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 nasal methylome and childhood atopic asthma.

BACKGROUND: Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. OBJECTIVE: We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. METHODS: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). RESULTS: We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively (P < 2.8 × 10-6 for differentially methylated regions and P < 7.8 × 10-10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. CONCLUSIONS: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

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.