Emphysema Idiopathic Pulmonary Fibrosis and

Idiopathic Pulmonary Fibrosis and Emphysema Mayra Mejía, Guillermo Carrillo, Jorge Rojas-Serrano, Andrea Estrada, Teresa Suárez, Delfino Alonso, Emilio Barrientos, Miguel Gaxiola, Carmen Navarro and Moisés Selman Chest 2009;136;10-15; Prepublished online February 18, 2009; DOI 10.1378/chest.08-2306

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CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 2007 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://www.chestjournal.org/site/misc/reprints.xhtml) ISSN:0012-3692

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CHEST

Original Research INTERSTITIAL LUNG DISEASE

Idiopathic Pulmonary Fibrosis and Emphysema Decreased Survival Associated With Severe Pulmonary Arterial Hypertension Mayra Mejía, MD; Guillermo Carrillo, MD; Jorge Rojas-Serrano, MD, MSc; Andrea Estrada, MD; Teresa Sua´rez, MD; Delfino Alonso, MD; Emilio Barrientos, MD; Miguel Gaxiola, MD; Carmen Navarro, MD; and Moise´s Selman, MD, FCCP

Background: It has been suggested that the presence of emphysema modifies the outcome of patients with idiopathic pulmonary fibrosis (IPF). In this article we compare clinical features, smoking history, pulmonary function, estimated systolic pulmonary artery pressure (eSPAP), and mortality in IPF with emphysema vs IPF without emphysematous changes. Methods: A cohort of 110 IPF patients was evaluated. Clinical data were collected from clinical charts. High-resolution CT (HRCT) scans were examined by an expert blinded to clinical data, and patients were classified into the following two groups: patients with IPF with emphysema; and patients with IPF without emphysema. The Kaplan-Meier method, log-rank test, and Cox regression model were used for statistical analyses. Results: The prevalence of emphysema in the IPF cohort was 28% (31 of 110 patients). IPF with emphysema was significantly associated with male gender (odds ratio 关OR兴, 18; 95% confidence interval 关CI兴, 2.7 to 773.7; p ⴝ 0.0003), and smoking (OR, 3.8; 95% CI, 1.36 to 11.6; p ⴝ 0.004). Patients with IPF and emphysema had a higher mean (ⴞ SD) decrease in oxygen saturation during rest and exercise (16.3 ⴞ 6.7% vs 13.5 ⴞ 4.6%, respectively; p ⴝ 0.04), a higher mean fibrosis HRCT scan score (1.75 ⴞ 0.36 vs 1.55 ⴞ 0.38, respectively; p ⴝ 0.015), a higher eSPAP (82 ⴞ 20 vs 57 ⴞ 15 mm Hg, respectively; p < 0.0001), and lower median survival time (25 vs 34 months, respectively; p ⴝ 0.01) than patients with IPF without emphysema. The Cox regression model showed that the two most important variables associated with mortality were FVC < 50% predicted (hazard ratio 关HR兴, 2.6; 95% CI, 1.19 to 5.68; p ⴝ 0.016) and eSPAP > 75 mm Hg (HR, 2.25; 95% CI, 1.12 to 4.54; p ⴝ 0.022). Conclusions: IPF patients with emphysema exhibited higher mortality compared with those with IPF without emphysema. This dire prognosis seems to be at least partially associated with the development of severe pulmonary arterial hypertension. (CHEST 2009; 136:10 –15) Abbreviations: CI ⫽ confidence interval; eSPAP ⫽ estimated systolic pulmonary artery pressure; HR ⫽ hazard ratio; HRCT ⫽ high-resolution CT; INER ⫽ National Institute of Respiratory Diseases; IPF ⫽ idiopathic pulmonary fibrosis; MMP ⫽ matrix metalloprotease; OR ⫽ odds ratio; PAH ⫽ pulmonary arterial hypertension; Spo2 ⫽ pulse oximetric saturation; TNF ⫽ tumor necrosis factor

pulmonary fibrosis (IPF) is a relentlessly I diopathic progressive and usually lethal lung disease of unknown etiology.1 Most patients experience a slowly progressive clinical course, but shorter survival times seem to be related to older age, male gender, smoking, higher deterioration of pulmonary function test results, and higher fibrotic score on a high-resolution CT (HRCT) scan at the time of diagnosis.2–7 10

