Abstract
Rationale and Hypothesis: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide.
Methods: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation ⩽ 88% during a baseline 6MWT. For patients with a baseline saturation ⩽ 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients.
Conclusion: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.
Idiopathic pulmonary fibrosis (IPF) is a uniformly fatal disease with a variable rate of progression. Identification of readily available baseline and short-term serial predictors of survival is critical for physicians and patients considering options such as lung transplantation and for the investigation of novel treatments. Recent studies have suggested several demographic (age, smoking), physiologic (diffusion capacity for carbon monoxide [DlCO], FVC, and desaturation), radiologic (high-resolution computed tomography [HRCT] fibrosis score), and histopathologic (fibroblastic foci) features are associated with survival (1–7). Serial change in FVC adds additional prognostic information to data obtained at baseline (8–11).
A central feature in the pathophysiology of IPF is impaired gas exchange, which worsens with exercise (12, 13). This exercise-induced widening of alveolar arterial O2 gradient and fall in PaO2 is believed to be secondary to multiple abnormalities, including V̇/Q̇ mismatch, decreased PvO2 and venous admixture (12–16). The six-min-walk test (6MWT) is a safe procedure for patients with IPF. Baseline desaturation during a 6MWT is a powerful predictor of subsequent mortality (4, 6, 7). The relative simplicity, low cost, and reproducibility (7) of the 6MWT makes it an attractive modality for the longitudinal study of patients with IPF.
Given these data, we elected to examine the prognostic value of a baseline and serial changes in 6MWT in relation to changes in FVC and DlCO in patients with IPF. We hypothesized that changes in distance walked and quantity of desaturation would add prognostic value to change in FVC or DlCO.
The study used patients in the database of the University of Michigan Specialized Center of Research in the Pathobiology of Fibrotic Lung Disease. Patients in this database were referred for enrollment in study protocols for suspected IPF based on typical symptoms and on physiologic and radiographic findings. Patients with an HRCT scan showing a definite pattern of usual interstitial pneumonia (11, 17) were not required to undergo a surgical lung biopsy (n = 51). Patients were treated with varied treatment regimens, including no therapy, prednisone alone, prednisone with azathioprine or cyclophosphamide, or zileuton. The lack of a prospectively defined treatment regimen and the overlap between treatment regimens in some patients precluded our ability to evaluate the effect of treatment on serial change in pulmonary function, 6MWT, or survival. We excluded patients with underlying connective tissue disease, obvious occupational exposure, or a histopathologic pattern other than usual interstitial pneumonia. Approval for the use of these data was obtained from the Institutional Review Board of the University of Michigan. A subgroup of these patients has been previously described (3, 4, 11, 18–21).
Pulmonary function tests including FVC, DlCO, and 6MWT were performed as previously described (4, 22). Desaturation area (DA; Figure 1) was defined as the total area above the curve created using desaturation percentage values observed during each minute of the 6MWT, thereby summing up the differences between a SaO2 of 100% and the patient's SaO2 at each minute. For example, a patient with a SaO2 of 98% at each minute during the 6MWT would have a DA of 12 (100 – 98 = 2 × 6 min = 12). For safety, we stopped the 6MWT when patients reached a SaO2 of 86%, and a desaturation score of 14% was assigned for that minute and all subsequent minutes of the 6MWT. A higher DA indicates higher overall quantity of desaturation during the 6MWT.
Figure 1. Desaturation area (DA) was defined as the total area above the curve created using desaturation percentage values observed at baseline and at each subsequent minute of the six-min-walk test (6MWT; i.e., summing up the differences between an SaO2 of 100% and the patient's SaO2 at each minute). For example, a patient with an SaO2 of 98% at each minute during the 6MWT would have a DA of 12. For safety, we stopped the 6MWT when patients reached an SaO2 of 86%, and a desaturation score of 14% was assigned for that minute and all subsequent minutes of the 6MWT. A higher DA indicates higher overall quantity of desaturation during the 6MWT.
[More] [Minimize]For each patient, 6-mo 6MWT distance walked, DA, FVC, FVC % predicted, DlCO and DlCO % predicted values were obtained as a result of fitting individual regression lines, provided that each patient was able to perform at least two 6MWT within the first 12 mo of follow-up and was alive at the 6-mo time mark. Using the log-rank test, survival experiences were compared overall and in the two groups with baseline SaO2 > 88% or ⩽ 88%. Univariate and multivariate Cox regression models adjusting for baseline and serial changes in distance walked, DA, FVC, FVC % predicted, DlCO, and DlCO % predicted values were constructed. Adjustments for baseline values, age, sex, and smoking years were made.
