Pulmonary emphysema and the idiopathic interstitial pneumonias, of which idiopathic pulmonary brosis (IPF) is the most frequent, are separate entities characterized by distinct clinical, functional, radiological, and pathological characteristics. However, recent studies have revealed that emphysema, among other comorbid conditions, is more frequently associated with IPF than previously appreciated, leading to consideration of CPFE as a distinct syndrome. Moreover, it has recently been better recognized that the combination of pulmonary brosis and emphysema alters the clinical presentation and outcome, with implications for clinical practice and trial design. A speci c research de nition and set of criteria for CPFE clinical syndrome has been proposed.

Historical Perspective

In 1948, Laurence L. Robbins reported on a form of IPF and emphysema [1]; areas of brosis were interspersed with areas of emphysema at chest radiograph, with emphysema described as thin-walled bullae or blebs. The same year, T. B. Mallory et al. described a young woman with pathologically con rmed IPF and emphysema [2].

In 1990, Wiggins and colleagues from the group headed by Dr Margaret Turner-Warwick at the Brompton hospital (London, UK) reported on eight patients with IPF (that was called “cryptogenic brosing alveolitis” at the time), in whom combined emphysema was observed on chest computed tomography (CT) [3]. The combination of ILD and emphysema was associated with dramatically decreased carbon monoxide transfer factor (DLco) in the setting of well-­ preserved total lung capacity (TLC) and a normal or nearly normal forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) ratio. This report mostly emphasized that

V. Cottin (*)

Department of Respiratory Medicine, National Coordinating Reference Centre for Rare Pulmonary Diseases (OrphaLung), Louis Pradel Hospital, University of Lyon, Lyon, France e-mail: vincent.cottin@chu-lyon.fr

high resolution (HR) CT of the chest was helpful to provide with a working diagnosis in patients with severe dyspnea and subnormal spirometry.

In 1997, Wells et al. [4] described the functional impact of emphysema in patients with “cryptogenic brosing alveolitis,” citing higher lung volumes, lower DLco, and decreased gas exchange in patients with emphysema as compared to those with pulmonary brosis alone. In 2003, Wells et al. [5] introduced a sophisticated approach to characterizing how emphysema impacts pulmonary function in IPF, and derived a score (the “composite physiologic index,” CPI) from disease extent on HRCT to correct the mortality risk calculation in IPF patients (which uses FVC and DLco) for the confounding effects of emphysema. Although this study contributed to a more accurate prognostic determination in IPF, and provided a useful tool for clinical research, it did not draw attention of the clinicians to the profound consequences of emphysema in IPF patients.

Despite isolated reports [6, 7] of observations similar to that of Wiggins et al. [3], it was not until 2005 that combined pulmonary brosis and emphysema (CPFE) was individualized as a distinct syndrome by the Groupe d’Etude et de Recherche sur les Maladies “Orphelines” Pulmonaires

(GERM“O”P) [8] (a French group of clinical research, now named OrphaLung), occurring in smokers or ex-smokers and representing more than a mere comorbid condition. CPFE was de ned at chest HRCT by the presence of upper lobe emphysema and pulmonary brosis of the lower lobes, with the interstitial lung disease (ILD) corresponding to IPF in most of the patients. This comprehensive description in a large group of patients (n = 61) lead to a greater appreciation for the high prevalence of CPFE and prognostic signi - cance of pulmonary hypertension (PH) in patients with the disorder [8].

Since then, nearly 100 original articles on CPFE have contributed to a more complete description of the syndrome, as reviewed in this chapter. The presence of emphysema in smokers with IPF is now systematically evaluated routinely. Causes other than tobacco smoking have been identi ed.