Published ahead of print on October 25, 2007, doi:10.1164/rccm.200612-1759OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200612-1759OC
Idiopathic Pulmonary FibrosisOutcome in Relation to Smoking Status1 Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom; 2 Department of Thoracic Medicine, University of Crete, Heraklion, Greece; 3 Department of Radiology, Royal Brompton Hospital, London, United Kingdom; 4 Department of Radiology, King's College Hospital, London, United Kingdom; and 5 Department of Histopathology, Royal Brompton Hospital, London, United Kingdom Correspondence and requests for reprints should be addressed to Athol U. Wells, M.D., Interstitial Lung Disease Unit, c/o Emmanuel Kaye Building, Manresa Road, London SW3 6LR, UK. E-mail: a.wells{at}rbh.nthames.nhs.uk
Rationale: The pathogenic importance of smoking status in idiopathic pulmonary fibrosis (IPF) is uncertain. In theory, increased oxidative stress in current and former smokers might promote disease progression. However, better survival has been reported for current smokers with IPF, although this might reflect less severe disease at presentation (a "healthy smoker effect"). Objectives: To determine whether smoking status is associated with survival differences in IPF. Methods: A total of 249 patients with IPF were studied (current smokers, n = 20; former smokers, n = 166; never-smokers, n = 63). Survival was evaluated against smoking status, using proportional hazards analysis, adjusting for sex, age, disease severity (extent of the disease on high-resolution computed tomography, composite physiologic index [CPI], percentage predicted diffusing capacity for carbon monoxide in separate models), and the degree of honeycombing. Measurements and Main Results: Current smokers had milder disease than did former smokers, with lower CPI scores (P < 0.0001), less extensive disease on high-resolution computed tomography (P < 0.005), and higher unadjusted survival (hazard ratio = 0.44; 95% confidence interval = 0.24, 0.80; P = 0.007). However, survival did not differ between current and former smokers (P = 0.39) after adjustment for CPI levels. By contrast, the increase in survival seen in nonsmokers than in former smokers (hazard ratio = 0.51; 95% confidence interval = 0.41, 0.83; P = 0.008) was amplified (P < 0.0005) by adjustment for CPI levels. Conclusions: In IPF, survival and severity-adjusted survival are higher in nonsmokers than in former smokers or the combined group of former and current smokers. By contrast, a better outcome in current smokers, compared with former smokers, reflects less severe disease at presentation and may represent a healthy smoker effect.
Key Words: idiopathic pulmonary fibrosis • cigarette smoking • outcome • survival
Idiopathic pulmonary fibrosis (IPF) is a lethal disease with a median survival of 3 years (1). The concept of IPF as an epithelial/fibroblastic disorder (2) requires injury to the pulmonary epithelium and an abnormal healing response (3), with evidence suggesting that oxidants contribute to epithelial damage (4–6). Oxidative stress from smoking might, in theory, contribute to pathogenesis in current and former smokers (as excessive oxidant activity persists after smoking cessation [7]), perhaps explaining the well-recognized association between IPF and smoking (8, 9). Paradoxically, better survival has been reported in current smokers with IPF (10), but this observation is difficult to interpret, as a "healthy smoker" effect (11, 12) cannot be excluded. Symptomatic patients with more severe disease may be more likely to stop smoking for perceived health reasons. It can, therefore, be argued that current smoking might be a marker of less advanced disease, associated with better survival. This problem requires rigorous adjustment for baseline disease severity in survival analyses. However, routine indices traditionally used to quantify severity (the diffusing capacity for carbon monoxide [DLCO] and FVC) are, themselves, influenced by coexistent smoking-related damage (13–15). In this regard, the composite physiologic index (CPI) offers theoretical advantages, because it adjusts for the confounding functional effects of concurrent emphysema (16). Some of the results of this study were previously reported in abstract form (17). In this retrospective study, we have explored relationships between survival in IPF and smoking status, adjusting for key severity variables. Our a priori goals were to determine (1) whether severity-adjusted survival is better in current than in former smokers; and (2) whether severity-adjusted survival differs between smokers and nonsmokers.
Study Population The study group consisted of 249 consecutive patients (age, 62.5 ± 10.3 yr; 184 males), with two patients excluded because of ambiguities in the case records regarding smoking status. The diagnosis of IPF was made in 39 cases by surgical biopsy (in the correct clinical context, detailed below) and in 210 cases on the basis of clinical and high-resolution computed tomography (HRCT) criteria: (1) bilateral basal or widespread crackles; (2) restrictive ventilatory defect or isolated depression of DLCO; (3) computed tomography (CT) appearances indicative of IPF with predominantly basal and subpleural microcystic or macrocystic honeycombing, with variably extensive ground-glass and reticular abnormalities but no consolidation, nodular abnormalities, or other parenchymal abnormalities (apart from centrilobular emphysema); and (4) no environmental exposure to a fibrogenic agent or connective tissue disease. A former smoker was defined as having smoked at least one cigarette per day for 1 year: smoking histories were collected as part of a routine prospective clinical protocol and were collated retrospectively. Precise pack-year smoking histories were recorded in 231of 249 cases (93%). Longitudinal smoking histories after presentation (i.e., smoking cessation) were not considered. Some of the patients were included in a previous study exploring functional–morphologic correlations in IPF (16). The study was approved by the Royal Brompton Hospital ethics committee.
