The Syndrome of Combined Pulmonary Fibrosis and Emphysema

Abstract

Coincidental cryptogenic fibrosing alveolitis (the British name for idiopathic pulmonary fibrosis [IPF]) and emphysema was reported in 1990 in a series of eight patients by Wiggins et al1Wiggins J Strickland B Turner-Warwick M Combined cryptogenic fibrosing alveolitis and emphysema: the value of high resolution computed tomography in assessment.Respir Med. 1990; 84: 365-369Abstract Full Text PDF PubMed Scopus (196) Google Scholar in London. In 2005, we characterized2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar this association as a distinct entity in a series of 61 patients. Increasingly acknowledged,3Mura M Zompatori M Pacilli AM et al.The presence of emphysema further impairs physiologic function in patients with idiopathic pulmonary fibrosis.Respir Care. 2006; 51: 257-265PubMed Google Scholar, 4Grubstein A Bendayan D Schactman I et al.Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature.Respir Med. 2005; 99: 948-954Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 5Jankowich MD Polsky M Klein M et al.Heterogeneity in combined pulmonary fibrosis and emphysema.Respiration. 2008; 75: 411-417Crossref PubMed Scopus (75) Google Scholar, 6Rogliani P Mura M Mattia P et al.HRCT and histopathological evaluation of fibrosis and tissue destruction in IPF associated with pulmonary emphysema.Respir Med. 2008; 102: 1753-1761Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 7Wells AU Desai SR Rubens MB et al.Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.Am J Respir Crit Care Med. 2003; 167: 962-969Crossref PubMed Scopus (505) Google Scholar this syndrome is a matter of growing interest by respiratory clinicians.The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is not just a distinct phenotype of IPF. It deserves the terminology of syndrome as a result of the association of symptoms and clinical manifestations, each with a probability of being present increased by the presence of the others. Hence, the syndrome of CPFE results from the association of distinct features, including tobacco smoking, severe dyspnea, unexpected subnormal spirometry findings, severely impaired transfer capacity for carbon monoxide, hypoxemia at exercise, characteristic imaging features (ie, centrilobular and/or paraseptal emphysema, and diffuse interstitial opacities suggestive of pulmonary fibrosis of the lower lobes),8Brillet P Cottin V Letoumelin P et al.Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis syndrome): CT imaging features and pulmonary function tests.J Radiol. 2009; 90: 43-51Crossref PubMed Scopus (36) Google Scholar and a high probability of severe pulmonary hypertension (PH).2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar Although the imaging features of CPFE, and especially of emphysema, may be semi-quantified, it is striking that the gross evaluation by the clinician of the presence of both “significant” emphysema and fibrosis is sufficient to delineate the syndrome of CPFE with excellent reproducibility with matching imaging and cardiopulmonary features (unpublished results), further emphasizing that CPFE is indeed a syndrome.In this issue of CHEST (see page 10), Mejia et al9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar report on a series of 110 patients with IPF, 28% of them with at least 10% of the lung affected with emphysema, and thus are considered to have CPFE. This study clearly confirms that the risk of the development of PH is notably higher in those patients with CPFE than in those with IPF without emphysema. In fact, 21 of 29 patients with CPFE had echocardiographic features of severe PH (systolic pulmonary artery pressure, > 75 mm Hg), compared to 8 of 68 patients with IPF without emphysema (odds ratio, 19; 95% confidence interval, 5.08 to 68.7; p < 0.0001).9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Further, this study is the first to demonstrate that the prognosis for patients with CPFE is worse than that for patients with nonemphysema IPF, which is an outcome determined by severe PH (and not only by the presence of associated emphysema).There are several reasons why it is of utmost importance to diagnose the CPFE syndrome. First, the risk of the development of PH is elevated (between 50% and 90%2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar, 9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar) and is associated with poor survival. Indeed, the 5-year survival rate was 25% for patients with PH vs 75% for patients without PH at echocardiography in our study2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar; the presence of severe PH at echocardiography was associated with an increased risk of death in the study by Mejia et al9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar (hazard ratio, 1.88; 95% confidence interval, 1.01 to 