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(Chest. 2006;130:1851-1856.)
© 2006 American College of Chest Physicians

Clinical and Radiographic Indices Associated With Airflow Limitation in Patients With Sarcoidosis*

Tomohiro Handa, MD; Sonoko Nagai, MD, PhD; Yasutaka Fushimi, MD; Shinji Miki, MD, PhD; Kosuke Ohta, MD; Akio Niimi, MD, PhD; Michiaki Mishima, MD, PhD and Takateru Izumi, MD, PhD

* From the Departments of Respiratory Medicine (Drs. Handa, Nagai, Mishima, and Niimi) and Diagnostic Imaging and Nuclear Medicine (Dr. Fushimi), Graduate School of Medicine, Kyoto University; Central Clinic of Kyoto (Drs. Ohta and Izumi); and Department of Cardiology, Kyoto Mitsubishi Hospital (Dr. Miki), Kyoto, Japan.

Correspondence to: Sonoko Nagai, MD, PhD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan; e-mail: nagai{at}kuhp.kyoto-u.ac.jp

Abstract

Background: Airflow limitation is found in some patients with sarcoidosis, and it is associated with a poor prognosis. The aim of this study was to investigate clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis.

Methods: A prospective, observational study was performed on 228 consecutive sarcoidosis patients followed up at our patient clinic at the Central Clinic of Kyoto. Patients underwent pulmonary function tests, and high-resolution CT (HRCT) of the lung was evaluated for the presence of lymph node enlargement, lung opacity, reticular shadow, and thickening of bronchovascular bundles (BVB). Airflow limitation was defined as FEV1/FVC < 70%. Airway reversibility was tested in subjects with airflow limitation. The frequency of airflow limitation was evaluated, and clinical and radiographic parameters were compared between patients with and without airflow limitation.

Results: Among all 228 subjects, 20 subjects (8.8%) had airflow limitation, and none showed airway reversibility. Patients with airflow limitation were predominantly male, smokers, and had advanced chest radiographic stage, increased frequency of lung opacities, reticular shadows, and thickened BVB on HRCT. Stepwise regression analysis showed that chest radiographic stage IV, higher age, smoking, and thickened BVB were independently associated with lower FEV1/FVC.

Conclusion: The frequency of airflow limitation was 8.8% in Japanese sarcoidosis patients. Chest radiographic stage IV, higher age, smoking, and thickened BVB were associated with airflow limitation in patients with sarcoidosis.

Key Words: airflow limitation • CT • pulmonary fibrosis • pulmonary function tests • sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown cause in which the lungs are affected in > 90% of patients. Although parenchymal lung disease is more common, the airways may also be involved, leading to airway obstruction and bronchiectasis.1 Pathology studies of sarcoidosis patients have shown peribronchial predilection for granulomatous lesions234 and their association with small airway stenosis.2 In physiology studies, it was reported that the frequency of an obstructive pattern on spirometry varies from 4 to 67% of patients, depending on the race of the study subjects and the definition of airway obstruction.5 Several factors are considered to be involved in the mechanisms of airflow limitation in sarcoidosis, including reversible airway inflammation, endobronchial masses, airway narrowing owing to extrinsic compression, and end-stage cicatrial bronchial stenosis and fibrosis.5 Although it was reported that airflow limitation is more common in sarcoidosis patients with advanced chest radiographic stage,6 clinical factors associated with airway obstruction have not been fully elucidated in patients with sarcoidosis. Based on the possible mechanisms of airflow limitation in sarcoidosis, we hypothesized that airflow limitation is more common in patients with enlarged mediastinal and/or hilar lymph nodes that can extrinsically compress airways, or those with advanced pulmonary lesions that can directly involve airways. In this study, we investigated the clinical factors associated with airflow limitation in patients with sarcoidosis.

Materials and Methods

Study Population
The study population comprised 228 Japanese sarcoidosis patients with histologic confirmation of disease diagnosis. All patients were consecutively followed up at the outpatient sarcoidosis clinic in the Central Clinic of Kyoto. Patients with concurrent lung diseases were excluded from the study. All study subjects underwent pulmonary function tests (PFTs), and high-resolution CT (HRCT) was performed on the same day. Classification of chest radiographs (stage 0, normal; stage I, bilateral hilar lymphadenopathy [BHL]; stage II, BHL with pulmonary infiltrations; stage III, pulmonary infiltrates without BHL; and stage IV, pulmonary fibrosis) was performed, and combined extrapulmonary lesions1 were also investigated. Serum angiotensin-converting enzyme (sACE) was measured on the same day. The study was approved by the ethics committee of Kyoto University, and informed, written consent was obtained from all subjects.

