İnflammatory bowel disease

1. Inflammatory bowel disease and lungProf Dr Berrin CeyhanMarmara Univ School of Medicine, ISTANBUL, TURKEY

2. İnflammatory bowel disease IBD is a chronic inflammatory disease commonly involving the gastrointestinal system characterised by mucosal inflammation and ulcers Etiology • İnfection • Food allergy • Environmental factors • Genetics • Immunologic factors Normal UC CD

3. İnflammatory bowel disease The incidence of ulcerative colitis is 1.5-20.3/100.000 person-yearsThe incidence of Crohn’s disease is 0.7-9.8/100.000 person-yearsFrequency of extraintestinal manifestations occur in %21-41 of patients with IBD Lung and gastrointestinal system are originated from primitiv gut and they have same pathogenetic changes

5. Extraintestinal manifestations of inflammatory bowel disease • Hematolojgic • Anemia • Leucocytosis • Leucopenia • Thrombocytosis • Thrombocytopenia • Coagulation abnormalities and hypercoaguable state • Neurologic • Neuropathy • Myopathy • Vasculopathy • Meningitis • Seizures Musculoskletal • Peripheral arthropathy • Ankylosing spondylitis • Sacroileitis • Hipertrophic osteoarthropathy • Osteopenia • Osteoporosis • Osteomalacia • Osteonecrosis • Relapsing polychondritis Dermatologic • Er. Nodosum • Pyoderma gangrenosum • Stomatitis • Psoriasis • Ert. Multiforme • Metastatic Crohn’s disease • Sweet’s syndrome • Epidermolysis

6. Extraintestinal manifestations of inflammatory bowel disease • Cardiovascular • Pleuropericarditis • Cardiomyopathy • Endocarditis • Myocarditis • Pancreatic • Granulomatous pancreatitis • Hepatobiliary • Primary sclerosing cholangitis • Pericholangitis • Cirrhosis • Cholangiocarcinoma • Steatosis • Granulomatous hepatitis • Cholelithiasis • Autoimmune hepatitis • Hepatic abscess • Portal vein trombosis Opthalmologic • Uveitis • Scleritis • Episcleritis • Retinal vascular disease • Conjunctivitis Genitourinary • Nephrolithiasis • Obstructive uropathy • Fistulas • Amiloidosis • Glomerulitis • Membranoglomerulonephritis

7. Ulcerative colitis and lung involvement Upper airway obstruction Tracheobronchitis Bronchiectasis Constrictive bronchiolitis Panbronchiolitis Necrobiotic nodule Lung bullae INterstitial lung disease BOOP Sarcoidosis Pulmonary vasculitis Pulmonary eosinophilia Wegener granulomatosis?(lack of kidney involvement) Apical fibrosis

8. Crohn’s disease and lung involvement BOOP ILD Subclinical lymhocyctic alveolitis Chronic bronchitis Chronic bronchial suppuration Bronchiectasis Granulomatous infiltration and peripheral eosinophilia Necrobiotic nodule

9. Milestones in the literature of lung involvement in IBDFirstly, Kraft et al reported 6 IBD cases (5 ulcerative colitis) with lung involvement in 1976 (1400 cases were screened in 40 years)Kraft et al Arch Intern Med 1976;454. 33 IBD cases(21 F, 12 M, 17-80 years old) , (27 ulcerative colitis and 8 Crohn’s disease) with lung involvement were reported and 57 IBD cases in literature were reviewedCamus et al Medicine 1993;151.400 IBD cases from literature and a review was published in 2003Storch I et al Inf Bowel Dis 2003; 9:104-115

10. Camus et al 1993 Diagnosis of lung involvement mean age: 42.7±2.9 yaş IBD diagnosis mean age: 35.3±2.9 yearsIBD diagnosis preceded 9.3±5.3 years the lung involvement (range: 1 week-36 years) 28/33 IBD diagnosis preceded lung involvement, 5/33 lung disease preceded IBD diagnosis Inactive bowel diease 17(%60.7) active 3(%10.7) postcolectomy 8(%28.6)

