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doi:10.1378/chest.06-2822
(Chest. 2007; 132:207-213)
© 2007 American College of Chest Physicians
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Six-Minute Walk Test and Health Status Assessment in Sarcoidosis*

Robert P. Baughman, MD, FCCP; Brian K. Sparkman and Elyse E. Lower, MD

* From the Department of Internal Medicine, University of Cincinnati, Cincinnati, OH.

Correspondence to: Robert P. Baughman, MD, FCCP, 1001 Holmes, Eden Ave, Cincinnati, OH 45627-0565; e-mail: bob.baughman{at}uc.edu

Abstract

Background: The 6-min walk test has proved useful in assessing impairment and prognosis in various lung diseases.

Methods: A prospective study of 142 sarcoidosis patients seen during a 6-week period at one tertiary sarcoidosis clinic. All patients completed spirometry, 6-min walk testing, St. George Respiratory Questionnaire (SGRQ), fatigue assessment scale, and dyspnea score. Parameters assessed included the 6-min walk distance (6MWD) and the initial and lowest oxygen saturations during the test.

Results: One hundred three of 142 patients had extrapulmonary manifestations, 10 patients had left ventricular dysfunction, and 14 patients had documented pulmonary hypertension. Seventy-three patients (51%) completed a 6MWD < 400 m, and 32 patients (22%) walked < 300 m. The 14 patients with documented pulmonary hypertension had a shorter 6MWD (median, 280 m; range, 61 to 404) than those without documented pulmonary arterial hypertension (median, 411 m; range, 46 to 747; p < 0.0001). Several components of the pulmonary function and quality of life correlated with 6MWD. Using a stepwise multiple regression analysis, only SGRQ activity component (t = – 7.498, p < 0.0001), FVC (t = 4.415, p < 0.0001), and lowest oxygen saturation (t = 2.55, p < 0.02) were independent predictors of 6MWD.

Conclusions: 6MWD was reduced in the majority of sarcoidosis patients. Several factors were associated with a reduced 6MWD, including FVC, oxygen saturation with exercise, and self-reported respiratory health. Both 6MWD and quality of life measures are useful in assessing the functional status of sarcoidosis patients.

Key Words: exercise • fatigue • quality of life • sarcoidosis

The 6-min walk test has been used to assess the functional status of patients with a wide variety of pulmonary diseases, including pulmonary hypertension, COPD, and idiopathic pulmonary fibrosis.12345 Because it has been shown to predict mortality for several end-stage lung diseases,6 it is often assessed in patients being considered for lung transplantation. The 6-min walk has largely replaced standardized exercise testing in the assessment of lung disease for many reasons,7 including its low cost, simplicity, ease of performance, reproducibility, and ability to perform in clinic with minimal equipment.38910 Results from several multicenter trials511 demonstrate that the test results are comparable across multiple sites.

In sarcoidosis, extrathoracic manifestations of the disease could affect the 6-min walk distance (6MWD). Several studies121314 have demonstrated a discrepancy between pulmonary function and the perception of dyspnea in patients with sarcoidosis. Nevertheless, the use of the 6-min walk may provide a better understanding of the pulmonary status of patients with sarcoidosis. Martin et al15 emphasized the need for better testing of overall lung function in sarcoidosis.

The aim of our study was to determine the range of 6MWD in an unselected group of sarcoidosis patients. We performed a prospective study of sarcoidosis patients followed up in one tertiary sarcoidosis clinic. In addition to 6-min walk data, we collected data on pulmonary function and chest radiography, and patients completed respiratory health- and fatigue-assessment questionnaires.