The baseline characteristics for the 197 patients in this study are outlined in Table 1. A total of 51 patients were diagnosed based on a typical HRCT and appropriate clinical scenario, whereas 146 were diagnosed with the use of surgical lung biopsy (SLB). On average, patients with an HRCT diagnosis were older (66 ± 10 vs. 62 ± 10 yr; p = 0.008) and had a greater exposure to tobacco (38 ± 31 vs. 19 ± 23 pack-years, p = 0.001) compared with patients undergoing surgical lung biopsy. There were no differences in FVC, FVC % predicted, DlCO, DlCO % predicted, DA, or proportion of patients with a saturation ⩽ 88% during the 6MWT in patients with compared with those without an SLB (data not shown). When comparing groups with SaO2 below or above 88% at any time during the 6MWT, no significant differences were detected in terms of patient age at enrollment, proportion of smokers, or number of pack-years. Patients with SaO2 > 88% throughout the 6MWT were more likely to be female; had significantly higher FVC, FVC % predicted, DlCO, and DlCO % predicted values; and walked significantly further, with a significantly lower DA, compared with patients with a SaO2 ⩽ 88% at any point during the 6MWT. Most patients with a SaO2 ⩽ 88% during the 6MWT were stopped before 6 min because they reached a SaO2 of 86%. Of the 93 patients in the SaO2 ⩽ 88% group, 84 stopped before completion of the baseline 6MWT. In contrast, 101 of the 104 patients with a baseline SaO2 > 88% throughout the entire 6MWT completed 6 min of ambulation.
All Patients (n = 197) | SaO2 > 88% (n = 104) | SaO2 ⩽ 88% (n = 93) | p Value | |
|---|---|---|---|---|
| Age, yr | 63 (10)* | 62 (10) | 64 (10) | 0.37 |
| Male/female | 127/70 | 65/39 | 62/31 | < 0.001 |
| Smokers, yes/no/NA | 141/53/3 | 72/29/3 | 69/24/0 | 0.23 |
| Pack-years | 23 (26) | 21 (25) | 25 (26) | 0.33 |
| FVC, L | 2.54 (0.86) | 2.74 (0.91) | 2.32 (0.76) | 0.001 |
| FVC, %predicted | 65 (17) | 70 (17) | 60 (16) | < 0.001 |
| DlCO, mm/min/mm Hg | 11.27 (4.29) | 13.68 (4.41) | 9.08 (2.88) | < 0.001 |
| DlCO, %predicted | 45 (15) | 52 (15) | 36 (11) | < 0.001 |
| Walk distance, ft | 928 (534) | 1314 (355) | 497 (333) | < 0.001 |
| Walk < 600 ft | 329 (136) | 362 (220) | 328 (134) | 0.81 |
| n = 72 | n = 3 | n = 69 | ||
| Walk between 600 and 1,200 ft | 945 (155) | 981 (141) | 886.98 (162) | 0.04 |
| n = 50 | n = 31 | n = 19 | ||
| Walk at least 1,200 ft | 1,491 (226) | 1,502 (230) | 1,349 (57) | < 0.001 |
| n = 75 | n = 70 | n = 5 | ||
| Desaturation area (10 U) | 5.52 (1.99) | 3.98 (1.46) | 7.23 (0.68) | < 0.001 |
Based on the distance walked during the initial 6MWT, the 197 patients were classified into three groups based on thresholds (600 and 1,200 ft). These thresholds were chosen a priori based on their approximation to tertiles (actual tertiles between 560 and 580 ft and between 1,246 and 1,260 ft) and for simplicity because they illustrate 100 ft/min structural increments. BD1 was defined as a walk distance of at most 599 ft, BD2 was defined as a walk distance between 600 and 1,199 ft, and BD3 was defined as a walk distance of at least 1,200 ft. Categorical baseline walk distance was a weak predictor of subsequent mortality in the entire cohort (p = 0.038) (Figure 2). Pair-wise comparisons indicate better survival in BD3 patients compared with BD1 patients (p = 0.011). However, the observed difference in survival for BD2 patients was not significant when compared with BD1 patients (p = 0.223) or BD3 patients (p = 0.199). Baseline distance categories did not maintain statistical significance when patients were stratified by the presence/absence of a SaO2 ⩽ 88% during the 6MWT (p = 0.94 when SaO2 > 88%; p = 0.43 when SaO2 ⩽ 88%). Similar mortality patterns were seen when baseline distance walked was evaluated as a continuous variable, with significant prediction of mortality in a univariate Cox model (hazard ratio [HR], 0.94; p = 0.005, 100-ft increase) that vanished in multivariate Cox models. These data suggest that baseline distance walked has little to no predictive value for predicting subsequent mortality when accounting for the stronger predictor of degree of desaturation at baseline.
