Journal of Crohn's and Colitis (2010) 4, 384–389

available at www.sciencedirect.com

REVIEW ARTICLE

Pulmonary diseases associated with inflammatory bowel diseases Giovanni Casella a , Vincenzo Villanacci c , Camillo Di Bella b , Elisabetta Antonelli d , Vittorio Baldini a , Gabrio Bassotti d,⁎ a

Division of Internal Medicine, Italy Pathology Unit, Desio General Hospital, Italy c 2nd Pathology Section, Spedali Civili di Brescia, Italy d Gastroenterology and Hepatology Section, Department of Clinical and Experimental Medicine, University of Perugia, Italy b

Received 2 December 2009; received in revised form 25 January 2010; accepted 17 February 2010 KEYWORDS Crohn's disease; Inflammatory bowel diseases; Lung pathology; Ulcerative colitis

Abstract Among the extra-intestinal manifestations of inflammatory bowel diseases, those involving the lung are relatively rare. However, there is a wide array of such manifestations, spanning from drug-related pathologies to airway disease, fistulas, granulomatous diseases, autoimmune and thromboembolic disorders. Although infrequent, people dealing with inflammatory bowel diseases must be aware of these conditions, sometimes life-threatening, to avoid further impairment of the health status of the patients and to alleviate their symptoms by prompt recognition and treatment. © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 2. Drug-related lung pathology . . . . . . . . . . . . . . . 2.1. Sulphasalazine and mesalazine . . . . . . . . . 2.2. Azathioprine (AZA) and 6-Mercaptopurine(6-MP) 2.3. Methotrexate . . . . . . . . . . . . . . . . . . . 2.4. Biological therapy . . . . . . . . . . . . . . . . 2.5. Cyclosporine. . . . . . . . . . . . . . . . . . . . 3. IBD-related lung pathology . . . . . . . . . . . . . . . . 3.1. Fistulas . . . . . . . . . . . . . . . . . . . . . . 3.2. Granulomatous diseases . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

385 385 385 385 385 386 386 386 386 386

⁎ Corresponding author. Clinica di Gastroenterologia ed Epatologia Ospedale Santa Maria della Misericordia Piazzale Menghini, 1 06156 San Sisto, Perugia, Italy. Fax: +39 075 5847570. E-mail address: [email protected] (G. Bassotti). 1873-9946/$ - see front matter © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2010.02.005

Lung pathology and IBD 3.3. Autoimmune disorders . . . . . . . . . . . 3.4. Thromboembolic pathologies . . . . . . . 3.5. Airway diseases . . . . . . . . . . . . . . . 4. Diagnostic techniques in lung disorders associated 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

385 . . . . . . . . . . . . to IBD . . . . . . . .

1. Introduction Inflammatory bowel diseases (IBD) may be complicated by extra-intestinal manifestations (EIMs) in up to 40% of patients, and almost every organ system may be affected.1–3 The incidence of EIMs increases with the disease duration, and their prevalence is estimated to be around 21–41%.4 The most important etiologic factors for EIMs in IBD are thought to be the presence of circulant immunocomplexes and complement's deposits.5 Moreover, an altered intestinal barrier accounts for the entry of numerous unfiltered alimentary antigens, digestive enzymes and bacteria that may cause local and systemic inflammatory reactions.6 Although rare (up to 2003 only about 400 cases were described in literature 4) a growing number of literature reports suggest that pulmonary disease occurs in association with IBD more frequently than previously recognized.4,7,8 The same embryological origin of lung and gastrointestinal tract by ancestral intestine may explain the association between lung involvement and IBD, and it has been shown a decrease of blood total IgA produced by mononucleate intestinal cells of IBD patients,9 that may favor pulmonary involvement. Compared to healthy controls, IBD patients show significantly decreased lung function tests, such as forced expiratory volume in 1 s, inspiratory vital capacity, Tiffeneau value, and lung CO transfer capacity, more pronounced during activity flares than during remission.10 These abnormalities are found in more than 50% of IBD patients, and are not predicted by the smoking status.11 It has been hypothesized that these alterations might be due to a high superoxide anion production by alveolar macrophages.12 The present article will examine pulmonary diseases associated with IBD.

2. Drug-related lung pathology Although drug-related diseases are not “properly” IBDassociated disease, since IBD patients use several drugs for prolonged periods of time, it is not surprising that some of these may also cause problems to the lungs; therefore, this kind of pathology will be considered here, taking into account that it can occur also in patients undergoing immunosuppression or other diseases.

