INTRODUCTION

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Inflammatory bowel disease (IBD) is associated with a variety of extraintestinal manifestations, although the lungs are not generally considered as a common site of involvement (1). However, pulmonary lesions have been reported in IBD, including chronic bronchial suppuration in patients with ulcerative colitis (UC) (2), localized obstruction of the upper airways (3), bronchiolitis obliterans organizing pneumonia (4), diffuse obstructive disease (5), bronchiectasis (6), granulomatous lung disease (6), pulmonary vasculitis (6), and diffuse or localized interstitial lung fibrosis (6). Latent pulmonary involvement has been reported in a pediatric population with active Crohn's disease (CD), despite a short duration of the disease and absence of smoking (7). An increased bronchial hyperresponsiveness in patients with IBD with no bronchopulmonary symptoms and with normal baseline lung function has recently been reported (8). This latter observation may indicate that an inflammation exists in the airways that is not detectable by routine pulmonary function tests (PFTs).

Small peripheral airways (less than 2 mm in diameter) contribute less than 20% of the total airway resistance, and lesions in this region are difficult to detect. However, it is likely that some of the earliest changes in the airways of patients with IBD would affect primarily the small airways, and thus it is of importance to assess the function of the peripheral airways. Therefore, the aim of this study was to investigate the function of small airways using the density dependence of airflow technique in order to clarify if small airways are affected in patients with IBD. To the best of our knowledge this information is not available in the literature.

	METHODS

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Subjects

Eighteen patients with UC (five female, 13 male; mean age, 48 yr) and 12 with CD (seven female, five male; mean age, 46 yr), both histologically confirmed, agreed to take part in the study and gave their informed consent, which was in turn approved by University Hospital Ethics Committee. Patient demographic data and smoking habits, as well as disease characteristics according to location, activity, duration, and drug treatment are shown in Table 1. The site and extent of the bowel disease were studied by radiologic and/or surgical examinations performed within the previous 3 yr. Clinical remission in patients with UC was considered to be established if patients had one or two stools a day without blood, no fever or tachycardia, along with normal hemoglobin determinations and erythrocyte sedimentation rates (9). Crohn's disease activity was assessed using the Crohn's disease activity index (CDAI) (10, 11). Clinical remission in patients with CD was defined as an index score of less than 150 (10, 11). Patients who had a CDAI score higher than 150 were classified in three stages: mild, moderate, and severe (9, 10). The severity of their ulcerative colitis was assessed primarily on the basis of clinical features using the criteria of Truelove and Witss (11). According to these criteria the severity of the disease is classified into three stages (mild, moderate, and severe).

None of the patients had evidence of ankylosing spondylitis or other connective tissue disease. The presence or absence of respiratory symptoms was not taken into account in the selection process. A control group of 16 healthy subjects (seven female, nine male; mean age [± SD], 38 ± 16 yr) agreed to participate in the study. They had no history of respiratory disease or evidence of upper or low respiratory infection for at least 2 mo prior to the study. No significant difference in smoking habits was noticed between the groups.

Protocol

Patients and control subjects were studied for two consecutive days. On the first day, history, physical examination, posterior-anterior and lateral chest radiographs, electrocardiogram (ECG), and hematological and biochemical analyses were performed. On the second day, spirometry, lung volumes, carbon monoxide transfer factor (TL_CO), and flow-volume curve breathing room-air and breathing a mixture of 80% He-20% O₂ were performed.

Spirometry, Lung Volumes, and TL_CO

Spirometry, lung volumes by the helium dilution technique (12), and the lung transfer factor for carbon monoxide (TL_CO) by the single-breath method (12) were measured using a computerized system (MasterLab 2.12; E. Jaeger, Würzburg, Germany). All data are expressed as percentages of the predicted values (12).

Assessment of Small Airways

Maximal flow-volume curves were measured by a No. 4 pneumotachograph (A. Fleisch, Lausanne, Switzerland) coupled to a differential pressure transducer for flow and by integration for volume (Model MCI-10; Validyne Engineering Corp., North Ridge, CA). The pneumotachograph was calibrated separately for air and He-O₂ and was linear with flows as great as 15 L/s. The flow-volume curve was stored as digital data and analyzed using the AT-MCA Codas package (1989- 1992) (Dataq Instruments, Akron, OH). The subject was seated and instructed to perform maximal expiratory flow-volume curves while breathing room air and the mixture of 80% He and 20% O₂. Flow-volume curves while breathing He-O₂ were measured after the subject had breathed at least three VC inspirations of the He-O₂ mixture. The two -V curves obtained breathing room air and the He-O₂ mixture were superimposed visually from TLC. A difference of less than 5% in VC between breathing room air and the He-O₂ mixture was considered acceptable (the mean was < 3%). When the -V curves did not have identical VC, they were superimposed from RV (13, 14). The volume at which the flow rates became identical was defined as Viso. The Viso was expressed as a percentage of the FVC, according to the method of Dosman and colleagues (14). The value of max₅₀ was calculated from the equation max₅₀ = (Emax₅₀He-Emax₅₀air/ Emax₅₀air) × 100, and was thus expressed as a percentage of Emax₅₀ while breathing room air (14).