The examination of HRCT scan images has revealed that a number of patients with IPF exhibit the combination of emphysematous lesions and pulmoFor editorial comment see page 1 nary fibrosis, which has been called combined pulmonary fibrosis and emphysema.8,9 Preliminary reports8,9 have suggested that patients with IPF and Original Research


emphysema have severe impaired carbon monoxide diffusing capacity with preserved lung volumes, and they may have a high prevalence of pulmonary arterial hypertension (PAH). There is scarce information about whether IPF with emphysema is a specific entity or represents a subgroup of IPF with a different prognosis. In this study, we analyzed our cohort of IPF patients with the aim of determining the prevalence of emphysema in the first evaluation and comparing clinical features, tobacco smoke exposure, lung function, PAH, and mortality among IPF patients with and without emphysematous changes. Materials and Methods We evaluated the clinical records of a cohort of consecutive IPF patients at the National Institute of Respiratory Diseases (INER), Mexico, from 1996 through 2006. The diagnosis of IPF was made based on established criteria and was confirmed by lung biopsy in 38% of the subjects.10 All patients in whom IPF had been diagnosed before the year 2000 were reevaluated to confirm that they met the American Thoracic Society/European Respiratory Society consensus guidelines.10 Clinical data (ie, smoking status, drug treatment, clinical findings, absence of previous environmental exposures, and collagen-vascular disease) were extracted from case records. Smoking status was characterized as “never,” “former” (patients who stopped smoking at least 12 months before presentation), or “current” (patients who were either still smoking or had stopped smoking ⬍ 1 year before presentation).11 Smoking index (in pack-years) was also documented. Pulmonary function tests (including spirometry and plethysmography), arterial blood gas measurements, and HRCT scans were performed as described elsewhere.12,13 We are reporting Pao2 and change in pulse oximetric saturation (Spo2) with exercise (Spo2 at rest ⫺ Spo2 at exercise) because these studies were performed in all patients and these parameters provided useful information about the gas exchange abnormalities in both cohorts. We are not reporting carbon dioxide diffusing capacity of the lung because before the year 2000 (when part of the cohort was recruited) we did not routinely measure this parameter. Patients with other interstitial lung diseases and those with atypical HRCT scan findings other than emphysema were excluded. The protocol was accepted by the Bioethic and Science Committee at INER. From the Instituto Nacional de Enfermedades Respiratorias (Drs. Mejía, Carrillo, Rojas-Serrano, Estrada, Suárez, Alonso, Barrientos, Gaxiola, Navarro, and Selman), Mexico City, Mexico; and the Universidad Nacional Auto´noma de Me´xico (Dr. RojasSerrano), Mexico City, Mexico. This study was supported by Universidad Nacional Auto´noma de Me´xico, grant No. SDI.PTID.05.6. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received September 24, 2008; revision accepted January 16, 2009. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/site/misc/reprints.xhtml). Correspondence to: Moise´s Selman, MD, FCCP, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Me´xico DF, Me´xico; e-mail: [email protected] DOI: 10.1378/chest.08-2306 www.chestjournal.org

