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Idiopathic Pulmonary Fibrosis Challenges for the Future FREE TO VIEW

Moisés Selman, MD, FCCP
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Affiliations: Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico 
 ,  Dr. Selman is Director of Research, Instituto Nacional de Enfermedades Respiratorias, Mexico. Corrrespondence to: Moisés Selman, MD, FCCP, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, México DF, CP 14080, México; e-mail: mselman@conacyt.mx

Affiliations: Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico 
 ,  Dr. Selman is Director of Research, Instituto Nacional de Enfermedades Respiratorias, Mexico. Corrrespondence to: Moisés Selman, MD, FCCP, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, México DF, CP 14080, México; e-mail: mselman@conacyt.mx



Chest. 2001;120(1):8-10. doi:10.1378/chest.120.1.8
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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal lung disease of no identifiable etiology, characterized by fibroblast proliferation and extracellular matrix accumulation resulting in irreversible distortion of the architecture of the lung.1IPF has been reported worldwide and does not have predilection by race or ethnicity. Incidence of IPF is estimated to be around 7 cases per 100,000 per year in women and 10 cases per 100,000 per year in men,2but it increases with older age.3The disease occurs primarily in individuals between 50 years and 70 years of age, and it appears to be infrequent in young people and extremely rare in children.46 The prevalence of IPF ranges from 13 cases per 100,000 for women to 20 cases per 100,000 for men,2 although these figures may underestimate the problem.

IPF begins insidiously, with the gradual onset of dyspnea or nonproductive cough. Dyspnea is usually progressive and is the most prominent and disabling symptom.6 In general, patients have symptoms for > 6 months before seeking medical attention and, unfortunately, most of them are assisted by lung specialists 1 year or 2 years after the beginning of symptoms. Patients present a typical restrictive functional pattern with decreased lung volumes and compliance, and hypoxemia at rest that usually worsens with exercise. The diffusing capacity of the lung for carbon monoxide corrected for hemoglobin is reduced, and its decline may precede abnormalities in lung volumes. An abnormal chest radiographic finding is seen at the time of presentation in > 95% of cases, and it is characterized by bilateral, peripheral reticular opacities, most profuse at the lung bases, commonly associated with decreased lung volumes. However, a confident diagnosis of IPF cannot be reliably made based solely on the chest radiograph.

High-resolution CT (HRCT) scanning allows earlier identification of diffuse parenchymal lung disease and increases the precision of the imaging diagnosis of IPF.6The HRCT pattern shows predominantly bilateral, peripheral, subpleural, lower-lung patchy reticular opacities. Actually, the earliest CT sign is faint subpleural opacification in the posterobasal segments of the lower lobes. Ground-glass attenuation is usually limited in extent and associated with areas of traction bronchiectasis and/or subpleural honeycombing. A confident diagnosis of IPF is made using HRCT evaluation in approximately two thirds of patients with biopsy-proven IPF.7 Thus, about one third of cases will be missed by relying on CT diagnosis alone. Certainly, less experienced observers have substantially lower accuracy than experienced observers in making a confident diagnosis of IPF, and in this sense, lung biopsy continues being the “gold standard” for diagnosis.

After many years of confusion, it is now accepted that the lung pathology of IPF is the so-called usual interstitial pneumonia (UIP).8 In this context, in the absence of typical and unambiguous clinical and HRCT findings, a definite diagnosis of IPF requires a surgical lung biopsy showing UIP. This is a critical issue because we know now that the condition previously designated as IPF comprised an spectrum of at least four morphologically distinct forms of idiopathic interstitial pneumonia that differed in a number of clinical features, particularly in the response to treatment, and prognosis. Actually, a major purpose of morphologic assessment is to distinguish UIP from other histologic subsets. Importantly, UIP is the only one of them exhibiting a morphologic variegated temporal appearance, that is, a heterogeneous distribution of the lesions with histologic variation from one field to another with alternating zones of normal lung, fibrosis, inflammation, and honeycombing.8

Therefore, when evaluating survival, prognostic factors, and novel therapies for this disease, the clinician must consider the correct histopathologic diagnosis. Since most pathologists included other morphologic patterns within the UIP definition, especially nonspecific interstitial pneumonia, the general believe was that this disease was heterogeneous in terms of response to treatment and prognosis, with some patients dying in 2 years or 3 years, while others survived > 10 years. However, it is important to emphasize that when patients with IPF/UIP are evaluated, the median length of survival from the time of diagnosis is usually of approximately 3 years.911

It is now clear that with the available treatment, IPF remains a progressive, irreversible, and lethal disease. Conventional management primarily based in the concept that inflammation leads to injury and fibrosis has had little, if any, effect on the natural history of the disease.10,12 Actually, there are no consistent data providing evidence that any of the current therapies improve survival or quality of life. In other words, we are dealing with an aggressive lung disorder having a mortality rate higher than many neoplastic diseases.