Materials and Methods

Patients were prospectively evaluated over a 6-week period. All patients with sarcoidosis were asked to participate in the study. However, patients were excluded for failure to consent to the protocol approved by the University of Cincinnati Institutional Review Board, or the inability to ambulate or insufficient time to perform all the studies. The age, race, and sex of the patient were noted along with the most recent chest roentgenogram stage using Scadding classification,16 and the use and type of systemic therapy was also noted. The presence of pulmonary and extrapulmary organ involvement was evaluated using standard criteria.17 Patients were considered to have specific organ involvement if definite or probable criteria were met. Specific organ activity at the time of testing was not recorded. Patients with possible pulmonary hypertension or left ventricular dysfunction underwent screening with echocardiography. The diagnosis of pulmonary hypertension was confirmed by right-heart catheterization. Patients were classified as sarcoidosis-associated pulmonary arterial hypertension if the mean pulmonary artery pressure was > 25 mm Hg and the pulmonary artery occluding pressure was < 15 mm Hg.4

Prior to pulmonary testing, the patient completed a St. George Respiratory Questionnaire (SGRQ).18 This 76-item questionnaire is composed of three domains (symptoms, activity, and impact) as well as a total score. All four scores are normalized to a score range from 0 to 100, with a lower number correlating with a better health status. A 10-question fatigue assessment scale (FAS) was also completed.19 After answering each question on a Likert scale from 1 (never) to 5 (always), the results were summed with the range from 5 to 50. Results from prior studies1920 found a fatigued patient to have a score > 22. In addition, the Medical Research Council (MRC) score21 was completed.

On the day of the 6-min walk, patients underwent pulmonary function evaluation. Using American Thoracic Society criteria for acceptable maneuver, spirometry was performed using a portable spirometer, and percentage of normal control values were calculated using Hankinson et al.22

Subsequently, the patient walked in a hallway for 6 min using American Thoracic Society guidelines.8 Patients requiring supplemental oxygen walked using their usual flow rates. Oximetry was monitored during the walk, and oxygen saturation was monitored throughout the walk. The total distance walked along with the initial and lowest oxygen saturations were recorded. Patient completed a Borg dyspnea index at the beginning and end of the 6-min walk.23

Statistical analysis was performed using statistical software (Version 9.1.0.1; Medcalc; Mariakerke, Belgium), with p < 0.05 considered significant. The results of several tests, especially the questionnaires, were not normally distributed. Therefore, the 6MWD was compared to various parameters using nonparametric testing including Spearman rank correlation ({rho}), Mann Whitney U test, and Kruskal Wallis analysis of variance as noted. In addition, a stepwise multiple linear regression model of the 6MWD was developed using those variables found to be significant (p < 0.05) in univariate analysis.

Results

Two hundred ninety sarcoidosis patients were seen in the University of Cincinnati Interstitial Lung Disease and Sarcoidosis Clinic during the 6-week period commencing June 2005. Of these, 142 patients (49%) completed all aspects of the study. All but six patients had a confirmation of the diagnosis of sarcoidosis from the lung and/or elsewhere. In the remaining six patients, the clinical presentation and BAL findings were consistent with sarcoidosis. The most common reasons for not participating were inability to walk or insufficient time to complete the study. Figure 1 is a histogram of the 6MWD. Median 6MWD for the group was 396 m. Seventy-three patients (51%) completed a 6MWD < 400 m; of these, 32 patients (22%) walked < 300 m.


Figure 1
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  		Figure 1. Histogram demonstrating the 6MWD for 142 sarcoidosis patients. Median 6MWD for the group was 396 m.

