© 2003 American Thoracic Society
Time Will TellPredicting Survival in Idiopathic Interstitial Pneumonia
a Pulmonary and Critical Care Section Yale University School of Medicine New Haven, Connecticut Idiopathic interstitial pneumonias are inflammatory and fibrotic disorders of the lung parenchyma that cause restrictive physiology and impair gas exchange. Recent changes in the classification of these disorders have led to a striking transition from lumping fibrosing interstitial pneumonias together to splitting them into unique pathologic and prognostic patterns based upon the American Thoracic Society/European Respiratory Society Consensus Criteria (1). Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia and, in the setting of these classification revisions, has become more clearly recognizable as a distinct clinical, physiologic, radiographic, and pathologic entity (2). Careful segregation of idiopathic interstitial pneumonias on the basis of pathology has led to a consensus that the pathologic pattern of usual interstitial pneumonitis (UIP) is the sine quo non of IPF. Recent studies adhering to these consensus criteria have revealed that the mean survival of IPF from time of diagnosis is closer to 2 to 3 years rather than the 5 years suggested by earlier data (2). Another very important outcome of this new classification scheme is the recognition of nonspecific interstitial pneumonia (NSIP) as a clinical and pathologic entity distinguishable from UIP on surgical lung biopsy; it manifests as either a predominantly cellular (inflammatory) or a fibrotic form. Patients with cellular NSIP pathologically appear to survive longer than do patients with fibrotic NSIP, and survival in both groups appears to surpass that of patients with IPF in general (1). Nevertheless, although the typically poor prognosis of IPF and the relative inefficacy of current therapies are broadly understood, highly variable rates of progression among individual patients remain both common and enigmatic. Therefore, developing an improved understanding of the predictors of progression and survival is critical, not only in helping patients and clinicians plan for the future and determine the optimal time for therapeutic intervention or lung transplantation, but also in designing clinical trials for new therapeutic agents. With these important clinical issues in mind, three major tertiary referral centers have generated important new data that provide needed insights. In this issue of AJRCCM (pp. 531–537), Latsi and colleagues (3) from the Royal Brompton Hospital retrospectively compare the prognostic significance of histopathology, baseline pulmonary function, and changes in pulmonary function at 6 and 12 months in 61 patients with IPF and 41 patients with NSIP between 1978 and 1998 (3). They confirm the previous findings that patients with UIP have a worse prognosis than those with NSIP, and that patients with more severe impairment in pulmonary function at presentation also have a poorer prognosis. The median survival for patients with UIP was 33 months versus 56 months for patients with NSIP. The important new information is that a downward trend in pulmonary function at 6 months (diffusing capacity for carbon monoxide, FVC, FEV1, and the composite physiologic index) is an independent determinant of survival. In fact, they found that the predictive power of the change in pulmonary function at 6 months is equivalent to the histopathologic diagnosis in predicting survival. At 12 months, downward trends in pulmonary function predicted mortality much more strongly than other covariates and histopathologic diagnosis had no independent prognostic value. In a separate study presented in this issue (pp. 538–542), Collard and colleagues (4) from the University of Colorado and National Jewish Medical and Research Center evaluate the significance of changes in physiologic variables in predicting survival, focusing, however, on IPF. Eighty one patients were evaluated between 1982 and 1996, and data were obtained in follow-up at 6 and 12 months. Median survival was 4.3 years in the 6-month group and 6.2 years in the 12-month group. Changes in dyspnea score and pulmonary function (total lung capacity, FVC, diffusing capacity for carbon monoxide, and alveolar–arterial oxygen gradient) were evaluated in both groups. A clinically relevant change in lung function was defined as 10%. A clinically relevant increase in alveolar–arterial oxygen gradient was defined as 5 mm Hg or more. Worsening in the dyspnea index as well as a clinically relevant decline in all parameters of pulmonary function and gas exchange were found to be predictive of survival time at both 6 and 12 months. This remained so even when adjusted for baseline values. Importantly, patients who failed to demonstrate a 10% decline in parameters of pulmonary function (i. e., remained stable) had improved survival as compared with patients who had a clinically relevant decline in lung function. This supports the previous work by Hanson and coworkers (5). Importantly, almost all patients were treated with either corticosteroids alone or a combination of corticosteroids and a cytotoxic agent.
Finally, in this issue (pp. 543–548), Flaherty and colleagues (6) report a retrospective analysis of 80 patients with UIP and 9 patients with NSIP referred to the University of Michigan Health System between 1989 and 2000. The median survival was 5.81 years. Analysis of the change in pulmonary function over time in relation to survival revealed that a decreased FVC of 10% or greater over 6 months was associated with increased mortality (when adjusted for baseline values), with the time of survival defined as the time alive after surgical lung biopsy. Interestingly, at 6 months, 19% of patients with UIP had a 10% improvement in FVC, 49% had between a 10% increase and a 10% decrease, and 32% had at least a 10% decrease. By 12 months, however, 54% had experienced more than a 10% decline in pulmonary function. In contrast, a recent report, in abstract form, of a prospective, double-blind, randomized clinical trial evaluating the efficacy of IFN- Although there are differences in the specific results from the centers, the fact that three large referral centers have all produced qualitatively similar observations is illuminating. A decline in parameters of pulmonary function—in particular FVC—as early as 6 months after referral to a tertiary referral center is predictive of increased mortality in idiopathic interstitial pneumonia. Time, it appears, will tell—perhaps even more than pathology or baseline physiology. These results have important ramifications for clinical practice as well as for the design of clinical trials in idiopathic interstitial pneumonias, particularly in IPF. Clearly, caution is warranted because patients who are rapidly declining may represent a specific subset of patients with distinct pathologic patterns, such as acute interstitial pneumonia superimposed on UIP. Further focused studies will be needed to better characterize the pathologic, clinical, and, ultimately, pathophysiologic features of patients with idiopathic interstitial pneumonias experiencing varying rates of physiologic and clinical decline. FOOTNOTES Conflict of Interest Statement: P.W.N. served as an advisor for Intermune Pharmaceuticals and Genzyme in 2001 and 2002 and has participated in CME programs as a speaker on IPF sponsored by Intermune Pharmaceuticals from 2001–2003 and has been paid for his participation; D.G.M. has no declared conflict of interest. REFERENCES
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in the treatment of IPF showed that only 25% of the 330 patients enrolled in either the IFN-
