a patient's asthma phenotype is needed to guide therapy. Determining asthma phenotypes is the foundation of precision medicine for this persistent, often difficult-to-treat disease.
Airway and serum biochemical correlates of refractory neutrophilic asthma
2017, Journal of Allergy and Clinical Immunology
Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood.
We sought to explore the relationship between neutrophils and other biomarkers of RA.
Sixty patients with RA, 30 patients with nonrefractory asthma (NRA), and 20 healthy subjects were enrolled. We performed a comprehensive characterization of these study subjects, which included laboratory and pulmonary function studies, chest computed tomography, and bronchoscopy with bronchoalveolar lavage (BAL). We analyzed BAL fluid and serum for a total of 244 biomolecules using a multiplex assay and correlated them with clinical and other laboratory parameters.
RA was significantly different from NRA with regard to pulmonary function indices, bronchial basement membrane thickness, and BAL fluid neutrophil and lymphocyte counts but not eosinophil counts. BAL fluid neutrophil counts negatively and positively correlated with forced vital capacity and age, respectively. Of the 244 biomolecules studied, 52 and 14 biomolecules from BAL fluid and serum, respectively, were significantly different among the study groups. Thirteen of these 52 molecules correlated with BAL fluid neutrophil counts. BAL fluid from 40% of patients with RA was positive for a pathogenic microbe. Infection-negative neutrophilic RA was associated with an increase in levels of select biomarkers of inflammation in the serum, suggesting the presence of systemic inflammation.
RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways. Subclinical infection was present in 40% of patients with RA, which likely contributed to neutrophilic inflammation. A subgroup of patients with noninfected neutrophilic RA was associated with systemic inflammation.

View all citing articles on Scopus

Funding/Support: The authors have reported to CHEST that no funding was received for this study.

James R. Murphy, PhD, is deceased (December 2010).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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Chest

Original ResearchAsthmaRefractory Asthma: Importance of Bronchoscopy to Identify Phenotypes and Direct Therapy

Background

Methods

Results

Conclusions

Section snippets

Patient Population

Results

Discussion

Acknowledgments

Lancet

J Allergy Clin Immunol

Chest

Ann Allergy Asthma Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

National Center for Biotechnology Information

Expert Panel Report 3 Guidelines for the Diagnosis and Management of Asthmas

Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study

Am J Respir Crit Care Med

Surveillance for asthma—United States, 1980-1999

MMWR Surveill Summ

Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases

Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions

Am J Respir Crit Care Med

Severe asthma in adults

Am J Respir Crit Care Med

Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program

Am J Respir Crit Care Med

Vocal cord dysfunction: what do we know?

Eur Respir J

The validity and reliability of the reflux finding score (RFS)

Laryngoscope

Original Research
Asthma
Refractory Asthma: Importance of Bronchoscopy to Identify Phenotypes and Direct Therapy