Figure 2. Kaplan-Meier survival curves for 197 patients with idiopathic pulmonary fibrosis stratified by baseline walk distance (circles = censored, solid line = walked 1–599 ft, continuous dashed line = walked 600–1199 ft, broken dashed line = walked at least 1,200 ft).
[More] [Minimize]Unlike distance walked, even mild baseline desaturation (SaO2 remained > 88% throughout the 6MWT, but DA increased) was a powerful predictor of subsequent mortality. Patients with a SaO2 ⩽ 88% during their initial 6MWT had a median survival time of 3.21 yr, which was lower than the 6.83 yr for those with baseline SaO2 > 88% (p = 0.006). A 10-point increase in baseline DA was predictive in the group of patients with initial SaO2 > 88% (univariate HR, 1.33; 95% confidence interval [CI], 1.08–1.63; p = 0.007). The magnitude and direction of this DA HR remained similar in a multivariate model adjusting for distance walked in feet, DlCO, FVC, age, sex, and smoking years (HR, 1.30; 95% CI, 0.97–1.75; p = 0.08], with marginal statistical significance; possibly due to the strong negative correlation between baseline DA and DlCO (ρ = −0.34; p < 0.001). These data confirm the importance of desaturation on subsequent mortality and highlight that even mild desaturation as measured by DA is an important predictor of subsequent mortality in patients not reaching the standard SaO2 ⩽ 88% endpoint during their baseline walk.
We examined if 6-mo changes in DA, FVC, distance walked, and DlCO were predictive of subsequent mortality. Separate models adjusting for baseline values and 6-mo change were constructed for each of these variables.
Analysis of longitudinal walk distance by baseline walk distance categories revealed stark differences in how these groups behave over time (as shown in Figures E1a–E2c in the online supplement). Minimal change over time was observed for BD1 and BD3 patients, with BD1 patients showing little improvement and the majority of BD3 patients maintaining their baseline walk distance. However, trajectories for BD2 patients displayed more fluctuations in serial walk distance over time. Of the 72 patients in BD1, nearly all (n = 69) developed an SaO2 ⩽ 88% at some point during the 6MWT. In contrast, nearly all patients in BD3 had an SaO2 that remained > 88% (n = 70 of 75). Patients in BD2 demonstrated a mix of SaO2 above (n = 31) or below 88% (n = 19).
We evaluated the association of changes in distance walked, DA, FVC, and DlCO with subsequent mortality using univariate Cox models accounting for the baseline value. These patterns varied according to SaO2 categorization during their baseline walk (Table 2). In the subgroup of patients with a SaO2 > 88% throughout the 6MWT, adjusting for baseline values, increased mortality was observed with a decrease of more than 200 ft in distance walked, worsening of DA treated as a continuous measurement, a 10% relative decrease in FVC, and a 15% relative decrease in DlCO. In the group of patients with a SaO2 ⩽ 88%, during their baseline 6MWT only a decrease in DlCO emerged as predicting subsequent mortality; changes in FVC, DA, or walk distance were not predictive in this group. The prognostic value of DlCO remained statistically significant after making additional multivariate adjustments for age, sex, and smoking history at baseline (HR, 2.95; 95% CI, 1.29–6.76; p = 0.01). Serial predictors uniformly outpredicted their baseline counterparts in terms of statistical and clinical significance.