2.1. Sulphasalazine and mesalazine These are commonly used drugs for long-term treatment of IBD (especially ulcerative colitis, UC), and their side effects may be dose-related or idiosyncratic, and should be separated from the respiratory involvement occurring in IBD and due to the underlying disease, although this is not always possible.13 Literature data report more than 50 cases

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

386 386 386 386 387 387

of lung pathology related to the use of these compounds,14 mostly due to interstitial disease,10,15,16 although eosinophilic pleuritis 17 and eosinophilic pneumonia18 have also been described. In most cases, symptoms appear after 2– 6 months from the drug's use, whereas in a few cases they appear after some days or after many years.1 The most common symptoms are dyspnea (76%), fever (68%), chest pain (65%) and cough (22%).1 Usually, interruption of the drug resolve the symptoms; rarely, these disappear decreasing the drug's dosage.19

2.2. Azathioprine (AZA) and 6-Mercaptopurine(6-MP) Pulmonary toxicity due to these drugs has been reported infrequently in literature, although interstitial pneumonitis,20 restrictive lung disease,21 Goodpasture-like syndrome and pulmonary hemorrhage 22 have been described after use of AZA and 6-MP. Infectious pneumonia is the most common cause of pulmonary symptoms in IBD pts on immunosuppressive therapy including AZA.20 However, in a series of over 100 IBD pts on AZA therapy, no episodes of pneumonia where reported,23 while others reported a 1–10% incidence of pneumonia in IBD pts on 6-MP therapy.24 The largest series of lung toxicity related to AZA with description of 7 cases on AZA therapy was reported in patients undergoing renal allograft transplant immunosuppression.25 Lung biopsies revealed interstitial pneumonitis in 5 patients and diffuse alveolar damage in 2 patients; 3 patients died and the other 4 improved after stopping AZA and in 2 of these patients cyclophosphamide therapy to resolve completely this side effect was needed. Thus, a history of recent purine analog use in the presence of diffuse pulmonary infiltrates, fever, hypoxia and respiratory failure should prompt cessation of the drug to prevent progression of the symptoms and catastrophic outcome.

2.3. Methotrexate Methotrexate may be useful in the treatment of Crohn's disease, but it may cause a lung drug reaction that, in some cases, is lethal.26 The main symptoms are increasing dyspnea, cough and fever. Hypoxemia and tachypnea are always present and chest radiograms reveal a diffuse interstitial lung disease or a “mixed” lung infiltration (interstitial and alveolar) localized to the lower portions of the lung. Lung functional tests show a restrictive picture with altered lung diffusion. Methotrexate may also cause fungal infections of the lungs.27,28 Thus, in patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended during the therapy with this drug.29

386

2.4. Biological therapy These new therapeutic approaches have become widespread in recent years, and serious side effects may occur, necessitating careful monitoring of therapy.30,31 An important caveat is the possible reactivation of tuberculosis in patients undergoing such treatments (most for IBD and rheumatoid arthritis),32 and before prescribing the drug physicians should screen patients for latent tuberculosis infection or disease.33 However, the possibility of tuberculosis reactivation despite a negative screening should always be considered.34 Moreover, the use of biological therapy has been associated with Pneumocystis carinii pneumonia,35 as well as with other pulmonary infections (coccidiomycosis, histoplasmosis, listeriosis and aspergillosis),36,37 especially in older patients.38 Although infective complications are the most feared after the use of biological agents, these may induce other uncommon effects on the lung, such as eosinophilic pneumonia,39 acute respiratory distress syndrome,40 diffuse alveolar hemorrhage,41 and interstitial pneumonitis.42

2.5. Cyclosporine Cyclosporine is a potent immunosuppressive medication also useful in severe cases of IBD.43 Apart from unusual effects due to aspiration of the drug,44 most of the effects on the lungs are due to opportunistic infections (Pneumocystis carinii).45,46

3. IBD-related lung pathology 3.1. Fistulas Up to 50% of patients with CD are affected by fistulas, which is a major problem given the considerable morbidity associated with this complication.47,48 Most of the fistulas appear in the perineal area 49; to date, only a few reports (mostly as single cases) are available on the occurrence of enteric-pulmonary fistulas in IBD, such as colo-bronchial,50 ileo-bronchial,51 and esophago-bronchial52,53 fistulas. Lung fistulas should be considered in patients with CD affected by frequent episodes of pneumonitis or in presence of intestinal anaerobic flora in the sputum.54

