Loyd, James E

Abstract Rationale Heterogeneous characteristics are observed in familial pulmonary fibrosis (FPF), suggesting that nongenetic factors contribute to disease manifestations. Objectives To determine the relationship between environmental exposures and disease characteristics of FPF, including the morphological characteristics on chest computed tomography (CT) scan, and timing of FPF symptom onset, lung transplantation, or death. Methods Subjects with FPF with an exposure questionnaire and chest CT were selected from a prospective cohort at Vanderbilt. Disease characteristics were defined by lung parenchymal findings on chest CT associated with fibrotic hypersensitivity pneumonitis (fHP) or usual interstitial pneumonia (UIP) and by time from birth to symptom onset or a composite of lung transplantation or death. After assessing the potential for confounding by sex or smoking, adjusted logistic or Cox proportional hazards regression models identified exposures associated with fHP or UIP CT findings. Findings were validated in a cohort of patients with sporadic pulmonary fibrosis enrolled in the LTRC (Lung Tissue Research Consortium) study. Results Among 159 subjects with FPF, 98 (61.6%) were males and 96 (60.4%) were ever-smokers. Males were less likely to have CT features of fHP, including mosaic attenuation (FPF: adjusted [for sex and smoking] odds ratio [aOR], 0.27; 95% confidence interval [CI], 0.09–0.76; P = 0.01; LTRC: aOR, 0.35; 95% CI, 0.21–0.61; P = 0.0002). Organic exposures, however, were not consistently associated with fHP features in either cohort. Smoking was a risk factor for honeycombing in both cohorts (FPF: aOR, 2.19; 95% CI, 1.12–4.28; P = 0.02; LTRC: aOR, 1.69; 95% CI, 1.22–2.33; P = 0.002). Rock dust exposure may also be associated with honeycombing, although the association was not statistically-significant when accounting for sex and smoking (FPF: aOR, 2.27; 95% CI, 0.997–5.15; P = 0.051; LTRC: aOR, 1.51; 95% CI, 0.97–2.33; P = 0.07). In the FPF cohort, ever-smokers experienced a shorter transplant-free survival (adjusted hazard ratio, 1.64; 95% CI, 1.07–2.52; P = 0.02), whereas sex was not associated with differential survival (male adjusted hazard ratio, 0.75; 95% CI, 0.50–1.14; P = 0.18). Conclusions In FPF, smoking contributes to shortened transplant-free survival and development of honeycombing, a finding that is also likely applicable to sporadic pulmonary fibrosis. Females are more likely to manifest CT features of fHP (mosaic attenuation), a finding that was incompletely explained by sex differences in exposures. These findings may have implications for pulmonary fibrosis classification and management.

Abstract The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.