n | Hazard Ratio (95% CI) | p Value | |
|---|---|---|---|
| Patients with baseline SaO2 > 88% | |||
| Baseline walk distance | 68 | 0.89 (0.78–1.02) | 0.094 |
| Decrease in WD > 200 ft | 17 | 4.81 (1.75–13.19) | 0.002 |
| Increase in WD or decrease < 200 ft | 51 | 1.00 | REF |
| Baseline DA, 10 U | 70 | 1.73 (1.17–2.54) | 0.006 |
| DA relative change | 70 | 3.47 (1.667.25) | 0.001 |
| Baseline FVC, % predicted | 86 | 0.41 (0.04–3.83) | 0.435 |
| Decrease in FVC (% predicted) relative change > 10% | 20 | 3.57 (1.57–8.10) | 0.002 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 66 | 1.00 | REF |
| Baseline DlCO, % predicted | 70 | 0.19 (0.01–2.90) | 0.233 |
| Decrease in DlCO (% predicted) relative change > 15% | 10 | 3.73 (1.44–9.65) | 0.007 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 60 | 1.00 | REF |
| Patients with baseline SaO2 ⩽ 88% | |||
| Baseline walk distance | 48 | 0.95 (0.84–1.08) | 0.443 |
| Decrease in WD > 200 ft | 16 | 2.25 (0.85–5.95) | 0.103 |
| Increase in WD or decrease < 200 ft | 32 | 1.00 | REF |
| Baseline DA, 10 U | 57 | 0.83 (0.43–1.60) | 0.583 |
| DA relative change | 57 | 0.53 (0.06–4.78) | 0.590 |
| Baseline FVC, % predicted | 74 | 0.54 (0.07–4.38) | 0.564 |
| Decrease in FVC (% predicted) relative change > 10% | 18 | 1.66 (0.76–3.64) | 0.208 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 56 | 1.00 | REF |
| Baseline DlCO, % predicted | 61 | 0.32 (0.01–10.05) | 0.514 |
| Decrease in DlCO (% predicted) relative change > 15% | 14 | 3.23 (1.41–7.37) | 0.006 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 47 | 1.00 | REF |
When each set of serial predictors identified in the subgroup of patients with an SaO2 > 88% throughout the 6MWT were added to a multivariate model together in pairs and adjusted for age, sex, and smoking history, the magnitude and direction of most hazards were similar. Exceptions were DlCO, which lost statistical significance when paired with serial FVC or serial DA, and WD, which lost statistical significance when paired with DA (Table 3). Baseline DA increased statistical significance when interpreted alongside serial DA in multivariate models. Serial FVC and serial DA measures maintained statistical significance in all pairwise models.
n | Hazard Ratio (95% CI) | p Value | |
|---|---|---|---|
| Baseline FVC, % predicted | 68 | 0.21 (0.01–8.61) | 0.408 |
| Baseline WD, 100 feet units | 68 | 0.96 (0.82–1.13) | 0.644 |
| Decrease FVC (% predicted) relative change > 10% | 13 | 3.01 (1.03–8.79) | 0.043 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 55 | 1.00 | REF |
| Decrease in WD > 200 ft | 17 | 5.12 (1.70–15.36) | 0.004 |
| Increase in WD or decrease < 200 ft | 51 | 1.00 | REF |
| Baseline FVC, % predicted | 69 | 0.34 (0.02–7.19) | 0.490 |
| Baseline DA, 10 U | 69 | 2.03 (1.24–3.31) | 0.005 |
| Decrease FVC (% predicted) relative change > 10% | 14 | 3.98 (1.27–12.46) | 0.018 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 55 | 1.00 | REF |
| DA relative change, 10% U | 69 | 1.10 (1.02–1.19) | 0.019 |
| Baseline FVC, % predicted | 70 | 0.23 (0.01–9.09) | 0.436 |
| Baseline DlCO, % predicted | 70 | 0.04 (0.01–1.24) | 0.066 |
| Decrease FVC (% predicted) relative change > 10% | 15 | 4.82 (1.30–17.81) | 0.018 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 55 | 1.00 | REF |
| Decrease in DlCO (% predicted) relative change > 15% | 10 | 1.39 (0.46–4.18) | 0.559 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 60 | 1.00 | REF |
| Baseline DA, 10 U | 62 | 2.59 (1.35–4.95) | 0.004 |
| Baseline DlCO, % predicted | 62 | 2.42 (0.05–117.02) | 0.656 |
| DA relative change, 10% U | 62 | 1.17 (1.05–1.30) | 0.004 |
| Decrease in DlCO (% predicted) relative change > 15% | 9 | 1.06 (1.00–1.12) | 0.101 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 53 | 1.00 | REF |
| Baseline DlCO, % predicted | 60 | 0.07 (0.01–3.41) | 0.177 |
| Baseline WD, 100 feet units | 60 | 0.87 (0.75–0.99) | 0.044 |
