Alterations in pulmonary function in inflammatory bowel disease are frequent and persist during remission

THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.

Vol. 97, No. 2, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(01)04035-7

Alterations in Pulmonary Function in Inflammatory Bowel Disease Are Frequent and Persist During Remission K. R. Herrlinger, M. K. Noftz, K. Dalhoff, D. Ludwig, E. F. Stange, and K. Fellermann Division of Gastroenterology, Department of Internal Medicine I, and Division of Pulmonology, Department of Internal Medicine II, Medical University of Luebeck, Luebeck; and Department of Internal Medicine I, Robert-Bosch-Hospital, Stuttgart, Germany

OBJECTIVES: Information on the occurrence and frequency of pulmonary involvement in patients with inflammatory bowel disease (IBD) is inconsistent. The aim of this prospective study was to determine the frequency and type of pulmonary dysfunction in patients with IBD. METHODS: Sixty-six patients with IBD (35 with Crohn’s disease [CD] and 31 with ulcerative colitis [UC]) and 30 control patients were investigated with respect to the following pulmonary function tests: forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC), Tiffeneau value (FEV1/IVC), and lung CO transfer capacity (DLCO). Disease activity in IBD patients was assessed by the CD activity index for CD and the Truelove index for UC, respectively. Smoking habits and medication were documented in every patient. RESULTS: Fourteen of 36 CD patients (39%) and 14 of 31 UC patients (45%) but only one of the controls exhibited at least one pathological (⬍80% of predicted value) pulmonary function test. In both CD and UC lung function tests were significantly decreased in comparison to the control group. This could be shown for FEV1 (⫺14% of predicted value in CD and ⫺17% in UC, p ⬍ 0.01), IVC (⫺10% in CD and ⫺12% in UC, p ⬍ 0.05), and DLCO (⫺20% in CD and ⫺31% in UC, p ⬍ 0.01) without significant differences between both disease entities. The impairment of pulmonary function tests was more pronounced in patients with active disease than in those with inactive disease (FEV1, 81.4% vs 93.4% predicted, p ⬍ 0.02; IVC, 84.4% vs 93.7%, p ⬍ 0.05; DLCO, 80.4% vs 95.8%, ns). CONCLUSIONS: IBD patients show significantly decreased lung function tests in comparison to healthy controls. The impairment in active disease exceeded that during remission. (Am J Gastroenterol 2002;97:377–381. © 2002 by Am. Coll. of Gastroenterology)

INTRODUCTION Several extraintestinal manifestations of inflammatory bowel diseases (IBD) have been characterized affecting the

skin, eyes, joints, liver, kidney, pancreas, and, in rare cases, the lung. Different pulmonary manifestations have been reported, including small and large airway dysfunction (1, 2) as well as obstructive and interstitial lung disorders (3). Also, case reports do not show a uniform picture of disease and describe various entities including bronchial hyperresponsiveness (4), bronchitis and bronchiectasis (5– 8), inflammatory tracheal stenosis (9), and interstitial pneumonitis (10) as well as bronchiolitis obliterans– organizing pneumonia (11–13). Some authors reported pulmonary impairment in IBD patients to be related to disease activity as well (14, 15). This would seem to be similar to a recent study by our group showing renal inflammatory involvement to be a frequent phenomenon in patients with IBD. Tubular proteinuria was found to be a sensitive marker of disease activity in both Crohn’s disease (CD) and ulcerative colitis (UC) (16). Apart from extraintestinal activity, side effects of treatment may contribute to pulmonary dysfunction in IBD patients. Aminosalicylates belong to the standard therapy in acute relapses as well as in remission maintenance therapy of IBD (17, 18). Hypersensitivity pneumonitis has been described during aminosalicylate treatment. This complication is rare (19), but has been reported in single cases for sulfasalazine (20 –25) and mesalazine (26 –30). Investigation of pulmonary function in IBD patients by standard lung function tests has revealed inconsistent results. Whereas some authors could not detect differences in routine pulmonary function tests between IBD patients and controls (31, 32), others documented a reduced lung transfer factor for carbon monoxide (DLCO), especially in patients with active IBD (1, 15, 33). The aim of this prospective study was to screen for pulmonary dysfunction in patients with IBD with respect to disease activity. Furthermore, the influence of medication, especially aminosalicylates, on pulmonary function was evaluated. It could be shown that pulmonary impairment was frequent during active disease but occurred even during remission.

