Abstract
Lymphangioleiomyomatosis (LAM), a disease that occurs primarily in women, is characterized by cystic lung lesions causing respiratory failure, which may require lung transplantation. Lung diffusion (DLCO) and/or FEV1 are decreased, but frequently not in parallel with each other. Because cardiopulmonary exercise testing (CPET) provides information that is not obtainable from resting cardiopulmonary tests, we performed CPET in 217 LAM patients and correlated exercise data with clinical markers of severity, computed tomography scans, lung function, and histology. V̇O2max was decreased in 162 patients, of whom 28 did not reach anaerobic threshold; 29 had low oxygen uptake at anaerobic threshold, and 54 developed hypoxemia. Hypoxemia occurred even in patients with near normal DLCO and FEV1. V̇O2max decreased with an increasing score of histologic LAM severity and was correlated with computed tomography scans, the use of oxygen, and resting PaO2. DLCO and FEV1, however, were the only significant predictors of V̇O2max. We conclude that CPET uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements in patients with LAM.
Lymphangioleiomyomatosis (LAM), a disease affecting primarily women, is characterized by progressive cystic lung lesions, recurrent pneumothoraces, chylous effusions, lymphatic tumors, and angiomyolipomas (1–3). The clinical course of LAM is highly variable. In some patients, the disease remains quiescent, and pulmonary function tests show only a slow decline in function. In others, a loss of function is rapid, and the time from the first symptoms to onset of respiratory failure and lung transplantation may be only a few years. Pulmonary function abnormalities in LAM consist primarily of impaired diffusion capacity (DlCO) and FEV1 (1–4). However, abnormalities of DlCO and FEV1, that is, severity of impairment and rates of decline, do not parallel each other (4), which raises the question of how the two tests should be employed to grade the severity and progression of disease. Although the functional limitation in some patients appears to be related to ventilatory problems caused by airflow obstruction, other patients have almost exclusively an impairment in DlCO with well-preserved flow rates. In patients with LAM, objective evidence of exercise limitation, along with exercise-induced hypoxemia, has led us to question whether standard pulmonary function tests are an adequate measure of disease severity.
Because cardiopulmonary exercise testing (CPET) evaluates all components of exercise responses and provides information that is not available from tests of pulmonary and cardiac function at rest (5), it may be a preferable method for grading the severity of disease in LAM. Based on this hypothesis, the principal aim of our study was to determine the causes of exercise intolerance in LAM and use the CPET data to grade the severity of disease. To accomplish these objectives, we compared cardiopulmonary exercise data with high-resolution lung computed tomography (CT) scans, pulmonary function tests, lung histology, and clinical markers of disease severity, in a large population of patients with LAM. Some of the results of these studies have been previously reported in the form of abstracts (6, 7).
The study population comprised 294 patients referred to National Institutes of Health for participation in an LAM protocol (NHLBI Protocol 95-H-0186) approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute. All subjects gave informed consent before enrollment. The diagnosis of LAM was made by tissue biopsy in 170 patients and in the remainder by clinical and roentgenographic data (1–4). After exclusions because of death (n = 7), transplantation (n = 20), recent surgery (n = 3), joint disease (n = 4), cardiac disease (n = 3), and missed appointments (n = 40), data for analysis were available from 217 patients. One patient who participated in the study died subsequently from complications of abdominal surgery.
Lung volumes, flow rates, and DlCO were measured using a computerized system (Master Screen PFT; Erich Jaeger, Würzburg, Germany), according to American Thoracic Society recommendations (8, 9). Percentages of predicted normal values were derived from standard equations (10–12).
