Abstract
Sarcoidosis is a systemic granulomatous disease with predominant manifestation in the lungs, often presenting as interstitial lung disease. Pulmonary function abnormalities in sarcoidosis include restriction of lung volumes, reduction in diffusing capacity of the lung for carbon monoxide (DL,CO), reduced static lung compliance (CL,s) and airway obstruction. The aim of the present study was to assess various lung function indices, including CL,s and DL,CO, as markers of functional abnormality in sarcoidosis patients.
Results from 830 consecutive patients referred for lung function tests with a diagnosis of sarcoidosis (223 in stage I, 486 in stage II and 121 in stage III) were retreospectively analysed. The mean±sd age of the patients was 40±11 yrs; 18% were active smokers and 24% were former smokers.
Normal total lung capacity was found in 772 (93%) patients. Of these cases, 24.5% had a low CL,s and 21.5% had a low DL,CO. At least one abnormality was observed in 39.3% of these patients, whereas, in restrictive patients, this figure was 88%. Airway obstruction was present in 11.7% of cases.
Lung volumes usually remain within the normal range and measurement of either CL,s or DL,CO often reveal impaired lung function in sarcoidosis patients, even when their lung volumes are still in the normal range; these two measurements provide complementary information.
Sarcoidosis is a systemic granulomatous disease of unknown aetiology characterised by the formation of granulomas in the lungs and intrathoracic lymph nodes 1. In progressive sarcoidosis, cellular infiltrates in the lung transform into fibrotic changes, causing interstitial lung disease (ILD) 2, 3.
Sarcoidosis forms part of a group of ILDs which are characterised by diverse clinical and histopathological manifestations, sharing a common basic pattern of functional impairment. The basic mechanism of lung function impairment is assumed to be decreased lung compliance (lungs become stiffer, less compliant) so that the static expiratory pressure–volume (P–V) curve of the lung is shifted downwards and to the right compared with normal subjects. The P–V curve is contracted along its volume axis, as both total lung capacity (TLC) and vital capacity decrease 4, 5. The transpulmonary pressure near TLC is increased, which reflects the greater mechanical advantage of the diaphragm, the force-generating capacity of which is enhanced at the diminished lung volume in ILD. Static lung compliance (CL,s), measured from the P–V curve, is one of the parameters that reflect the mechanical properties of the lung tissue, but it is rarely measured in clinical settings. Figure 1 shows an example of CL,s measurement in a patient with sarcoidosis and a low TLC.
An example of a set of five pressure–volume curves in a patient with sarcoidosis and restriction of lung volumes. The slopes of the tangents on the expiratory limbs of the curves represent static lung compliance (CL,s). ·····: expected normal CL,s (3.62 L·kPa−1); —: predicted residual volume; ---: predicted total lung capacity (TLC). The patient's CL,s was very low. -Ptp: negative transpulmonary pressure.
An increased alveolar–arterial oxygen tension gradient and resting hypoxaemia also occur with more severe ILD 6. The arterial carbon dioxide tension is usually normal but may be reduced at rest in a proportion of patients due to alveolar hyperventilation 6. The diffusing capacity of the lung for carbon monoxide (DL,CO) is characteristically reduced in ILDs, and to a greater extent than the TLC at which it is measured 7. Spirometry and DL,CO measurements are recommended tests in the initial evaluation of the magnitude of functional lung involvement, but the prognostic value of DL,CO in sarcoidosis is poor 1, 8.
Although a restrictive ventilatory defect, characterised by the reduction in static lung volumes, and impaired gas exchange, expressed as reduced DL,CO, are classically considered the most prevalent pattern of lung function abnormality in ILD, airway obstruction has also been reported 7, 9–13.
The National Tuberculosis and Lung Diseases Research Institute (Warsaw, Poland) serves as the regional referral centre for patients with sarcoidosis and other ILDs. All patients with chronic interstitial markings on chest radiographs or lung computed tomography (CT) scans seen by their pulmonary specialists are referred to the pulmonary function testing (PFT) laboratory for measurement of lung volumes, single-breath DL,CO and CL,s. This practice provided the opportunity to describe patterns of lung function abnormality from a much larger group of patients with sarcoidosis than previously reported 7, 9, 10, 12–16. One study reported a comparable number of subjects, but PFT results were not reported 17.
The main purpose of the present investigation was to describe lung function abnormalities and determine the rates of lung function impairment expressed as reduced DL,CO and/or reduced CL,s in patients with sarcoidosis, especially those with no volume restriction.
This study was approved by the local Ethics Committee (National Tuberculosis and Lung Diseases Research Institute).
