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Jornal de Pneumologia

Print version ISSN 0102-3586On-line version ISSN 1678-4642

J. Pneumologia vol.29 no.6 São Paulo Nov./Dec. 2003 



Predicting Survival in Idiopathic Pulmonary Fibrosis: Are We Getting Any Better?



Harold R. Collard; Talmadge E. King Jr.

From the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO (HRC) and Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA (TEK)



Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse lung disease characterized by progressive dyspnea and the histopathologic pattern of usual interstitial pneumonia (UIP).1 The prominence of histopathology in its definition underscores the recent recognition of IPF/UIP as a unique form of idiopathic interstitial pneumonia with minimal responsiveness to treatment and a distinctly poor prognosis.2-5 Further, there is mounting evidence to suggest that the traditional pathophysiological paradigm of chronic inflammation leading to fibrosis (relevant to many forms of diffuse lung disease) may not apply to IPF/UIP.6 Instead, abnormalities of tissue remodeling and repair may lead to a primarily fibroproliferative disorder.7-8

The histopathologic pattern of UIP is defined by temporal heterogeneity of fibrosis, with areas of normal lung adjacent to areas of end-stage fibrosis and honeycombing.9 Characteristic of UIP pattern are sub-epithelial collections of loose connective tissue and myofibroblasts, which have been termed "fibroblastic foci". The fibroblastic focus appears relatively unique to IPF/UIP as it occurs infrequently, if at all, in the other histopathological patterns of idiopathic interstitial pneumonia. It has been proposed that the fibroblastic focus represents the "leading edge" of disease, with the eventual progression of this lesion to end stage fibrosis.6

Given the hypothesis that IPF/UIP is a primarily fibroproliferative disorder, and that fibroblastic foci may represent the areas of active collagen deposition and tissue remodeling, several centers have looked at the relationship between histopathological features, including fibroblastic foci, and survival in carefully defined populations of patients with IPF/UIP.10-14 In 1998, Gay and colleagues from the University of Michigan reviewed surgical lung biopsy specimens from 38 patients with IPF/UIP and found no relationship between "interstitial young connective tissue" (i.e. fibroblastic foci) and survival.12 This study very likely included cases of NSIP and was under-powered to identify a significant relationship. In 2001, we reported on 87 patients seen at National Jewish Medical and Research Center with the diagnosis of IPF/UIP.10 Using the same histopathological scoring system as the study by Gay, we found a significant relationship between fibroblastic foci and survival (risk ratio 1.93, 95% CI 1.31 to 2.83, p=0.0009). In 2002, Nicholson and colleagues from the Royal Brompton Hospital reviewed 53 patients with IPF/UIP using a different histological scoring system and found a significant relationship between fibroblastic foci and survival (p=0.006).11 Most recently, Flaherty and colleagues, again from the University of Michigan reviewed 99 patients with IPF/UIP and, using a third histological scoring system, found no relationship between fibroblastic foci and survival (hazard ratio 1.33, 95% CI 0.86 to 2.05), p=0.20).13

It is in the context of these discordant studies that the paper by Coletta and colleagues in the current issue of this journal is reported.15 In this study, 51 patients with IPF/UIP were identified by strict clinical and histopathological criteria. The selection criteria appear adequate, although the results find a higher degree of cellularity than would be expected for UIP pattern, raising the concern that some patients with fibrotic non-specific interstitial pneumonia were included. Using a similar histopathological scoring system to that used by other centers, the authors found fibroblastic foci and myointimal thickness to correlate significantly with survival (p < 0.05). Kaplan-Meier survival curves for patients dichotomized by fibroblastic foci scores of less than two (considered sparse) and two or greater revealed median survivals of greater than 70 months (n=14) and 29 months (n=37), respectively.