Patients were exercised on a bicycle ergometer or treadmill and a computerized metabolic cart (Vmax 229 Cardiopulmonary Exercise System; Sensormedics, Yorba Linda, CA) using standard incremental protocols (5, 13). SaO2 was measured using a pulse oximeter (Nellcor Puritan Bennett, model 295). Tests were stopped when the patient reached an oxygen uptake plateau, when SaO2 fell below 88%, or when the patient became exhausted. The following variables were measured: work rate (watts), V̇o2max, heart rate, oxygen pulse (V̇o2/heart rate), blood pressure, V̇e, respiratory rate, tidal volume, respiratory gas exchange ratio, and ventilatory equivalent for CO2 at anaerobic threshold (AT). Breathing reserve was calculated as MVV-V̇e/MVV × 100 where MVV is the maximal voluntary ventilation (5, 13). MVV was estimated as FEV1 × 40. AT was determined by the dual-methods approach (5, 13). V̇o2max was defined as the highest oxygen uptake observed during any 30-second measurement period. Oxygen-dependent patients (n = 31) were exercised while breathing from a 30-L bag filled with a gas mixture containing oxygen at concentrations set by a blender fed by compressed air and oxygen tanks. Tests were supervised by a physician. Predicted values for V̇o2max were calculated from standard equations (14) with a correction for body weight (13). For patients exercised on treadmill, predicted V̇o2max was obtained by multiplying ergocycle values by 1.11 (13). V̇o2max values below 85% of predicted and a decline in SaO2 of 4% or more were considered abnormal (5).
The grade of severity of disease was determined from high-resolution CT scans, as previously reported (15). The extent of involvement of the lungs was graded as follows: grade 0, no involvement; grade 1, less than 30% involved; grade 2, from 30 to 60% involved; and grade 3, more than 60% involved.
An LAM histology score (LHS), based on the extent of replacement of lung tissue by cystic lesions and infiltration by LAM cells, was determined using open lung biopsy specimens and was scored as follows: LHS-1 = less than 25%, LHS-2 = 25 to 50%, and LHS-3 = more than 50% (16).
To determine the best predictors of V̇o2max, we first estimated the correlation coefficient between V̇o2max and explanatory variables, including duration of disease, oxygen therapy requirements (no oxygen, oxygen during physical activities, and continuous oxygen therapy), grade of CT scan abnormality, resting PaO2, and pulmonary function tests, to quantify any linear relationship between V̇o2max and any of these variables. Then, using a stepwise procedure, we conducted a multivariate regression analysis with V˙o2max as the dependent variable and all the independent variables found to be statistically significant at a 0.1 level in the univariate analysis.
To determine whether exercise capacity correlated with a measure of disease severity that was independent of pulmonary function tests, we defined disease severity scores based on CT scan grade: a severity score was 1, 2, or 3 if the CT scan grade was 1, 2, or 3. Because 31 of the CT scan grade 3 patients were receiving continuous supplemental oxygen, we defined an additional severity score of 4 for these patients. Then we used a one-way analysis of variance with a Bonferroni adjustment to compare the four severity groups. Analysis of variance was also used to compare other patient groups.
Unpaired Student's t test was employed to compare exercise and lung function data in patients exercised on room air with those exercised on supplemental oxygen and in patients with LHS of 1 with those with LHS of 2. All reported p values are two sided. Data are shown as mean ± SEM.
The mean age of the 217 patients at the time of testing was 45.0 ± 0.6 years (range of 19 to 77) and the time from diagnosis was 5.7 ± 0.3 years (range of 8 months to 22 years). Two patients were smokers (25.2 ± 2.7 pack-years), and 24 were ex-smokers (13.8 ± 1.9 pack-years).
Dyspnea was the major exercise-limiting symptom (40%), followed by leg fatigue (28%), severe hypoxemia (11%), and a combination of dyspnea and leg fatigue (7%). Three patients stopped because of dizziness and three more because of abdominal pain, whereas 14 reached a V̇o2max plateau. The remaining patients stopped because of general fatigue.