11. Airway DiseaseUpper airway obstructionSubglottic inflammation and stenosis in tracheal obstruction (3/33 cases in Camus’s cases) Symptoms: Stridor, severe dyspnea during 2-3 weeksDifferential diagnosis of subglottik stenosis: Intubation, tuberculosis, sarkoidosis, amiloidosisBronchoscopy: Fragile, bleeding tissue and %50-80 obstruction in the lumen

12. Biopsy: Granulation tissue and inflammation (plasma cells, lymphocytes, neutrophils, and erythrocytes) in airway, epithelial ulceration and thin fibrin layerClinical progress:IBD was diagnosed 10 and 20 years before in two cases , IBD was diagnosed 1 month after pulmonary disease in the other case Treatment: Good response to inhaled and oral steroids, one case stayed in remission state during 8 years Rupture following biju dilatation was noted in one case who was unresponsive to previous steroid treatment and he died with pneumomediastinum

13. Large airway involvementChronic bronchitis and bronchiectasis Symptoms; cough, sputum and dyspnea( mucopurulent sputum up to 800 ml/day) 15/33 cases in Camus’ cases (13UC, 2 Crohn)Camus et al Medicine 1993;151. 9 cases with colectomy and 1 case with asthma Airway disease was diagnosed in 9/22pulmonary involvement cases with Crohn’s disease Omori H et al Inf Bowel Dis 2004

14. Radiology: Tubuler bronchial opacities, bronchiectasis in CTLung function test: FEV1/FVC Bronchoscopy: Eritematous and edematous mucosa and inflammation in the wall

15. Bronchial biopsy revealed submucosal lymphocytes, plasma cells, neutrophilic infiltration, mucosal ulceration, chronic inflammation with abundant plasma cells=Bronchial biopsy is mimicking colon biopsy

16. BAL commonly reveals leucocytes, but lymhocytes in one case 9 cases were in postcolectomy state, airway disease occured in days and weeks after colectomy The mean interval after IBD diagnosis was 7.4±1.9 yearsExtraintestinal manifestations were detected in 10/15 cases Camus et al Medicine 1993;151. In the other study of 7 cases with large airway disease, interval was 12 years (4 months-35 years) Spira et al Chest 1998

17. Airway involvement was not associated with intake of sulphasalazin and 5-ASA Symptoms of bronchiectasis and bowel were activated at the same time Bronchiectasis was activated after colectomy (3/7 cases 1-4 months after colectomy)

18. TREATMENT Steroids are more effective in chronic bronchitis than bronchiectasis, therefore inhaled steroids should be started in the early stage and progression to bronchiectasis should be slowed.Lung function test and bronchoscopy show response with inhaled +/- oral steroid Bronchial steroid lavage is helpful, (40-80 mg metil prednisolon in serum physiologic in 2-3 days) There was no response in 2 cases of Camus’ cases, they were in waiting list of transplantation Immuran and cyclophosphamide were not effective treatment choices

19. Small airway disease (Chronic bronchiolitis)Less common presentationThis disease was diagnosed in 2 UC patients in Camus’ casesBoth of them had inactive disease and open lung biopsy revealed chronic and stenotic chronic bronchiolitis=diffuse panbronchiolitis

20. Chronic bronchiolitis

22. Diffuse panbronchiolitis (DPB) is diagnosed in non Asian people1 patient with DPB has been reported 5 years before UC diagnosis Limited treatment, mild-moderate response to oral steroids 1 patient of Camus’ cases responded to steroid, the other one was transplanted Macrolid effect??

23. Bronchiolitis obliterans organised pneumonia (BOOP) 6 patients in Camus’ cases (5UC, 1 Crohn’s disease) Interval 2 months- 36 yearsBOOP was diagnosed 6 months before the onset of IBD in one case LFT: Restriction in all subjects BAL: One case with neutrophilia, one with lymphocytosis

24. TREATMENT: Steroids were used in 4 patients and led to complete remission, two patients with mild symptoms improved without any tretment in 2 and 6 monthsThere was no relation to sulphasalazine and 5-ASA intake, remission occured in one case while taking the drugThere was no association with colectomy

26. Pyoderma gangrenosum in skin (lung and skin biopsies are similar) have been reported4 cases with necrobiotic nodules are reported in the literature2 new cases were included in Camus’ serie, in one of them had p. gangrenosum and pANCA(+). IBD has been diagnosed 11 ve 25 years earlier, both of them were inactive and one was taking low dose steroid and sulfasalazine Nekrobiotic parenchymal nodulesRounded and cavitated nodules Biopsy: Neutrophilic infiltration in necrotic area