3.2. Granulomatous diseases Crohn's disease and sarcoidosis are chronic inflammatory barrier diseases that share several clinical and immunological features, including the occurrence of granulomas. Since these two conditions also share common susceptibility loci,55 it is not surprising that these two diseases may simultaneously appear in the same patient, with pulmonary involvement,56 even though this happens quite rarely (there are about 50 such reports in literature) and the two diseases usually follow an independent clinical course.57 However, it is thought that due to the similarities between these two entities, a differential diagnosis is difficult and sometimes impossible.58

G. Casella et al. Even though CD has been described associated to Wegener's granulomatosis,59 the genetic background between the two conditions seems different.60

3.3. Autoimmune disorders Among the EIMs of IBD, the vasculitides may be accounted very rarely,61 with sporadic reports of UC complicated by lung vasculitis,62 and of CD associated to Wegener's granulomatosis.59 However, since the paucity of reports, it is still unclear whether there is an actual association or whether these conditions happens by chance in the same individual.

3.4. Thromboembolic pathologies Pulmonary embolism (PE) should be always considered in IBD patients with breathing difficulties,63 since these patients have an increased risk of vascular complications.64,65 The most important of these complications are arterial and venous thromboembolism, which represent a significant cause of morbidity and mortality in IBD patients,66 and are higher in patients younger than 50.67 IBD-related PE was described, for the first time, by Bargen et al more than 70 years ago 68; since then, arterial and venous embolisms have been reported with a percentage of 1–8%,69 with a mortality in large series higher than 25%.70 Interestingly, about 80% of IBD patients has active disease when PE occurs,71 and the incidence of deep venous thrombosis (DVT) or PE has been calculated at 40/10,000 persons year for CD and 50/10,000 persons year for UC.69 The hypercoagulability state documented in IBD patients has led to the research of risk factors; among these there is an association between hyperhomocysteinemia and a history of arterial thrombosis in IBD patients, and a high prevalence of factor V Leiden in IBD patients with a history of venous thrombosis.72,73 In the majority of IBD patients with previous thromboembolic complications, at least one prothrombotic risk factor is usually detected.74

3.5. Airway diseases Infrequently, in IBD patients developing new, persistent and unexplained symptoms of respiratory disease, particularly chronic productive cough, the presence of bronchiectasies may be demonstrated.75 Small airway disease, such as bronchiolitis, has also been reported in these patients.76 An association between airways disease and IBD, particularly non-asthmatic airways disease with productive cough77 seems to be present; moreover, the finding of asthma as the most common comorbidity increased in CD patients compared with the general population is novel,78 and probably merits further investigation.

4. Diagnostic techniques in lung disorders associated to IBD The main diagnostic techniques are summarized in Table 1.79 Chest X-ray with diffuse patchy interstitial infiltrates may be suggestive for infectious or drug-related lung disease as

Lung pathology and IBD Table 1

387

Diagnostic techniques in lung disorders associated to IBD (adapted from Ref. 75).

Diagnostic examination

Bacterial pneumonia

Drug-related pneumonia

Opportunistic Granulomatous lung infection pneumonia disorders

Pulmonary embolism

Chest X-ray

Lobe infiltrates

Aspecific infiltrates in upper and lower lobes “Ground-glass” opacities in upper and lower lobes Increased percentage of eosinophils in BAL

Lobe infiltrates

Patchy opacities and increased mediastinal shadow

Normal

Patchy opacities

Bilateral lung infiltrates and Filling defects in the main, hilar lymphadenopathies segmental and lobular branches of the pulmonary arteries

Chest computed tomography (CT) Bronchoalveolar Increased lavage (BAL) percentage of neutrophils in BAL Sputum Search bacterial agent in 3 samples Histology by bronchoscopy