Actual Value | Percentage Predicted | |
|---|---|---|
| TLC | 4.93 ± 0.06 | 95.2 ± 0.9 |
| FRC | 2.76 ± 0.04 | 97.9 ± 1.5 |
| RV | 1.79 ± 0.03 | 103.7 ± 2.0 |
| RV/TLC | 36.2 ± 0.5 | |
| FVC | 3.12 ± 0.04 | 89.7 ± 1.2 |
| FEV1 | 2.01 ± 0.05 | 75.5 ± 1.7 |
| FEV1/FVC | 63.6 ± 1.1 | |
| DLCO | 15.3 ± 0.3 | 73.5 ± 1.8 |
| DLCO/VA | 3.5 ± 0.08 | 88.6 ± 2.0 |
| Work rate | 109.0 ± 2.8 | 88.8 ± 2.1 |
| V̇O2max | 1,186 ± 29 | 71.5 ± 1.7 |
| HR max | 151.4 ± 1.3 | 86.9 ± 0.7 |
| V̇O2/HR max | 7.7 ± 0.1 | 80.3 ± 1.6 |
| BR | 30.7 ± 1.3 | |
| RER-AT | 0.99 ± 0.002 | |
| V̇E/V̇CO2-AT | 38.1 ± 0.6 | |
| PaO2 (rest) | 81 ± 1 |
The patients on continuous oxygen therapy who were exercised while breathing supplemental oxygen were significantly older and had significantly lower V̇o2max, oxygen pulse, breathing reserve, DlCO, FEV1, and resting PaO2 than patients exercised on room air (Table 2)
Room Air | Oxygen | |
|---|---|---|
| Number of patients | 186 | 31 |
| Age | 44.1 ± 0.6 (19, 67) | 50.9 ± 1.7 (35, 77)† |
| FEV1 | 2.18 ± 0.05 (0.59, 3.75) | 1.02 ± 0.06 (0.47, 1.83)† |
| FEV1, % | 81.2 ± 1.6 (23, 132) | 41.7 ± 2.6 (21, 69)† |
| FEV1/FVC | 67.6 ± 1.0 (25, 96) | 39.7 ± 2.0 (21, 74)† |
| DLCO | 16.7 ± 0.3 (7.2, 29.0) | 7.4 ± 0.3 (3.9, 10.7)† |
| DLCO, % | 79.5 ± 1.7 (33, 128) | 37.1 ± 1.6 (21, 54)† |
| DLCO/VA | 3.77 ± 0.07 (1.5, 6.4) | 1.90 ± 0.08 (1.03, 3.96)† |
| DLCO/VA, % | 95.2 ± 1.9 (37, 175) | 48.8 ± 2.2 (23, 73)† |
| Work rate | 115.6 ± 2.7 (24, 218) | 62.2 ± 4.6 (24, 104)† |
| Work rate, % | 94.2 ± 2.2 (18, 192) | 56.8 ± 3.9 (27, 105)† |
| HR max | 155.3 ± 1.3 (105, 200) | 128.2 ± 3.0 (84, 163)† |
| HR max, % | 88.7 ± 0.7 (61, 107) | 75.9 ± 1.7 (52, 98)† |
| V̇O2max | 1,256 ± 30 (406, 2,446) | 768 ± 46 (283, 1,147)† |
| V̇O2max, % | 75.1 ± 1.6 (22, 172) | 49.8 ± 2.7 (20, 81)† |
| V̇O2/HR max | 8.03 ± 0.17 (2.9, 14.6) | 6.0 ± 0.37 (2.2, 10.5)† |
| V̇O2/HR, % | 83.1 ± 1.7 (29, 182) | 63.7 ± 3.5 (30, 112)† |
| V̇Emax | 55.9 ± 1.2 (20, 103) | 32.7 ± 2.2 (12.2, 60.3)† |
| BR | 32.4 ± 1.4 (−36, 70) | 20.1 ± 2.8 (−22, 55)† |
| V̇E/V̇CO2-AT | 37.9 ± 0.6 (24, 59) | 47.3 ± 2.6 (30, 61)† |
| RER-AT | 0.99 ± 0.002 (0.86, 1.0) | 0.99 ± 0.005 (0.87,1.0) |
| FIO2 | 0.209 | 0.34 ± 0.06 (0.27, 0.42) |
| PaO2, rest | 84 ± 1 | 63 ± 2† |
| SaO2, rest | 97.1 ± 0.2 (88, 100) | 98.9 ± 0.2 (95, 100)† |
| SaO2, peak exercise | 94.3 ± 0.3 (83, 100) | 97.3 ± 0.5 (88, 100)† |
| Δ SaO2 | −2.8 ± 0.2 (−13, 1) | −1.6 ± 0.4 (−8, −1)† |
Multiple abnormalities of ventilatory, gas exchange, and cardiovascular responses to exercise were observed in our patients. One hundred sixty-two of the 217 patients (75%) had low V̇o2max. Among these patients, 28 (17%) failed to reach AT and 29 (18%) reached AT at an oxygen uptake of less than 40% Vo2max predicted. Of the 162 patients, 98 (60%) showed evidence of inefficient gas exchange, of whom 54 (33%) developed hypoxemia; 114 of the 162 patients (70%) had abnormal cardiovascular responses, of which 39 (24%) appeared to be limited by low heart rate reserve and 24 (15%) by low breathing reserve. Twenty-eight patients were limited by symptoms that could not be directly attributed to cardiorespiratory limitation.