METHODS
The study group consisted of 830 patients with sarcoidosis (387 females and 443 males, all Caucasian) referred consecutively for PFT evaluation, at the time of diagnosis or during follow-up, over a period of almost 4 yrs. Only the first result was considered if the patient was assessed on more than one occasion; usually, this was the initial PFT evaluation, and so the majority of patients were not being treated at the time of the present investigation. In the majority of cases (85%), the diagnosis was confirmed by histopathological examination. In most cases, endobronchial biopsy was performed, but mediastinoscopy, transbronchial biopsy, video-assisted thoracoscopy or open-lung biopsy were also used. In a minority of patients with no histopathological confirmation (15%), clinical features, such as Löfgren's syndrome, regression of the disease without treatment and exclusion of other causes of hilar lymphadenopathy, were used to establish the diagnosis of sarcoidosis with a high degree of confidence, in agreement with the European Respiratory Society (ERS)/American Thoracic Society (ATS) 1999 statement on sarcoidosis 1. Radiographic stages were defined in accordance with the same statement 1. The study group characteristics are presented in table 1.
All patients underwent a standard evaluation that included history, physical examination, chest radiography, spirometry and flow–volume curve, whole-body plethysmography, CL,s and single-breath DL,CO. All treated patients were asked not to use any inhalers ≤24 h before the tests. ERS guidelines were followed for all lung function measurements 18, 19. All PFTs were performed using a MasterScreen system (software version 4.65; Jaeger, Würzburg, Germany).
Semi-static lung compliance was measured from quasi-static expiratory P–V curves using the standardised oesophageal pressure method 19. Details are provided in the online supplementary material. This measurement is routine procedure in our laboratory (Lung Function Laboratory, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland; ∼1,000 measurements annually) and is only sporadically refused by patients. Adverse effects (e.g. nasal and throat bleeds, vomiting and nausea) occur a few times a year and are not threatening. In general, this procedure is safe for patients.
Reference equations for spirometry were taken from the study of Falaschetti et al. 20 and those for lung volumes and DL,CO from the ERS guidelines 18, 21. For CL,s, reference values taken from Colebatch et al. 22 were used. DL,CO results were corrected for haemoglobin concentration 23. Following the ATS/ERS 2005 guidelines, the lower limit of normal (LLN) was set at the level of the 5th percentile (or mean − 1.645 sd) of each reference population 24. Results were expressed as percentage predicted, as is conventional; however, as the mean predicted value falls with age and the scatter does not fall proportionately, percentage predicted leads to an age-, height- and sex-related bias. Therefore, standardised residuals (SR = (observed – predicted)/residual sd) 18, which are free of such bias, were also calculated. Data are presented as mean (95% CI). For each disease stage, the percentage of subjects whose pulmonary function index was below the LLN was also calculated.
Statistical analysis
Differences between the various disease stages were analysed using the general linear model ANOVA, with pulmonary function expressed as percentage predicted or SR as the outcome variable, disease stage and sex as predictors, and age, height and smoking exposure expressed as daily tobacco consumption, years smoked or pack-years as confounding variables. Levene's test did not disclose inhomogeneity of variance. A p-value of <0.05 was regarded as significant. Group comparisons were made using paired t-tests for independent samples to clarify whether significant differences detected with ANOVA translated into significant differences between all groups; applying Bonferroni correction, a p-value of <0.017 was considered significant. The Chi-squared test was used to test for differences in the prevalence of observations below the LLN. Statistical analyses were performed using STATISTICA, version 8.0 (StatSoft, Inc., Bedford, UK).
RESULTS
The mean±sd age of the patients was 40.3±10.9 yrs (range 19–75 yrs). There were 223 (26.9%) patients in stage I, 486 (58.6%) in stage II and 121 (14.6%) in stage III of the disease. Only six cases were classified as stage IV and their lung function indices were not statistically different from those patients in stage III, and so they were included in stage III for the present analysis.
Analysis of variance revealed that, after taking into account age, height and sex, disease stage was a significant (p<0.01) predictor for all PFT indices, except the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and residual volume/TLC ratios, and forced expiratory flow at 25–75% FVC (FEF25–75%). Smoking variables were only related to DL,CO. The most frequent PFT abnormalities in all patients were reduced CL,s (27.8%) and reduced DL,CO (25.7%) (table 2).
Only 58 of the 830 patients with sarcoidosis had a low TLC (the classic pattern of restriction). In this restrictive group of patients, DL,CO and CL,s were reduced in 81 and 72.4% of cases, respectively, at least one abnormal finding being observed in 88% of these patients. Another 33 patients showed a reduced FVC but normal TLC (a nonspecific pattern). Of the 772 patients with normal lung volumes, figure 2 shows those with a low DL,CO and/or low CL,s. The distributions of DL,CO and CL,s results in the 772 patients are presented in figure 3, showing a shift towards abnormally low values.