Opportunistic agent evident in BAL

Polymerase chain reaction (PCR) for Pneumocystis in oral washes

opacities are present in both lower lobes.21 A drug-related lung disorder may be confirmed by a chest computed tomography (CT) with evidence of “ground-glass” opacities (localized in the upper lobes or at the lung bases bilaterally).21,80 “Ground-glass” opacities are defined as an increased attenuation of the lung with preserved bronchial and vascular margins in contrast to “consolidation”, where a “blurring” of the bronchiolar and vascular margins is evident.80 The differential diagnosis of “ground-glass” opacities is extremely broad and only broncoscopy with bronchoalveolar lavage (BAL) can allow the final diagnosis,81 since it can distinguish between pulmonary alveolar proteinosis, diffuse alveolar hemorrhage, malignant tumours and a variety of opportunistic infections.80 BAL is often complementary to histopathology.82 The cellular material of BAL derives from small airways and near 1 million alveoli.80 Typically, 85 to 93% of all BAL cells are macrophages, 10% are lymphocytes and less than 2% are neutrophils and eosinophils.80 In case of diffuse alveolar damage, BAL neutrophil cells are markedly increased, while a percentage more than 25% of BAL eosinophil cells is suggestive for idiopathic acute eosinophilic pneumonia that may be a clinical sign of drug-related lung disease.80 In case of fungal infection (such as Histoplasma, Coccidioides, and Aspergillus), a serologic test with beta-O-glucan or galactomannan has a negative predictive value of up to 99%.83 Chest CT with intravenous administration of contrast medium permits to evidence the presence of filling defects in the main, segmental and lobular branches of the pulmonary arteries and these radiological signs are suggestive for pulmonary embolism.84 Oral washes have high specificity and sensitivity, and are non invasive procedures for the detection of Pneumocystis

Granulomas, macrophages in alveolar spaces, neutrophilic infiltrates in blood capillaries

colonization; the use of molecular techniques (PCR) may be used in the general population, particularly in patients undergoing immunosuppressive therapies.85 Oral washes to perform PCR for Pneumocystis in IBD patients may identify the subjects that should undergo prophylaxis for this infection.86

5. Conclusions The involvement of the respiratory system is a relatively rare but sometimes potentially harmful EIM of IBD. Since lung involvement is relatively rare, all those dealing with IBD patients must be aware of this possibility, to avoid further complications and morbidity in the patients, and to recognize a prompt treatment for these events.

References 1. Su CG, Judge TA, Lichtenstein GR. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:307–27. 2. Ardizzone S, Puttini PS, Cassinotti A, Porro GB. Extraintestinal manifestations of inflammatory bowel disease. Dig Liver Dis 2008;40(Suppl 2):S253–S2599. 3. Williams H, Walker D, Orchard TR. Extraintestinal manifestations of inflammatory bowel disease. Curr Gastroenterol Rep 2008;10:597–605. 4. Storch I, Sachar D, Katz S. Pulmonary manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2003;9:104–15. 5. Veloso F, Carvalho J, Magro F. Immune-related manifestations of inflammatory bowel disease: a prospective study of 792 patients. J Clin Gastroenterol 1996;23:29–34.