Ten of 24 patients (41%) with DlCO between 60 and 70% predicted and 7 of 29 patients (21%) with DlCO between 70 and 80% predicted, exercised breathing room air, experienced exercise-induced hypoxemia. Of 69 patients with DlCO and FEV1 of 80% or more predicted exercised on room air, 7 (10%) had exercise-induced hypoxemia. DlCO was the single best predictor of exercise-induced hypoxemia (r = 0.550, p < 0.0001) (Figure 1)
Figure 1. Correlation between lung diffusion (DLCO) and change in oxygen saturation at peak exercise. DLCO is shown as the percentage predicted of the normal value and change in SaO2 in percentage saturation.
[More] [Minimize]One hundred twenty five of the 217 patients did not use supplemental oxygen. Sixty one used oxygen during physical activities, and 31 used oxygen continuously. There were significant differences among these groups of patients. As seen in Figure 2
Figure 2. V̇O2max, DLCO, and FEV1, in patients who never used supplemental oxygen (white bars), patients who used supplemental oxygen during physical activities (black bars), patients using supplemental oxygen continuously (thin cross-hatched bars), and four patients just before undergoing lung transplantation (thick cross-hatched bars). V̇O2max, DLCO, and FEV1 are shown as percentage predicted values. *Significantly different by analysis of variance (p < 0.001) from patients not receiving supplemental oxygen. **Significantly different (p < 0.001) from patients not receiving supplemental oxygen and patients using supplemental oxygen only during exercise.
[More] [Minimize]Four of the 217 patients underwent lung transplantation. CPET and pulmonary function tests performed before transplantation showed a V̇o2max of 712 ± 140 ml/min (10.5 ml/kg/min, 41.7 ± 8.1% predicted), DlCO of 7.3 ± 0.9 ml/min/mm Hg (34.0 ± 3.9% predicted) and FEV1 of 0.93 ± 0.1 L (33.7 ± 4.5% predicted). These values are significantly lower than those observed in patients not on supplemental oxygen or patients who used oxygen only during physical activities.
