CHEST 2013; 144(1):234–240 R1 정수웅 Christopher J. Ryerson, MD ; Thomas Hartman, MD ; Brett M. Elicker, MD ; Brett Ley, MD ; Joyce S. Lee, MD ; Marta Abbritti, MD ; Kirk D. Jones, MD ; Talmadge E. King Jr, MD ; Jay Ryu, MD, FCCP ; and Harold R. Collard, MD, FCCP Clinical Features and Outcomes in Combined Pulmonary Fibrosis and Emphysema in Idiopathic Pulmonary Fibrosis

B ACKGROUND Combined pulmonary fibrosis and emphysema (CPFE)  The presence of emphysema and parenchymal fibrosis in the same patient  Previous studies have shown that patients with CPFE have distinct clinical features, and possibly different outcomes. commonly men with a heavy smoking history severe dyspnea on exertion relatively preserved lung volumes with disproportionate impairment of gas exchange appear to develop severe pulmonary arterial hypertension and more frequent lung cancer the reported impact of CPFE on survival is inconsistent 2

B ACKGROUND Most previous studies of CPFE have significant limitations  imprecise definitions of CPFE,  heterogeneous patient populations (a variety of causes of pulmonary fibrosis with different natural histories)  lack of controlling for confounder The objectives of evaluation of two large cohorts of patients with well-characterized IPF  the prevalence of CPFE in IPF  the clinical features of CPFE in IPF  the prognostic importance of CPFE in IPF 3

M ATERIALS AND M ETHODS 4 ILD (interstitial lung disease) UCSF (the University of California San Francisco) Mayo (Mayo Clinic Rochester ) A total of 365 patients from ILD database of UCSF and Mayo between ~ from USCF, 173 from Mayo Inclusion criteria a diagnosis of IPF based on multidisciplinary review according to established criteria a high-resolution CT (HRCT) scan within 1 year of their initial clinic consultation

M ATERIALS AND M ETHODS 5 Baseline information, questionnaires at the time of initial consultation Dyspnea severity The self-administered dyspnea component of the Clinical, Radiographic, a nd Physiologic scoring system Resting oxygen saturation, the need for long-term oxygen therapy, and pul monary artery pressures Pulmonary function testsSystolic pulmonary artery pressures by echocardiogramThe use of inhaler therapies based on chart review Date of death or transplant

M ATERIALS AND M ETHODS 6 HRCT were reviewed by two experienced thoracic radiologists by a blind fashion estimating the percent of reticular change and honeycombing Fibrosis score estimating the percent of a hyperlucent area of lung that lacked a distinct wall a total emphysema score of threshold of 10% to define CPFE Emphysema score A 10% threshold corresponds to GOLD stage II or worse in patients with isolated COPD, suggesting that this amount of emphysema is expected to have symptomatic and physiologic consequences. GOLD (Global Initiative for Chronic Obstructive Lung Disease)

7 R ESULTS Distribution of emphysema score. Scores were averaged for the two radiologists. CPFE = combined pulmonary fibrosis and emphysema. 49 patients (13.4%) : >5% emphysema 106 patients (29.0%) : at least some emphysema detectable on HRCT scan. 17 patients, the extent of emphysema was greater than that of fibrosis

8 R ESULTS Mean extent of fibrosis and emphysema in upper, mid, and lower lung zone. Scores were averaged for the corresponding areas in the right and left lungs. See Figure 1 legend for expansion of abbreviation. Overall agreement between the two radiologists on the presence of CPFE was 96%

9 R ESULTS

10 R ESULTS Similar risk of death between CPFE and IPF HR, 1.08 (95% CI, ; P 5.75) on unadjusted analysis HR, 1.14 (95% CI, ; P 5.69) on adjustment for baseline fibrosis score Follow-up pulmonary function test data at 12 months : 190 patients (52% of combined cohort) Disease progression during the initial 12 months : 135 patients out of 190 pt. (71%) No association between the diagnosis of CPFE and disease progression

11 R ESULTS

12 R ESULTS Kaplan-Meier survival curves stratified by CPFE vs non-CPFE. Survival curves and P value represent time to death or transplant. See Figure 1 legend for expansion of abbreviation. Median transplant-free survival : 2.8 years in patients with CPFE : 2.8 years in IPF patients without emphysema

Patients with CPFE : less physiologic restriction and worse gas exchange  The higher FVC in patients with CPFE partially explained by less severe fibrosis in these patients because of the difference in FVC that remains after adjustment for fibrosis score.  Emphysema could mitigate the impact of the fibrosis on ventilatory physiology.  Fibrosis and emphysema had similar and cumulative effects on gas exchange, reflected by disproportionate oxygen requirement, low DLco, and pulmonary hypertension in CPFE. 13 D ISCUSSION

Milder radiographic fibrosis of the patients with CPFE at presentation  Earlier medical attention due to additional symptoms of emphysema  Underestimation of extent of fibrosis on HRCT scans in the presence of emphysema less likely in our cohort given the strong agreement for both fibrosis and emphysema scores between two experienced thoracic radiologists the consistently lower fibrosis score in upper, mid, and lower lungs of patients with CPFE  Inclusion of some patients with non-IPF ILD who had less severe fibrosis 14 D ISCUSSION

No clear difference in survival between CPFE and non-CPFE  Balanced mortality risk factors CPFE: worse oxygenation and pulmonary hypertension IPF without emphysema : more fibrosis  Confounding factor differences in the rates of other unmeasured co-morbidities could confound the result.  Relatively small number of patients with CPFE could limit our ability to detect a true difference in mortality. The 95% CI of HR ( ) suggests that any difference in mortality, if present, is relatively modest. 15 D ISCUSSION

C ONCLUSION CPFE is a distinct clinical phenotype of IPF. Prospective, population-based studies are required for generalization of our findings to a broader IPF population. A remaining question is  Is CPFE a biologically distinct condition or just IPF and emphysema in the same patient ???  Why does some smoker deveolop emphysema, some IPF, some CPFE ???  evaluation of underlying biologic pathways 16