Thurlbeck, William M.

Abstract The early stage of idiopathic pulmonary fibrosis (IPF) is thought to involve a smaller number of alveoli and to be characterized predominantly by cellularity and minimal fibrosis, whereas advanced disease involves a large number of alveoli and is characterized predominantly by fibrosis with minimal cellularity. In addition, correlative studies have indicated that prognosis and response to therapy is determined in part by the extent of fibrosis and cellularity. This study was undertaken to determine whether pulmonary function assessment would help distinguish between the cellular and fibrotic phases of this disorder, as determined by a semiquantitative pathology scoring system that comprised four factor scores: fibrosis, cellularity, granulation/connective tissue, and desquamation. Ninety-six untreated patients with biopsy-confirmed IPF (27 never smokers, 32 current smokers, and 37 ex-smokers) were evaluated. In the group as a whole, there was no significant relationship between the fibrosis or the connective/granulation tissue factor scores and any of the physiologic parameters. The Dl co correlated with the “desquamation” and the total pathology scores, whereas the TLC and FVC correlated with the cellularity factor score. In the current smokers, the coefficient of elastic retraction, Dl co/Va, and FEV1/FVC ratio were significantly lower than in never smokers and ex-smokers, and TLC and FVC were higher than in never smokers. Also, the mean cellularity and granulation/connective tissue factor scores were significantly lower, and the desquamation factor score was significantly higher than those in never smokers and ex-smokers. Both age and smoking status were significant for the cellularity factor score, whereas for the connective/granulation tissue factor score, age was not significant but smoking status was. For the desquamation factor score, age was significant but smoking status was not. There were significant differences between never smokers and ever smokers in the relationship between the pathology factors and measurements of respiratory function, and this may explain some of the difficulty in assessing structure-function correlation in patients with IPF. In the never smokers, the correlations between structure and function were likely the direct result of IPF per se. In the current smokers, bronchiolar and/or emphysematous changes associated with cigarette smoking may have complicated the pathologic alterations caused by IPF, as well as influencing the functional derangements.

Abstract It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not “alveolitis” but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.