Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

RATIONALE: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease. OBJECTIVES: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. METHODS: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects. MEASUREMENTS AND MAIN RESULTS: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans. CONCLUSIONS: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

Efficacy of esophageal impedance/pH monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy.

BACKGROUND & AIMS: Intraluminal impedance monitoring has given new dimensions to the diagnosis of reflux disease. However, there is no defined algorithm for evaluating refractory reflux symptoms. We studied whether combined impedance/pH monitoring in patients on therapy can predict acid reflux in patients off therapy and whether testing should be carried out when patients are on or off therapy. METHODS: Thirty-nine adults (mean age, 50 years; 24 female) with refractory reflux symptoms were evaluated by impedance/pH monitoring while on therapy, followed by wireless pH monitoring while off therapy. Non-acid reflux events in patients on therapy were correlated with acid reflux parameters studied off therapy. In addition, the likelihood of test abnormalities on and off therapy was determined. RESULTS: In 25 of 39 patients (64%) on therapy, impedance testing was normal, with a median of 69 events (interquartile, 63.0-78.0). The percentage of time at pH <4 was within the normal range for all patients who were on therapy. The pH test results were abnormal in 28 of 39 patients (72%) when studied off therapy. Ninety-three of patients with abnormal impedance on therapy also had abnormal acid reflux off therapy. When both groups were off therapy, the patients with abnormal impedance parameters on therapy had significantly higher median (interquartile) 2-day baseline levels of esophageal acid exposure (8.7%, 6.9%-12.5%), compared with those of patients with normal impedance parameters while on therapy (6.0%, 2.8%-9.4%; P = .026). CONCLUSIONS: Abnormal impedance in patients on therapy predicts acid reflux in patients off therapy. In patients with refractory reflux, combined impedance/pH monitoring might provide the single best strategy for evaluation of reflux symptoms.

Bronchoscopic cryobiopsy for the diagnosis of diffuse parenchymal lung disease.

BACKGROUND: Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease. METHODS: A retrospective study of subjects who had undergone bronchoscopic cryobiopsy for evaluation of DPLD at an academic tertiary care center from January 1, 2012 through January 15, 2013 was performed. The procedure was performed using a flexible bronchoscope to acquire biopsies of lung parenchyma. H&E stained biopsies were reviewed by an expert lung pathologist. RESULTS: Twenty-five eligible subjects were identified. With a mean area of 64.2 mm(2), cryobiopsies were larger than that typically encountered with traditional transbronchial forceps biopsy. In 19 of the 25 subjects, a specific diagnosis was obtained. In one additional subject, biopsies demonstrating normal parenchyma were felt sufficient to exclude diffuse lung disease as a cause of dyspnea. The overall diagnostic yield of bronchoscopic cryobiopsy was 80% (20/25). The most frequent diagnosis was usual interstitial pneumonia (UIP) (n = 7). Three of the 25 subjects ultimately required surgical lung biopsy. There were no significant complications. CONCLUSION: In patients with suspected diffuse parenchymal lung disease, bronchoscopic cryobiopsy is a promising and minimally invasive approach to obtain lung tissue with high diagnostic yield.