388 6. Levine J, Lukawaski J, Trubish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:633–46. 7. Casey MB, Tazelaar HD, Myers JL, Hunninghake GW, Kakar S, Kalra SX, et al. Noninfectious lung pathology in patients with Crohn's disease. Am J Surg Pathol 2003;27:213–9. 8. Black H, Mendoza M, Murin S. Thoracic manifestations of inflammatory bowel disease. Chest 2007;131:524–32. 9. MacDermott R, Nash G, Nulum M. Antibody secretion by human interstitial mononuclear cells from normal controls and inflammatory bowel disease patients. Immunol Invest 1989;18:449–57. 10. Herrlinger KR, Noftz MK, Dalhoff K, Ludwig D, Stange EF, Fellermann K. Alterations in pulmonary function in inflammatory bowel disease are frequent and persist during remission. Am J Gastroenterol 2002;97:377–81. 11. Godet PG, Cowie R, Woodman RC, Sutherland LR. Pulmonary function abnormalities in patients with ulcerative colitis. Am J Gastroenterol 1997;92:1154–6. 12. Wallaert B, Aerts C, Bonniere P, Cortot A, Tonnel AB, Paris JC, et al. Superoxide anion generation by alveolar macrophages in Crohn's disease. N Engl J Med 1985;312:444–5. 13. Camus P, Piard F, Ashcroft T, Gal AA, Colby TV. The lung in inflammatory bowel disease. Medicine (Baltimore) 1993;72: 151–83. 14. Foster RA, Zander DS, Mergo PJ, Valentine JF. Mesalaminerelated lung disease: clinical, radiographic, and pathologic manifestations. Inflamm Bowel Dis 2003;9:308–15. 15. Reinoso MA, Schroeder KW, Pisani RJ. Lung disease associated with orally administered mesalamine for ulcerative colitis. Chest 1992;101:1469–71. 16. Bitton A, Peppercorn MA, Hanrahan JP, Upton MP. Mesalamineinduced lung toxicity. Am J Gastroenterol 1996;91:1039–40. 17. Trisolini R, Dore R, Biagi F, Luinetti O, Pochetti P, Carrabino N, et al. Eosinophilic pleural effusion due to mesalamine. Report of a rare occurrence. Sarcoidosis Vasc Diffuse Lung Dis 2000;17: 288–91. 18. Saltzman K, Rossoff LJ, Gouda H, Tongia S. Mesalamine-induced unilateral eosinophilic pneumonia. AJR Am J Roentgenol 2001;177:257. 19. Sossai P, Cappellato MG, Stefani S. Can a drug-induced pulmonary hypersensitivity reaction be dose-dependent? A case with mesalamine. Mt Sinai J Med 2001;68:389–95. 20. Nagy F, Molnar T, Makula E, Kiss I, Milassin P, Zollei E, et al. A case of interstitial pneumonitis in a patient with ulcerative colitis treated with azathioprine. World J Gastroenterol 2007;13:316–9. 21. Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, et al. Severe pulmonary toxicity after Azathioprine/6-Mercaptopurine initiation for the treatment of inflammatory bowel disease. J Clin Gastroenterol 2007;41 682– 628. 22. Fauroux B, Meyer-Milsztain A, Boccon-Gibod L, Leverger G, Clément A, Biour M, et al. Cytotoxic drug-induced pulmonary disease in infants and children. Pediatr Pulmonol 1994;18:347–55. 23. Ardizzone S, Maconi G, Sampietro GM, Russo A, Radice E, Colombo E, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn's disease. Gastroenterology 2004;127:730–40. 24. Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111: 641–9. 25. Bedrossian CW, Sussman J, Conklin RH, Kahan B. Azathioprineassociated interstitial pneumonitis. Am J Clin Pathol 1984;82: 148–54. 26. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J 2000;15:373–81.

G. Casella et al. 27. Baughman RP, Lower EE. Fungal infections as a complication of therapy for sarcoidosis. QJM 2005;98:451–6. 28. Kleiman MB, Wheat LJ, Bowyer S. Histoplasmosis in a child with JRA on low-dose methotrexate. Rheumatology (Oxford) 2007;46: 1215–6. 29. Pavy S, Constantin A, Pham T, Gossec L, Maillefert JF, Cantagrel A, et al. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine 2006;73:388–95. 30. Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology 2009;136: 1182–97 Erratum in: Gastroenterology 2009, 136:1844. 31. Hoentjen F, van Bodegraven AA. Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease. World J Gastroenterol 2009;15:2067–73. 32. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098–104. 33. Mayordomo L, Marenco JL, Gomez-Mateos J, Rejon E. Pulmonary miliary tuberculosis in a patient with anti-TNF-alpha treatment. Scand J Rheumatol 2002;31:44–5. 34. Garcia-Vidal C, Rodríguez-Fernández S, Teijón S, Esteve M, Rodríguez-Carballeira M, Lacasa JM, et al. Risk factors for opportunistic infections in infliximab-treated patients: the importance of screening in prevention. Eur J Clin Microbiol Infect Dis 2009;28:331–7. 35. Kaur N, Mahl T. Pneumocystis jiroveci (Carinii) pneumonia after infliximab therapy: a review of 84 cases. Dig Dis Sci 2007;52: 1481–4. 36. Colombel JF, Loftus Jr EV, Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology 2004;126:19–31. 37. Tsiodras S, Samonis G, Boumpas DT, Kontoyiannis DP. Fungal infections complicating tumor necrosis factor alpha blockade therapy. Mayo Clin Proc 2008;83:181–94. 38. Toruner M, Loftus Jr EV, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008;134:929–36. 39. Villenueve F, St-Pierre A, Haraoui P. Interstitial pneumonitis associated with infliximab therapy. J Rheumatology 2006;33: 1189–93. 40. Riegert-Johnson DL, Godfrey JA, Myers JL, Hubmayr RD, Sandborn WJ, Loftus Jr EV. Delayed hypersensitivity reaction and acute respiratory distress syndrome following infliximab infusion. Inflamm Bowel Dis 2002;8:186–91. 41. Panagi S, Palka W, Korelitz BI, Taskin M, Lessnau KD. Diffuse alveolar hemorrhage after infliximab treatment of Crohn's disease. Inflamm Bowel Dis 2004;10:274–7. 42. Ostör AJ, Chilvers ER, Somerville MF, Lim AY, Lane SE, Crisp AJ, et al. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis. J Rheumatol 2006;33:622–8. 43. Schwartz M, Cohen R. Optimizing conventional therapy for inflammatory bowel disease. Curr Gastroenterol Rep 2008;10:585–90. 44. Gould K, Freeman R, Odom NJ, Locke TJ, McGregor CG. Pulmonary “cyclosporinoma” mimicking infection after heart transplantation. J Heart Transplant 1987;6:375–7. 45. Quan VA, Saunders BP, Hicks BH, Sladen GE. Cyclosporin treatment for ulcerative colitis complicated by fatal Pneumocystis carinii pneumonia. BMJ 1997;314:363–4. 46. Van Gossum A, Schmit A, Adler M, Chioccioli C, Fiasse R, Louwagie P, et al. Short-and long-term efficacy of cyclosporin administration in patients with acute severe ulcerative colitis. Belgian IBD Group. Acta Gastroenterol Belg 1997;60:197–200. 47. Marrero F, Qadeer MA, Lashner BA. Severe complications of inflammatory bowel disease. Med Clin North Am 2008;92:671–86.