Data for the four severity groups, divided according to CT scan grades and continuous use of supplemental oxygen, are shown in Table 3
1 | 2 | 3 | 4 | |
|---|---|---|---|---|
| Patients, n | 100 | 40 | 46 | 31 |
| Age | 42.2 ± 0.8 | 47.0 ± 1.4* | 45.6 ± 1.2 | 50.9 ± 1.5* |
| FEV1, % | 93.1 ± 1.6 | 69.9 ± 3.5* | 65.2 ± 3.1* | 41.7 ± 2.6‡ |
| DLCO, % | 94.6 ± 1.8 | 0.2 ± 2.3* | 55.1 ± 1.7† | 37.1 ± 1.6‡ |
| DLCO/VA, % | 112.6 ± 2.0 | 86.8 ± 2.6* | 64.7 ± 1.8† | 48.8 ± 2.2‡ |
| Work rate, % | 106.7 ± 2.7 | 87.5 ± 3.8* | 72.8 ± 4.0* | 58.5 ± 3.6‡ |
| HR, % | 91.5 ± 0.8 | 87.7 ± 1.5 | 83.5 ± 1.5* | 75.9 ± 1.7† |
| V̇O2/HR, % | 92.8 ± 2.1 | 76.0 ± 3.1* | 68.2 ± 3.0* | 63.7 ± 3.5† |
| V̇O2max | 1,453 ± 36 | 1,116 ± 54* | 948 ± 48* | 768 ± 46‡ |
| V̇O2max, % | 84.7 ± 2.0 | 69.4 ± 2.7* | 59.5 ± 2.8† | 49.8 ± 2.7‡ |
| V̇E | 61.1 ± 1.4 | 51.5 ± 2.4 | 45.5 ± 2.6* | 32.7 ± 2.2‡ |
| BR | 38.0 ± 1.6 | 25.6 ± 3.0* | 26.3 ± 3.2* | 20.1 ± 2.8* |
| V̇E/V̇CO2-AT | 33.8 ± 0.6 | 40.6 ± 1.1* | 44.7 ± 1.2* | 47.3 ± 2.6† |
| RER-AT | 0.99 ± 0.003 | 0.99 ± 0.003 | 1.0 ± 0.004 | 0.99 ± 0.005 |
| PaO2, rest | 89 ± 1‡ | 81 ± 2‡ | 75 ± 2‡ | 63 ± 2‡ |
| SaO2, rest | 97.9 ± 0.1 | 96.9 ± 0.2 | 95.5 ± 0.4 | 98.9 ± 0.2 |
| SaO2, exercise | 96.5 ± 0.2 | 93.6 ± 0.5 | 90.3 ± 0.5‡ | 97.3 ± 0.5 |
| Δ SaO2 | −1.4 ± 0.2 | −3.3 ± 0.4 | −5.2 ± 0.4‡ | −1.6 ± 0.4 |
Of the 102 patients who underwent open lung biopsy, 18 and 12 patients, respectively, with LHSs of 1 and 2, had had lung biopsies within the year before CPET. We found that V̇o2max in patients with an LHS of 2 (991 ± 95 ml/min, 58.6 ± 5.2% predicted) was significantly lower (p = 0.005) than that in patients with an LHS score of 1 (1,359 ± 105 ml/min, 80.0 ± 4.6% predicted). In addition, DlCO was significantly lower (p = 0.043) in patients with an LHS score of 2 (15.2 ± 1.7 ml/min/mmHg, 71.3 ± 7.0% predicted) than in patients with an LHS score of 1 (19.6 ± 1.2 ml/min/mmHg, 91.9 ± 5.1% predicted). There was no significant difference (p = 0.183) in FEV1 between patients with an LHS score of 1 (2.25 ± 0.17 L, 80.8 ± 4.7% predicted) and patients with an LHS score of 2 (2.02 ± 0.22 L, 76.0 ± 8.5% predicted).
We found that of all the independent variables that were statistically significant at the 0.1 level in the univariate analysis (Table 4)
Variables | Correlation (r) | p Value |
|---|---|---|
| Length of disease | −0.096 | 0.1569 |
| Use of oxygen | −0.377 | < 0.0001 |
| CT scan grade | −0.559 | < 0.0001 |
| FEV1 | 0.619 | < 0.0001 |
| FEV1/FVC | 0.494 | < 0.0001 |
| RV | −0.341 | < 0.0001 |
| RV/TLC | −0.470 | < 0.0001 |
| DLCO | 0.674 | < 0.0001 |
| DLCO/VA | 0.557 | < 0.0001 |
| PaO2, rest | 0.499 | < 0.0001 |
In this study, which was conducted in a large population of patients with LAM, we found a high prevalence of abnormal exercise responses, suggesting the presence of gas exchange abnormalities, abnormal cardiovascular function, ventilatory abnormalities, and muscle fatigue. These heterogeneous abnormalities caused a decrease in exercise capacity in three fourths of the patients. A multivariate regression analysis showed that the only significant predictors of V̇o2max were DlCO and FEV1. Of note, exercise-induced hypoxemia occurred even in patients with seemingly mild compromise of lung function, with DlCO being the best predictor of exercise-induced hypoxemia.
