BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of “rapid” and “slow” progressors with IPF.Methods and Findings26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238±98% versus 123±29% (p<0.05) and 30±17% (p<0.01)].Conclusions/SignificanceA subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

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The clinical course of chronic pigeon breeder's lung (CPBL) is unknown, especially in comparison with usual interstitial pneumonia (UIP). We studied a cohort of 125 consecutive patients with interstitial lung diseases, including 78 patients with CPBL (74 biopsied) and 47 patients with UIP in the lung biopsy. Patients with UIP were divided into 17 without bird exposure (UIP) and 30 with bird exposure (UIP + BE). All patients were treated with corticosteroids and followed for 33 +/- 23 months. The best predictors of mortality (Cox proportional hazards model) were age > 44 yr, with a relative risk (RR) of 2.5 and 95% confidence interval (CI) of 1.4 to 4.7, masculine gender (RR 4.0, CI 2.1 to 7.6), x-ray honeycombing (RR 7.0, CI 3.8 to 12.7), and severity of fibrosis in the lung biopsy (RR 4.8, CI 2.3 to 9.7). Survival in CPBL 5 yr after diagnosis was 0.71 (SEM 0.08) and in UIP was 0.23 (SEM 0.08), with no statistical difference between UIP + BE and UIP. After adjusting for severity of fibrosis and honeycombing, however, the correlation of diagnosis with survival disappeared. In conclusion, mortality in CPBL is considerable, but lower than in UIP. Lung fibrosis and honeycombing seem to be a final common pathway for the ILD. Adjusting for them, the effect of diagnosis in survival is not significant.

Hypersensitivity pneumonitis (HP) is characterized by a T-cell-mediated alveolitis, and the putative role of other inflammatory cells in its pathogenesis remains unclear. In this study we determined whether increased quantities of neutrophils were present in HP lungs, and if they were positive for gelatinase B and collagenase-2. Fifteen nonsmoking patients with subacute/chronic active HP were included. Lung samples were analyzed using myeloperoxidase antibody, and neutrophil/total cell ratio was evaluated by digital processing. All HP tissue samples exhibited variable quantities of neutrophils located inside vessels, and in the interstitial and alveolar spaces. Lung neutrophil percentage ranged from 0.7% to 4.8% (2.1 +/- 1.4%). There was a positive correlation between the percentage of lung neutrophils and the percentage of lung fibrosis (r = 0.6, p < 0.02). Tissue neutrophils showed intense immunoreactive collagenase-2 and gelatinase B staining. Additionally, gelatinolytic activities corresponding to progelatinases A and B and their activated forms, were several-fold increased in the bronchoalveolar lavage fluid (BALF) from patients with HP as compared with control subjects. These findings suggest that in HP lungs there is a persistent traffic of neutrophils loaded with gelatinase B and collagenase-2 that may play a role in the lung damage and in the fibrotic response.