Logo of ajrccmIssue Featuring ArticlePublisher's Version of ArticleSubmissionsAmerican Thoracic SocietyAmerican Thoracic SocietyAmerican Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med. Mar 1, 2009; 179(5): 402–407.
Published online Dec 12, 2008. doi:  10.1164/rccm.200802-241OC
PMCID: PMC2648909

The Prognostic Value of Cardiopulmonary Exercise Testing in Idiopathic Pulmonary Fibrosis

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea, impaired gas exchange, and ultimate mortality.

Objectives: To test the hypothesis that maximal oxygen uptake during cardiopulmonary exercise testing at baseline and with short-term longitudinal measures would predict mortality in patients with idiopathic pulmonary fibrosis.

Methods: Data from 117 patients with IPF and longitudinal cardiopulmonary exercise tests were examined retrospectively. Survival was calculated from the date of the first cardiopulmonary exercise test.

Measurements and Main Results: Patients with baseline maximal oxygen uptake less than 8.3 ml/kg/min had an increased risk of death (n = 8; hazard ratio, 3.24; 95% confidence interval, 1.10–9.56; P = 0.03) after adjusting for age, gender, smoking status, baseline forced vital capacity, and baseline diffusion capacity for carbon monoxide. We were unable to define a unit change in maximal oxygen uptake that predicted survival in our cohort.

Conclusions: We conclude that a threshold maximal oxygen uptake of 8.3 ml/kg/min during cardiopulmonary exercise testing at baseline adds prognostic information for patients with IPF.

Keywords: idiopathic pulmonary fibrosis, exercise test, mortality

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Prognosis in idiopathic pulmonary fibrosis (IPF) is poor. Predicting prognosis by examining exercise performance with the six-minute-walk test has led to conflicting results.

What This Study Adds to the Field

This study shows that equation M1o2max predicts mortality in patients with IPF. Patients with equation M2o2max less than 8.3 ml/kg/min at baseline had an increased risk of death.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by progressive dyspnea and ultimate mortality (1). Mean survival from time of diagnosis to death is 3 years (1). However, the disease course is variable: some patients progress rapidly and others remain stable for many years (2). There is no effective treatment and many patients, if eligible, are referred for lung transplantation. Identification of surrogate short-term measures of mortality is critical to the management and study of patients with IPF.

Several factors have been identified that predict poor survival in patients with IPF, including age, sex, smoking history, diffusion capacity for carbon monoxide (DlCO), FVC, degree of fibrosis on high-resolution computerized tomography of the chest, and number of fibroblastic foci on histopathology (311). Longitudinal changes in FVC or DlCO have been found to have important prognostic value. A decrease in FVC of at least 10% or DlCO of at least 15% over 6 or 12 months is associated with decreased survival (1015).

Gas exchange worsens with exercise in IPF (1, 16, 17). Several studies have examined this feature using either cardiopulmonary exercise tests (CPET) or the 6-minute-walk test (6MWT). A decrease in PaO2 during CPET in patients with IPF contributes up to 10.5% of the total clinical, radiographic, and physiologic (CRP) score (5) used to estimate prognosis in IPF. Desaturation during CPET has been shown to predict mortality in some (16) but not all (18, 19) studies. Desaturation below 88% during 6MWT is a more consistent marker of increased risk for mortality (7, 9, 10), whereas shorter walk distance is less predictive (15). Longitudinal change in 6MWT data predicts mortality in patients who do not desaturate less than 88% at baseline (15).