| Decrease in DlCO (% predicted) relative change > 15% | 8 | 6.47 (1.68–24.87) | 0.007 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 52 | 1.00 | REF |
| Decrease in WD > 200 ft | 15 | 7.94 (2.28–27.65) | 0.001 |
| Increase in WD or decrease < 200 ft | 45 | 1.00 | REF |
| Baseline DA, 10 U | 68 | 1.40 (0.79–2.48) | 0.253 |
| Baseline WD, 100 feet units | 68 | 0.90 (0.77–1.06) | 0.199 |
| DA relative change, 10% U | 68 | 1.13 (0.99–1.28) | 0.067 |
| Decrease in WD > 200 ft | 17 | 2.38 (0.63–8.96) | 0.201 |
| Increase in WD or decrease < 200 ft | 51 | 1.00 | REF |
In patients with an SaO2 ⩽ 88%, during their baseline 6MWT only a relative decrease in DlCO of at least 15% consistently predicted subsequent mortality, although a decrease in WD of at least 200 ft was significant when paired with DA (Table 4). Limitations in the sample size of our study precluded studying triplets of serial predictors in a single multivariate model.
n | Hazard Ratio (95% CI) | p Value | |
|---|---|---|---|
| Baseline FVC, % predicted | 49 | 0.13 (0.01–4.41) | 0.259 |
| Baseline WD, 100 feet units | 49 | 1.00 (0.87–1.15) | 0.996 |
| Decrease FVC (% predicted) relative change > 10% | 10 | 1.34 (0.41–4.39) | 0.633 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 39 | 1.00 | REF |
| Decrease in WD > 200 ft | 15 | 1.72 (0.59–4.98) | 0.320 |
| Increase in WD or decrease < 200 ft | 34 | 1.00 | REF |
| Baseline FVC, % predicted | 54 | 0.06 (0.01–2.14) | 0.124 |
| Baseline DA, 10 U | 54 | 0.64 (0.28–1.49) | 0.304 |
| Decrease FVC (% predicted) relative change > 10% | 13 | 1.95 (0.62–6.13) | 0.255 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 41 | 1.00 | REF |
| DA relative change, 10% U | 54 | 0.87 (0.66–1.15) | 0.322 |
| Baseline FVC, % predicted | 61 | 0.60 (0.02–14.73) | 0.752 |
| Baseline DlCO, % predicted | 61 | 0.40 (0.01–27.36) | 0.669 |
| Decrease FVC (% predicted) relative change > 10% | 13 | 0.87 (0.29–2.61) | 0.803 |
| Increase in FVC (% predicted) relative change or decrease < 10% | 48 | 1.00 | REF |
| Decrease in DlCO (%f predicted) relative change > 15% | 14 | 3.08 (1.25–7.55) | 0.014 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 47 | 1.00 | REF |
| Baseline DA, 10 U | 47 | 0.67 (0.25–1.77) | 0.414 |
| Baseline DlCO, (% predicted) | 47 | 0.25 (0.01–54.06) | 0.609 |
| DA relative change (10% units) | 47 | 0.80 (0.59–1.15) | 0.165 |
| Decrease in DlCO (% predicted) relative change > 15% | 9 | 5.77 (1.66–20.05) | 0.006 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 38 | 1.00 | REF |
| Baseline DlCO, % predicted | 44 | 0.20 (0.01–85.07) | 0.602 |
| Baseline WD, 100 feet units | 44 | 1.12 (0.94–1.34) | 0.197 |
| Decrease in DlCO (% predicted) relative change > 15% | 9 | 7.72 (1.42–41.95) | 0.018 |
| Increase in DlCO (% predicted) relative change or decrease < 15% | 35 | 1.00 | REF |
| Decrease in WD > 200 ft | 14 | 0.41 (0.07–2.31) | 0.313 |
| Increase in WD or decrease < 200 ft | 30 | 1.00 | REF |
| Baseline DA, 10 U | 51 | 0.41 (0.12–1.43) | 0.162 |
| Baseline WD, 100 feet units | 51 | 0.83 (0.66–1.05) | 0.119 |
| DA relative change, 10% U | 51 | 0.87 (0.66–1.15) | 0.339 |
| Decrease in WD > 200 ft | 16 | 3.67 (1.12–12.07) | 0.032 |
| Increase in WD or decrease < 200 ft | 35 | 1.00 | REF |
IPF is a uniformly fatal disease with a variable rate of progression. In this study, we explored the impact of baseline and serial changes in FVC, DlCO, DA, and walk distance on subsequent survival in a large cohort of patients with IPF, including those diagnosed with typical HRCT and those requiring SLB for diagnosis. We demonstrate that (1) subtle desaturation defined by increased DA during a baseline 6MWT (without reaching a threshold of ⩽ 88%) increases the risk of subsequent mortality even if saturation remains greater than 88%; (2) baseline walk distance is a reasonable predictor of subsequent walk distance but does not consistently predict risk of subsequent mortality in multivariate analyses; and (3) the predictive ability of serial change in FVC, DlCO, walk distance, and DA varies when patients are stratified by the presence/absence of desaturation greater than 88% during a baseline 6MWT. A graphical representation of the how serial change in DlCO, FVC, walk distance, and DA varies when stratified by the presence/absence of desaturation greater than 88% during a baseline 6MWT is provided in Figure 3. These data provide clear guidance for the care and study of patients with IPF.
