Donald Rollins

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.

Airway and serum biochemical correlates of refractory neutrophilic asthma

Background: 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. Objective: We sought to explore the relationship between neutrophils and other biomarkers of RA. Method: 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. Results: 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. Conclusions: 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. Graphical abstract Figure. No Caption available.

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.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.

Clarifying the link between sleep disordered breathing and tracheal collapse: a retrospective analysis

BackgroundSymptoms of acquired tracheobronchomalacia (TBM) include wheezing, shortness of breath, and chronic cough, and can negatively affect quality of life. Successful treatment of TBM requires identification of the disorder and of contributing factors. Acquired TBM is generally associated with a number of conditions, including asthma, chronic obstructive pulmonary disease (COPD), and gastroesophageal reflux. Although a possible relationship with obstructive sleep apnea (OSA) has been observed, data illuminating such an interaction are sparse.MethodsIn the present study, we analyzed the percent tracheal collapse (as measured on dynamic chest CT) and detailed sleep reports of 200 patients that had been seen at National Jewish Health, half of which had been diagnosed with OSA and half which did not have OSA.ResultsTracheal collapse ranged from 0 to 99% closure in the population examined, with most subjects experiencing at least 75% collapse. OSA did not relate significantly to the presence or severity of tracheobronchomalacia in this population. Sleep disordered breathing (SDB) did show a strong association with TBM (p < 0.03).ConclusionsTracheobronchomalacia may develop as a result of increased negative intrathoracic pressure created during attempts at inhalation against a closed or partially closed supraglottic area in patients experiencing apneic or hypopneic events, which contributes to excessive dilation of the trachea. Over time, increased airway compliance develops, manifesting as tracheal collapse during exhalation. Examining TBM in the context of SDB may provide a reasonable point at which to begin treatment, especially as treatment of sleep apnea and SDB (surgical or continuous positive airway pressure) has been shown to improve associated TBM.

Increased Frequency Of Dual Positive Th2/Th17 Cells In Bronchoalveolar Lavage Characterizes a Population Of Severe Asthmatic Patients

Background Th2 cells can further differentiate into dual positive Th2/Th17 cells. The presence of dual positive Th2/Th17 cells in the airways and its impact on asthma severity are unknown.