Measurement of sACE
sACE activity was measured by the method of Kasahara and Ashihara7 using optical density measurements at 505 nm and 800 nm with a spectrophotometer. Serum samples were considered to be positive if they contained > 21.4 IU/L.

HRCT
The HRCT scans (Pronto SE; Hitachi Medical; Tokyo, Japan) were obtained using 2-mm collimation, scan time of 1.0 s, 120 kilovolt peak, and 200 mA. The HRCT images were assessed for the presence of the following: (1) mediastinal and/or hilar lymph node enlargement with diameters > 1 cm; (2) opacities in the lung field; (3) reticular shadows; and (4) thickening of bronchovascular bundles (BVB). The CT scans were assessed in random order by two independent assessors (T.H. and Y.F.). When diagnoses differed between the two observers, the two observers discussed the findings to reach a final consensus of diagnosis.

Lung Function Testing
All PFTs were performed according to the American Thoracic Society guidelines.89 Vital capacity (VC), FVC, FEV1, mean forced expiratory flow during the middle half of the FVC (FEF25–75), and maximum expiratory flow at the quartile of FVC (MEF25) were measured using Chestac-8800 (Chest M.I.; Tokyo, Japan). Published equations for adults were used to determine predicted values of each parameter.1011 Airflow limitation was defined as an FEV1/FVC ratio < 70%.

Airway Reversibility Test
Subjects with airflow limitation underwent airway reversibility testing. Reversibility testing was performed according to Global Initiative for Chronic Obstructive Lung Disease12 guidelines. Briefly, 400 µg of a short-acting ß2-agonist (salbutamol sulfate) was administered. Increases in FEV1 30 min after bronchodilator administration of > 12% and 200 mL above the prebronchodilator FEV1 were considered to indicate reversible airway obstruction.

Statistical Analysis
Statistical analysis were performed using Statview software (SAS Institute; Cary, NC). Univariate analyses were performed for all the variables noted above (current patient age, onset age, disease duration, gender, ratio of smokers to nonsmokers, sACE, number of extrathoracic lesions, ratio of patients treated with immunosuppressants, chest radiographic stage, chest HRCT findings, and lung function parameters), comparing subjects with airflow limitation and those without airflow limitation. Comparisons of categorical data were made using the {chi}2 test or the Fisher exact probability test. Continuous variables were compared with unpaired t test if normally distributed, and Mann-Whitney U test when the distribution was not normal. Variables that were significant at the p = 0.2 level in the univariate analysis were included as covariates in stepwise regression analyses to investigate the independent clinical indices that affect FEV1/FVC. A p value < 0.05 was considered to be statistically significant.

Results

Frequency of Airflow Limitation
Twenty of the 228 subjects (8.8%) had prebronchodilator FEV1/FVC < 70%, which fulfilled the criteria of airflow limitation. Postbronchodilator increase in FEV1 ranged from – 20 to 220 mL (average, 60 mL), and percentage increase in FEV1 ranged from – 2.3 to 9.7% (average, 3.8%). Thus, all of these subjects were considered to have irreversible airflow limitation. In all of these subjects, postbronchodilator FEV1/FVC was also < 70%.

Comparison of Patient Characteristics
Patient characteristics of the study subjects are shown in Table 1 . Univariate analyses showed that there was a higher ratio of men and smokers among the patients with airflow limitation. Disease duration and prior treatment with immunosuppressants were not statistically significantly different between the groups.


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  		Table 1.. Comparison of Patient Characteristics*

 
Comparison of Chest Radiograph Stage and HRCT Findings
As shown in Table 2 , patients with airflow limitation had advanced chest radiographic stage. In the comparison of chest HRCT findings, the frequency of lung opacities, reticular shadows, and thickened BVB were statistically significantly increased in patients with airflow limitation. When the frequency of lung opacities without reticular shadows was compared between the patient groups, the difference was not statistically significant (data not shown). Clinical parameters that showed significant association with airflow limitation in univariate analysis were selected, and the results of the comparisons are shown in Figure 1 .


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  		Table 2.. Comparison of Chest Radiograph and HRCT Findings*

 

Figure 1
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  		Figure 1.. Clinical and radiographic indices that showed significant association with airflow limitation in the univariate analyses were selected, and the results of comparisons are shown. There was a higher ratio of men and smokers among the patients with airflow limitation. In the comparison of chest HRCT findings, the frequency of lung opacities, reticular shadows, and thickened BVB were statistically significantly higher in patients with airflow limitation.