Figure 3. Graphic representation of how the predictive ability of serial changes in FVC, diffusion capacity of carbon monoxide (DlCO), change in walk distance, and change in desaturation varies by the presence/absence of desaturation to ⩽ 88% during a baseline 6MWT. These data suggest that decline in DlCO over 6 mo is the sole predictor of increased risk of subsequent mortality and that declines in DlCO, FVC, walk distance, and worsening desaturation can be used to follow patients who do not desaturate ⩽ 88% during a baseline 6MWT.
[More] [Minimize]Our data highlight that even mild desaturation is a risk factor for subsequent mortality. Previous studies demonstrate that desaturation during a 6MWT is associated with increased risk of subsequent mortality when evaluated as a continuous variable (6, 23) or using a threshold of ⩽ 88% (4, 7). Furthermore, the latter threshold was noted to be a reproducible parameter during short-term testing (7). In the current study, we extend these findings by illustrating that even subtle degrees of desaturation, as assessed by DA, increases a patient's risk for subsequent mortality even if a threshold of ⩽ 88% is not surpassed. A recent study has used a similar approach as an endpoint of a therapeutic trial, although mortality was not rigorously assessed during this short-term study (24).
Baseline distance walked failed to be a strong predictor of subsequent mortality once information on SaO2 was accounted for. This finding differs from previous studies (6, 23) and likely reflects differences in walk protocols. In the current study, patients were tested without supplemental oxygen, and the walk was halted if SaO2 decreased to 86%. Previous studies allowed the use of supplemental oxygen and also tolerated greater degrees of desaturation (6, 23). In the current study, 87 (44%) of the patients failed to complete the 6MWT; 84 (97%) of these patients were stopped due to an SaO2 of less than 86%. The early termination of the 6MWT due to desaturation may have diluted the possible effects of walk distance as an outcome measure.
Baseline walk distance tended to predict subsequent walk distance in that patients with a high level of performance (long walk distance) tended to preserve their walk distance throughout the study, whereas patients with poor performance (short walk distance) rarely improved. The most variation in change in walk distance was in the group of patients with an intermediate baseline walk distance. This illustrates the importance of baseline function when considering walk distance as an outcome measure in clinical trials for patients with IPF. These data suggest that “ceiling” (patients too mild to get detectably better with treatment) and “basement” (patients too sick to get detectably better with currently available treatment) exist when change in 6MWT distance is used as an outcome variable. This effect has been reported in studies of patients with primary pulmonary hypertension where patients with a higher baseline 6MWT distance showed less improvement in distance walked when treated with an endothelin receptor antagonist (25). It is possible that pulmonary hypertension was present in some of the more severe patients in our population. These concepts are important because 6-min walk testing has become increasingly used as an outcome measure in IPF therapeutic trials (24, 26).