3.48). Second, since lung volumes are relatively preserved in patients with CPFE (as opposed to patients with IPF without emphysema) and the main determinant of mortality is represented by PH, it is expected that lung volumes, which are usually evaluated in the course of IPF, may not be relevant for the follow-up of patients with CPFE. While FVC may not accurately reflect progression of disease, it may be anticipated that variations in diffusion capacity, hypoxemia, or pulmonary artery pressure, could represent better surrogates for the progression of disease and mortality. Third, the inclusion of patients with CPFE syndrome in IPF clinical trials may lead to spurious underevaluation of the effect of treatment in IPF patients, as the inclusion criteria of several international clinical trials10King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (454) Google Scholar, 11Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar, 12Demedts M Behr J Buhl R et al.High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242Crossref PubMed Scopus (838) Google Scholar in patients with IPF were likely compatible with the inclusion of patients with CPFE. We consider that patients with CPFE should thus be carefully excluded from future IPF trials (or at least a stratification should be anticipated to account for the presence of emphysema). Fourth, it is currently not clear whether pathologic features of CPFE reflect the sole combination of emphysema and a pattern of usual interstitial pneumonia, or whether non-usual interstitial pneumonia patterns (some of which have been reported in CPFE patients2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar, 5Jankowich MD Polsky M Klein M et al.Heterogeneity in combined pulmonary fibrosis and emphysema.Respiration. 2008; 75: 411-417Crossref PubMed Scopus (75) Google Scholar) may be frequent. Last, the diagnostic criteria for IPF may not apply to all patients with CPFE, who may have normal lung volumes despite advanced disease and the need for long-term nasal oxygen therapy.There are some limitations to the study by Mejia et al.9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar First, the authors used IPF American Thoracic Society/European Respiratory Society criteria for the diagnosis of CPFE (eg, IPF with emphysema), which might have selected patients with more advanced fibrosis than emphysema, thus limiting the generalization of their results to a broader population of patients with CPFE. Hence, the restrictive pattern seen in this series (with a mean FVC of 62% predicted9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar) may reflect selection bias, as the mean (± SD) FVC was 90 ± 18% predicted in our series2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar with inclusion criteria based on imaging features regardless of pulmonary function. Second, no hemodynamic evaluation was performed, what may be justified by the lack of evidence that any treatment for PH may be beneficial for patients with CPFE with PH. Third, diffusion capacity was not reported, although it represents a cardinal feature of the syndrome.2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar Fourth, the possible role of hypoxemia in the risk of PH may be increased by altitude; this confounding factor is particularly relevant for patients living in Mexico City (altitude, 2,200 m).It is clear than many aspects of the CPFE syndrome remain to be explored. The pathophysiology of the syndrome is unclear,13Cottin V Fabien N Khouatra C et al.Anti-elastin autoantibodies are not present in combined pulmonary fibrosis and emphysema.Eur Respir J. 2009; 33: 219-221Crossref PubMed Scopus (40) Google Scholar although tobacco smoking is definitely a major cause, and possible other risk factors have been identified, such as exposure to agrochemical compounds.14Daniil Z Koutsokera A Gourgoulianis K Combined pulmonary fibrosis and emphysema in patients exposed to agrochemical compounds.Eur Respir J. 2006; 27: 434Crossref PubMed Scopus (27) Google Scholar It is likely that an individual's genetic background may predispose some smokers to the development of CPFE. A polymorphism in the promoter of the matrix metalloproteinase-1 gene may, for example, represent a good candidate.15Mercer BA Wallace AM Brinckerhoff CE et al.Identification of a cigarette smoke-responsive region in the distal MMP-1 promoter.Am J Respir Cell Mol Biol. 2009; 40: 4-12Crossref PubMed Scopus (68) Google Scholar The respective role of male gender and tobacco smoking should be investigated (do they represent independent, or linked, etiologic factors?). Obviously, much progress is required regarding the management and treatment of patients with CPFE, with and without severe PH, as no treatment is currently available to save them from a dire prognosis. Coincidental cryptogenic fibrosing alveolitis (the British name for idiopathic