 
Comparison of PFTs
Several indices of pulmonary function were compared between patients with and without airflow limitation. VC and FVC were also decreased in subjects with airflow limitation (Table 3 ).


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  		Table 3.. Comparison of PFT Results*

 
Independent Factors Associated With Airflow Limitation
Due to the low incidence of subjects with airflow limitation, logistic regression analysis was not performed to investigate independent factors associated with airflow limitation. Instead, stepwise regression analysis was performed to investigate independent factors that affect FEV1/FVC. Aside from indices of pulmonary function, variables that were significant at the p = 0.2 level in the univariate analysis were included as covariates. Chest radiographic stage was categorized into stage IV and others (stage 0 to stage III) to be included in the analysis. Both forward and backward analysis showed that chest radiographic stage, patient age, smoking history, and thickening of BVB were the variables accepted into the regression analysis. Based on the result, stage IV (regression coefficient, – 15.5), higher age (regression coefficient, – 0.20), smoking (regression coefficient, – 5.2), and thickened BVB (regression coefficient, – 3.6), were independently associated with a lower FEV1/FVC (p < 0.0001, R2 = 0.29).

Discussion

Although pulmonary sarcoidosis mainly affects parenchyma of the lung, studies of physiologic,61314 radiologic,151617 and pathologic approaches2341819 have revealed that airway lesions are not rare in patients with sarcoidosis. It was also reported that sarcoidosis patients with FEV1/FVC < 70% had increased mortality risk (odds ratio, 1.9) compared with those with FEV1/FVC ≥ 70%.20 However, clinical indices associated with airflow limitation have not been fully elucidated in sarcoidosis.

In this study, we investigated clinical and radiographic indexes associated with airflow limitation in patients with sarcoidosis. Based on the result of the regression analysis, higher age, smoking, thickened BVB, and chest radiographic stage IV (pulmonary fibrosis) were independently associated with lower FEV1/FVC.

Base on spirometric data of normal subjects showing that FEV1/VC decreased with higher age,11 it was reasonable to find that higher age was associated with lower FEV1/FVC in patients with sarcoidosis. The regression coefficient of age in this study was – 0.20, which means that FEV1/FVC decreases 0.20% per year of aging. This rate was not higher than the 0.37% decrease per year found in normal subjects,11 suggesting that the influence of age on FEV1/FVC is not exaggerated in sarcoidosis patients compared with normal subjects. It is also possible that cigarette smoking, a major risk factor of COPD,12 affects airflow limitation in sarcoidosis, although patients with emphysematous change in HRCT were excluded from this study.

Although mediastinal and hilar lymph node swelling had no association with FEV1/FVC, thickening of BVB was independently associated with lower FEV1/FVC. Among five subjects who showed thickening of BVB and airflow limitation (Table 2), two subjects had stage I disease, and their lung opacities were minimal even in HRCT. Both of them had never smoked, and they had no history of asthma. Thus, the airflow limitation in these cases was attributed to thickened BVB.

Harrison et al6 investigated pulmonary function in 107 patients with newly diagnosed sarcoidosis, and found increasing frequency of airway obstruction with progressive radiographic staging. Hansell et al15 recorded five CT patterns in 45 sarcoidosis patients, and investigated their correlation with lung functions. They found that the extent of reticular pattern was independently associated with airflow obstruction. They concluded that pulmonary fibrosis has the most profound effect on obstructive lung impairment in sarcoidosis. Based on these reports, pulmonary fibrosis might influence airflow limitation. In univariate analyses, advanced chest radiographic stage, HRCT findings of lung opacity and reticular shadows were associated with airflow limitation. However, when patients with reticular shadows on HRCT were excluded from the analysis, the frequency of patients with lung opacities was not significantly different between the groups. Thus, the influence of lung opacities other than reticular shadows on airflow limitation was not considered to be significant. Stepwise regression analysis showed that, among these radiographic variables, chest radiographic stage was accepted into the analysis. When chest radiographic stage was categorized as stage III or more and stage II or less, chest radiographic stage was not accepted into the analysis, and reticular shadow on HRCT was accepted alternatively. These results suggested that radiographic findings of pulmonary fibrosis were associated with airflow limitation in sarcoidosis. The fibrosis on chest radiograph stage IV is usually found in the advanced stage when compared with those detected on chest HRCT. Then, the stage IV can be evaluated as a strong independent factor that relates to chronic airflow limitation. Further investigations with the quantification of reticular shadows in HRCT might reveal the significant effect of these factors on airflow limitation in sarcoidosis, as shown by Hansell et al.15

Next, to further investigate the association between pulmonary fibrosis and airflow limitation, VC and FVC were compared between patients with and without airflow limitation (Table 3). Although a negative correlation was reported between VC and FEV1/VC in patients with cryptogenic fibrosing alveolitis,21 patients with reduced FEV1/FVC in this study had reduced percentage of predicted VC and percentage of predicted FVC, which further suggested that the fibrosing process might contribute to the development of airflow limitation in sarcoidosis.

