What Is Known
- Pulmonary function test abnormalities are common in adult with inflammatory bowel disease.
- Studies involving pulmonary function test abnormalities in pediatric inflammatory bowel disease are lacking with contradictory results and usually performed as cross-section studies.
What Is New
- It is the first longitudinal study that followed pulmonary function tests in pediatric inflammatory bowel disease patients at first diagnosis and for 3 years of the disease.
- Pulmonary function tests abnormalities are more common in pediatric inflammatory bowel disease than previously reported and expected and these abnormalities were more severe during disease activity but still present at remission.
Inflammatory bowel diseases (IBDs) are diverse groups of idiopathic chronic inflammatory intestinal conditions, the most common subtypes are Crohn disease (CD) and ulcerative colitis (UC) (1,2). Although IBD mainly affects gastrointestinal tract, yet, extraintestinal organ involvement occurs in up to half of the cases such as skin, eye, joint, and respiratory system (3). Many studies reported pulmonary involvement in adult IBD patients in the form of large and small airways affection, interstitial, and obstructive lung dysfunction (4–7). Other pulmonary involvement includes: interstitial pneumonitis, panbronchiolitis, bronchiolitis obliterans organizing pneumonia (BOOP), inflammatory tracheal stenosis, serositis, pulmonary vasculitis, apical fibrosis, and sarcoidosis (8). Moreover, higher incidence of asthma was reported in adults with IBD in many studies (9).
Interestingly, pulmonary function test (PFT) abnormalities are frequently found in IBD patients without the presence of any respiratory symptoms and these abnormalities persist even after remission, so it is widely assumed to be the earliest lung changes in these patients (4,10,11). However, studies in children are deficient with contradictory results. Few studies in pediatric IBD reported latent pulmonary function abnormalities but failed to correlate these changes with disease activity (12,13). Moreover, European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) did not consider pulmonary involvement as a feature of pediatric IBD that warrants regular investigation (14).
The aim of this work was to evaluate PFTs in newly diagnosed children with IBD at the beginning of the disease and during 3 years of follow-up and to evaluate the correlation between PFTs and IBD activity.
PATIENTS AND METHODS
This is a prospective observational case-control study that was carried out at Pediatric Gastroenterology and Chest departments, Tanta University Hospital between June 2012 and June 2017. One hundred newly diagnosed children with IBD were included in the study as the patient group. They were further subdivided into patients with UC and patients with CD. All patients were diagnosed on basis of their history, clinical, endoscopic findings, and pathological reports of their biopsy samples according to ESPGHAN Porto criteria (13) for patients recruited before June 2014 and ESPGHAN revised Porto criteria (15) for patients recruited after that. Fifty healthy children of matched age, sex, height, and body mass index (BMI) with no history of asthma, atopy, or snoring were enrolled as a control group. The study was approved by local Ethical Committee of our faculty of medicine. Informed consent was signed by the parents of all children included in the study.
Newly diagnosed children with IBD.
Children with pathological findings in chest X-ray, lower respiratory tract infections (within 4 weeks before recruitment), allergic diseases, asthma, smoking, obesity, lack of compliance in performing PFTs, or chronic diseases such as cardiac, endocrine, or connective tissue disease.
All children included in the study were subjected to thorough physical examination, routine laboratory investigation (such as complete blood count, C-reactive protein, erythrocyte sedimentation rate, and liver function test), and PFTs.
Pulmonary Function Tests
Spirometry (Erich Jaeger GmbH, Hoechberg, Germany) was used to evaluate PFTs in all included children in the form of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, residual volume (RV), total lung capacity (TLC), and mid-forced expiratory flow of 25% to 75% (FEF 25%–75%). PFTs were done in sitting position, at 9.00 to 11.00 AM, repeated for 3 times and the mean value was recorded. Data were recorded as measurement values and the percentage of predicted values for age, sex, and height (16). Moreover, diffusing capacity of the lung for carbon monoxide (DLCO) was measured by single-breath method and was corrected to hemoglobin level (17,18). Values below 80% or above 120% of the predicted were considered abnormal.
All PFTs were performed on the same instruments by the same technologists who were blinded to the study. PFTs were done for all subjects at the start of the study, then every 6 months for patients group only for 3 years during remission, and at least once during disease activity (total of 7 PFTs for each patient).