Nevertheless, some new ways of thinking about its pathogenesis will likely yield more effective therapeutic approaches. There is a growing body of evidence suggesting that IPF is a model of abnormal wound healing in response to multiple, microscopic sites of acute alveolar epithelial injury/activation associated with the formation of patchy areas of fibroblast/myofibroblast foci, which in turn evolve into fibrosis.1,8 Therefore, future therapies should be directed to prevent or inhibit the fibroproliferative response, to avoid alveolar epithelial cell damage, and to enhance normal alveolar re-epithelialization. Some agents that may have an effective antifibrotic effect and that are currently under study in the human disease include interferon γ-1b13and pirfenidone.14

The progression of pulmonary fibrosis or disease-associated conditions may cause death in patients with IPF.15 Since patients inevitably experience worsening during the course of their illness, it may be difficult to distinguish between IPF progression and disease-related complications. However, the most frequent reason for clinical deterioration appears to be progression of the disease, with death occurring by respiratory failure. Other causes of death include heart failure, bronchogenic carcinoma, ischemic heart disease, infection, and pulmonary embolism.15

The occurrence of an acute life-threatening respiratory failure during the course of IPF may require admission to a respiratory ICU and the use of mechanical ventilation. However, studies regarding behavior and outcome under these conditions are scanty. Nava and Rubini16 assessed the mechanics of the respiratory system during mechanical ventilation in seven IPF patients with end-stage disease and showed a noteworthy increase in lung elastance while chest wall elastance was only slightly increased. The authors suggested that the hypercapnia observed in the very end stages of the disease might be related to the severe compliance decrement and increase of resistances to such a point that the respiratory muscles can no longer sustain the workload.

In this issue of CHEST (see page 209), Blivet and colleagues retrospectively studied the outcome of 15 consecutive IPF patients displaying acute respiratory failure and who were referred to the respiratory ICU of Croix-Rousse Hospital in Lyon, France. The findings are disturbing. Of these patients, 11 patients died in the ICU, either from hypoxemia or septic shock, 2 of the 4 patients discharged alive died shortly thereafter, and 1 patient was unavailable for follow-up. Despite the retrospective nature of the analysis and the limited number of patients, this study suggests that IPF referral to an ICU is infrequent (15 patients in almost 10 years in this study) and that the prognosis in these conditions is extremely poor.

It is obvious that our current state of knowledge about IPF is rather limited and several complex challenges are evident for the future. Firstly, the natural history of the disease needs to be characterized (for example, we should have an estimation of how many years of subclinical illness precede the beginning of symptoms, and what kind of criteria could allow an early [subclinical] diagnosis). Secondly, the pathogenic mechanisms and the sequence of events evolving to the aberrant lung parenchymal remodeling need to be clarified. In this context, all (or almost all) articles dealing with IPF state that this disease is a chronic inflammatory disorder, in terms that inflammation precedes the fibrotic response and that it plays a major role in lung fibrogenesis. However, several pieces of evidence strongly suggest that IPF is rather an epithelial/fibroblastic disease,1 and if this hypothesis proves to be true, physiologic and pathologic bidirectional communication between alveolar epithelial cells and fibroblasts/myofibroblasts should become the main target for research.1 In the same line of thought, we need to understand why bronchiolitis obliterans organizing pneumonia is typically reversible while IPF/UIP is usually progressive and irreversible, despite the striking similarity between Masson’s bodies and fibroblast foci.1 Thirdly, we need to generate new therapeutic approaches to improve survival and the quality of life and, if possible (and it surely will be), to cure this terrible disease.