Echocardiographic Evaluation Echocardiograms were obtained using a commercially available echocardiography system (GE Vivid Five; GE Healthcare; Horten, Norway) during the first evaluation at INER. A 2.5-MHz transducer was used to obtain the images in the parasternal and apical views (corresponding to the standard long-axis, and twochamber and four-chamber images, respectively). Standard twodimensional and color Doppler data were digitally saved. The estimated systolic pulmonary artery pressure (eSPAP) was calculated as previously described.14 PAH was defined by an eSPAP ⱖ 45 mm Hg, as previously described.9 HRCT Scanning HRCT scanning was performed with 1.0- or 1.5-mm-thick axial sections taken at 1-cm intervals throughout the entire thorax and were reconstructed using a high-spatial frequency algorithm. Between 20 and 25 CT scan images were acquired in each patient. HRCT scans were evaluated by one expert who was blinded to clinical data, and patients were classified into the following two groups: IPF patients with emphysema; and IPF patients without emphysematous changes. Emphysema was defined as the presence of areas of abnormally low attenuation delimited by a very thin wall (⬍ 1 mm) or no wall. Emphysematous lesions were graded as a percentage of affected lung, as has been described.15 Patients were classified as having IPF with emphysema only if there was ⬎ 10% of the lung affected with emphysematous changes (Fig 1). We evaluated the interobserver agreement between the absence or presence of emphysema with a second radiologist who was blinded to the first evaluation and previously trained about the definitions we used to classify the patients as having emphysema. The interobserver agreement was ␬ ⫽ 0.89 (p ⬍ 0.0001). The fibrotic component, defined as reticular opacities and honeycombing, was graded by one expert according to the Kazerooni score.16 Our reader had a high concordance. The intraclass correlation coefficient was 0.90 (95% confidence interval 关CI兴, 0.84 to 0.94; p ⬍ 0.0001兴). Clinicians blinded to the HRCT scan results examined the demographic and clinical data, smoking history, lung volumes, gas exchange data, and the eSPAP. These data corresponded to the first medical visit at INER. At this time, none of the patients had been treated with corticosteroids or immunosuppressive drugs. The vital status of each patient was obtained by reviewing the clinical charts and using telephone or telegrams in all patients who had been lost to follow-up. We obtained the vital status on 85% of the patients; for the remaining patients, their vital status was considered to be “alive.” Then, the time from diagnosis to death or last visit was established.

Figure 1. HRCT scan imaging of a patient with IPF and emphysema. Upper zones of the lungs showing paraseptal emphysema and mild patchy peripheral reticular lesions (A). Lower zones of the lungs showing patchy peripheral reticular and honeycombing lesions (B). CHEST / 136 / 1 / JULY, 2009


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Statistical Analysis For continuous variables, we used the t test or the Wilcoxon rank sum test according to their distribution. For categorical variables, we used the ␹2 test. We calculated the odds ratio (OR) with 95% CIs as a measure of the strength of the associations. The survival analysis was done with the Kaplan-Meier method and the log-rank test. We compared the survival at different levels of eSPAP (50 and 75 mm Hg), which were arbitrarily chosen after a preliminary stratification of the data. The relationship between prognostic factors and mortality was examined by univariate Cox regression analysis, and then a stepwise Cox regression model was performed with the variables showing influence on mortality. The proportional hazards assumption was evaluated with log-log survival curves and the scaled Schoenfeld residual goodness-of-fit test. All hypothesis testing was two sided, with a 5% threshold for statistical significance. All statistical analyses were done with a statistical software package (Stata, version 9.2; StataCorp; College Station, TX).

Results We evaluated 198 patients with a diagnosis of IPF. From them, 113 patients had available the chest HRCT scan corresponding to the first medical evaluation; 3 patients were excluded from the study because they had HRCT scan findings that were nontypical for IPF and had not undergone a biopsy. Seventy-two percent of the 110 patients were men (mean 关⫾ SD兴 age, 64 ⫾ 9.5 years), and 56% had a history of cigarette smoking. Male gender and smok-

ing history were highly associated, as follows: 56 smokers among 77 men (73%) vs 4 smokers among 30 women (13.3%) 关OR, 17.3; 95% CI, 5.02 to 74; p ⬍ 0.0001兴. Comparison Between Patients With IPF With Emphysema and Without Emphysema The prevalence of emphysema in the first medical evaluation was 28% (31 of 110 patients) 关Table 1兴. The emphysematous changes were usually localized at the upper lobes (Fig 1). IPF with emphysema was associated with male gender (30 of 31 vs 49 of 79 patients, respectively; OR, 18; 95% CI, 2.7 to 773.7; p ⫽ 0.0003) and smoking (24 of 31 vs 36 of 76 patients, respectively; OR, 3.8; 95% CI, 1.36 to 11.6; p ⫽ 0.004). Patients displaying IPF with emphysema also had more pack-years of smoking (median: 5 pack-years 关minimum, 0 pack-years; maximum, 60 pack-years兴 vs 0 pack-years 关minimum, 0 pack-years; maximum, 78 pack-years兴, respectively; p ⫽ 0.001). IPF with emphysema was highly associated with severe PAH (eSPAP, 82.3 ⫾ 20.2 vs 56.7 ⫾ 15.3 mm Hg, respectively; p ⬍ 0.0001). Moreover, 19 of 68 patients with IPF alone had normal eSPAP values, whereas none of the IPF patients with emphysema showed normal values. In addition, the following gradient effect was observed: the association became stronger when we stratified the levels of PAH in

