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.

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.

Update on infection and antibiotics in asthma.

Asthma pathogenesis seems to be a result of a complex mixture of genetic and environmental influences. There is evidence that Mycoplasma pneumoniae and Chlamydophila pneumoniae (formerly known as Chlamydia pneumoniae) play a role in promoting airway inflammation that could contribute to the onset and clinical course of asthma. Evidence also indicates that when antimicrobial therapy can eradicate or suppress these organisms, it may be possible to alter the course of the disease. Certain macrolide antibiotics have been shown to improve control of asthma symptoms and lung function in patients diagnosed with acute C. pneumoniae or M. pneumoniae infection. Positive polymerase chain reaction studies for C. pneumoniae or M. pneumoniae are needed to select asthma patients for chronic treatment. Macrolide antibiotics may also have independent anti-inflammatory activity that may be useful in the management of asthma and other inflammatory diseases.

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.

Performance of a new screening spirometer at a community health fair.

OBJECTIVE: Compare the results from a new screening spirometer (EasyOne) with the results from a standard laboratory spirometer (Vmax) approved by the American Thoracic Society. SETTING: A health fair at a community hospital. METHODS: We measured forced expiratory volume in the first second (FEV(1)) and forced expiratory volume in the first 6 seconds (FEV(6)). With the screening spirometer, good quality testing was achieved in 359 of 394 subjects (91%), and 115 subjects were also tested with the standard laboratory spirometer. The best test values for FEV(1) and FEV(6) were taken for 3 tests that agreed within 3%. FEV(6) was extrapolated from forced vital capacity on the printouts from the standard laboratory spirometer. RESULTS: Correlations between the screening spirometer results and the standard laboratory spirometer were excellent for FEV(1) (r = 0.93), FEV(6) (r = 0.96), and FEV(1)/FEV(6) (r = 0.72) (p = 0.001 for all comparisons). The 95% limits of agreement (mean difference between the 2 spirometers +/- 1.96 standard deviations) were: -0.18 and 0.69 for FEV(1); -0.24 and 0.81 for FEV(6); and -0.12 and 0.13 for FEV(1)/FEV(6). CONCLUSION: The new screening spirometer is suitable for clinical use.

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.