Patients with IPF have impaired ventilatory and cardiovascular responses to exercise (20) due to multiple abnormalities, including low tidal volume; a failure to decrease ventilatory dead space; a rapid, shallow breathing pattern; impaired gas exchange due to interstitial fibrosis; pulmonary hypertension; ventilation/perfusion mismatching; and low mixed venous O2.

equation M3o2max is an integrated measure of cardiovascular, respiratory, and neuromuscular function (21). In prior studies of patients with interstitial lung disease, equation M4o2max correlated poorly with measures of lung volume, suggesting that it more accurately reflects derangements in hemodynamics as well as ventilation during exercise (20). Although change in FVC is a good surrogate for subsequent mortality, it is imperfect as some patients die without a 10% decline in FVC, whereas others can live for prolonged periods even after a 10% decline in FVC (2, 22). Therefore we chose to examine longitudinal change in equation M5o2max a priori because it is an integrated measure of cardiovascular, respiratory, and neuromuscular function (21). We tested the hypothesis that a decrease in equation M6o2max during baseline and short-term longitudinal CPETs predicts mortality in patients with IPF.

METHODS

Patient Selection

This is a retrospective analysis of 117 patients in the University of Michigan Specialized Center of in the Pathobiology of Fibrotic Lung Disease Database. Patients in this database were referred for enrollment in study protocols for suspected IPF based on typical symptoms, physiologic findings, and radiographic findings (1). Patients with a high-resolution computerized tomography scan showing a definite pattern of usual interstitial pneumonitis (23) were not required to undergo surgical lung biopsy (n = 42) (24, 25). Patients with underlying connective tissue disease, occupational or environmental exposures, or histopathologic pattern on surgical lung biopsy other than usual interstitial pneumonitis were excluded. Patients were treated with varied regimens, including no therapy, immunosuppression (prednisone ± azathioprine or cyclophosphamide), colchicine, and experimental protocols. The lack of a standardized treatment regimen prevented an analysis of the data based on therapy. Approval for the use of these data was provided by our Institutional Review Board. Subgroups of these patients have been previously described (7, 15, 26).

Pulmonary Function, 6-Minute Walk, and Cardiopulmonary Exercise Tests

Pulmonary function and exercise tests, including FVC, DlCO, 6MWT, and CPET, were performed as described (7, 18). Desaturation during a 6MWT was defined a priori as less than 88% based on published data (7).

Statistical Analysis

The date of the first CPET was used as the start date for survival analysis. Death date was supplemented by searching the Social Security Death Index (27); patients not listed in this index were censored 3 months prior to the analysis date to account for potential lags in reporting. Multivariate Cox proportional hazard models (28) adjusted for age, sex, baseline forced vital capacity percent predicted, baseline DlCO percent predicted, and smoking status were constructed for potential equation M7o2max thresholds ranging from 4.4 ml/kg/min to 25.1 ml/kg/min, in increments of 0.3 ml/kg/min. Resulting hazard ratios were plotted against equation M8o2max to determine if a threshold equation M9o2max could be identified that correlated with increased risk of mortality. Similar secondary analyses were performed on resting PaO2. Baseline characteristics between patients with equation M10o2max above and below the thresholds were compared using t tests (29) for continuous measures and chi-square (30) tests for categorical measures. Data are expressed as mean ± standard deviation (SD) or frequency (%). In secondary analyses, index of concordance (31) was used compare the equation M11o2max threshold, desaturation less than 88% during a 6MWT, and resting PaO2 to determine which was the strongest predictor of survival. Survival between patients with baseline equation M12o2max above and below thresholds was examined with unadjusted Kaplan Meier survival curves (32) and log-rank tests (33, 34). Multivariate Cox proportional hazard models studied the predictive value of the equation M13o2max threshold adjusted for age, gender, smoking status, baseline FVC percent predicted (FVC%), and baseline DlCO percent predicted (DlCO%). Statistical significance was set at P = 0.05. Statistical analysis was performed with R software (http://www.r-project.org/index.html) and SPSS (version 14.0; SPSS Inc., Chicago, IL).

RESULTS

Data from 117 patients with at least two cardiopulmonary exercise tests were analyzed. Seventy-five (64%) patients were diagnosed with a surgical lung biopsy. Patients who did not undergo a lung biopsy were significantly older (66.73 ± 8.50 vs. 63.07 ± 8.23 y, P = 0.024) but otherwise not different than those with a lung biopsy (data not shown).

