Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma.

BACKGROUND: The mechanism of TH2/TH17-predominant and TH2/TH17-low asthma is unknown. OBJECTIVE: We sought to study the immune mechanism of TH2/TH17-predominant and TH2/TH17-low asthma. METHODS: In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups. RESULTS: Patients with TH2/TH17-predominant asthma had increased IL-1ß, IL-6, IL-23, C3a, and serum amyloid A levels in BAL fluid, and these correlated with IL-1ß and C3a levels. TH2/TH17 cells expressed higher levels of the IL-1 receptor and phospho-p38 mitogen-activated protein kinase. Anakinra, an IL-1 receptor antagonist protein, inhibited BAL TH2/TH17 cell counts. TH2/TH17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with TH2/TH17-predominant and TH2-predominant asthma, which included neutrophilic asthma in 6% and 0% of patients, respectively. BAL fluid neutrophils strongly correlated with BAL fluid myeloperoxidase, IL-8, IL-1α, IL-6, granulocyte colony-stimulating factor, and GM-CSF levels. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection. CONCLUSION: We uncovered a critical role for the IL-1ß pathway in patients with TH2/TH17-predminant asthma. A subgroup of patients with TH2/TH17-low asthma had neutrophilic asthma and increased BAL fluid IL-1α, IL-6, IL-8, granulocyte colony-stimulating factor, and GM-CSF levels. IL-1α was directly involved in IL-8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.

Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33.

BACKGROUND: Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen exposure. OBJECTIVE: We sought to elucidate factors contributing to the persistence of asthma. METHODS: We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence. RESULTS: Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)(-/-) bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2(-/-)γc(-/-) bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity. CONCLUSIONS: We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling.

The effects of airway microbiome on corticosteroid responsiveness in asthma.

RATIONALE: The role of airway microbiome in corticosteroid response in asthma is unknown. OBJECTIVES: To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. METHODS: 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. MEASUREMENTS AND MAIN RESULTS: Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-ß-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. CONCLUSIONS: A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.

Importance of fiberoptic bronchoscopy in identifying asthma phenotypes to direct personalized therapy.

PURPOSE OF REVIEW: This review summarizes the phenotyping of refractory asthma with an emphasis on how direct bronchoscopic observation and analysis of bronchoalveolar lavage (BAL), biopsy, and brushings of the airways helps direct specific personalized therapy. Additional testing used in phenotyping asthmatic patients is reviewed. RECENT FINDINGS: Several studies and publications over the past decade have emphasized the importance of phenotyping refractory asthmatic patients to offer a better understanding of the pathobiology of disease. Bronchoscopy is a useful tool in phenotyping asthma with objective data obtained from BAL, endobronchial biopsy, and brushings. Phenotyping asthma with bronchoscopy affords personalized and successful therapy. SUMMARY: By using fiberoptic bronchoscopy, specific asthma phenotypes can be identified: laryngopharyngeal reflux with silent aspiration; subacute bacterial infection; tissue eosinophilia; a combination of two or three of these; and nonspecific. Identifying these phenotypes and personalizing therapy with bronchoscopy leads to improved outcomes.

Macrolides in the treatment of asthma.

PURPOSE OF REVIEW: This review summarizes the importance of macrolide therapy in the treatment of asthma, discusses macrolide mechanisms of action, and outlines new clinical data supporting their use. The effects of macrolides on both the innate and adaptive immune responses are discussed. RECENT FINDINGS: Subacute bacterial infection with both typical and atypical organisms contributes to poor asthma control. Identification of pathogens using polymerase chain reaction (PCR) and cultures from bronchoscopic samples directs antibiotic therapy and improves asthma control. PCR identification of Mycoplasma pneumoniae and Chlamydophila pneumoniae in asthmatics best identifies the macrolide responsive phenotype. SUMMARY: Because of their effect on protein synthesis, macrolides have both antimicrobial and anti-inflammatory properties. Both mechanisms appear to be important in their clinical efficacy in treating a wide variety of pulmonary disorders, including asthma.