The disease activity in CD group was assessed using Pediatric Crohn disease Activity Index (PCDAI) (19) with score ranges from 0 to 100, higher scores indicates more active disease. A score of less than 10 is consistent with inactive disease, 11 to 30 mild, 30 to 40 moderate, and more than 40 indicates severe disease. A decrease of 12.5 points is considered an evidence of improvement.
The disease activity in UC group was assessed using Pediatric Ulcerative Colitis Activity Index (PUCAI) (20). The PUCAI score ranges from 0 to 85. A score less than 10 denotes remission, 10 to 34 mild disease, 35 to 64 moderate and more than 64 denotes severe disease. A clinically significant improvement is defined as a decrease of more than 20 in PUCAI score.
The primary outcome was to evaluate the frequency and type of PFT abnormalities in newly diagnosed children with IBD. The secondary outcome was to correlate PFT abnormalities with disease activity in both UC and CD patients.
All quantitative data were expressed as mean ± standard deviation. Categorical variable was expressed using percentage. Data were tested for normal distribution by Shapiro-Wilk test. Differences between means of more than 2 groups were analyzed by one way analysis of variance (ANOVA) followed by post-hoc analysis. Paired t test was used to compare means within the same group. Unpaired t test was used to compare means between the 2 groups of IBD. Correlation coefficients were calculated using Spearman correlation between disease activity and lung function data. All the analyses were conducted using SPSS V.20 (SPSS, Chicago, IL). Statistical significance level was considered if P < 0.05.
This study included 100 patients with IBD ages 8 to 17 years, 52 patients with CD (28 boys and 24 girls) with mean age of (13.8 ± 2.6) years and 48 patients with UC (25 boys and 23 girls) with mean age of (14.2 ± 2.7) years. Fifty healthy children (25 boys and 25 girls) served as controls with mean age of (13.5 ± 3.1) years. There was no significant difference among the 3 groups as regards age, sex, height, BMI or PFTs at the start of the study (Table 1).
There was significant decrease in FEV1, FVC, FEF 25% to 75%, and DLCO in patient groups at the end of the study compared with their ratio at the start of the study (P < 0.05). Whereas, there was no significant difference as regards FEV1/FVC, RV, and TLC in IBD groups at the end of the study when compared with the start of the study (P > 0.05). Interestingly, 25 patients (14 CD and 11 UC) had diffusion capacity impairment, 15 patients (9 CD and 6 UC) had restrictive pulmonary dysfunction and 19 patients (8 CD and 11 UC) had small airway obstruction (Table 2).
Comparing PFTs between CD and UC patients at the end of the study showed that there was no significant difference for all PFTs between the 2 groups (P > 0.05; Table 3). Mild nonchronic respiratory symptoms were recorded in our patients during the study period in the form of nonproductive cough in 6 patients (3 with CD and 3 with UC) and wheezy chest for less than 3 days in only 1 patient with CD.
For IBD patients, there was significant deteriorations during disease activity in FEV1 (P = 0.01, P < 0.001), FVC (P = 0.02, P = 0.01), FEF 25% to 75% (P < 0.001, P = 0.03), and DLCO (P < 0.001, P < 0.001) for CD and UC patients, respectively, compared with their values during remission with nosignificant difference in FEV1/FVC, RV, and TLC (P > 0.05) (Table 4).
With correlation analysis for IBD patients using Spearman correlation coefficient, we found a significant negative correlation between the disease activity in both UC and CD groups and predicted FEV1%, FVC%, FEF 25% to 75% and DLCO% (P < 0.05; Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B350)
Respiratory affection occurring in IBD may consist merely of subclinical abnormal lung function. As PFTs abnormalities can occur in IBD without any obvious clinical or radiological findings, this reflects the importance of PFTs in detection of latent respiratory affection in IBD before it turns into a manifest disease (21). Results of PFTs in children with IBD are variable and contradictory in the few studies involving that topic, so we performed our study to evaluate the type and frequency of PFT abnormalities in children with IBD.
Our study confirmed that PFTs of children with newly diagnosed IBD were not different from those of healthy children at the start of the disease. The most prevalent PFT changes detected in our IBD patients during follow-up were decreased FEV1, EVC, FEF 25% to 75%, and DLCO. Deterioration in PFTs was more severe during activity period indicating the strong impact of the disease on PFTs that could not be explained by the mere effect of generalized weakness and fatigue during disease activity. Furthermore, patients at remission still had lower PFTs than normal controls, which confirmed that PFT abnormalities are real effects of IBD on the lung.