Pulmonary diseases can result in multiple abnormalities of both ventilatory, gas exchange, and cardiovascular responses to exercise (5, 17). Consistent with the clinical and functional heterogeneity of LAM, no single, unique pattern of response was observed in our patients. In some patients, there appeared to be a predominance of gas exchange abnormalities characterized by hypoxemia and/or an excessive ventilatory response to exercise. In others, low V̇o2 at AT, or failure to reach anaerobic threshold in the absence of ventilatory limitation, was observed. In a third group of patients, ventilatory abnormalities were a major component of exercise limitation (18). Finally, decreased exercise capacity without evidence of cardiorespiratory abnormalities was observed in some patients. The relative contributions of these factors into limiting exercise capacity varied from patient to patient in a manner that was not completely accounted for by their lung function, that is, DlCO, FEV1. This probably explains the wide variance in V̇o2max. Our study, however, does not allow for specific identification of all the pathophysiologic processes involved in causing low exercise capacity in LAM.
The close correlation of V̇o2max with DlCO and FEV1 and between the decline in SaO2 and DlCO may suggest that CPET is of no more value than standard pulmonary function tests in assessing the severity of disease in LAM. V̇o2max, however, cannot be fully explained by DlCO and FEV1, and exercise-induced hypoxemia occurred in the presence of near normal DlCO and FEV1, suggesting that in LAM, lung function tests do not consistently predict gas exchange abnormalities during exercise. Although correlating well with DlCO and FEV1, as previously reported (15, 19), CT scan grades of severity also appeared not to be good predictors of gas exchange abnormalities in LAM. Indeed, despite having the same CT scan grade as severity score group 3, severity group 4 patients were on continuous oxygen therapy and had significantly lower V̇o2max and resting PaO2. This finding is of importance because the prevalence and severity of exercise-induced hypoxemia in patients with LAM are probably even greater than those observed in our study. Indeed, the stipulated criterion of a decline in SaO2 of 4% or more is too stringent, and the most severely affected patients were tested on supplemental oxygen.
There was a close association between V̇o2max and LHSs. Patients with more severe scores had significantly lower V̇o2max. In addition, and as shown previously (4), DlCO more closely followed LHSs than did FEV1. Because LHSs are a predictor of death and time to transplantation (16), V̇o2max may also be a predictor of survival in patients with LAM. Long-term studies, however, will be required to determine whether V̇o2max is of value in predicting survival and time to transplantation.
In conclusion, the occurrence of exercise-induced hypoxemia in patients with mild degrees of impairment in lung function makes CPET an important measure of disease severity in LAM. This finding has both therapeutic, that is, treatment with oxygen, and prognostic implications. Measurement of DlCO provides some general guidance regarding need for oxygen therapy, but exercise testing should be performed to determine the severity of gas exchange abnormality and supplemental oxygen requirements for the patients' level of physical activity.
CPET may also be of value in evaluating patients for referral to a lung transplantation center. V̇o2max was correlated with use of supplemental oxygen and was lowest in patients who subsequently underwent lung transplantation. Based on our pretransplant data and the fact that the waiting time on a transplantation list can be several years, patients with V̇o2max below 50% predicted and DlCO under 40% predicted should probably be considered for referral to a lung transplantation center.
The authors thank Drs. Martha Vaughan, Vincent C. Manganiello, and Stewart Levine for their helpful discussions and critical review of the article. They thank Xiaoling Chen for her assistance in compilation and analysis of the data (Ms. Xiaoling Chen was supported in part by a grant from the LAM Foundation). The authors also thank the LAM Foundation and the Tuberous Sclerosis Alliance for their assistance in recruiting patients, and they thank Mark Barton, CRTT, PFT, Pete McGraw, CRTT, PFT, and Clara Jolley, PFT, for performing the exercise tests. This study would not have been possible without the cooperation of patients with LAM, who in many cases traveled great distances to participate in our clinical research protocols.
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