High-Resolution CT
Pulmonary Function Tests
Statistical Analysis Survival was evaluated against smoking status by proportional hazards analysis, adjusting for age, sex, HRCT coarseness score, and disease severity (using extent of disease on HRCT, the CPI, and percentage predicted DLCO in separate models): models satisfied the assumptions of proportional hazards analysis, as judged by tests of Schoenfeld residuals.
Demographic findings, pulmonary function variables, and CT features are tabulated against smoking status in Table 1. Significant subgroup differences in disease severity across the three groups were largely due to milder disease in current smokers, as judged by pulmonary function variables and the extent of disease on CT. Paired comparisons showed that FVC levels (P < 0.0005) and DLCO levels (P = 0.03) were lower, and CT disease extent (P < 0.005) and CPI scores were higher (P < 0.0005) in ex-smokers than in current smokers. Similarly, FVC levels (P < 0.0005) and DLCO levels (P = 0.05) were lower, and CT disease extent (P = 0.02) and CPI scores were higher (P < 0.0005) in nonsmokers than in current smokers. There were no significant or marginal differences between former smokers and nonsmokers for the three cardinal measures of disease severity (DLCO, CPI, and CT extent), although FVC levels were higher in former smokers (P < 0.005).
Follow-up was complete to death (n = 189, 76%) or to 3 years in 232 of 249 patients (93%). The median survival was 26 months and 5-year survival was 23%.
Survival Compared between Current and Former Smokers
Findings were unchanged, with no major differences in the statistical strength of trends, with the exclusion of known smokers with (1) a pack-year smoking history less than 10 (n = 14) or (2) no precise pack-year smoking history recorded in the case notes. Findings were also unchanged when the presence of emphysema (current smokers, n = 16; former smokers, n = 65) was taken into account in survival analysis, with the presence of emphysema having no influence on survival. On the basis of these findings, survival of never-smokers was compared with survival of (1) former smokers and of (2) the combined group of current/former smokers.
Survival Compared between Never-Smokers and Former Smokers
Findings were unchanged, with no major differences in the statistical strength of trends, with the exclusion of known smokers with (1) a pack-year smoking history less than 10 (n = 14) or (2) no precise pack-year smoking history recorded in the case notes.
Survival Compared between Never-Smokers and Current/Former Smokers
Post Hoc Subanalyses Because the current smoker subgroup was small, limiting the interpretation of comparisons with former smokers, survival was also compared between current and never-smokers. In a proportional hazards model also containing age, sex, and CPI levels, a slightly higher mortality among current smokers was not statistically significant (HR = 1.31; 95% CI = 0.87, 1.97; P = 0.20).
We observed higher mortality in former smokers than in current smokers, as in a previous report (10). However, severity-adjusted survival did not differ significantly between the two groups with the use of the CPI as a severity variable. This finding justified separate analyses comparing (1) former smokers with nonsmokers and (2) combined current/former smokers (viewed as a single group with respect to outcome) with nonsmokers. In both analyses, the significant survival advantages enjoyed by nonsmokers increased strikingly when functional and morphologic severity was taken into account. Adjustment for baseline disease severity is essential in mortality studies, especially in disorders in which a healthy smoker effect is possible. Smoking is generally viewed as a risk factor for IPF, based on an association between cigarette smoking and fibrotic lung disease in familial fibrotic lung disease (20), and associations between smoking and IPF in case-control studies grouped in a meta-analysis (21). Thus, the observation of higher survival in IPF among current smokers is, at first sight, surprising. However, current smokers were characterized by strikingly better preservation of pulmonary function indices at presentation, both in the present study and in the cohort of King and coworkers (10). The healthy smoker effect, most studied in chronic obstructive pulmonary disease (11, 12), applies to comparisons between current and former smokers. From our findings, it appears possible that unadjusted survival in IPF is lower among former smokers because of a healthy smoker effect (i.e., smoking cessation may be a marker of more advanced disease). This problem needed to be addressed by adjusting for disease severity in the present study, before meaningful outcome comparisons could be made between smokers and nonsmokers. Thus, the choice of severity variables was pivotal. In preliminary analyses, the CPI and, to a lesser degree, DLCO levels predicted mortality across the whole cohort better than other lung function indices, probably reflecting better correlations with CT morphologic extent (12, 22, 23). However, smoking-related lung damage and, especially, concurrent emphysema have a major confounding effect in IPF, giving rise to a relative preservation of lung volumes and a disproportionate reduction in gas transfer (12, 14, 15). Estimation of CT disease extent partially overcomes the problem, but imprecision is unavoidable in some lung regions because emphysema can be difficult to distinguish from honeycomb change in IPF when the processes are admixed (18, 24, 25). The CPI is the only current severity variable to take smoking-related damage completely into account. In effect, the CPI quantifies functional impairment specifically due to pulmonary fibrosis, while excluding that due to emphysema (16). This rationalization of the CPI was confirmed in a study of 42 patients with IPF, including 21 with concurrent emphysema: the CPI correlated with the extent of IPF on CT more strongly than other pulmonary function variables but had no significant or marginal correlation with the extent of emphysema (25). This is likely to explain the prognostic advantages of this index