Our data illustrate that the predictive ability of serial change in FVC or DlCO varies with baseline desaturation during exercise. In univariate Cox models among patients with a baseline SaO2 greater than 88% during the 6MWT, we observed an increased risk of subsequent mortality associated with a relative decrease in FVC of 10%, a relative decrease in DlCO of 15%, a decrease in walk distance of at least 200 ft, or an increase in DA. In the group of patients with a baseline SaO2 ⩽ 88%, during the 6MWT only a serial decline in DlCO predicted subsequent mortality. This variability was also reflected in multivariable models where the predictive ability of these variables changed depending on patient stratification by the level of baseline desaturation. This suggests that in a group of patients already at risk for subsequent mortality (i.e., SaO2 ⩽ 88%) (4), serial change in DlCO can further refine the prognosis, whereas change in DA, walk distance, and FVC do not. In contrast, in patients with a baseline SaO2 during a 6MWT greater than 88%, a decrease in walk distance of at least 200 ft, a relative decrease in FVC of at least 10%, and relative decrease in DA predicted subsequent mortality to varying degrees, whereas change in DlCO was less useful. These data extend the concept that serial change in FVC is most predictive of subsequent mortality in IPF longitudinal studies (8–11, 27) and provide a rationale for previously discordant observations regarding the predictive ability of DlCO (8, 9, 11). These data highlight the importance of stratification by baseline level of desaturation when selecting dynamic outcome measures for clinical trials and/or patient treatment decisions. These concepts should prove valuable in decision making during clinical care, in optimizing timing of lung transplantation, and in the design and conduct of therapeutic trials in patients with IPF.
The explanation for the variable predictive ability of FVC or DlCO based on stratification by degree of desaturation remains conjectural. Although FVC and DlCO are related, they reflect different aspects of pulmonary physiology. The degree of restriction is reflected by FVC, whereas abnormal gas exchange, which can involve pulmonary vasculopathy or mismatches in ventilation and perfusion, is reflected by DlCO. Patients with a baseline SaO2 ⩽ 88% during a 6MWT had a lower FVC compared with patients with saturation above 88%. Therefore, we initially considered that their FVC was already decreased to a level where further change was unlikely. This is not a likely explanation because a similar number of patients experienced a decline in FVC of at least 10% even when patients were stratified by baseline desaturation. Previous studies have also illustrated that patients may remain stable for prolonged periods of time and then present with an acute exacerbation and death (27–29). Further research is required to understand the mechanisms associated with decline in pulmonary physiology and subsequent mortality.
Strengths of this study include a large sample size and the inclusion of patients with an SLB and also patients with a typical HRCT not requiring a SLB for diagnosis. This latter point reflects the usual care of patients with IPF and helps generalize the results of this study. Weaknesses of this study include its retrospective study design, the lack of predefined data collection points, the format for terminating 6-min walk testing based on saturation, and the lack of prospectively defined treatment regimens. The effect of varied treatments on study outcome is likely minimal given the lack of rigorous, positive efficacy data for the treatments used during the course of this study. Additional prospective data collection is required to confirm our findings.
In conclusion, this study highlights that desaturation at baseline increases the risk of subsequent mortality; baseline walk distance is a good predictor of subsequent walk distance but does not reliably predict risk of subsequent mortality; and the predictive ability of serial change in FVC, DlCO, walk distance, and DA varies when patients are stratified by the presence/absence of a saturation greater than 88% during a baseline 6MWT. This study highlights the importance of stratifying patients by degree of desaturation at baseline before examining changes in physiology as outcomes in clinical trials or when making treatment decisions for individual patients (e.g., when the risk of subsequent mortality justifies the risk of interventions such as lung transplantation).