Critique of the Methods

The methods of density dependence used to calculate maximal expiratory flow rates have been criticized for their variability and their validity for detecting narrowing of the small airways (15). Some studies have correlated density-dependence tests with small airways disease (16, 17), whereas others could not confirm these findings (18). The present study was not designed to investigate these controversies but to apply the methods of density dependence to a group of patients (IBD) with presumed abnormal airway function (2, 8).

Statistical Analysis

All data are expressed as mean ± SD. For multiple comparisons among groups of patients and the control group, the Kruskal-Wallis test was used. For comparisons between two groups the Mann-Whitney U test was used. The difference of percentages among the groups was estimated using the chi-square test. All analyses were performed using the statistical package SPSS 6.0 for Windows (1989-1993); a p value less than 0.05 was considered statistically significant.

	RESULTS

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The mean values of the two parameters of small airways function in the patients with CD or UC and in the normal subjects are shown in Figure 1. The mean value (± SD) of Viso in patients with CD was statistically significantly greater than in control subjects (24.99 ± 1.5 versus 20.1 ± 1.39; p < 0.01). Similarly, the mean value of Viso (± SD) in patients with UC was greater than in control subjects (25.95 ± 1.35 versus 20.1 ± 1.39; p < 0.001) (Figure 1). No statistically significant difference in the mean values of Viso was found between patients with CD and those with UC (24.99 ± 1.5 versus 25.95 ± 1.35; p > 0.05). Similarly, no statistically significant difference in mean values of max₅₀ was found between patients with CD and those with UC (41.9 ± 7.5 versus 30.5 ± 5.9, p > 0.05) or between patients and control subjects (p > 0.05) (Figure 1).

View larger version (36K): [in this window] [in a new window]   Figure 1.   Mean values (± SD) of the indices of the small airways function (max 50 and Viso) in patients with Crohn's disease (CD) or ulcerative colitis (UC) and control subjects.

The mean values (± SD) of pulmonary function tests in patients with either active CD or UC and those with inactive CD or UC as well as the control group are shown in Figure 2. The mean value (± SD) of DL_CO in active CD (n = 5) was lower than in remission (n = 7) (78.5 ± 4.7 versus 98 ± 5.1; p < 0.05) (Figure 2). Similarly, the mean value (± SD) of DL_CO in active UC (n = 9) was lower than in remission (n = 9) (78.5 ± 4.7 versus 98 ± 5.1; p < 0.05) (Figure 2). Nonsignificant differences in the mean values of FVC, FEV₁, FEV₁/FVC, and TLC were found between patients and control subjects (Figure 2). The mean values (± SD) of the indices of small airways function in patients with either active CD or UC or inactive CD or UC and control subjects are shown in Figure 3. The mean Viso (± SD) was lower only in the nine patients with active UC when compared with the nine patients in remission (23.4 ± 6 versus 28.5 ± 4.3; p < 0.05) (Figure 3). No difference in Viso was found between active and nonactive CD (24.1 ± 1.4 versus 25.7 ± 1.2; p > 0.05) (Figure 3). Similarly, no statistically significant difference of max₅₀ was found between patients with active and those with inactive CD (43 ± 6 versus 33.8 ± 5; p > 0.05) or between those with active and those with inactive UC (29 ± 3.6 versus 42.9 ± 5.2; p > 0.05) (Figure 3).

View larger version (64K): [in this window] [in a new window]   Figure 2.   PFT (mean ± SD) indices of patients with either active or inactive CD or UC and control subjects.

View larger version (37K): [in this window] [in a new window]   Figure 3.   Small airways indices (mean ± SD) of patients with either active or inactive CD or UC and control subjects.

All of the subjects were classified into three categories according to the type of the treatment they received: treatment with mesalazine for at least 3 wk prior to the study (n = 20), treatment with both oral steroids and mesalazine for at least 3 wk prior to the study (n = 5), or no treatment (n = 5). The mean value of Viso in untreated patients was statistically significantly greater than in control subjects (30.2 ± 2.6 versus 20.1 ± 1.39; p < 0.05) (Figure 4). Similarly, the mean value of Viso in the patients treated with mesalazine was statistically significantly greater than in the control group (25.6 ± 1.14 versus 20.1 ± 1.39; p < 0.05) (Figure 4). In contrast, the mean value of Viso in patients treated with both steroids and mesalazine did not differ from that in the control subjects (20.96 ± 2.02 versus 20.1 ± 1.39; p > 0.05), but it was statistically significantly lower than in the group of untreated patients (20.96 ± 2.02 versus 30.24 ± 2.59; p < 0.05) (Figure 4). Finally, no statistically significant difference was found between patients receiving mesalazine and untreated patients (25.61 ± 1.14 versus 30.24 ± 2.59; p > 0.05) (Figure 4). Among all the foregoing groups there was no significant difference in any of the other indices (max₅₀, spirometry, lung volumes).