We explored the predictive value of equation M14o2max on survival. equation M15o2max did not predict survival when examined as a continuous variable (hazard ratio [HR], 0.969; 95% confidence interval [CI], 0.88–1.07; P = 0.55). Exploratory analyses revealed a threshold equation M16o2max of 8.3 ml/min/kg that was associated with an increased risk of subsequent mortality (Figure 1). This threshold effectively captures patients with a higher risk of mortality and discriminates these patients from those with a lower risk of mortality.

Figure 1.
Determination of a equation M17o2max threshold of 8.3 ml/kg/min. Multivariate Cox proportional hazard models adjusted for age, sex, baseline FVC percent predicted, baseline diffusion capacity of carbon monoxide percent predicted, and smoking status were constructed ...

Demographic data and baseline physiologic data for patients with an initial equation M20o2max above or below 8.3 ml/min/kg are presented in Table 1. Patients whose baseline equation M21o2max was below threshold were more often female (P = 0.04), had significantly lower FVC% (P = 0.01) and DlCO% (P = 0.006), shorter 6-minute walk distance (P = 0.002), and significantly lower exercise capacity during baseline CPET compared with those with baseline equation M22o2max above threshold (Table 1). Surprisingly, not all patients with equation M23o2max below threshold at baseline desaturated during a baseline 6MWT.

TABLE 1.
BASELINE CHARACTERISTICS OF PATIENTS WITH BASELINE equation M24o2max ABOVE OR BELOW THE 8.3 ml/kg/min THRESHOLD

Multivariate relationships between equation M27o2max and baseline demographic and pulmonary function variables were explored (Table 2). In multivariate linear regression models, age, male gender, history of smoking, and baseline FVC were predictors of equation M28o2max. A linear predictor incorporating these variables significantly predicted whether a patient's baseline equation M29o2max would be below threshold (Table 3). With this model, patients who are younger, male, never smokers, with higher FVC% and DlCO% are more likely to have a equation M30o2max above 8.3 ml/min/kg, and thus are predicted to have overall improved survival than older, female, ever smokers with lower FVC% and DlCO%.

TABLE 2.
MULTIVARIATE LINEAR REGRESSION MODEL DETECTING ASSOCIATIONS WITH equation M31o2max
TABLE 3.
LOGISTIC REGRESSION MODEL OF PREDICTORS OF equation M33o2max < 8.3 ml/kg/min

Survival in patients with baseline equation M35o2max below the 8.3 ml/kg/min threshold was lower than that of patients above the threshold over time (log rank P < 0.001, Figure 2). This difference was maintained in multivariate Cox proportional hazard survival models adjusting for patient age, smoking status, male sex, baseline FVC%, and baseline DlCO% (HR for being below threshold, 3.24; 95% CI, 1.10–9.56; P = 0.03) (Figure 3 and Table 4).

Figure 2.
Unadjusted Kaplan-Meier survival curves for patients whose baseline equation M36o2max was greater than 8.3 ml/min/kg (Above Threshold, n = 99) or less than 8.3 ml/min/kg (Below Threshold, n = 8). Survival time was calculated from the date of the first ...
Figure 3.
Cox proportional hazard survival curves for patients with baseline equation M37o2max greater than 8.3 ml/kg/min (solid line) and less than 8.3 ml/kg/min (dashed line) adjusted for age, sex, smoking status, baseline FVC percent predicted, and baseline DlCO percent ...
TABLE 4.
MULTIVARIATE COX PROPORTIONAL HAZARD SURVIVAL MODEL ASSESSING THE PREDICTIVE VALUE OF equation M38o2max < 8.3 ml/min/kg

In the majority of patients studied, equation M41o2max did not change between baseline and 6 months (n = 99). Of the 109 patients with equation M42o2max above threshold at baseline, 5 had a further decline in equation M43o2max below the threshold with longitudinal measures. However, we were unable to define a unit change in equation M44o2max that predicted survival in our cohort (data not shown).