pulmonary fibrosis [IPF]) and emphysema was reported in 1990 in a series of eight patients by Wiggins et al1Wiggins J Strickland B Turner-Warwick M Combined cryptogenic fibrosing alveolitis and emphysema: the value of high resolution computed tomography in assessment.Respir Med. 1990; 84: 365-369Abstract Full Text PDF PubMed Scopus (196) Google Scholar in London. In 2005, we characterized2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar this association as a distinct entity in a series of 61 patients. Increasingly acknowledged,3Mura M Zompatori M Pacilli AM et al.The presence of emphysema further impairs physiologic function in patients with idiopathic pulmonary fibrosis.Respir Care. 2006; 51: 257-265PubMed Google Scholar, 4Grubstein A Bendayan D Schactman I et al.Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature.Respir Med. 2005; 99: 948-954Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 5Jankowich MD Polsky M Klein M et al.Heterogeneity in combined pulmonary fibrosis and emphysema.Respiration. 2008; 75: 411-417Crossref PubMed Scopus (75) Google Scholar, 6Rogliani P Mura M Mattia P et al.HRCT and histopathological evaluation of fibrosis and tissue destruction in IPF associated with pulmonary emphysema.Respir Med. 2008; 102: 1753-1761Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 7Wells AU Desai SR Rubens MB et al.Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.Am J Respir Crit Care Med. 2003; 167: 962-969Crossref PubMed Scopus (505) Google Scholar this syndrome is a matter of growing interest by respiratory clinicians. The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is not just a distinct phenotype of IPF. It deserves the terminology of syndrome as a result of the association of symptoms and clinical manifestations, each with a probability of being present increased by the presence of the others. Hence, the syndrome of CPFE results from the association of distinct features, including tobacco smoking, severe dyspnea, unexpected subnormal spirometry findings, severely impaired transfer capacity for carbon monoxide, hypoxemia at exercise, characteristic imaging features (ie, centrilobular and/or paraseptal emphysema, and diffuse interstitial opacities suggestive of pulmonary fibrosis of the lower lobes),8Brillet P Cottin V Letoumelin P et al.Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis syndrome): CT imaging features and pulmonary function tests.J Radiol. 2009; 90: 43-51Crossref PubMed Scopus (36) Google Scholar and a high probability of severe pulmonary hypertension (PH).2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar Although the imaging features of CPFE, and especially of emphysema, may be semi-quantified, it is striking that the gross evaluation by the clinician of the presence of both “significant” emphysema and fibrosis is sufficient to delineate the syndrome of CPFE with excellent reproducibility with matching imaging and cardiopulmonary features (unpublished results), further emphasizing that CPFE is indeed a syndrome. In this issue of CHEST (see page 10), Mejia et al9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar report on a series of 110 patients with IPF, 28% of them with at least 10% of the lung affected with emphysema, and thus are considered to have CPFE. This study clearly confirms that the risk of the development of PH is notably higher in those patients with CPFE than in those with IPF without emphysema. In fact, 21 of 29 patients with CPFE had echocardiographic features of severe PH (systolic pulmonary artery pressure, > 75 mm Hg), compared to 8 of 68 patients with IPF without emphysema (odds ratio, 19; 95% confidence interval, 5.08 to 68.7; p < 0.0001).9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Further, this study is the first to demonstrate that the prognosis for patients with CPFE is worse than that for patients with nonemphysema IPF, which is an outcome determined by severe PH (and not only by the presence of associated emphysema). There are several reasons why it is of utmost importance to diagnose the CPFE syndrome. First, the risk of the development of PH is elevated (between 50% and 90%2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar, 9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar) and is associated with poor survival. Indeed, the 5-year survival rate was 25% for patients with PH vs 75% for patients without PH at echocardiography in our study2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar; the presence of severe PH at echocardiography was associated with an increased risk of death in the study by Mejia et al9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar (hazard ratio, 1.88; 95% confidence interval, 1.01 to 3.48). Second, since lung volumes are relatively preserved in patients with CPFE (as opposed to patients with IPF without emphysema) and the main determinant