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* From the Pulmonary and Critical Care Medicine Service, Walter Reed Army Medical Center, Washington, DC.
Correspondence to: Andrew F. Shorr, MD, MPH, Pulmonary and Critical Care Medicine Service, Walter Reed Army Medical Center, 6900 Georgia Ave, NW, Washington, DC 20307; e-mail: afshorr{at}dnamail.com
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Abstract |
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Design: Prospective series of consecutive patients.
Setting: Pulmonary clinic of a military, tertiary-care teaching hospital.
Patients: Patients with newly diagnosed sarcoidosis.
Interventions: All patients undergoing bronchoscopy for the diagnosis of sarcoidosis underwent an evaluation that included history, physical examination, chest radiography, and spirometry. Bronchoprovocation testing was done using methacholine. During bronchoscopy, six endobronchial biopsy (EBB) specimens were obtained. In patients with abnormal-appearing airways, four specimens were obtained from abnormal areas and two specimens were obtained from the main carina. In patients with normal-appearing airways, four specimens were obtained from a secondary carina and two specimens were obtained from the main carina. A biopsy specimen was considered positive if it demonstrated nonnecrotizing granulomas with special stains that were negative for fungal and mycobacterial organisms. Only patients with histologic confirmation of sarcoidosis were included in the data analysis.
Measurements and results: The study cohort included 42 patients (57.1% were men, 61.9% were African American, and mean age [± SD] was 37.3 ± 6.6 years). AHR was present in nine patients (21.4%), while EBB revealed nonnecrotizing granulomas in 57.1% of patients. All patients with AHR had positive EBB findings compared to 45.5% of individuals without AHR (p = 0.005). There was a trend toward lower lung volumes and flow rates in patients with AHR, but this did not reach statistical significance. The mean serum angiotensin-converting enzyme level was higher in patients with AHR (79.3 ± 53.9 IU/L vs 37.5 ± 26.7 IU/L, p = 0.05). No other clinical variable correlated with the presence of AHR.
Conclusions: AHR may be seen in patients with sarcoidosis. Endobronchial involvement significantly increases the risk for AHR and may play a role in the development of AHR in patients with sarcoidosis. Other clinical factors are not clearly associated with AHR in patients with sarcoidosis.
Key Words: airway • angiotensin-converting enzyme • endobronchial • hyperreactivity • sarcoidosis
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Airway hyperreactivity (AHR) has been reported3 4 5 6 to occur in 5 to 83% of patients with sarcoidosis. For example, Marcias and coworkers3 observed AHR in 20.6% of patients with sarcoidosis, while Bechtel et al4 noted AHR in 50.0% of patients with sarcoidosis. The wide reported range in the incidence of AHR in patients with sarcoidosis likely reflects differences in study design and patient selection. Earlier studies on this topic have included patients lacking a formal histologic diagnosis, employed differing definitions of AHR, and were completed prior to the development of formal guidelines7 for the conduct and interpretation of bronchoprovocation testing.
Identifying AHR in patients with sarcoidosis may have important clinical implications. Some individuals with sarcoidosis, despite normal spirometric findings and normal lung parenchyma shown on CXR, complain of dyspnea, cough, and wheeze.1 2 8 The presence of AHR may explain these symptoms. Similarly, AHR may also indicate that patients have symptoms that might respond to treatment with inhaled rather than oral corticosteroids. Chronic airflow obstruction, a possible sequelae of untreated AHR, has been shown to portend a worse prognosis in patients with sarcoidosis.9 Fixed airflow obstruction in sarcoidosis is associated not only with parenchymal lung involvement, but it also has been shown9 to nearly double the risk for mortality.
Factors associated with AHR in patients with sarcoidosis remain unknown. Some have suggested that AHR is associated with worse pulmonary function as measured by spirometry, while others have found no link between the results of pulmonary function tests (PFTs) and AHR.3 4 5 6 Moreover, the mechanism of AHR in patients with sarcoidosis has not been elucidated. Endobronchial granulomas, which are noted in approximately half of the patients with sarcoidosis, may lead to AHR by either elaborating mediators that promote inflammation or by altering cholinergic receptors in the airways. No studies have correlated the finding from endobronchial biopsy (EBB) with the results of bronchoprovocation testing in patients with sarcoidosis. We hypothesized that endobronchial involvement would be a risk factor for AHR. To test our hypothesis, we conducted a prospective study in consecutive patients with newly diagnosed sarcoidosis to explore the relationship between the results of EBB and bronchoprovocation challenge.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Evaluation
All subjects underwent a standard evaluation that included a
history and physical examination, a CXR, and PFTs with measurement of
the single-breath diffusion capacity of the lung for carbon monoxide
(DLCO). Radiographic stages were defined as follows: stage
0, normal CXR finding; stage I, bilateral hilar lymphadenopathy alone;
stage II, bilateral hilar lymphadenopathy with interstitial
infiltrates; and stage III, interstitial infiltrates alone. The PFTs
and DLCO were interpreted in accordance with the guidelines
of the American Thoracic Society (ATS).11
Normal values
were derived from Crapo et al,12
and corrections for race
were made. DLCO was further corrected for hemoglobin.