Prior studies have shown that resting PaO2 predicts survival in IPF. In secondary analyses, resting PaO2 was a significant predictor of mortality (HR, 0.934; 95% CI, 0.88–0.99; P = 0.02), when adjusted for age, sex, smoking status, and baseline FVC% and DlCO%. A clear threshold for resting PaO2 could not be determined (data not shown). An adjusted multivariate Cox model with the equation M45o2max threshold (HR, 2.66; 95% CI, 0.74–9.5; P = 0.13) and resting PaO2 (HR, 0.95; 95% CI, 0.89–1.00; P = 0.09) did not show significance of either predictor. When the equation M46o2max threshold, resting PaO2, and desaturation below 88% during a 6MWT were included in an adjusted Cox model, the equation M47o2max threshold was a significant predictor of mortality (HR, 3.48; 95% CI, 1.16–10.43; P = 0.03), whereas desaturation less than 88% was not (HR, 1.49; 95% CI, 0.617–3.62; P = 0.37). Index of concordance analysis demonstrated that the equation M48o2max threshold is a more robust predictor of survival than resting PaO2 or desaturation less than 88% during a 6MWT (Table 5).

TABLE 5.
INDEX OF CONCORDANCE ANALYSIS COMPARING THE STRENGTH OF equation M49o2max < 8.3 ml/kg/min, DESATURATION < 88% DURING A 6-MINUTE WALK TEST, AND RESTING PaO2 AS PREDICTORS OF SURVIVAL IN IDIOPATHIC PULMONARY FIBROSIS

DISCUSSION

In this study, we examined the relationship between maximal oxygen uptake during cardiopulmonary exercise testing and mortality. We hypothesized that equation M52o2max measured during cardiopulmonary exercise testing predicts mortality in patients with IPF. We found that equation M53o2max examined as a continuous variable does not predict mortality in IPF. However, baseline threshold equation M54o2max of 8.3 ml/kg/min predicts mortality in these patients. This threshold is a robust predictor of survival when compared with desaturation less than 88% during a 6MWT and resting PaO2. Demographic and pulmonary function data can be used to estimate whether equation M55o2max is above or below the 8.3 ml/kg/min threshold.

We found a threshold baseline equation M56o2max less than 8.3 ml/kg/min predicts mortality in patients with IPF. A similar threshold value has not been reported in fibrotic lung disease. In a study of 86 patients with primary pulmonary hypertension, Wensel and colleagues (35) found a equation M57o2max threshold of 10.4 ml/kg/min predicts mortality. Various measures of exercise capacity have been examined for their ability to predict survival in IPF. A CRP score was developed by Watters and colleagues (36) as a tool to assess and follow patients' clinical impairment from IPF. The score used an exercise gas exchange score, which assigned points based on change in saturation during exercise, change in Vo2, and predicted equation M58o2max. The maximum points attributable to exercise gas exchange in the CRP score was 30, greater than the radiological, symptoms, and pulmonary function components of the score, reflecting the importance of exercise gas exchange in clinical impairment in IPF. More recently, Miki and colleagues (37) calculated the change in PaO2 per change in Vo2 during CPET (ΔPaO2/ΔVo2 or PaO2 slope) and found this relationship to predict mortality in patients with IPF. However, not all studies show that CPET measurements of gas exchange predict survival (18, 19). Studies that have used multistep scores (CRP score) or slope calculations (PaO2 slope) to define the risk of mortality attributable to exercise gas exchange in IPF may be too cumbersome for routine use outside of clinical trials. Our data suggest that a simple threshold for equation M59o2max of 8.3 ml/kg/min predicts mortality in patients with IPF, without the need for lengthy calculations.

Several authors have examined the prognostic value of the 6MWT or other walk tests in IPF. Desaturation during 6MWT (7, 9), distance walked (9), and progressive impairment in longitudinal 6MWTs (15) have been found to predict mortality in IPF. One criticism of the 6MWT is that it is a patient-driven, symptom- and effort-limited test. This may explain the controversy in the literature about whether distance walked or desaturation is a better predictor of mortality. It may also explain why not all patients in this study with a baseline equation M60o2max below threshold had desaturation during 6MWT: these patients might not have walked sufficiently fast or far enough to produce desaturation.