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Table 1. Demographic Data of Patient Groups n Mean age (yr) Male/female Smoking (%) Steroids (%) Aminosalicylates (%) CDAI ⬎ 200 (%) Truelove moderate/severe (%)

CD

UC

Controls

35 37 16/19 17 68 80 37

31 38 15/16 10 77 74

30 42 15/15 33

68

PATIENTS AND METHODS Patients Sixty-six patients with IBD and 30 control patients were enrolled in this prospective study. In the IBD group 35 had CD (CD activity index [CDAI] range ⫽ 25–514) and 31 had UC. Thirty healthy persons served as a control group. All three groups (CD, UC, and control) were similar in age and sex (Table 1). The mean age in IBD patients was 36 yr (range ⫽ 15– 66), and the mean age in control patients was 41 yr (range ⫽ 20 –73). The mean duration of disease in IBD patients was 80 months (range ⫽ 1–354). Fifty-two of 66 patients were receiving aminosalicylates (between 2 and 4 g/day) for at least 5 days, 48/66 patients were on corticosteroids (mean dose ⫽ 35 mg [range ⫽ 2.5–100]). None of the patients had ever received methotrexate. Smoking habits were documented in every patient. Exclusion Criteria Reasons for exclusion from the study were major operations, abnormal chest X-ray, signs of infectious bronchitis or pneumonia, use of nonsteroidal anti-inflammatory drugs, and lack of compliance in performing lung function tests. Disease Activity Disease activity was assessed by the CDAI for CD or the Truelove index for UC, respectively. In CD, Best’s CDAI (34) was calculated from the number of liquid stools, general well-being, abdominal pain, relative Hct, body weight in relation to standard weight, and administration of antidiarrheal drugs. Patients with a score of ⬎200 were considered to have active disease. Disease activity in patients with UC was assessed using the Truelove score (35). This score includes stool frequency, fever, the occurrence of blood in stool, and, for laboratory findings, the Hb value and erythrocyte sedimentation rate. Patients with Truelove indices of mild were considered to be in remission, and patients with indices moderate or severe had active disease. Pulmonary Function Tests Spirometry was used to determine forced expiratory volume in 1 s (FEV1), the inspiratory forced vital capacity (IVC), and the Tiffeneau value (FEV1/IVC). Results were expressed as the percentage of the normal value for gender, age, and height (percent predicted). The diffusing capacity for carbon monoxide (DLCO) was measured by the single breath method.

Table 2. Analysis of Variance (Depending on Variables FEV1, IVC, and DLCO) Testing the Fix Factors Disease Entity, Disease Activity, 5-Aminosalicylate, and Smoking FEV1 Disease entity Mean square F p Disease activity Mean square F p 5-Aminosalicylate Mean square F p Smoking Mean square F p

IVC

DLCO

327.15 1.03 0.32

0.02 0 1.0

255.36 0.52 0.49

1777.30 5.6 0.03

1284.10 7.0 0.01

57.78 0.12 0.74

355.83 1.1 0.30

29.0 0.16 0.70

343.84 0.70 0.43

2348.61 7.4 0.01

257.55 1.40 0.25

330.63 0.67 0.44

Statistics Statistical analysis was performed by analysis of variance. Data were tested for normal distribution. Simple regression was used to calculate correlation coefficients. All analyses were performed using the statistical package SPSS 8.0 for Windows (SPSS, Chicago, IL). Values are expressed as mean ⫾ 1 SEM if not indicated otherwise. p ⬍ 0.05 was considered to be statistically significant.