Values for PFTs and DLCO were considered abnormal if they
fell outside the 95% confidence interval (CI) for the predicted
values. The erythrocyte sedimentation rate (ESR) and the
angiotensin-converting enzyme (ACE) level were measured. The ACE level
was determined via an enzymatic assay (Quest Diagnostics; Baltimore,
MD). The normal range for this at our institution varies from 8.0 to
52.0 IU/L. The presence of pulmonary symptoms (dyspnea, cough, and
wheezing) was determined from a standard questionnaire completed by all
subjects on enrollment.
Bronchoprovocation Testing
For bronchoprovocation testing, we used methacholine. The
five-breath dosimeter method originally described by Chai et
al13
was used, with patients inhaling increasing doses of
methacholine: 0.025, 0.25, 2.5, 10.0, and 25.0 mg/mL. AHR was
considered present at the provocative dose of methacholine causing a
20% fall in FEV1 (PD20).
After the initiation of this study, the ATS published new
guidelines7
for methacholine challenge testing that
recommended a different dosing regimen and proposed an alternative
interpretive strategy based on the provocative concentration of
methacholine causing a 20% fall in FEV1. These
guidelines became available after our study began enrollment.
Therefore, for the sake of consistency and reproducibility, we relied
on the dosing schedule of Chai et al.13
The severity of
AHR was graded as follows: PD20 < 20 breath
units (BUs), severe; 21 to 50 BUs, moderate; 51 to 188.88 BUs, mild.
However, after our initial data analysis of the relationship between
the yield of EBB and AHR based on the PD20, we
reassessed the data employing the currently proposed definition of a
positive methacholine challenge result. Under the most recent
rubric,7
a methacholine challenge test result is
considered positive if the provocative concentration of methacholine
causing a 20% fall in FEV1 is 
16 mg/mL.
Bronchoscopy
Fiberoptic bronchoscopy was performed in standard fashion in all
patients, with six EBB specimens obtained. For patients with
abnormal-appearing airways, four specimens were obtained from the
abnormal-appearing airways and two specimens were obtained from the
main carina. In patients with normal-appearing airways, four specimens
were obtained from a secondary carina and two specimens were obtained
from the main carina. An 18-mm, smooth-edged jaws forceps (Boston
Scientific; Watertown, MA) was used. Pathologists reviewing the
specimens were blinded not only to the patient’s clinical presentation
(eg, symptoms, CXR findings) but also to the results of the
bronchoprovocation testing. An EBB specimen was considered positive if
it revealed nonnecrotizing granulomas with specials stains that failed
to show either mycobacterial or fungal organisms.
Statistical Analysis
Patients with AHR were compared to those with negative
bronchoprovocation challenge findings with respect to the following:
(1) the results of EBB, and (2) the variables noted above. The
Student’s t test was used for the analysis of continuous
variables. The 
2 was employed to compare
categorical variables except in cases when expected values were small.
In these instances, we relied on the Fisher’s Exact Test. The
distribution of CXR stages was analyzed via the Wilcoxon rank-sum test.
All tests were two tailed, and a p < 0.05 was assumed to represent
statistical significance. Ninety-five percent CIs are reported where
appropriate. Analyses were done using software (SPSS version 9.0; SPSS;
Chicago, IL).
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The methacholine challenge test result was positive in nine patients (21.4%; 95% CI, 10.3 to 36.8%). In four patients, AHR was mild, while it was moderate in three patients. In only two patients was AHR severe. As shown in Table 1 , 24 patients (57.1%) had EBB specimens demonstrating nonnecrotizing granulomas. All nine of the patients (100%) with AHR had positive EBB findings, as compared to 15 of the 33 patients (45.5%) with negative bronchoprovocation challenge results (p = 0.005). The relative risk for AHR associated with the presence of nonnecrotizing granulomas on EBB was estimated to be 11.9 (95% CI, 1.5 to 103.9). There was no association between AHR and airway appearance. The incidence of abnormal-appearing airways (defined as either erythema or mucosal thickening) was similar among those with AHR and those without AHR.