of mortality is represented by PH, it is expected that lung volumes, which are usually evaluated in the course of IPF, may not be relevant for the follow-up of patients with CPFE. While FVC may not accurately reflect progression of disease, it may be anticipated that variations in diffusion capacity, hypoxemia, or pulmonary artery pressure, could represent better surrogates for the progression of disease and mortality. Third, the inclusion of patients with CPFE syndrome in IPF clinical trials may lead to spurious underevaluation of the effect of treatment in IPF patients, as the inclusion criteria of several international clinical trials10King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (454) Google Scholar, 11Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar, 12Demedts M Behr J Buhl R et al.High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242Crossref PubMed Scopus (838) Google Scholar in patients with IPF were likely compatible with the inclusion of patients with CPFE. We consider that patients with CPFE should thus be carefully excluded from future IPF trials (or at least a stratification should be anticipated to account for the presence of emphysema). Fourth, it is currently not clear whether pathologic features of CPFE reflect the sole combination of emphysema and a pattern of usual interstitial pneumonia, or whether non-usual interstitial pneumonia patterns (some of which have been reported in CPFE patients2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar, 5Jankowich MD Polsky M Klein M et al.Heterogeneity in combined pulmonary fibrosis and emphysema.Respiration. 2008; 75: 411-417Crossref PubMed Scopus (75) Google Scholar) may be frequent. Last, the diagnostic criteria for IPF may not apply to all patients with CPFE, who may have normal lung volumes despite advanced disease and the need for long-term nasal oxygen therapy. There are some limitations to the study by Mejia et al.9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar First, the authors used IPF American Thoracic Society/European Respiratory Society criteria for the diagnosis of CPFE (eg, IPF with emphysema), which might have selected patients with more advanced fibrosis than emphysema, thus limiting the generalization of their results to a broader population of patients with CPFE. Hence, the restrictive pattern seen in this series (with a mean FVC of 62% predicted9Mejia M Carrillo G Rojas-Serrano J et al.Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension.Chest. 2009; 136: 10-15Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar) may reflect selection bias, as the mean (± SD) FVC was 90 ± 18% predicted in our series2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar with inclusion criteria based on imaging features regardless of pulmonary function. Second, no hemodynamic evaluation was performed, what may be justified by the lack of evidence that any treatment for PH may be beneficial for patients with CPFE with PH. Third, diffusion capacity was not reported, although it represents a cardinal feature of the syndrome.2Cottin V Nunes H Brillet PY et al.Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.Eur Respir J. 2005; 26: 586-593Crossref PubMed Scopus (771) Google Scholar Fourth, the possible role of hypoxemia in the risk of PH may be increased by altitude; this confounding factor is particularly relevant for patients living in Mexico City (altitude, 2,200 m). It is clear than many aspects of the CPFE syndrome remain to be explored. The pathophysiology of the syndrome is unclear,13Cottin V Fabien N Khouatra C et al.Anti-elastin autoantibodies are not present in combined pulmonary fibrosis and emphysema.Eur Respir J. 2009; 33: 219-221Crossref PubMed Scopus (40) Google Scholar although tobacco smoking is definitely a major cause, and possible other risk factors have been identified, such as exposure to agrochemical compounds.14Daniil Z Koutsokera A Gourgoulianis K Combined pulmonary fibrosis and emphysema in patients exposed to agrochemical compounds.Eur Respir J. 2006; 27: 434Crossref PubMed Scopus (27) Google Scholar It is likely that an individual's genetic background may predispose some smokers to the development of CPFE. A polymorphism in the promoter of the matrix metalloproteinase-1 gene may, for example, represent a good candidate.15Mercer BA Wallace AM Brinckerhoff CE et al.Identification of a cigarette smoke-responsive region in the distal MMP-1 promoter.Am J Respir Cell Mol Biol. 2009; 40: 4-12Crossref PubMed Scopus (68) Google Scholar The respective role of male gender and tobacco smoking should be investigated (do they represent independent, or linked, etiologic factors?). Obviously, much progress is required regarding the management and treatment of patients with CPFE, with and without severe PH, as no treatment is currently available to save them from a dire prognosis.