RESULTS Lung Function Tests in IBD Patients Versus Controls Fourteen of 36 CD (39%) and 14 of 31 UC patients (45%) but only one of the controls showed at least one pathological (⬍80% of predicted value) pulmonary function test. In both CD and UC lung function tests were significantly diminished in comparison to the control group. This could be shown for FEV1 (⫺14% of predicted value in CD and ⫺17% in UC, p ⬍ 0.01), IVC (⫺10% in CD and ⫺12% in UC, p ⬍ 0.05), and DLCO (⫺20% in CD and ⫺31% in UC, p ⬍ 0.01) without significant differences between both disease entities. Also, in the analysis of variance there was no influence of the disease entity on pulmonary function (Table 2). Influence of Disease Activity, Smoking Habits, and Aminosalicylate Medication Regarding the three groups—1, IBD patients with active disease (CDAI ⬎ 200, Truelove moderate/severe, n ⫽ 34); 2, IBD in remission (CDAI ⬍ 200, Truelove mild, n ⫽ 32); and 3, healthy controls (n ⫽ 30)—an analysis of variance was performed to evaluate the influence of disease activity on lung function. When compared to healthy controls even patients in remission showed diminished results in all lung function tests (FEV1, 104.0 ⫾ 1.9% vs 93.4 ⫾ 3.3%, p ⬍ 0.05; IVC, 101.0 ⫾ 2.2% vs 93.7 ⫾ 2.7%, p ⫽ 0.17; DLCO, 113.3 ⫾ 3.7% vs 95.8 ⫾ 6.8%, p ⬍ 0.05). In comparison to

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DISCUSSION

Figure 1. Influence of disease activity on pulmonary function tests comparing three groups: healthy controls (C), patients in remission (R), and patients with active disease (A).

patients in remission, patients with active disease performed significantly worse regarding FEV1 (81.4 ⫾ 3.3% vs 93.4 ⫾ 3.3%, p ⬍ 0.02) and IVC (84.4 ⫾ 2.9% vs 93.7 ⫾ 2.7%, p ⬍ 0.05). Differences in DLCO did not reach statistical significance between these two groups (80.4 ⫾ 4.0% vs 95.8 ⫾ 6.8%). There were no significant differences between the three groups regarding the Tiffeneau value (97.2 ⫾ 2.4% vs 100.4 ⫾ 2.9% vs 104.6 ⫾ 2.0%). To evaluate the influence of disease entity, activity, and the influence of aminosalicylate medication on pulmonary function tests, another analysis of variance was performed for only IBD patients, testing the fix factors 1, disease entity (CD vs UC); 2, disease activity (inactive vs active); 3, aminosalicylate medication (“on” vs “off” aminosalicylates); and 4, smoking (“yes” vs “no”). Consistent with the results described above (Fig. 1), FEV1 and IVC were significantly dependent on disease activity, whereas DLCO was not. As expected, smoking had a significant influence on FEV1 (73.8 ⫾ 7.4% vs 93.3 ⫾ 3.0%, p ⬍ 0.02). There was no significant influence of disease entity or 5-aminosalicylate medication on pulmonary function tests. Furthermore, there were no significant interactions between the investigated fix factors (Table 2). Regarding patients with disease onset during their (pre-) adolescent years (age at diagnosis 16 and younger, n ⫽ 7), there were no significant differences when compared to the 59 patients older at disease onset (FEV1, 88.4 vs 87.1%; IVC, 80.1 vs 90.0%; Tiffeneau, 107.4 vs 97.7%; DLCO, 110.0 vs 86.1%). To search for a possible connection between renal and pulmonary dysfunction, results from pulmonary function tests were correlated with tubular proteinuria. Although both renal and pulmonary extraintestinal manifestations were linked to disease activity, there was no correlation between results from pulmonary function tests and proteinuria (data not shown).