Table 1—Comparison of Demographic Characteristics, Pulmonary Function Test Results, HRCT Scan Fibrotic Score, and PAH Between IPF Patients With and Without Emphysema Variables Gender, No. Male Female Age, yr Smoking status Yes No Pack-yrs FVC, % predicted FEV1, % predicted FEV1/FVC ratio Pao2,* mm Hg Spo2, % At rest During exercise Change eSPAP, mm Hg PAH eSPAP ⬎ 50 mm Hg eSPAP ⬎ 75 mm Hg Fibrotic HRCT scan

Patients With IPF Alone (n ⫽ 79)

Patients With IPF and Emphysema (n ⫽ 31)

49 30 63 ⫾ 10

30 1 67 ⫾ 7

OR (95% CI)

p Value

18 (2.7–773.7)

0.001

3.8 (1.36–11.6)

0.12 0.004

36 40 0 (0–78) 58.7 ⫾ 18 67.4 ⫾ 20.3 92.6 ⫾ 10.9 50.3 ⫾ 8.9

24 7 5 (0–60) 62.1 ⫾ 15.6 69.9 ⫾ 14.9 90.5 ⫾ 8.5 48.7 ⫾ 8.2

0.001 0.37 0.63 0.33 0.39

88.2 ⫾ 3.7 74.8 ⫾ 5.9 13.5 ⫾ 4.6 56.7 ⫾ 15.3

87.1 ⫾ 3.6 71.0 ⫾ 6.9 16.3 ⫾ 6.7 82.3 ⫾ 20.2

0.16 0.01 0.04 0.0001

39/68 (58) 8/68 (11.7) 1.55 ⫾ 0.38

26/29 (90) 21/29 (72) 1.75 ⫾ 0.36

6.2 (1.6–34.7) 19 (5.8–68.7)

0.0025 ⬍ 0.0001 0.015

Values are given as the mean ⫾ SD, median (range), or No/No. (%), unless otherwise indicated. *The study was performed in Mexico City at an altitude of 2,240 m above sea level at a mean barometric pressure of 583 mm Hg. Normal Pao2, 67 ⫾ 3 mm Hg. 12

Original Research


0.75 0.50

IPF

IPF/emphysema 0.25

Survival (%)

1.00

Table 2—Relationship Between Prognostic Factors and Mortality by Univariate Analysis

0.00

P=0.014 (log-rank)

0

20

40

60

Variables

HR

95% CI

p Value

Male gender Emphysema HRCT scan fibrotic score FVC ⬍ 50% predicted PAH eSPAP ⬎ 50 mm Hg eSPAP ⬎ 75 mm Hg

1.84 1.99 2.18 2.45

0.95–3.56 1.12–3.53 1.11–4.29 1.29–4.67

0.069 0.018 0.023 0.006

1.13 1.88

0.58–2.18 1.01–3.48

0.71 0.04

80

Months Figure 2. The Kaplan-Meier survival curve for patients with IPF and IPF plus emphysema. Survival time was significantly lower in the group of patients with IPF combined with emphysema (p ⫽ 0.01 关log-rank test兴).