32. Early nodules show neutrophils and fibrinous exudateThese nodules undergo central necrosis and cavitated to form large necrotic nodules resembling necrotic granulomas There are no giant cells, no severe vasculitis (there were secondary inflammatory cells in vascular walls), and no non-necrotizing granuloma IBD complicated by pulmonary vasculitis (Wegener granulomatosis?) There are vasculitis( inflammatory cells in vascular walls, giant cells, granuloma, cANCA, pANCA and intestinal manifestations (25 cases)

33. Parencymal necrobiotic nodules Relationship with skin neutrophilic dermatosis? Pyoderma gangrenosum was reported in a patient with cavitated lung nodules,who had no IBD history 1 of the 8 patients with neutrophilic dermatosis originally described by Sweet had ulcerative colitis, however pulmonary lesions could not be found

34. Pulmonary infiltrates and eosinophilia Churg Strauss syndrome was considered in a case with face swelling, arthralgia, wheezing, nasal congestion, and skin vasculitisOral steroids are effective 3/33 ( 2UC, 1 Chron) cases were reported in Camus’ paper involvement was concomitant, preceding, or following the onset of IBDThere was no history of sulfasalazine and 5-ASA intake There were peripheral eosinophilia in all subjects and 18% eosinophilia in BAL in one patient

35. Serositis developed in 41 literature cases (32 UC, 9 Crohn)and one case in Camus’ paperPleural fluid was rich in neutrophils and lymphocytesTamponade was reported in 3 casesResponse to steroids was excellentRecurrent episodes of serositis are reported Serositis

36. DRUG EFFECT Sulfasalazin induced pneumonitis; fever, infiltration in upper lobes, skin rash, and peripheral eosinophilia (38 cases, 2weeks-8 years) Drug induced BOOP, granulomatous reaction, interstitial fibrosis, and lupus (15 cases) were reported Mesalamin(5-ASA); it induces hepatitis and nephritis in addition to the same adverse reactions(7 cases, 5 days-44 months) Other drugs; methodrexate, azathioprin, anti-TNF Treatment: Withdrawal of the agent, steroids

37. 1 case inCamus’ paper; ANA (+) and UC onset was 7 years before12 cases were reported in literature (2 DIP, 6 sarcoidosis )3 cases were preceding the IBD diagnosis Drug effect?: 4 case with sulfasalazin, 3 cases with 5-ASA, and 5 cases with no medicationTreatment: Steroids are effective İnterstitial lung disease

38. Fistulae (1/3in CD cases) Ileobronchial fistula (1 case) Colobronchial fistula (5 cases) Osephagobronchial fistula (4 cases) Anal fistül Enterokütanöz fistül Pulmonary embolism Thromboembolism risk is high (%1-8) Homocystein, genetics, drugs, cardiolipin ? Overlap syndrome Granulomatous lung disease (46 cases, negative ACE and gallium scanning) Alpha 1 antitrypsin deficiency (12 cases, 8 had lung involvement)

39. LABORATORY Eosinophil (BOOP, drug effect, and eosinophilia+lung infiltration)ANA pANCA RF

40. SUBCLINIC, LATENT PULMONARY INVOLVEMENT Hastalarda akciğer sorunu gözden kaçıyor. Subclinic alveolitis was describedIn Crohn’s disease caseswithout respiratory symptoms and with normal X-Ray. Ratio of CD4/CD8 in induced sputum samples was high in 65% of cases Wallaert B et al Chest 1985 Fireman Z Am J Gastroenterol 2000 A latent pulmonary involvement was reported with abnormal Tc-99mDTPA aerosol scintigraphy in patients with UC but without respiratory symptoms, and was not related to the disease activity Gursoy S ve ark Inf Bow Dis 2005 P-A chest X-Ray occasionally shows bronchiectasis and HRCT is not routinely performed in each patient