View larger version (27K): [in this window] [in a new window]   Figure 4.   Mean values (± SD) of Viso in control subjects and in patients with IBD being treated with mesalazine, a combination of mesalazine and oral steroids, or no treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The question addressed by the present study was whether small airways function was affected in patients with inflammatory bowel disease. The main finding was that the inflammatory bowel disease is indeed accompanied by dysfunction of the small airways. We found that both groups of patients with IBD showed increased Viso despite their normal baseline spirometric values. Contrarily, no significant change was found in max₅₀ between patients and control subjects or between patients with CD or UC. These findings, to the best of our knowledge, are reported here for the first time.

Since 1936, the influence of gas density on lung function has been of interest to scientists (19). During a FVC maneuver, the increase of maximal flow at high lung volumes while breathing 80% He-20% O₂ has been related to reduced gas density and its effect on turbulent flow. In contrast, at low lung volumes (which involve the small airways), flows become equal whether breathing air or He-O₂, because the flow in this region is laminar. It has been assumed that when Viso increases this is because of a narrowing of the lumen of the airways caused by an increase in the area of laminar flow (19). Despas and colleagues (13) reported that early manifestation of peripheral airway obstruction can be detected in patients with mild asthma using the He-O₂ mixture. Moreover, Dosman and colleagues (14) showed that the use of He during a maximal expiratory flow-volume maneuver was capable of detecting functional abnormalities in smokers at a stage when spirometric indices were within the normal range. A considerable number of clinical studies have followed these observations and have shown that alterations in small airways function could be detected, at a subclinical level, in a population at risk for developing obstructive airway disease.

In the present study, the measurement of Viso was the most sensitive method for detecting alterations in the function of the small airways. We failed to detect a statistically significant difference between patients and control subjects using the max₅₀ index. This is in accordance with the study of Dosman and colleagues (14). They reported that Viso was the most sensitive test for detecting dysfunction of the small airways in "healthy" smokers. It has been reported by Bode and coworkers (20) and Dosman and colleagues (14) that airway disease, and not loss of elasticity, is the major determinant for increased Viso. In the same studies a decrease of Viso after smoking cessation further supported the theory that increased Viso is due to airway obstruction and not to loss of elasticity (14, 20).

Alteration in small airways function in patients with IBD seen in this study could be attributed to an obstruction of the peripheral (less than 2 mm in diameter) airways not detectable by routine lung function tests. Supportive evidence for the presence of a subclinical obstruction can also be derived from the recent report of Louis and colleagues (8). They found an increased subclinical nonspecific bronchial hyperresponsiveness, independent of the presence of atopy, in patients with IBD and no pulmonary symptoms and normal baseline spirometry. Mild airway inflammation, secondary to the primary inflammation of the intestinal mucosa, could explain the alteration in the small airways seen in our study. Changes in the bronchial epithelium, consisting of basal cell hyperplasia, basement membrane thickening, submucosal inflammation, and an overall increase in thickness of the epithelium have been reported in bronchial biopsies from patients with ulcerative colitis and coexisting bronchial suppuration (2).

Alteration in small airways function was not detected in our patients with IBD being treated with a combination of mesalazine and steroids. In contrast, however, small airways dysfunction was present in both those patients receiving mesalazine and those in the untreated group. Our findings about the influence of the treatment mode on small airways function might be due to the occurrence of airway inflammation in one category of patients, including both untreated patients and patients treated with mesalazine, which had been suppressed in the other group by anti-inflammatory effect of steroids. This is in agreement with the study of Higenbottam and colleagues (2) who reported that in patients with UC and coexistent bronchial suppuration, inhaled beclomethasone dipropionate proved to be a satisfactory therapy in airway disease (2). However, a longitudinal design studying the patients before and after treatment is necessary in order to sort out this observation.

In addition, our data showed that impairment in diffusing capacity (TL_CO) was statistically significantly greater in both groups of patients with active disease (Figure 2). This finding is in accordance with the recently reported study of Munck and colleagues (7) who observed a higher prevalence of impaired TL_CO in pediatric patients with active phase Crohn's disease when compared with those in remission. The reduction in gas transfer factor may indicate an involvement of the lung parenchyma. High proportions of alveolar lymphocytes (alveolar lymphocytosis) have been reported in patients with CD who are free of pulmonary symptoms and have normal chest radiographs (21). This observation indicates that subclinical interstitial lung disease may be present in patients with IBD since it is known that a reduction in the diffusing capacity of the lungs is a common and early manifestation of interstitial lung disease (22). The observed reduction of TL_CO in this study in conjunction with an active disease might well be consistent with the presence of a subclinical alveolitis (23). The findings of studies using bronchoalveolar lavage fluid (21, 23, 24) lend additional support to the foregoing hypothesis of the migration of an inflammation, via the bloodstream, from the intestine into both the airway mucosa (8) and the lung parenchyma (25).

In conclusion, this study has shown that there is a dysfunction of the small airways in patients with IBD despite their normal PFTs. This observation, along with the observed impairment of the lung transfer factor for carbon monoxide shown to be present in the active phase of the disease supports the hypothesis that a subclinical inflammation in both the airways and the lungs accompanies the main inflammation in the bowel. However, further studies that include transbronchial biopsies are needed to verify the precise nature of our observations.