 
Table 1 summarizes the characteristics of the patients studied as well as the difference in 6MWD. There was no correlation between age and 6MWD ({rho} – 0.014, p > 0.10). Female and white patients had shorter 6MWDs. The majority of the patients in the study were receiving systemic therapy, which reflects the bias of the tertiary care clinic. Patients could be receiving systemic therapy for nonpulmonary reasons, including ocular, cutaneous, hepatic, and neurologic diseases. Patients with limited ambulation from neurologic disease did not participate in the study. Patients receiving therapy had shorted 6MWDs (p < 0.05). The majority of patients had multiorgan disease, with 39 patients (27%) having only pulmonary disease. The presence of pulmonary disease alone was not associated with a significant difference in 6MWD. Cardiac evaluation with echocardiography and/or right-heart catheterization were performed in 49 patients (35%) within 2 years of the 6-min walk test. We documented left ventricular cardiac dysfunction in 10 patients. Fourteen patients had documented pulmonary arterial hypertension with no evidence of left ventricular dysfunction. Only pulmonary arterial hypertension was associated with a significantly shorter 6MWD (p < 0.0001). Of the 28 patients undergoing right-heart catheterization, there was no correlation between either the pulmonary artery systolic pressure or pulmonary artery mean pressure and the 6MWD.


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  		Table 1. Characteristics of Patients Studied

 
We assessed pulmonary function using pulmonary function testing (FEV1 and FVC), chest roentgenogram stage, and level of dyspnea using the MRC score. The results are shown in Table 2 . At the time of evaluation, 30 of the patients (21%) had no evidence of thoracic disease by chest roentgenogram. Four of these patients had a FVC < 80% of predicted. Of the 30 patients with a stage 0 chest roentgenogram, 6 patients reported level 2 dyspnea and 1 patient reported level 3 dyspnea. Table 2 reports the MRC dyspnea level of all patients. There was a significant difference between the chest roentgenogram stage and the 6MWD (differences between groups using Kruskal Wallis, p < 0.01). While the higher chest roentgenogram tended to have a lower 6MWD, the correlation between the chest roentgenogram stage and 6MWD was not significant ({rho} = – 0.150, p > 0.05). When we analyzed the data comparing the three groups of chest roentgenogram pattern of those with no parenchymal disease (stage 0 and 1), those with parenchymal disease (stage 2 and 3), and those with fibrosis (stage 4), there was no difference between the groups based on analysis of variance or rank correlation (data not shown). The 6MWDs for the levels of MRC dyspnea score were significantly different (p < 0.0001). The higher the level of dyspnea, the shorter the 6MWD ({rho} = – 0.581, p < 0.0001). There was a significant correlation between FAS and MRC dyspnea score ({rho} = 0.550, p < 0.0001).


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  		Table 2. Results of Pulmonary Function Studies, Chest Roentgenogram, and Level of Dyspnea of Patients Studied

 
The effect of sarcoidosis on the quality of life was assessed using two instruments. The level of fatigue was assessed using the FAS. The values of the 10 questions were summed (with answers for questions 4 and 10 reversed prior to summing) as per Michielsen et al,20 with a scale from 10 to 50 (maximal fatigue). Figure 2 demonstrates the histogram results of the FAS for all 142 patients. Ninety-eight patients (69%) had a score > 22, consistent with fatigue.1924 In addition, FAS score did correlate with 6MWD (Fig 3 ; {rho} = – 0.412, p < 0.0001); FAS score also correlated with the MRC dyspnea score ({rho} = 0.550, p < 0.0001).


Figure 2
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  		Figure 2. Histogram demonstrating the number of patients vs the FAS score results.

 

Figure 3
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  		Figure 3. Relationship between 6MWD and FAS score; the correlation was significant ({rho} = – 0.412, p < 0.0001). There is some overlap in the symbols for individual patients.

 
The extent that the patients’ respiratory disease affected their health was assessed using the SGRQ. This instrument has three components: symptoms, activity, and impact. The total score ranges from 0 (best condition) to 100 (worse status). The total SGRQ mean score was 46. There were significant correlations between total SGRQ and FAS score ({rho} = 0.675, p < 0.0001) and MRC dyspnea score ({rho} = 0.785, p < 0.0001). There were significant correlations between all three components of the SGRQ and FAS and MRC dyspnea scores (p < 0.0001 for all correlations).