eSPAP ⬎ 50 mm Hg (26 of 29 vs 39 of 68 patients, respectively; OR, 6.2; 95% CI, 1.6 to 34.7; p ⫽ 0.0025) and eSPAP ⬎ 75 mm Hg (21 of 29 vs 8 of 68 patients, respectively; OR, 19.7; 95% CI, 5.8 to 68.7; p ⬍ 0.0001). Also, there was a positive correlation between eSPAP and the extent of emphysema (Spearman ␳ ⫽ 0.58; p ⬍ 0.0001). As shown in Table 1, patients with IPF and emphysema also showed a higher mean HRCT scan fibrotic score (1.75 ⫾ 0.38 vs 1.55 ⫾ 0.36, respectively; p ⫽ 0.015). The baseline FVC, FEV1, Pao2, and Spo2 levels at rest were similar in both groups. By contrast, Spo2 during exercise displayed a significant mean decrease in patients with IPF and emphysema (74.8 ⫾ 5.9 vs 71 ⫾ 6.9, respectively; p ⬍ 0.01). As a consequence, the change in Spo2 (rest ⫺ exercise) was significantly elevated in these patients compared with patients with IPF alone (16.3 ⫾ 6.7 vs 13.5 ⫾ 4.6, respectively; p ⬍ 0.04). Survival Rate The survival rate in patients with IPF and emphysema was significantly lower compared with those with IPF without emphysematous changes (p ⫽ 0.01 关log-rank test兴) 关Fig 2兴. This result did not change when the patients with unknown vital status were excluded. Other variables associated with lower survival rate were the presence of eSPAP ⬎ 75 mm Hg (p ⬍ 0.04 关log-rank test兴) and FVC ⬍ 50% predicted (p ⬍ 0.005 关log-rank test兴). The results of the univariate Cox regression are shown in Table 2. After stratification by eSPAP ⬎ 75 mm Hg, the presence of emphysema lost statistical significance (p ⬍ 0.14 关stratified log-rank test兴), but FVC ⬍ 50% predicted and eSPAP ⬎ 75 mm Hg maintained their statistical significance after stratification with the presence of emphysema and with each other (data not shown). www.chestjournal.org

We then performed a stepwise Cox regression model, and the variables associated with lower survival were severe pulmonary hypertension (eSPAP ⬎ 75 mm Hg; hazard ratio 关HR兴, 2.25; 95% CI, 1.12 to 4.54; p ⫽ 0.022) and FVC ⬍ 50% predicted (HR, 2.6; 95% CI, 1.19 to 5.68; p ⫽ 0.016). All the variables fulfilled the evaluation of proportional hazards assumption according to the log-log plots; the global p value of the scaled Schoenfeld residual goodnessof-fit test was 0.27. Discussion A growing body of evidence suggests that IPF evolves with different clinical phenotypes. Thus, for example, in 2007 we described5 an accelerated variant of the disease in which patients consulted a physician a few months after the beginning of symptoms with severe physiologic impairment and showing a significantly lower survival rate. Also, it is well known that the disease occurs more frequently in smokers9,17,18 and that emphysematous changes develop in a number of these patients. In this context, the association of IPF with emphysema has been proposed as a new clinical entity in smokers or a different clinical phenotype in smokers developing IPF. Honeycombing, reticular opacities, and traction bronchiectasis are the most frequent findings seen on HRCT scans in the lower lungs; the upper lungs show paraseptal and centrilobular emphysema. However, in some cases, emphysema and fibrosis may cooccur in the same area of the lung. The pathogenic mechanisms implicated in the combination of both types of lung destruction (emphysema and fibrosis) are unknown. However, some experimental models have revealed important clues to the problem. The overexpression of tumor necrosis factor (TNF)-␣ in mouse lungs provokes dramatic changes in both lung structure and function that include airspace dilatation coupled with consolidation and fibrosis.19 Likewise, the up-regulation of platelet-derived growth factor induced distinct abnormalities in the adult mouse lung, leading to a CHEST / 136 / 1 / JULY, 2009