Distribution of abnormally low static lung compliance (CL,s; ░), abnormally low diffusing capacity of the lung for carbon monoxide (DL,CO; ▒), both low CL,s and low DL,CO (▪), and normal CL,s and DL,CO (□) in patients without restriction of lung volumes in a) all subjects (n = 772), and in groups stratified by stage of sarcoidosis: b) stage I (n = 217), c) stage II (n = 260) and d) stage III (n = 95).
Distribution of a) diffusing capacity of the lung for carbon monoxide and b) static lung compliance in 772 patients with sarcoidosis but normal lung volumes. ·····: lower limit of normal (LLN); -----: predicted values based on the standardised residuals (SR). ––––: expected normal distribution for healthy adults.
Airflow obstruction (FEV1/FVC <LLN) was detected in 97 (11.7%) patients. Using ATS/ERS guidelines to grade severity 24, obstruction was mild (FEV1 >70% pred) in the majority (n = 77), moderate in 15 patients and severe in four patients. The mean duration of smoking in the 153 current smokers and 201 former smokers was 9.0 yrs.
In the 772 patients with a TLC within normal limits, CL,s identified more subjects with abnormal lung compliance than did DL,CO (24.5 (189 out of 772) versus 21.5% (166/772), but the difference (3%-points, 95% CI 0.072–-0.012) was nonsignificant (Chi-squared test). The detailed distribution of patients with different types of lung function disturbances, stratified according to stage of disease, is presented in table 3 (and figures in the online supplementary material).
The patient characteristics of those with normal DL,CO and normal CL,s (n = 476) were compared with those with abnormal DL,CO and/or abnormal CL,s, irrespective of a restrictive ventilatory defect. A reduced CL,s was more frequently observed in females and in older patients (table 4). Ever-smokers with a greater number of pack-yrs of smoking exposure were more likely than other patients to exhibit a low CL,s and low DL,CO.
DISCUSSION
The lung function measurements in this large group of patients with pulmonary sarcoidosis revealed that only 7% presented with restriction of lung volumes, despite parenchymal involvement visible on the chest radiograph in approximately three-quarters of these patients (stages II–IV). Previous investigators have also reported normal lung volumes in the majority of patients with stage I or II sarcoidosis 15, 26. The cause of a restrictive ventilatory defect in sarcoidosis patients may be more complex and respiratory muscle weakness should also be considered 27.
DL,CO and CL,s tests were much more sensitive than lung volumes in detecting functional disturbances in sarcoidosis. This corroborates findings from previous smaller studies 1, 16, 28–30. When only hilar lymphadenopathy is seen on the chest radiogaph (stage I sarcoidosis), parenchymal involvement is present in some patients and is often noted on high-resolution lung CT scans 31. This may explain the low DL,CO and CL,s in the present patients with stage I sarcoidosis (low DL,CO in 13% and low CL,s in 17%). In previous studies, a reduced CL,s was frequently observed in ILD patients with reduced lung volumes 32–36. However, in only one study was lung compliance measured in patients with ILD but normal lung volumes 37. In the present study, CL,s was abnormally low in 72.4% of patients with lung volume restriction (TLC < LLN). The proportion of findings of abnormal DL,CO and CL,s correlated well with the clinical staging of the disease (table 2), underlining that these indices reflect clinically relevant disease-related lung damage.
DL,CO, a measure of gas transfer in the lungs, is highly dependent upon pulmonary vascular blood volume. Therefore, a low DL,CO usually suggests alveolitis or vasculitis in sarcoidosis patients 38, 39. Other causes of a low DL,CO (e.g. emphysema or marked uneven ventilation distribution) cannot explain the findings in the present patients. However, a low CL,s may not be due solely to parenchymal pathology. Fibrotic changes or infiltrates in the airway walls may stiffen the bronchi, which act as a supporting frame for lung tissue; thus pathological changes in small airways may contribute to apparent lung stiffness.
Patients with both low CL,s and low DL,CO were more likely to exhibit airway obstruction, perhaps because of more widespread disease involving both parenchyma and airways. They were also more likely to be ever-smokers with more pack-years of smoking exposure (table 4). ANOVA revealed no relation between PFT results and smoking status (including ever-/never-smokers as categorical predictor and pack-years of smoking as continuous predictor). Differences were found between ever-smokers and never-smokers, and were statistically significant, but only for TLC and DL,CO; however, they were too small to be clinically important. Interestingly, lung function indices attributed to airway obstruction (which are expected to be affected by smoking) were comparable between ever- and never-smokers (table in online supplementary material). This observation is in agreement with some data suggesting that smoking may even play a protective role in sarcoidosis 40, 41.