Using index of concordance techniques, we compared the ability of desaturation less than 88% during a 6MWT and the equation M61o2max threshold to predict mortality in IPF. Despite the small number of patients with equation M62o2max below threshold at baseline, this variable was a stronger predictor than desaturation less than 88% in our cohort in multivariate Cox models. The equation M63o2max threshold is also more robust than resting PaO2 and desaturation less than 88% during a 6MWT in concordance analyses.

We were unable to identify a unit change in equation M64o2max per time that predicts survival in short-term follow-up. This may be due to the small number of patients who had a decline in equation M65o2max during the follow-up period. This could suggest that equation M66o2max is more stable over time compared with other measures, such as FVC or DlCO. It could also reflect a selection bias in that as patients became sicker they may have declined exercise testing but still been able to perform pulmonary function testing. Further prospectively collected data are needed to explore the changes in equation M67o2max over time and their impact on survival.

There are several limitations to this study. Patients in this study were not evaluated for the presence of pulmonary hypertension. Pulmonary hypertension has been shown to be an important predictor of mortality in IPF (3840), although its presence does not universally portend a poor outcome (40). Patients included in this study were enrolled in a number of treatment protocols; the varied nature of the protocols prevents an analysis of the data based on therapy. However, none of the therapies in use in these protocols has been found to slow, halt, or reverse pulmonary fibrosis in this population, and prior analyses of the effects of therapy on this population have shown no benefit (7, 18, 41). In our cohort of 117 patients, 8 had a baseline equation M68o2max below threshold and 5 had a decrease in equation M69o2max to below threshold over the course of follow-up, yet 46% of the patients died during follow-up. Other measures that demonstrate significant change over time, such as serial measures of FVC%, may be more sensitive predictors of mortality in this population. Alternately, deaths could have been due to acute exacerbations of IPF or other acute events, which we did not measure.

In this study, we examined the prognostic value of CPET in IPF. A baseline equation M70o2max less than 8.3 ml/kg/min threshold was identified, below which the risk of death was greatly increased. This study provides an easy-to-use threshold for equation M71o2max for patients with IPF that predicts an increased risk of death. An unexpected finding was that not all patients with equation M72o2max below threshold desaturated during a 6MWT. Direct comparison of baseline equation M73o2max less than 8.3 ml/kg/min during CPET and desaturation less than 88% during a 6MWT shows that the equation M74o2max threshold is a better predictor of survival in IPF. CPET and the 8.3 ml/kg/min threshold provide additional information to clinicians and their patients to help guide therapeutic decisions in IPF.

Notes

Supported by National Institute of Health NHLBI grant P50HL-56402, NHLBI, 2 K24 HL04212, 1 K23 HL68713, and 1K23 HL077719. C.D.F. was supported by the Alberta Heritage Foundation for Medical Research.

Originally Published in Press as DOI: 10.1164/rccm.200802-241OC on December 12, 2008

Conflict of Interest Statement: C.D.F. has been compensated for serving on an advisory board in 2007 for Actelion. L.X.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.A.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.H.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.D.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.V.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.B.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.J.M. is a consultant for Altana Pharma and has received compensation greater than $10K. F.J.M. has been a member of several Advisory Boards, CME committees, and the Speaker's Bureau for Boehringer Ingelheim, Pfizer, and GlaxoSmithKline. His total compensation per company is greater than $10K. In addition, F.J.M. is on the advisory board for Novartis and the Speaker's Bureau for Sepracor, Schering Plough, and Astra, receiving less than $10K per company. F.J.M. has been an investigator for industry-sponsored studies for GlaxoSmithKline, Boehringer Ingelheim, and Actelion. K.R.F. has served as a consultant for companies evaluating novel treatments for idiopathic pulmonary fibrosis, including Genzyme, Intermune, and Boehringer Ingelheim.

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