We investigated the prevalence and type of abnormal pulmonary function in patients with IBDs in comparison with healthy controls. The influence of medication, especially aminosalicylates, was analyzed. We detected abnormal results in pulmonary function tests (defined as ⬍80% of predicted values) in a surprisingly large proportion of IBD patients (42%). Consistent with earlier results (32), there were no differences between both disease entities, UC and CD. Furthermore, medication with aminosalicylates did not have an influence on pulmonary function tests. Although mesalamine-induced pneumonitis has been described in several cases (26 –28), our results support the notion that aminosalicylate-induced lung toxicity is a rare complication (19). The influence of disease activity on pulmonary function tests in IBD patients is still under debate. Whereas several studies did not find an influence of disease activity, especially regarding the transfer factor for carbon monoxide (DLCO) (36, 37), two recent studies (1, 15) found DLCO to be significantly diminished in active disease. In the present study patients with active disease showed significantly decreased lung function tests when compared to patients in remission. Thus, our results suggest an influence of disease activity but do not emphasize the role of DLCO as a specific marker of disease activity, because in our study FEV1 and IVC were also significantly reduced in active disease. The reduction in both FEV1 and IVC without alteration of the Tiffeneau value suggests a restrictive pattern of lung function impairment. It may be difficult to distinguish between disease-related complications and the influence of general well-being on these tests because patients with severe disease activity may perform worse because of general sickness and fatigue. Apart from poor compliance in performing the tests being an exclusion criterion in our study, a strong argument for the influence of disease is the fact that patients in remission without clinical symptoms performed significantly worse than healthy controls. This is a strong argument for the influence of the disease itself and strengthens the hypothesis that the observed abnormalities in lung function tests represent a real extraintestinal manifestation of IBD. Pulmonary complications have been described in other autoimmune disorders not primarily affecting the lung as well—for example, in rheumatoid arthritis (38 – 42), Sjogren’s syndrome (43– 48), and ankylosing spondylitis (49). The mechanism of pulmonary involvement in autoimmune diseases is unclear. On the one hand, circulating cytokines may be responsible for systemic manifestations of IBD—as, in this case, a kind of interstitial pneumonitis. A key mediator of inflammation in IBD seems to be tumor necrosis factor ␣. Serum levels of tumor necrosis factor ␣ (50, 51) and interleukin 6 (52, 53) are raised, especially in CD, probably because of circulating activated inflammatory cells. These cytokines play a relevant role in another inter-

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stitial lung disorder very similar to CD, sarcoidosis (54 –56), but also in the pathogenesis of other interstitial lung diseases (57, 58). On the other hand, lymphocytes sensitized from the GI tract may induce inflammation on mucosal surfaces of other organs. In CD, alveolar lymphocytosis has been reported among patients free of clinical symptoms (37, 59). A recent study investigating induced sputum in CD patients found the CD4/CD8 quotient to be abnormally high in patients with active disease relative to patients in remission (60). In a recent case we have even observed the association of CD and pulmonary sarcoidosis (61). Proteinuria of ␣1 microglobulin was described to be a sensitive marker of disease activity in both disease entities, UC and CD (16). Interestingly, although both pulmonary and renal dysfunctions were frequent in patients with active IBD, there was no correlation between these two extraintestinal manifestations (data not shown). Therefore, both cannot simply be related to systemic inflammation but rather form specific extraintestinal symptoms in different patients. Therefore these different complications of IBD may serve to define different subgroups of disease. Taken together, subclinical pulmonary dysfunction is frequent in IBD, dependent on disease activity, but persists even during remission. Because alterations were subclinical and none of the patients showed pulmonary symptoms, there was no need for specific therapy. Pathophysiological mechanisms and clinical relevance are to be further clarified.

ACKNOWLEDGMENT We are indebted to H. J. Friedrich, M.D., who performed the statistical analysis. Reprint requests and correspondence: Klaus Herrlinger, M.D., Department of Internal Medicine I, Division of Gastroenterology, Hepatology and Endocrinology, Robert-Bosch-Krankenhaus, Auerbachstr. 110, D-70397 Stuttgart, Germany. Received Mar. 26, 2001; accepted Aug. 14, 2001.

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