CL,s was most frequently reduced in females (35.9 versus 20.7%). This finding is independent of the choice of reference equations; using those from Begin et al. 25, the prevalence was 36.4 and 28.5%, respectively. Older patients were also more likely than younger patients to show a low CL,s, perhaps because long-standing disease causes more fibrosis.
Airway obstruction is more common in sarcoidosis than in other ILDs. Approximately 6% of the present patients in stage I and 13–16% of those in stages II and III exhibited a low FEV1/FVC; however, statistical analysis (ANOVA) did not confirm the relationship between this index and stage of disease. These rates are lower than those reported by others, perhaps because of differences in the definition of airway obstruction 42, 43. Judged by a low FEF25–75%, as was done in previous studies, airway obstruction was about twice as prevalent as when using FEV1/FVC. However, current ATS/ERS guidelines for the interpretation of PFTs discourage using FEF25–75% to define airway obstruction 24. Moreover, the physiological meaning of a low FEF25–75% in sarcoidosis patients is unclear. Other studies may have used FEV1/FVC <0.70 to define airway obstruction, but this causes considerable misclassification 24, 44.
Study limitations
The present study was a retrospective, cross-sectional analysis based on the group of sarcoidosis patients seen in the laboratory over a 4-yr period. The number of cases required to demonstrate significant differences was not established beforehand. The numbers of cases in each group and proportion of them reflects the real distribution of patients in our laboratory and hospital.
Ideally, statistical analyses would have made use of matched controls; however, this was not feasible for this study, thus reference values were used. The reference values for the various PFTs that were performed did not come from a single source, but relate to different samples of healthy subjects. Thus the predicted values and LLNs from each of these studies may have caused some misclassification of abnormality rates in the present patients. Predicted values for CL,s are poorly established and the present techniques may not have exactly matched those used by the reference study. We chose the predicted values of Colebatch et al. 22 because they were based on the highest number of healthy subjects (83 males and 40 females) and included information about the scatter of the results (sd). However, the present findings on lung compliance are, to a minor extent, influenced by such a choice. Using the prediction equations of Begin et al. 25 (based on only 40 healthy males and 26 healthy females), somewhat higher percentages of an abnormally low CL,s were obtained in all groups. Additional reference values for CL,s based on an even higher number of subjects have recently been published 45, but they were limited to males and did not include variance data and could, therefore, not be used in the present study. If the true LLN range for CL,s were lower for the present patients (or the true LLN for TLC were higher), the number of abnormal (decreased) CL,s measurements would have been overestimated.
The use of specific CL,s (e.g. CL,s/functional residual capacity ratio) has the potential advantage that it can be regarded as a parameter of lung mechanics that is independent of lung volume. However, only very limited reference value data are available. Moreover, the large majority of patients exhibited normal lung volumes, so adjusting for lung volume would have had limited impact on the results.
Quasi-static expiratory P–V curves were used to assess CL,s (slow expiration from TLC, without interruptions forced by a shutter). This may lead to underestimation of CL,s in patients with increased airway resistance, particularly if airflow is not very low 19. However, airway obstruction with increased airway resistance (>0.35 kPa·L−1·s) occurred in only eight cases (<1% of the group) and expiratory flow during measurements was low (0.3 L·s−1). Moreover, the comparative studies in some patients showed good agreement between semi-static lung compliance and CL,s (online supplementary material).
This was a cross-sectional study of patients at various stages of disease. Some patients may have had above-average PFT results before the onset of disease, and, despite having lost lung function, the test results may have remained within normal limits. Measurement of change in lung function over a prolonged period would be more sensitive in such cases.
We believe that lung function assessment in sarcoidosis patients should include CL,s measurement as a method of evaluation of the mechanical properties of the lungs, as it discloses abnormalities in pulmonary function that are not detected by measurement of lung volumes and DL,CO. CL,s and DL,CO concern different aspects of respiratory pathophysiology, and they complement, rather than overlap, each other in revealing lung function disturbances at all stages of the disease. The functional abnormalities are likely to reflect parenchymal involvement and correlate well with clinical staging, but further studies are required in order to assess the prognostic value of a low CL,s in patients with sarcoidosis.
Acknowledgments
We thank J. Zielinski (2nd Dept of Respiratory Medicine, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland) for unfailing support and guidance, and the patients, who did not complain when we inserted the oesophageal balloons for CL,s measurements. We also thank the reviewers for their very helpful comments.
Footnotes
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Statement of Interest
None declared.
- Received October 21, 2009.
- Accepted March 26, 2010.
- ©ERS 2010
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