Literature Review |

Top Ten List in Idiopathic Pulmonary Fibrosis* FREE TO VIEW

Katerina M. Antoniou, MD; Demosthenes Bouros, MD, FCCP; Nikolaos M. Siafakas, MD, PhD, FCCP
Author and Funding Information

*From the Department of Thoracic Medicine (Drs. Antoniou and Siafakas), University General Hospital of Heraklion, Medical School of Crete, Heraklion, Greece; and the Department of Pneumonology (Dr. Bouros), University General Hospital of Alexandroupolis, Medical School of Thrace, Alexandroupolis, Greece.

Correspondence to: Nikolaos M. Siafakas, MD, PhD, FCCP, Professor of Thoracic Medicine, University General Hospital, 71110 Heraklion, Crete, Greece; e-mail: siafak@med.uoc.gr

Chest. 2004;125(5):1885-1887. doi:10.1378/chest.125.5.1885
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1. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001; 345:517–524

2. Selman M, King TE Jr, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136–151

The presumption hypothesis that inflammation is necessary and sufficient to produce fibrosis in patients with idiopathic pulmonary fibrosis (IPF) has been widely held, but currently this hypothesis is being questioned for several reasons. While research has largely focused on inflammatory mechanisms for initiating the fibrotic response, some evidence has strongly suggested that disruption of the alveolar epithelium is the underlying event.

Emerging concepts suggest that IPF is the result of epithelial-mesenchymal interaction and aberrant wound healing, with little or no inflammatory component. The data by Selman et al suggest that the persistence of the inflammatory process, rather than its initial magnitude, correlates better with the fibroproliferative response observed in patients with IPF. According to Gross and Hunninghake, the initiation of this fibrotic response probably depends on genetic factors, the predominant inflammatory phenotype (T-helper type 1 or T-helper type 2), and various environmental triggers.

This new approach improves our knowledge about the biopathologic principles of the disease and has opened up several promising therapeutic avenues.

3. King TE Jr, Schwartz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001; 164:1025–1032

This article focused on the histopathologic subclassification of IPF, and the relationship with patient survival. In this carefully executed, prospective cohort study of 87 patients with biopsy-proven usual interstitial pneumonia (UIP), a greater degree of granulation/connective tissue deposition (characteristic of fibroblastic foci) was correlated with shorter survival. The median survival time was 23 months in patients with scores of > 2, compared with a median survival time of 66 months for those with scores of < 1.8. This finding is consistent with the view that UIP is not a disease of active inflammation, but one of abnormal lung fibroblast proliferation and dysregulated fibrogenesis. Moreover, these findings suggest that we should refocus our efforts on controlling the ongoing epithelial damage and its repair process, which is associated with persistent fibroblastic proliferation, rather than on stopping inflammation.

4. Nicholson AG, Fulford LG, Colby TV, et al. The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002; 166:173–177

The relationship between individual histologic features (in particular, the extent of fibroblastic foci) and disease progression in patients with IPF/UIP was addressed using biopsy material from the Royal Brompton Hospital (London, UK). The most important findings of this study were a strong correlation between an increase in the extent of fibroblastic foci, and both mortality and a decrease in both the diffusing capacity of the lung for carbon monoxide and FVC at both 6 months and 12 months after biopsy. These data suggest a reproducible method on biopsy for predicting the rate of disease progression in patients with IPF.

5. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement; American Thoracic Society (ATS) and European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161:646–664

This fundamental article more accurately defines IPF as a distinct clinical entity, with certain characteristic clinical, radiologic, and morphologic features, specifically, the pattern of UIP found in surgical lung biopsy specimens. All known aspects of IPF are considered, and a number of useful guidelines for the diagnosis, management, and therapy of the disease are provided.

6. Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 164:193–196

Surgical lung biopsy traditionally has been the “gold standard” for the diagnosing of UIP and other interstitial lung diseases. In the article, Hunninghake and colleagues address the question of whether biopsy is required in all cases.

The researchers conclude that surgical lung biopsy is indicated mainly for patients in whom the diagnosis is not certain after careful clinical evaluation, but it is not necessary in patients with typical clinical and radiologic features. This study also provides evidence that the diagnosis of IPF can be accurately established in some patients without a surgical lung biopsy.

Whether the accuracy of the clinical diagnosis is sufficiently high, however, to replace lung biopsy in investigative studies of IPF remains to be proven.

7. Ziesche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon γ-1b and low dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341:1264–1269.

8. Ziesche R, Block L-H. Interferon γ-1b in idiopathic pulmonary fibrosis: reanalysis of a published study. In: King TE, ed. New approaches to managing idiopathic pulmonary fibrosis. New York, NY: American Thoracic Society, 2000; 36–43

Based on the strong antifibrotic properties of interferon-γ, Ziesche et al combined low-dose glucocorticoids with interferon γ-1b in the treatment of patients with IPF. This pilot investigation demonstrated that interferon-γ treatment was associated with substantial improvements in the condition of patients with IPF who had had no response to glucocorticoid therapy alone.

A number of questions were raised because it was unclear that all patients had IPF, as their length of survival was atypical, and the difference in outcome between treated patients and the control group did not appear to be clinically significant.

After reanalyzing the data from a phase II clinical trial by Ziesche et al, an expert panel independently concluded that 15 of the 18 patients had definite or probable IPF, and confirmed the improvement in gas exchange and lung volumes among those treated with interferon γ-1b. These conclusions were published by the American Thoracic Society.

A phase III clinical trial with larger numbers of patients who have received accurate diagnoses is needed to confirm the potential benefits of interferon γ-1b therapy in patients with steroid-resistant IPF.

9. Timmer SJ, Karamzadeh AM, Yung GL, et al. Predicting survival of lung transplantation candidates with idiopathic interstitial pneumonia: does Pao2 predict survival? Chest 2002; 122:779–784

In this retrospective study, the aim of the authors was to find a parameter that would discriminate between patients who survived and had undergone transplantation, and those who had died while waiting for transplantation. Forty-eight transplant candidates who met the inclusion criteria were evaluated; and, at the end, 28 were still alive, while 20 had died. The results of the study showed, for the first time, that the severity of hypoxemia at rest was the only significant difference in both groups.

Selman, in the related editorial (Chest 2002; 122:759–761), summarizes that drugs have been unable to improve the condition of IPF patients in the long term, and that the global survival rate for patients undergoing transplantation is relatively poor. In this context, therapeutic trials of newer putative antifibrotic agents are required straight away.

10. Crystal RG, Bitterman PB, Mossman B, et al. Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group (NHLBI workshop summary). Am J Respir Crit Care Med 2002; 166:236–246

In 2002, a working group of the National Heart, Lung, and Blood Institute met to discuss potential directions for future research in IPF, the cause and course of which before diagnosis are unknown, and for which existing treatments are of limited benefit.

The specific areas of future research that were recommended by the working group include elucidating the etiology of IPF, developing novel diagnostic techniques and molecular diagnostics, and establishing a program for the identification of molecular targets for IPF treatment. Many of the recommendations concern the requirement to create centers that would focus on the development of target-based drugs, innovative diagnostic techniques, and new drug delivery systems.

Abbreviations: IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia




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