Further pathology studies of airways are needed in sarcoidosis patients with airflow limitations to elucidate the association between pulmonary fibrosis and airway obstruction. Based on this hypothesis, the frequency of airflow limitation in sarcoidosis might vary in different ethnic groups depending on the severity of lung lesions. The low frequency of subjects with airflow limitation in this study (8.8%) might be because lung lesions of sarcoidosis tend to be mild in Japan, where the most frequent cause of death from sarcoidosis is myocardial involvement.1

However, our study has several limitations. The first is that the frequency of airflow limitation varies depending on the definition of airflow limitation. This might explain the lower incidence of airflow limitation in this study compared with those of airway hyperreactivity (20 to 50%)12223 and endobronchial granulomas (57%)14 in sarcoidosis reported previously. Harrison et al6 used FEV1/FVC together with MEF25 and maximum expiratory flow at 50% of FVC to define airflow limitation, and found airflow limitation in 61 of 107 patients with sarcoidosis. Although there is a hypothesis that MEF25, maximum expiratory flow at 50% of FVC, and FEF25–75 might be decreased in an earlier phase of the airway disease of sarcoidosis,5 there is no consensus as to the reference values and cut-off values in these parameters to specifically detect airway obstructions. In this study, FEV1/FVC was used based on the Global Initiative for Chronic Obstructive Lung Disease standard definition of airflow limitation, which described FEV1/FVC as a sensitive measure of airflow limitation, and that this approach to defining airflow limitation is a pragmatic one in view of the fact that universally applicable reference values for FEV1 and FVC are not available.12

Second, a substantial number of the subjects in this study had long disease durations (average, 101 months), which might have affected the frequency of airflow limitation in sarcoidosis compared with that evaluated at the first presentation. Although the patients referred to the Central Clinic of Kyoto have no specific characteristics compared with the general population of Japanese sarcoidosis patients, it should be noted that the frequency of airflow limitation evaluated in this study was that of patients with various disease durations, including those in the chronic phase of the disease.

Third, subjects with concurrent bronchial asthma or COPD were not completely excluded from the study. Although subjects with prior diagnosis of asthma and those with emphysema on HRCT were excluded from the study, there is a possibility that asthmatic subjects without airflow limitation and COPD patients without detectable emphysematous changes might have been included in the study population.

In addition, previous treatment might have affected the frequency of airflow limitation. It is noteworthy that none of the subjects with airflow limitation in this study showed airway reversibility. Cieslicki et al24 reported that 8 of 17 sarcoidosis subjects with FEV1/VC < 70% showed response to ß2-agonists, although they also excluded subjects with history of asthma. They used the first spirometric data of all subjects before starting the treatment, whereas many of the study subjects in this study (12 of 20 subjects with airflow limitation) were receiving treatment with immunosuppressants. Thus, previous treatments might have decreased the reversible component of airflow limitations in the subjects of this study. Nonetheless, this study comprised a large number of consecutively enrolled subjects from a single race, and is the first to elucidate a number of risk factors for development of airflow limitation in sarcoidosis.

In conclusion, the frequency of airflow limitation was 8.8% in Japanese sarcoidosis patients. Higher age, smoking, thickening of BVB, and chest radiographic stage IV were independently associated with a lower FEV1/FVC in patients with sarcoidosis. Considering the poor outcome reported in these patients, sarcoidosis patients with airflow limitation should be carefully followed up.

Acknowledgements

We thank Mr. S. Ueda, Ms. M. Aoki, Ms. M. Koshimura, and Ms. K. Tanaka for technical assistance.

Footnotes

Abbreviations: BHL = bilateral hilar lymphadenopathy; BVB = bronchovascular bundles; FEF25–75 = mean forced expiratory flow during the middle half of the FVC; HRCT = high-resolution CT; MEF25 = maximum expiratory flow at the quartile of FVC; PFT = pulmonary function test; sACE = serum angiotensin-converting enzyme; VC = vital capacity

The authors have no financial or other potential conflicts of interest to disclose.

Received for publication February 20, 2006. Accepted for publication June 24, 2006.

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