Decreased DLCO was the earliest and most frequent PFT abnormality in children with IBD. It was demonstrated in 25 children with IBD (25%) and was more severe during disease activity than remission. Deterioration of DLCO denotes early sign of interstitial lung disease. Endothelial damage is common in IBD and hence the lung endothelium was affected as well. Similar results were recorded in different adult studies such as Douglas et al (6) who reported that 16% of patients with IBD had decreased DLCO and Kuzela et al (5) who concluded deterioration in PFTs may be an early predictor of interstitial lung diseases in IBD adult patients before any clinical or radiological abnormalities. Moreover, Tzanakis et al (10) concluded same results and recorded that such deterioration increased during activity of IBD. Marvisi et al (22) recorded that deterioration in DCLO reached 81% during activity of UC compared with 53% during remission. Furthermore, few studies in pediatric IBD recorded similar results (12,23). So, we may consider decreased DLCO as a valuable marker of lung involvement in children with IBD. On the contrary to our results, Yammine et al (24) found no significant difference between DLCO of children with IBD and that of healthy controls. This can be because of lower sample size of their IBD patients (30 patients, and only 21 of them completed DLCO study). Furthermore, they measured PFTs once, but we have repeated measurements of PFTs every 6 months for a period of 3 years, so any change in PFTs was more accurately detected in our study.
The second most common PFT abnormalities in our IBD patients was decreased FEF 25% to 50% that was detected in 19 children with IBD (19%) and was more severe during disease activity reflecting small airways obstruction. Similar results were recorded by Yilmaz et al (25) who reported that 17 out of 66 (43.6%) IBD patients had abnormal small airway flow and obstruction.
Our study also showed significant decrease in FEV1 and FVC without alternation in FEV1/FVC ratio suggesting a restrictive lung dysfunction. This restrictive pattern of lung dysfunction was detected in 15 out of 100 IBD patients (15%). Similar results were reported by other investigators (4,26).
The exact cause of pulmonary involvements in IBD is still unknown, and it is largely related to multiple underlying mechanisms, including the widespread inflammatory process and pulmonary damage caused by circulating inflammatory mediators and immune complex occurred in IBD (27,28). The common embryonic origin of both colonic and respiratory epithelia from the primitive foregut and the similarity of the mucosal immune system may cause the same pathological changes (29). Furthermore, the activated inflammatory cells in the bowel tissues such as lymphocytes are able to produce several circulating cytokines that can damage lung tissues (30,31). Consequently, alveolocapillary membrane is affected with impairment of alveolar gas exchange. These theories can explain lung involvement in IBD at various levels leading to interstitial lung disease and airway disease that were presented early by asymptomatic abnormal PFTs.
The effect of IBD activity on PFTs is still a matter of debate. Whereas, some studies reported that PFT changes were not correlated to disease activity (12,32), other studies reported significant correlation between IBD activity and PFT abnormalities (4,11). Interestingly, our study revealed a significant negative correlation between the disease activity in both UC and CD patients and predicted FEV1%, FVC%, FEF 25% to 75%, and DLCO%. This indicates that PFT abnormalities are primarily dependent on the intestinal disease and its activity. To a lesser degree, however, PFT abnormalities persist at remission suggesting that there are other co-factors involved in the development of PFT changes. This can be the duration of the disease, as IBD is a state of chronic inflammation, regardless the apparent intestinal disease activity status. Thus, the ongoing inflammatory process might chronically impact the respiratory system and cause PFT changes with time.
Contradictory results regarding pulmonary function abnormalities in pediatric IBD patients in many researches can be because of different sample size, different genetics, effect of different drugs used for treatment of IBD on PFTs, different age groups involved, different method of measurements of PFTs in pediatrics, different time of estimation of PFTs either in activity or in remission, different duration, and severity of the disease.
In summary, IBD is a systemic disease that has extra-intestinal affection, especially the lung. Pulmonary involvement in children with IBD may be more prevalent than what was previously reported or clinically suspected. Thereby, further studies regarding pulmonary involvement in large number of IBD children are highly recommended and routine regular PFT evaluation would be valuable in such children.
Limitation of the study: evaluation of the effect of the drug taken for the treatment of IBD on PFTs was not studied. All of our patients, however, were new cases and followed the same protocol of treatment with same drugs. Strengths of our study were the large sample size of the cohort, inclusion of both UC and CD patients, inclusion of newly diagnosed patients, and long period of follow-up for these patients.
Subclinical PFTs abnormalities are common in children with IBD even during remission period. So, periodic PFTs evaluation should be considered in the routine follow-up of IBD children.
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