41. RADIOLOGY 17 cases with respiratory symptoms (14 UC and 3 CD) IBD diagnosis preceded lung involvement in 16/17 (1-25 years) 7 patients with colectomy and 3 with extraintestinal manifestationsSmoking: 7 ex-smoker bırakmış, 3 current, and 7 nonsmoker Smoking negatively correlated with severe colitis and colectomy HRCT showed Bonchiectasis 13 /17 (11UC, 2CD)Tree in bud 5/17Air trapping 11/17 ILD 1/17Groung glass 1/17Mahadeva et al Eur Respir J 2002;15:41-48

42. LUNG FUNCTION TEST Abnormal lung function tests have been found in patients without any respiratory symptoms Low DLCO has been found in 17/ 32 (53%) nonsmoker UC patients with no symptoms and normal HRCT, DLCO associated with disease activity Marvisi et al Eur Respir J 2000

43. 30/55 (%55) random UC patients had abnormal LFT 15/55 obstructive19/55 abnormal diffusion1/55 restrictive5/55 obstructive+abnormal diffusionNo relation with smoking, family history, occupation, drugsGodet et al Am J Gastroenterol 1997 LFT in 17 IBD patients with respiratory symptoms revealed4 restrictive5 obstructive2 obs+rest4 Low DLCO 6 normal LFT (bronchiectasis, air trapping, tree in bud) Mahadeva et al Eur Respir J 2000

44. BHR and asthma in IBD 3 month-follow-up of 44 random (22 UC, 22Crohn) IBD patients 21/44 (%48) respiratory symptoms 11/44 bronchitis 4/44 allergic rhinitis 1/44 pleuritis 4/44(%10) asthma 14/44 (%32) abnormal LFT, 7/44 (%16) abnormal DLCO, and relation to disease activity have been found with FRC and RV Douglas et al Respir Med 1989

45. BHR has been shown in 10/14 (%71) children with CD using metacholine challenge test ( no history of clinic, radiologic, and functional airway disease ) 2/14 (%17) asthma was diagnosed 3/14 (%21) skin prick test was positive No relation to disease activity, drug, and disease duration Mansi et al Am J Respir Crit Care Med 2000

46. BHR has been found in 20% of asymptomatic 25 Crohn patients and 8% of asymptomatic 35 UC patients using metacholine. Female sex and extraintestinal manifestations are risk factors No relation with smoking, disease activity and disease duration Kullmann et al Am Respir Crit Care Med 1998 BHR has been found in 45% of IBD patients with normal LFT and without respiratory symptoms. Skin prick tests were positive in 42% of patients Louis E et al Allergy 1995 IBD patients without allergic symptoms revaled high serum IgE levels Levo et al Ann Allergy 1986

47. Atopism and BHR Study population 30 patients with IBD (19 UC, 11CD) followed in Gastroenterology Dept of Marmara University Hospital 5.3+/- 4.8 years disease duration, 15 non-smoker, 8 current smoker, 7 ex-smoker Results: 15/30 respiratory symptoms14/30 allergic symptoms (more common in UC )3/30 asthma (1 case concurrent, 1 case diagnosed 6 years before IBD onset, 1 case10 years after IBD onset)Ceyhan B ve al Respiration 2003

48. LFTabnormal 8/30 (27%)BHR 5/30 (17%) (2 CD, 3 UC)6/30(20%) rhinitis/sinusitis history8/30 (27%) urticaria history Skin prick test 15/30(50%) 11/30(37%) High IgE level7/30(24%) positive skin prick test+high IgE level Ceyhan B et al Respiration 2003

49. IBD and lung involvement- Summary In 83% of patients, IBD onset precedes respiratory symptomsIn 10% of patients lung involvement precedes gastrointestinal symptoms In 7% of patients, diagnosis of lung disease and IBD is concurrent Colectomy history is positive in half of IBD patients with airway disease. Colonic surgey may aggravate prior airway disease Untreated airway inflammation puts the patient at risk of developing irreversible airway disease Local and systemic steroids are effective against airway diseases Small airway disease is usually refractory to inhaled steroids, oral steroid effect is slight to modest

50. The drugs sulfasalzine and 5-ASA may play a role in some cases Interstitial lung disease is more common in inactive patients taking drugsMost cases of ILD, necrotic nodules and serositis are very responsive to steroids The true incidence of pulmonary involvement in IBD patients is unknown because of subclinical pulmonary involvement Although the incidence of colorectal cancer is known to be increased among patients with UC, the incidence of lung cancer is not increased