in some survival analyses (16) and the fact that the use of the CPI was more influential than other severity variables, amplifying the survival advantages associated with nonsmoking status, but reducing survival differences between current and former smokers. However, the small size of the current smoker subgroup should be stressed. Although the better survival in this group was, at least partially, ascribable to less severe disease at presentation, an additional smaller protective effect from current smoking, compared with former smoking, cannot be wholly excluded. Interestingly, in models containing the CPI, current smokers had marginally lower mortality than do former smokers, but marginally higher mortality compared with never-smokers, although neither comparison was statistically significant. This suggests that in terms of severity-adjusted survival, current smokers may lie somewhere between the other two groups, but much larger numbers of current smokers with IPF will need to be studied to resolve this question. The divergence in our findings from those reported by King and colleagues (10) is deceptive. In both studies, current smokers were a relatively small subgroup with less functional impairment at presentation and better survival, and the different conclusion reached in the present study was purely a function of the method used to adjust for baseline severity. More importantly, longer term survival, as shown by survival curves, was somewhat better in nonsmokers than in ex-smokers in the earlier study (10), although the authors did not emphasize this point and the effect was more pronounced in our cohort, with adjustment for disease severity using the CPI. It is important to stress the striking similarities between the observations in the two studies because inclusion criteria differed and this, in turn, led to different biases in the two cohorts. The patients with IPF studied by King and colleagues all underwent a surgical biopsy. Although a histologic diagnosis improved diagnostic confidence, an important selection bias was thereby introduced: patients undergoing biopsy are younger and have less functional impairment at presentation (26, 27). By contrast, most of our cohort consisted of consecutive patients with typical clinical and HRCT features. This allowed us to study a wider spectrum of disease severity, including patients too compromised to undergo a diagnostic surgical procedure. In theory, absence of a diagnostic surgical biopsy might have led to the inclusion of a small subgroup of patients with nonspecific interstitial pneumonia. However, an HRCT appearance typical of IPF, as in the present study, has a positive predictive value for IPF of more than 95%, even before clinical features are considered (19, 28), and the overall survival was typical of patients with biopsy-proven IPF. Our study and that of King and colleagues are complementary, with different methodologic limitations but similar subgroup trends. There are several other issues that merit consideration. We have never, as a matter of policy, analyzed outcome in IPF according to cause of death. Opinion differs on this point but we argue that even when cardiac disease or malignancy is the obvious immediate fatal event, it is impossible to exclude a major contribution from IPF, due to hypoxia (leading to cardiac stress) or linkage between more extensive pulmonary fibrosis and neoplasia. Furthermore, it is impossible to determine the cause of death in some patients (29). For these reasons, we continue to favor all-cause mortality analyses, in the knowledge that most deaths among patients with IPF tend to be IPF related (30). A further limitation was the retrospective nature of the study, but it should be stressed that all patients were investigated according to a prospective clinical protocol, with the expectation of a full smoking history and routine baseline HRCT and pulmonary function testing. This was, therefore, a prospective data set from consecutive patients, analyzed retrospectively in response to the provocative observations of King and colleagues, and not subject to the selection biases seen in some retrospective cohorts, in which investigations are not determined according to a rigorous protocol. The better survival among nonsmokers was the major positive finding in our study, but it is not clear whether this was linked to pathogenesis. Cigarette smoke may prime the lung toward a fibrotic response when other injuries are encountered (31, 32) and may injure lung fibroblasts, partly by means of oxidative stress, which may have a critical role in the gene expression of a variety of profibrotic factors (31, 33, 34). It is also possible that some of the excess mortality in smokers represents smoking-related comorbidity, including cardiac disease and lung cancer. However, the absence of any relationship between mortality in smokers and the pack-year smoking history provides limited indirect evidence against a smoking comorbidity hypothesis. In conclusion, we report that life-long nonsmokers have a better outcome than former smokers, and the combined group of current and former smokers in IPF, although pathogenic differences have yet to be elucidated. Our findings provide support for the hypothesis that the better outcome previously reported for current smokers with IPF is compatible with a healthy smoker lead-time effect.
Originally Published in Press as DOI: 10.1164/rccm.200612-1759OC on October 25, 2007 Conflict of Interest Statement: K.M.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.B.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.R.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.G.N. received $2,500 in 2005–2007 and £2,700 in 2007 for reviewing slides in multicenter trials for Intermune Ltd., £9,500 in 2006 and £3,500 in 2007 for reviewing slides for a multicenter trial for Actelion Ltd., and £600 for lecturing on behalf of AstraZeneca in 2005 and 2006. R.M.d.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.U.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form December 5, 2006; accepted in final form October 25, 2007
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