We compared 6MWD results to the pulmonary and quality of life instruments, including Borg score and oxygen saturations at the beginning and completion of the 6-min walk test. The results of the univariate analysis are shown in Table 3 . While both the absolute value and percentage of predicted for the FEV1 and FVC negatively correlated with 6MWD, the absolute values had a better correlation.


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  		Table 3. Univariate Analysis Comparing 6MWD vs Pulmonary and Quality of Life Assessments

 
A stepwise multiple regression model used those factors found to be significant by univariate analysis. The factors placed in the model included the following: gender; race; use of systemic therapy; presence of pulmonary arterial hypertension; FEV1; FVC; initial and lowest oxygen saturations during 6-min walk; initial and final Borg scores; MRC dyspnea; SGRQ of all three components, as well as total; and FAS. In this model, the following factors were identified as significant independent variables: SGRQ activity (Fig 4 , t = – 7.498, p < 0.0001), FVC (Fig 5 ; t = 4,415, p < 0.0001), and lowest oxygen saturation (t = 2.55, p < 0.02). The relationship between SGRQ activity and 6MWD was nonlinear, with a regression equation calculation as follows: SGRQ activity = 109.7485 – 0.0908 (6MWD) – 0.0001(6MWD)2 [F ratio = 43.08, p < 0.001].


Figure 4
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  		Figure 4. Relationship between 6MWD and SGRQ activity (SGRQ-A) score; the correlation was significant ({rho} = – 0.668, p < 0.0001). All patients completed the SGRQ. There is some overlap in the symbols for individual patients.

 

Figure 5
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  		Figure 5. Relationship between 6MWD and FVC; this was a significant positive correlation ({rho} = 0.529, p < 0.0001). All patients completed the FVC maneuver. There is some overlap in the symbols for individual patients.

 
Discussion

We performed a prospective study of 6MWD compared to other functional assessments in a large group of unselected sarcoidosis patients followed up in one clinic. 6MWD was ≤ 400 m in 73 patients (51%). This impairment in 6MWD was associated with several factors, including pulmonary function and patient perception of level of dyspnea. The best predictors of 6MWD were SGRQ, vital capacity, and initial oxygen saturation.

Traditionally, the effect of sarcoidosis on pulmonary status is assessed by pulmonary function studies and chest roentgenogram.25 In particular, changes in FVC have been used to assess extent and progression of disease and response to therapy.262728 However, it has been suggested that other testing should also be used to better understand the impact of sarcoidosis on the pulmonary status of the patient.15 In this study, we did not measure the diffusion capacity, which has provided more information regarding exercise capacity than that obtained by the lung volumes alone.29

Abnormalities in exercise testing are commonly encountered in patients with sarcoidosis.30313233 Even patients with normal pulmonary function may still have impaired exercise testing.34 Changes in exercise capacity can be due to multiple factors, including lung function, cardiac status, respiratory muscle strength,35 and skeletal muscle strength.2536 There was no difference in the 6MWD for those with pulmonary alone vs those with extrapulmonary disease. A history of cardiac dysfunction was not associated with a shorter 6MWD in this study. Pulmonary hypertension is common in dyspneic patients with sarcoidosis3738 and may also affect exercise capacity.39 In our experience, up to 50% of persistently dyspneic patients may have pulmonary hypertension.38 Leuchte et al40 have shown that pulmonary hypertension can be an independent factor in the 6MWD in pulmonary fibrosis. We identified 14 sarcoidosis patients with pulmonary arterial hypertension in this study group. They had a significantly shorted 6MWD.

Skeletal muscle weakness has been found in sarcoidosis patients.36 Patients were not studied if they believed that their walking was limited by muscle weakness or pain. There was no specific measurement of skeletal muscle strength or myalgias. This may affect the 6MWD.

In sarcoidosis, the 6 MWD can be affected by multiple factors, including respiratory status, cardiac function, muscle strength, and joint disease. Thus, the 6MWD may have a different prognostic importance in sarcoidosis than in other interstitial lung diseases.