| 1. | King T Jr, Tooze J, Schwarz M, Brown K, Cherniack R. Predicting survival in idiopathic pulmonary fibrosis: Scoring system and survival model. Am J Respir Crit Care Med 2001;164:1171–1181. |
| 2. | King T Jr, Schwarz M, Brown K, Tooze J, Colby T, Waldron J Jr, Flint A, Thurlbeck W, Cherniack R. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025–1032. |
| 3. | Flaherty K, Toews G, Travis W, Colby T, Kazerooni E, Gross B, Jain A, Strawderman R III, Paine R III, Flint A, et al. Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 2002;19:275–283. |
| 4. | Lama V, Flaherty K, Toews G, Colby T, Travis W, Long Q, Murray S, Kazerooni E, Gross B, Lynch J III, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:1084–1090. |
| 5. | Mogulkoc N, Brutsche MH, Bishop PW, Greaves SM, Horrocks AW, Egan JJ. Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation. Am J Respir Crit Care Med 2001;164: 103–108. |
| 6. | Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG, Raghu G. The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 2005;25:96–103. |
| 7. | Eaton T, Young P, Milne D, Wells AU. Six-minute walk, maximal exercise tests: reproducibility in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171:1150–1157. |
| 8. | Jegal Y, Kim DS, Shim TS, Lim CM, Do Lee S, Koh Y, Kim WS, Kim WD, Lee JS, Travis WD, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171:639–644. |
| 9. | Latsi PI, du Bois RM, Nicholson AG, Colby TV, Bisirtzoglou D, Nikolakopoulou A, Veeraraghavan S, Hansell DM, Wells AU. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003;168:531–537. |
| 10. | Collard H, King T, Bartelson B, Vourlekis J, Schwarz M, Brown K. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:538–542. |
| 11. | Flaherty K, Mumford J, Murray S, Kazerooni E, Gross B, Colby T, Travis W, Flint A, Toews G, Lynch J, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:543–548. |
| 12. | Agusti AG, Roca J, Rodriguez-Roisin R, Xaubet A, Agusti-Vidal A. Different patterns of gas exchange response to exercise in asbestosis and idiopathic pulmonary fibrosis. Eur Respir J 1988;1:510–516. |
| 13. | American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000;161:646–664. |
| 14. | Jernudd-Wilhelmsson Y, Hornblad Y, Hedenstierna G. Ventilation-perfusion relationships in interstitial lung disease. Eur J Respir Dis 1986;68:39–49. |
| 15. | Wagner PD. Ventilation-perfusion matching during exercise. Chest 1992; 101:192S–198S. |
| 16. | Hansen J, Wasserman K. Pathophysiology of activity limitation in patients with interstitial lung disease. Chest 1996;109:1566–1576. |
| 17. | Hunninghake G, Lynch D, Galvin J, Muller N, Schwartz D, King T Jr, Lynch JIII, Hegele R, Waldron J Jr, Colby T, Hogg J. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124:1215–1223. |
| 18. | Flaherty K, Thwaite E, Kazerooni E, Gross B, Toews G, Colby T, Travis W, Mumford J, Murray S, Flint A, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143–148. |
| 19. | Flaherty K, Travis W, Colby T, Toews G, Kazerooni E, Gross B, Jain A, Strawderman R III, Flint A, Lynch J III, et al. Histologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164:1722–1727. |
| 20. | Flaherty KR, King TE Jr, Raghu G, Lynch JP III, Colby TV, Travis WD, Gross BH, Kazerooni EA, Toews GB, Long Q, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004;170:904–910. |
| 21. | Fraley C, Martinez F, Lama V, Colby T, Travis W, Toews G, Flint A, Chang A, Flaherty K. Distance walking during a six minute walk test (6MWT) relative to the quantity of desaturation predicts mortality in patients with idiopathic pulmonary fibrosis (IPF). Proc Am Thorac Soc 2005;2:A316. |
| 22. | Gay S, Kazerooni E, Toews G, Lynch J III, Gross B, Cascade P, Spizarny D, Flint A, Schork M, Whyte R, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:1063–1072. |
| 23. | Kawut SM, O'Shea MK, Bartels MN, Wilt JS, Sonett JR, Arcasoy SM. Exercise testing determines survival in patients with diffuse parenchymal lung disease evaluated for lung transplantation. Respir Med 2005;99:1431–1439. |
| 24. | Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040–1047. |
| 25. | Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, Robbins IM, Shapiro S, Tapson VF, Zwicke D, et al. The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Pharmacol 2005;43:36–39. |
| 26. | Bosentan studies in pulmonary fibrosis show no effect on primary exercise improvement endpoint: secondary endpoints related to death or disease worsening provide strong rationale for Phase III mortality/ morbidity study in Idiopathic Pulmonary Fibrosis (IPF).Available from: www.actelion.com/uninet/www/www_main_p.nsf/Content/me+ 28+Nov+2005 (accessed April 4, 2006). |
| 27. | King TE Jr, Safrin S, Starko KM, Brown KK, Noble PW, Raghu G, Schwartz DA. Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. Chest 2005;127: 171–177. |
| 28. | Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142:963–967. |
| 29. | Egan JJ, Martinez FJ, Wells AU, Williams T. Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification. Thorax 2005;60:270–273. |