New insights in the diagnosis of chronic refractory cough.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ±â€¯1.6) associated with chronic cough. With directed therapy 71/76 (93%) patients had resolution or improvement in cough symptoms. CONCLUSIONS: 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.

The role of atypical infections and macrolide therapy in patients with asthma.

For many years, the clinical benefit of macrolide use has been recognized in specific groups of patients with pulmonary disease. Dramatic improvement in survival of patients with diffuse panbronchiolitis is the most striking example of successful macrolide use as well as treatment of community acquired pneumonia caused by the atypical bacteria Mycoplasma, Chlamydophila, and Legionella. There also has been documentation of reduction in the exacerbation rate and of improvement in quality of life in patients with cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, and reduction in post-lung transplantation bronchiolitis frequency. There has long been an interest in treating patients with severe asthma by using macrolides, but research results have not shown consistent clinical benefit in their use in the "general" population of patients with severe asthma. Rather, the successful use of macrolides seems to be in those patients with either documented Mycoplasma or Chlamydophila infection, or noneosinophilic asthma. Patients with neutrophil predominant phenotype severe asthma tend to show a decline in exacerbation rate, improved peak expiratory flows, and improved quality of life when treated with macrolides. This article will review the use of macrolides in the treatment of asthma.

An index to objectively score supraglottic abnormalities in refractory asthma: learning, validation, and significance.

BACKGROUND: Patients with refractory asthma frequently have elements of laryngopharyngeal reflux (LPR) with potential aspiration contributing to their poor control. We previously reported on a supraglottic index (SGI) scoring system that helps in the evaluation of LPR with potential aspiration. However, to further the usefulness of this SGI scoring system for bronchoscopists, a teaching system was developed that included both interobserver and intraobserver reproducibility. METHODS: Five pulmonologists with expertise in fiber-optic bronchoscopy but novice to the SGI participated. A training system was developed that could be used via Internet interaction to make this learning technique widely available. RESULTS: By the final testing, there was excellent interreader agreement (κ of at least 0.81), thus documenting reproducibility in scoring the SGI. For the measure of intrareader consistency, one reader was arbitrarily selected to rescore the final test 4 weeks later and had a κ value of 0.93, with a 95% CI of 0.79 to 1.00. CONCLUSIONS: In this study, we demonstrate that with an organized educational approach, bronchoscopists can develop skills to have highly reproducible assessment and scoring of supraglottic abnormalities. The SGI can be used to determine which patients need additional intervention to determine causes of LPR and gastroesophageal reflux. Identification of this problem in patients with refractory asthma allows for personal, individual directed therapy to improve asthma control.

An Index to Objectively Score Supraglottic Abnormalities in Refractory Asthma.

BACKGROUND: Patients with refractory asthma frequently have elements of laryngopharyngeal reflux (LPR) with potential aspiration contributing to their poor control. We previously reported on a supraglottic index (SGI) scoring system that helps in the evaluation of LPR with potential aspiration. However, to further the usefulness of this SGI scoring system for bronchoscopists, a teaching system was developed that included both interobserver and intraobserver reproducibility. METHODS: Five pulmonologists with expertise in fiber-optic bronchoscopy but novice to the SGI participated. A training system was developed that could be used via Internet interaction to make this learning technique widely available. RESULTS: By the final testing, there was excellent interreader agreement (κ of at least 0.81), thus documenting reproducibility in scoring the SGI. For the measure of intrareader consistency, one reader was arbitrarily selected to rescore the final test 4 weeks later and had a κ value of 0.93, with a 95% CI of 0.79 to 1.00. CONCLUSIONS: In this study, we demonstrate that with an organized educational approach, bronchoscopists can develop skills to have highly reproducible assessment and scoring of supraglottic abnormalities. The SGI can be used to determine which patients need additional intervention to determine causes of LPR and gastroesophageal reflux. Identification of this problem in patients with refractory asthma allows for personal, individual directed therapy to improve asthma control.

Refractory asthma: importance of bronchoscopy to identify phenotypes and direct therapy.

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.