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.
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.
This study shows that o2max predicts mortality in patients with IPF. Patients with o2max less than 8.3 ml/kg/min at baseline had an increased risk of death.
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 (3–11). 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 (10–15).
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.
o2max is an integrated measure of cardiovascular, respiratory, and neuromuscular function (21). In prior studies of patients with interstitial lung disease, o2max 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 o2max a priori because it is an integrated measure of cardiovascular, respiratory, and neuromuscular function (21). We tested the hypothesis that a decrease in o2max during baseline and short-term longitudinal CPETs predicts mortality in patients with IPF.
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 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).
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 o2max 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 o2max to determine if a threshold o2max could be identified that correlated with increased risk of mortality. Similar secondary analyses were performed on resting PaO2. Baseline characteristics between patients with o2max 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 o2max 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 o2max 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 o2max 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).
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 o2max on survival. o2max 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 o2max 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.
Demographic data and baseline physiologic data for patients with an initial o2max above or below 8.3 ml/min/kg are presented in Table 1. Patients whose baseline o2max 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 o2max above threshold (Table 1). Surprisingly, not all patients with o2max below threshold at baseline desaturated during a baseline 6MWT.
|Age, yr||64.0 ± 8.4||69.1 ± 8.6||0.10|
|Male||78 (78.8%)||3 (37.5%)|
|Female||31 (31.3%)||5 (62.5%)|
|Diagnosed with lung biopsy||70 (70.7%)||5 (62.5%)||0.92|
|Never smokers||28 (28.3%)||4 (50%)|
|Former smokers||76 (76.7%)||4 (50%)|
|Current smokers||5 (5.0%)||0|
|Pack-years||39.2 ± 24.9||42.0 ± 44.4||0.84|
|Spirometry at baseline|
|FVC, L||2.8 ± 0.9||1.8 ± 0.6||0.002|
|FVC%||69.0 ± 17.8||53.0 ± 9.6||0.01|
|DlCO, ml/min/mm Hg||12.3 ± 4.4||7.1 ± 1.3||0.002|
|DlCO%||47.8 ± 14.9||31.9 ± 7.7||0.006|
|Exercise at baseline|
|Exercise PaO2||67.4 ± 15.0||59.4 ± 12.6||0.25|
|Exercise Aa gradient||41.0 ± 14.7||42.2 ± 13.3||0.85|
|Exercise saturation||89.5 ± 4.9||88.0 ± 5.7||0.41|
|Minutes of exercise||7.4 ± 1.9||4.2 ± 1.5||<0.001|
|Work, W||95.2 ± 35.0||40.0 ± 11.6||<0.001|
|o2max, ml/kg/min||14.0 ± 4.2||6.9 ± 1.4||<0.001|
|Exercise gas exchange score||12.4 ± 9.8||20.0 ± 14.2||0.04|
|6MWT at baseline|
|Desaturation < 88%||38 (38.4%)||5 (62.5%)||0.12|
| Distance, ft||1,116.6 ± 456.0||582.2 ± 386.1||0.002|
Multivariate relationships between o2max 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 o2max. A linear predictor incorporating these variables significantly predicted whether a patient's baseline o2max 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 o2max 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%.
Survival in patients with baseline o2max 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).
|o2max below threshold||3.24||1.10–9.56||0.03|
In the majority of patients studied, o2max did not change between baseline and 6 months (n = 99). Of the 109 patients with o2max above threshold at baseline, 5 had a further decline in o2max below the threshold with longitudinal measures. However, we were unable to define a unit change in o2max 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 o2max 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 o2max threshold, resting PaO2, and desaturation below 88% during a 6MWT were included in an adjusted Cox model, the o2max 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 o2max threshold is a more robust predictor of survival than resting PaO2 or desaturation less than 88% during a 6MWT (Table 5).
|o2max < 8.3 ml/kg/min||0.716||2342.5|
|Desaturation < 88%||0.708||2316.5|
In this study, we examined the relationship between maximal oxygen uptake during cardiopulmonary exercise testing and mortality. We hypothesized that o2max measured during cardiopulmonary exercise testing predicts mortality in patients with IPF. We found that o2max examined as a continuous variable does not predict mortality in IPF. However, baseline threshold o2max 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 o2max is above or below the 8.3 ml/kg/min threshold.
We found a threshold baseline o2max 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 o2max 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 o2max. 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 o2max 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 o2max 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 o2max threshold to predict mortality in IPF. Despite the small number of patients with o2max below threshold at baseline, this variable was a stronger predictor than desaturation less than 88% in our cohort in multivariate Cox models. The o2max 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 o2max 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 o2max during the follow-up period. This could suggest that o2max 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 o2max 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 (38–40), 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 o2max below threshold and 5 had a decrease in o2max 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 o2max 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 o2max for patients with IPF that predicts an increased risk of death. An unexpected finding was that not all patients with o2max below threshold desaturated during a 6MWT. Direct comparison of baseline o2max less than 8.3 ml/kg/min during CPET and desaturation less than 88% during a 6MWT shows that the o2max 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.
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