Chronic hypersensitivity pneumonitis is associated with an increased risk of venous thromboembolism: a retrospective cohort study

Background Idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis share commonalities in pathogenesis shifting haemostasis balance towards the procoagulant and antifibrinolytic activity. Several studies have suggested an increased risk of venous thromboembolism in IPF. The association between venous thromboembolism and chronic hypersensitivity pneumonitis has not been studied yet. Methods A retrospective cohort study of IPF and chronic hypersensitivity pneumonitis patients diagnosed in single tertiary referral center between 2005 and 2018 was conducted. The incidence of symptomatic venous thromboembolism was evaluated. Risk factors for venous thromboembolism and survival among those with and without venous thromboembolism were assessed. Results A total of 411 (259 IPF and 152 chronic hypersensitivity) patients were included (mean age 66.7 ± 8.4 vs 51.0 ± 13.3 years, respectively). There were 12 (4.6%) incident cases of venous thromboembolism in IPF and 5 (3.3%) in chronic hypersensitivity pneumonitis cohort. The relative risk (RR) of venous thromboembolism in chronic hypersensitivity pneumonitis was not significantly different to that found in patients with IPF (7.1 vs 11.8/1000 person-years, RR 1.661 95% CI 0.545–6.019, respectively). The treatment with systemic steroids (OR 5.38; 95% CI 1.65–18.8, p = 0.006) and GAP stage 3 (OR 7.85; 95% CI 1.49–34.9; p = 0.037) were significant risk factors for venous thromboembolism in IPF. Arterial hypertension and pulmonary hypertension significantly increased risk of venous thromboembolism in chronic hypersensitivity pneumonitis. There were no significant differences in survival between patients with and without venous thromboembolism. Conclusions The patients with chronic hypersensitivity pneumonitis have a marked increase in the risk of venous thromboembolism, similar to the patients with IPF. Venous thromboembolism does not affect the survival of patients with IPF and chronic hypersensitivity pneumonitis.

Barriers to antigen detection and avoidance in chronic hypersensitivity pneumonitis in the United States

Background Chronic hypersensitivity pneumonitis (CHP) is an interstitial lung disease (ILD) caused by long term exposure to an offending antigen. Antigen avoidance is associated with improved outcomes. We are unable to identify the antigen source in approximately half of patients. When an antigen is successfully identified, patients have difficulty with avoidance. Methods We conducted three structured group discussions with US based ILD specialists utilizing the nominal group technique (NGT). Participants listed barriers to antigen detection and avoidance in CHP. Each participant ranked what they perceived to be the top three barriers in the list in terms of importance. The master list of barriers was consolidated across the three groups into themes that were prioritized based on receiving the highest rankings by participants. Results Twenty-five physicians participated; 56% had experience caring for CHP patients for ≥ 16 years. Sixty barriers to antigen detection were categorized into seven themes of which the top three were: 1. unclear significance of identified exposures; 2. gaps in clinical knowledge and testing capabilities; 3. there are many unknown and undiscovered antigens. Twenty-eight barriers to antigen avoidance were categorized into five themes of which the top three were: 1. patient limitations, financial barriers and lack of resources; 2. individual patient beliefs, emotions and attachments to the antigen source; and 3. gaps in clinical knowledge and testing capabilities. Conclusions This study uncovered challenges at the individual patient, organizational, and societal levels and ranked them in terms of level of importance. These findings provide information to guide development and validation of multidisciplinary support and interventions geared towards antigen identification and avoidance in CHP.

Airway-specific autoantibodies identify a subset of patients with fibrotic interstitial lung disease

Fibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airway remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD and assessed association with disease severity and outcome. Bronchoalveolar lavage (BAL) was collected from a cohort of fILD patients and total airway antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 124 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls. A subset of patients with fILD but not healthy controls had a local autoimmune signature in their airways that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function in the cohort as a whole. Patients with IPF had increased airway total IgA and IgG1 while subjects with CHP had increased airway IgA, IgG1 and IgG4. In patients with CHP, increased airway total IgA was associated with reduced survival probability. The presence of airway autoantibodies identifies a unique subset of patients with fILD and the mechanisms by which these autoantibodies contribute to disease requires further investigation.

Prognostic accuracy of a peripheral blood transcriptome signature in chronic hypersensitivity pneumonitis

The prognostic value of peripheral blood mononuclear cell (PBMC) expression profiles, when used in patients with chronic hypersensitivity pneumonitis (CHP), as an adjunct to traditional clinical assessment is unknown. RNA-seq analysis on PBMC from 37 patients with CHP at initial presentation determined that (1) 74 differentially expressed transcripts at a 10% false discovery rate distinguished those with (n=10) and without (n=27) disease progression, defined as absolute FVC and/or diffusing capacity of the lungs for carbon monoxide (DLCO) decline of ≥10% and increased fibrosis on chest CT images within 24 months, and (2) classification models based on gene expression and clinical factors strongly outperform models based solely on clinical factors (baseline FVC%, DLCO% and chest CT fibrosis).

Cumulative Incidences of Lung Cancer in Various Interstitial Lung Diseases

Background Interstitial lung disease (ILD) patients often develop lung cancer. However, previous studies on the incidences of lung cancer in ILD patients focused on specific aetiologies, such as idiopathic pulmonary fibrosis (IPF). The lung cancer incidences in these patients have not been investigated, and thus, we aimed to evaluate them here. Methods ILD patients at our hospital were retrospectively reviewed. The cumulative incidences of lung cancer in patients with various ILDs were estimated with Kaplan-Meier curves and compared between ILD groups using log-rank tests. The association between several variables at initial diagnosis and lung cancer development was assessed with Cox proportional hazards regression analysis to identify predictors. Results In all, 606 ILD patients, including 161 with IPF, 133 with non-IPF idiopathic interstitial pneumonias, 160 with chronic hypersensitivity pneumonitis, 87 with connective tissue disease-related ILDs, 19 with pulmonary sarcoidosis, and 46 with other ILDs, were included. Twenty-eight patients developed lung cancer. The cumulative incidences of lung cancer at 1, 3, and 5 years were: 1.9, 5.7, and 12.3% with IPF, respectively; 0.8, 0.8, and 4.0% in non-IPF idiopathic interstitial pneumonias; 2.0, 4.6, and 11.0% in chronic hypersensitivity pneumonitis; and 1.1, 1.1, and 2.9% in connective tissue disease-related ILDs. IPF patients had a higher incidence of lung cancer than non-IPF idiopathic interstitial pneumonia patients (p = 0.036). A radiological usual interstitial pneumonia pattern, forced vital capacity value, and pack-years were associated with lung cancer development (hazard ratios 2.959, 1.031, 1.011; 95% confidence intervals 1.257–6.963, 1.006–1.057, 1.002–1.020, p = 0.013, 0.017, 0.020, respectively). Conclusions The lung cancer incidence is higher in IPF patients than in non-IPF idiopathic interstitial pneumonia patients and is equally high in patients with chronic hypersensitivity pneumonitis and IPF.