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complex phenotype that includes aspects of both emphysema and fibrotic lung disease.20 In a recent study21 of human disease, no differences in the expression of TNF-␣ by macrophages or bronchiolar epithelial cells was found among IPF patients with and without emphysema, although this immunohistochemical observation cannot exclude a role for TNF-␣ in the inflammatory process of emphysema associated with IPF. In the same study,21 several matrix metalloproteases (MMPs) 关MMP-2, MMP-9, MMP-7, and membrane type-MMP兴 were found to be expressed at similar levels in the fibroblastic foci of patients with IPF alone and those with IPF with emphysema.21 Therefore, the putative mechanisms involved in IPF associated with emphysema are largely unknown. Moreover, although this disorder occurs mainly in smokers, this pathologic entity does not develop in many patients with IPF who smoke. Additionally, it is unclear whether emphysematous and fibrotic lesions progress independently or whether the development of one of them (ie, emphysema) modifies the progression of the other. The association of male gender and smoking with IPF and emphysema observed in this and other studies is similar to that observed in patients with emphysema alone, suggesting that similar pathogenic mechanisms may be involved in the emphysematous changes. In addition, several potential pathogenic mechanisms of emphysema, such as apoptosis of alveolar epithelial cells, increased oxidative stress, and loss of telomerase activity leading to a failure of lung maintenance and repair,22 also occur during the development of IPF. However, whether IPF with emphysema is a distinct disease entity or simply a different clinical phenotype in male smokers in whom IPF develops is currently unclear. In the present study, we aimed to determine the prevalence of emphysema in our cohort of IPF patients at the first medical visit, and to compare the clinical and physiologic behavior as well as the outcome between IPF patients with and without emphysema. Importantly, our results revealed that the presence of emphysema is more frequent than previously suspected, showing a prevalence close to 30%. In all of these cases, emphysema and fibrosis were discovered concomitantly with the HRCT scan obtained during the first visit to our institute. As shown in Figure 1, the spatial distribution of the emphysematous abnormalities was very similar to that described in other series and in emphysema presenting alone. Thus, emphysematous lesions usually showed upper-zone predominance, whereas fibrotic lesions were observed in the lower lobes in all the patients. Also, as previously indicated,9,17 almost all patients with IPF and emphysema had a history of smoking 14

tobacco (OR, 3.8) and were of male gender (OR, 18.4). Nevertheless, both variables (tobacco smoking history and male gender) were highly associated (OR, 17.3), so, in this context, a possible confounder cannot be ruled out. The sample size of the cohort did not allow us to stratify to answer that question. Cottin et al9 described that the prevalence of PAH is high among patients with pulmonary fibrosis associated with emphysema. In the present work, we confirmed this association and found a strong correlation between eSPAP and the extent of emphysema. Furthermore, most IPF patients with emphysema displayed severe PAH. By the Cox regression analysis of survival, the two most important variables that predicted time to death were severe restriction measured by FVC and severe PAH. The presence of emphysema as a significant predictor of survival was lost in the stratified analysis and in the Cox regression model because of the strong association with severe pulmonary hypertension. In the study by Cottin et al,9 which included 61 patients, the only statistically significant difference in survival was found between patients with PAH at diagnosis.9 The limitations of this study are the relatively small number of patients and its retrospective nature. Also, because it is an invasive technique, right cardiac catheterization was not used to confirm the diagnosis of PAH. Nevertheless, our findings confirm that the presence of emphysema in patients with IPF is an important prognostic factor, which may be due to the increased incidence of severe restriction and pulmonary hypertension. In conclusion, the association of IPF and emphysema is more frequent than usually thought; patients with IPF and emphysema had a higher mortality rate compared with those with IPF without emphysema. Emphysematous lesions seen on HRCT scans are strongly associated with high eSPAP, supporting the notion that the worse prognosis for these patients is related to severe PAH. ACKNOWLEDGMENT: The authors thank Dr. Fortunato Jua´rez for her expert evaluation of the HRCT scans in the concordance analysis.

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Idiopathic Pulmonary Fibrosis and Emphysema Mayra Mejía, Guillermo Carrillo, Jorge Rojas-Serrano, Andrea Estrada, Teresa Suárez, Delfino Alonso, Emilio Barrientos, Miguel Gaxiola, Carmen Navarro and Moisés Selman Chest 2009;136; 10-15; Prepublished online February 18, 2009; DOI 10.1378/chest.08-2306 This information is current as of July 27, 2009 Updated Information & Services

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