The 6MWD has been useful and reproducible in other interstitial lung diseases.129 However, systematic studies of 6MWD in sarcoidosis have not been previously reported. Abnormalities in 6MWD were noted in the majority of patients. Kadikar et al41 considered pulmonary patients with a 6MWD < 400 m to be candidates for transplant evaluation. The study by Kadikar et al41 did not include patients with sarcoidosis. Half of our patients had a 6MWD < 400 m. For other interstitial lung diseases, a 6MWD < 300 m is associated with an increased mortality. Twenty percent of the study patients had a 6MWD < 300 m.

The systemic effects of sarcoidosis can affect patient quality of life.14424344 The SGRQ is a widely used questionnaire developed initially for patients with obstructive lung disease.18 Compared to a healthy population, a score ≥ 20 was associated with lung diseases such as COPD or asthma.45 Patients recruited for clinical trials of pharmacologic agents for COPD had a median SGRQ score ≥ 40.4647 In the current study, 117 of the sarcoidosis patients (82%) had a score ≥ 20, and 84 of the sarcoidosis patients (54%) had scores ≥ 40. Only a few studies have evaluated the SGRQ for sarcoidosis patients. In a study of chronic sarcoidosis patients, Cox et al14 reported a median SGRQ total score of 44, similar to our study findings. Whether the quality of life affects the 6MWD or the 6MWD affects the quality of life could not be determined by the current study.

Fatigue is a specific complaint reported by sarcoidosis patients.24 Using the FAS, which was developed and validated by Dr. Drent’s group in Maastrecht, an increased rate of fatigue was noted in their sarcoidosis patients.1924. The median FAS score for the Dutch patients was 22, similar to scores reported in this study. Not surprisingly, fatigue has been associated with decreased exercise capacity.2436

The current study found that the 6MWD was affected by multiple factors, including race, gender, concurrent use of medications, pulmonary function, fatigue, respiratory health status, and dyspnea. Age was not a contributing factor. In studying healthy control subjects, women and older patients had shorter 6MWDs.10 In this study, women had shorter 6MWDs; however, women also have smaller lung volumes. Treatment was possibly a marker of more advanced disease. Both of these factors fell out in the multiple regression analysis.

Using a multiple regression analysis of the independent factors affecting 6MWD, the only predictive factors were the SGRQ, FVC, and lowest oxygen saturation. As has been previously noted, the SGRQ is related to exercise capacity.43 The FAS and dyspnea score were highly correlated to the SGRQ score. Therefore, their effect on 6MWD appears to be captured in the SGRQ. The strongest predictor of the 6MWD in the multiple regression model was the SGRQ activity score rather than FVC. Others29 have noted that FVC will affect exercise capacity in sarcoidosis, but they did not study the SGRQ.

Traditionally, measured changes in the vital capacity and chest roentgenogram4849 have been utilized to assess treatment efficacy. Newer agents that may be more effective therapies for sarcoidosis are becoming available.28 Use of the 6MWD may allow for a better assessment of these drugs on respiratory status.15

In conclusion, we found that the 6MWD was abnormal in many patients with sarcoidosis. The decrease in 6MWD was due to multiple factors, including the self-reported assessment of lung health as measured by the SGRQ, as well as the self-reported level of fatigue. These three tests provided complimentary information about the functional status of the patient.

Footnotes

Abbreviations: FAS = fatigue assessment scale; MRC = Medical Research Council; 6MWD = 6-min walk distance; SGRQ = St. George Respiratory Questionnaire

The author have no potential or actual conflicts of interests to disclose.

Received for publication November 12, 2007. Accepted for publication March 12, 2007.

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E. E. Lower, S. Harman, and R. P. Baughman
Double-Blind, Randomized Trial of Dexmethylphenidate Hydrochloride for the Treatment of Sarcoidosis-Associated Fatigue
Chest, May 1, 2008; 133(5): 1189 - 1195.
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