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When we reanalyzed our findings employing the new, stricter definition of AHR proposed in the most recent ATS guidelines, two patients who had been categorized as having AHR no longer met the criteria for AHR. The relationship between EBB and AHR remained statistically significant (p = 0.014). The difference in ACE levels observed when using the PD20 criteria for AHR was no longer present. Additionally, there continued to be no relationship between any of the other variables we examined and the results of bronchoprovocation testing.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies3 4 5 6 have examined either the clinical implications of endobronchial granulomas or risk factors for AHR in patients with sarcoidosis. None of these efforts, however, has investigated a possible relationship between the two. In an early study of AHR in patients with sarcoidosis, Bechtel et al4 noted positive methacholine challenge results in 50.0% of patients. They further observed that subjects with AHR had worse spirometry results as measured by FVC, FEV1/FVC ratio, and DLCO. The disparity of these findings as compared to our observations regarding both the incidence of and possible clinical markers for AHR likely results from the fact that Bechtel et al4 studied a convenience sample rather than an unselected sample of consecutive patients, and included patients currently being treated with corticosteroids.4 Presas and colleagues14 examined the incidence of AHR in patients with stage I sarcoidosis using methacholine. In their sample of 12 subjects, 6 subjects demonstrated AHR. However, they failed to find a relationship between baseline spirometry and the results of bronchoprovocation testing. Confirming the lack of a correlation between prechallenge PFTs and AHR, Marcias et al3 reported AHR in 26.6% of individuals with sarcoidosis but found responders and nonresponders had similar baseline FEV1, FVC, and FEV1/FVC ratios. For example, the mean FEV1 in subjects with AHR was 91% of predicted compared to 103% of predicted in those without AHR. Although we noted a statistical trend toward worse PFT results in association with AHR, our findings build on these earlier studies. By validating in a larger, untreated sample of patients with sarcoidosis that spirometry is unlikely to be of value in determining if AHR is present, our results suggest that formal bronchoprovocation testing to evaluate persistent symptoms may be indicated irrespective of normal screening spirometry results.
We also noted a higher serum ACE level in patients with AHR. Although the initial relationship between ACE and sarcoidosis was described in 1975,15 most prior investigations into AHR and sarcoidosis have not reported data regarding either serum markers of disease activity or inflammation. However, Niimi et al16 examined the relationship between ACE gene polymorphisms and AHR in patients with sarcoidosis; in a study of 21 patients, they found differences in AHR based on the ACE genotype. They further observed a weak correlation between the serum ACE level and AHR as measured by changes in respiratory resistance. Since ACE inhibits the breakdown of bradykinin, a potent bronchoconstrictor and inflammatory mediator, the link between serum ACE levels and AHR suggests that ACE may directly mediate AHR in patients with sarcoidosis. Nonetheless, the role for ACE is likely limited. Specifically, when a more stringent definition of AHR was employed, the relationship we noted between AHR and ACE was no longer present.
Patients with endobronchial involvement from sarcoidosis are at significantly increased risk for AHR. Endobronchial granulomas may play a role in the development of AHR in one of several ways. First, endobronchial granulomas may lead to airway narrowing. Some researchers have postulated that a smaller airway lumen directly increases the risk for AHR.17 Second, the presence of endobronchial granulomas may disrupt, uncover, or stimulate cholinergic receptors, which, in turn, may enhance AHR. Supporting this possibility, Laitinen et al17 reported that electron microscopy of EBB specimens in three subjects with sarcoidosis and AHR revealed damaged superficial afferent nerve endings. Electron microscopy further demonstrated extensive epithelial damage and injury to the basement membrane. Finally, the granulomas themselves may elaborate mediators that directly promote AHR.18 Irrespective of the possible mechanisms for the association between endobronchial involvement and AHR in patients with sarcoidosis, other factors must also be involved. More specifically, the majority of patients with positive EBB results failed to demonstrate AHR. Similarly, no patients with a negative EBB result had AHR. This suggests that endobronchial involvement likely is a necessary precondition for the development of AHR. Conversely, the isolated presence of endobronchial granulomas is insufficient to explain AHR pathophysiologically in this disease.
Our study has several limitations. The first limitation is that the majority of the patients in this study were men, while sarcoidosis is seen more frequently in women.1 2 This may limit the generalizability of our findings. The study population, though, was similar to the typical sarcoidosis population in the United States, in that it predominantly consisted of young, African-American patients with stage I CXR findings. Second, because of the sample size, the study may have been underpowered to identify variables that would segregate patients with AHR from those with negative methacholine challenge results. For example, the trend toward a difference in spirometry findings between patients with and without AHR might have reached statistical significance with a larger sample. This fact also explains why the p value increased when we reanalyzed our results using the stricter definition of AHR. With a lower incidence of AHR, the relationship between AHR and EBB was not as strong. Nonetheless, our study was larger than earlier investigations3 4 5 6 of AHR in sarcoidosis and was less subject to bias in that we prospectively enrolled consecutive patients. Third, EBB may be prone to sampling error. In other words, patients who were categorized as lacking endobronchial involvement may have had endobronchial granulomas identified if more samples were taken from other parts of the airway. Finally, we examined patients at only one point in time. Our study does not preclude the possibility that AHR may develop later in the course of sarcoidosis.
In conclusion, AHR may be seen in patients with sarcoidosis. The presence of endobronchial granulomas significantly increases the risk for AHR. Additionally, endobronchial granulomas likely play a role in the development of AHR in patients with sarcoidosis. Other clinical variables are not clearly associated with AHR in patients with sarcoidosis. Further studies are warranted to elucidate the clinical significance of endobronchial involvement in sarcoidosis and to examine if AHR in patients with sarcoidosis changes over time or with treatment.
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Acknowledgements |
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Footnotes |
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The opinions expressed herein are not to be construed as official or as reflecting the policy of either the Department of the Army or the Department of Defense.
Received for publication January 23, 2001. Accepted for publication March 28, 2001.
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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