References

Selman, M, King, TE, Jr, Pardo, A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med134,136-151. [PubMed]
 
Coultas, DB, Zumwalt, RE, Black, WC, et al The epidemiology of interstitial lung disease.Am J Respir Crit Care Med1994;150,967-972. [PubMed]
 
Mannino, DM, Etzel, RA, Parrish, RG Pulmonary fibrosis deaths in the United States, 1979–1991: an analysis of multiple-cause mortality data.Am J Respir Crit Care Med1996;153,1548-1552. [PubMed]
 
Johnston, IDA, Prescott, RJ, Chalmers, JC, et al British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management.Thorax1997;52,38-44. [PubMed] [CrossRef]
 
Fan, LL, Kozinetz, CA Factors influencing survival in children with chronic interstitial lung disease.Am J Respir Crit Care Med1997;156,939-942. [PubMed]
 
American Thoracic Society.. Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med2000;161,646-664. [PubMed]
 
Swensen, S, Aughenbaugh, G, Myers, J Diffuse lung disease: diagnostic accuracy of CT in patients undergoing surgical biopsy of the lung.Radiology1997;205,229-234. [PubMed]
 
Katzenstein, ALA, Myers, JL Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification.Am J Respir Crit Care Med1998;157,1301-1315. [PubMed]
 
Bjoraker, JA, Ryu, JH, Edwin, MK, et al Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1998;157,199-203. [PubMed]
 
Douglas, WW, Ryu, JH, Schroeder, DR Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival.Am J Respir Crit Care Med2000;161,1172-1178. [PubMed]
 
Pérez-Padilla, R, Salas, J, Chapela, R, et al Mortality in Mexican patients with chronic pigeon breeders lung compared to those with usual interstitial pneumonia.Am Rev Respir Dis1993;148,49-53. [PubMed]
 
Selman, M, Carrillo, G, Salas, J, et al Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial.Chest1998;114,507-512. [PubMed]
 
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 Med1999;341,1264-1269. [PubMed]
 
Raghu, G, Johnson, WC, Lockhart, D, et al Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.Am J Respir Crit Care Med1999;159,1061-1069. [PubMed]
 
Panos, RJ, Mortenson, RL, Niccoli, SA, et al Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment.Am J Med1990;88,396-404. [PubMed]
 
Nava, S, Rubini, F Lung and chest wall mechanics in ventilated patients with end stage idiopathic pulmonary fibrosis.Thorax1999;54,390-395. [PubMed]
 

Figures

Tables

References

Selman, M, King, TE, Jr, Pardo, A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med134,136-151. [PubMed]
 
Coultas, DB, Zumwalt, RE, Black, WC, et al The epidemiology of interstitial lung disease.Am J Respir Crit Care Med1994;150,967-972. [PubMed]
 
Mannino, DM, Etzel, RA, Parrish, RG Pulmonary fibrosis deaths in the United States, 1979–1991: an analysis of multiple-cause mortality data.Am J Respir Crit Care Med1996;153,1548-1552. [PubMed]
 
Johnston, IDA, Prescott, RJ, Chalmers, JC, et al British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management.Thorax1997;52,38-44. [PubMed] [CrossRef]
 
Fan, LL, Kozinetz, CA Factors influencing survival in children with chronic interstitial lung disease.Am J Respir Crit Care Med1997;156,939-942. [PubMed]
 
American Thoracic Society.. Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med2000;161,646-664. [PubMed]
 
Swensen, S, Aughenbaugh, G, Myers, J Diffuse lung disease: diagnostic accuracy of CT in patients undergoing surgical biopsy of the lung.Radiology1997;205,229-234. [PubMed]
 
Katzenstein, ALA, Myers, JL Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification.Am J Respir Crit Care Med1998;157,1301-1315. [PubMed]
 
Bjoraker, JA, Ryu, JH, Edwin, MK, et al Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1998;157,199-203. [PubMed]
 
Douglas, WW, Ryu, JH, Schroeder, DR Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival.Am J Respir Crit Care Med2000;161,1172-1178. [PubMed]
 
Pérez-Padilla, R, Salas, J, Chapela, R, et al Mortality in Mexican patients with chronic pigeon breeders lung compared to those with usual interstitial pneumonia.Am Rev Respir Dis1993;148,49-53. [PubMed]
 
Selman, M, Carrillo, G, Salas, J, et al Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial.Chest1998;114,507-512. [PubMed]
 
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 Med1999;341,1264-1269. [PubMed]
 
Raghu, G, Johnson, WC, Lockhart, D, et al Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.Am J Respir Crit Care Med1999;159,1061-1069. [PubMed]
 
Panos, RJ, Mortenson, RL, Niccoli, SA, et al Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment.Am J Med1990;88,396-404. [PubMed]
 
Nava, S, Rubini, F Lung and chest wall mechanics in ventilated patients with end stage idiopathic pulmonary fibrosis.Thorax1999;54,390-395. [PubMed]
 
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