Why has identifying predictors of survival been such a challenge in IPF, a disease with a mortality rate similar to cancer? There are several important reasons. First, the diagnosis of IPF/UIP has only recently been redefined, and many studies included, and continue to include, patients with alternative diagnoses under the rubric of IPF. Secondly, IPF/UIP is a relatively rare disease and meaningful sample sizes are difficult to accrue. Thirdly, most published predictor models are derived from regression analysis of multiple variables increasing the possibility of identifying predictors by chance alone (type I error). Finally, the majority of studies rely on retrospective reviews of clinical databases, which inevitably lead to potential bias and confounding in their results.

How then is the clinician caring for a patient with IPF/UIP to approach predicting survival? Most importantly, the diagnosis of IPF/UIP should be confirmed by strict clinical and radiographic (and if indicated, histopathologic) criteria as described by the recent American Thoracic Society/European Respiratory Society (ATS/ERS) consensus statement.1 The diagnosis of IPF/UIP has been consistently shown to have a uniquely poor prognosis with median survival time of approximately 2-3 years.1, 3-5, 16At this point in time, histopathological grading of fibroblastic foci (or any other factor) should not be used to predict survival in IPF/UIP. Predictor models based on combining multiple baseline clinical and/or physiological measurements have been derived from large groups of carefully selected patients with IPF/UIP and appear to perform well.17, 18Additionally, several groups have reported that changes in clinical variables (e.g. forced vital capacity) and high-resolution computed tomography imaging over time are accurate predictors of survival time in IPF/UIP.19-24 Using clinical predictor models and evaluating changes in measured clinical and radiographic variables over time can help further tailor the prognosis for patients with IPF. It is important to remember, however, that no predictor of survival can ever reliably predict an individual patient’s prognosis. Physicians should realize this limitation, and use predictor tools, as general prognostic guides, not crystal balls.



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2. Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301-15.

3. Bjoraker JA, Ryu JH, Edwin MK. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199-203.

4. Nicholson A, Colby TV, du Bois RM, Hansell DM, Wells AU. The prognostic significance of the histologic pattern of interstitial pneumonia in patients with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000;162:2213-7.

5. Flaherty KR, Toews GB, Travis WD. Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 2002; 19:275-83.

6. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136-51.

7. Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2002;3:3.

8. Pardo A, Selman M. Idiopathic pulmonary fibrosis: new insights in its pathogenesis. The International Journal of Biochemistry & Cell Biology 2002;34:1534-8.

9. Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol 2002;26:1567-77.

10. King TE, Jr., Schwarz MI, Brown K. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025-32.

11. Nicholson AG, Fulford LG, Colby TV, du Bois RM, Hansell DM, Wells AU. The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002;166:173-7.

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13. Flaherty KR, Colby TV, Travis WD. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med 2003;167:1410-5.

14. Flaherty KR, Colby T, Travis WD. Prognostic value of fibroblastic foci in patients with usual interstitial pneumonia. Chest 2001;120:76S-77S.

15. Coletta E, Pereira C, Ferreira R. Histological features and survival in idiopathic pulmonary fibrosis. J Pneumol 2003;29:371-8.

16. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277-304.

17. King TE, Jr., Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001;164:1171-81.

18. Wells AU, Desai SR, Rubens MB. Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography. Am J Respir Crit Care Med 2003;167:962-9.

19. Martinez F, Bradford W, Safrin S, Starko K, Brown K. Rates and characteristics of death in patients with idiopathic pulmonary fibrosis (IPF). Chest 2003;124:117S.

20. Latsi PI, du Bois RM, Nicholson AG. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003;168:531-7.

21. Flaherty KR, Mumford JA, Murray S. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:543-8.

22. Collard HR, Jr TEK, Bucher-Bartelson B, Vourlekis JV, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; In press.

23. Hanson D, Winterbauer RH, Kirtland SH, Wu R. Changes in pulmonary function test results after 1 year of therapy as predictors of survival in patients with idiopathic pulmonary fibrosis. Chest 1995;108:305-310.

24. Nagao T, Nagai S, Hiramoto Y. Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia. Respiration 2002;69:413-9.

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