Lung pathology and IBD 48. Nielsen OH, Rogler G, Hahnloser D, Thomsen OØ. Medscape. Diagnosis and management of fistulizing Crohn's disease. Nat Clin Pract Gastroenterol Hepatol 2009;6:92–106. 49. Felley C, Mottet C, Juillerat P, Pittet V, Froehlich F, Vader JP, et al. Fistulizing Crohn's disease. Digestion 2007;76:109–12. 50. Karmy-Jones R, Chagpar A, Vallieres E, Hamilton S. Colobronchial fistula due to Crohn's disease. Ann Thorac Surg 1995;60: 446–8. 51. Gumbo T, Rice TW, Mawhorter S. Recurrent pneumonia from an ileobronchial fistula complicating Crohn's disease. J Clin Gastroenterol 2001;32:365–7. 52. Ho IK, Guarino DP, Pertsovskiy Y, Cerulli MA. Infliximab treatment of an esophagobronchial fistula in a patient with extensive Crohn's disease of the esophagus. J Clin Gastroenterol 2002;34:488–9. 53. Rieder F, Hamer O, Gelbmann C, Schölmerich J, Gross V, Feuerbach S, et al. Crohn's disease of the esophagus: treatment of an esophagobronchial fistula with the novel liquid embolic polymer “onyx”. Z Gastroenterol 2006;44:599–602. 54. Brittenden J, Hosker HS, Healey C, Porter G. Oesophagobronchial fistula causing cough and recurrent lower respiratory tract infections in a patient with Crohn's disease. Hosp Med 2005;66:310–1. 55. Franke A, Fischer A, Nothnagel M, Becker C, Grabe N, Till A, et al. Genome-wide association analysis in sarcoidosis and Crohn's disease unravels a common susceptibility locus on 10p12.2. Gastroenterology 2008;135:1207–15. 56. Fellermann K, Stahl M, Dahlhoff K, Amthor M, Ludwig D, Stange EF. Crohn's disease and sarcoidosis: systemic granulomatosis? Eur J Gastroenterol Hepatol 1997;9:1121–4. 57. Fries W, Grassi SA, Leone L, Giacomin D, Galeazzi F, Naccarato R, et al. Association between inflammatory bowel disease and sarcoidosis. Report of two cases and review of the literature. Scand J Gastroenterol 1995;30:1221–3. 58. Reynolds HY. Sarcoidosis: impact of other illnesses on the presentation and management of multi-organ disease. Lung 2002;180:281–99. 59. Wechsler B, Couderc JL, Tucat G, Beaufils H, Godeau P. Crohn's disease associated with Wegener's granulomatosis. Gastroenterol Clin Biol 1980;4:356–61. 60. Newman B, Rubin LA, Siminovitch KA. NOD2/CARD15 gene mutation is not associated with susceptibility to Wegener's granulomatosis. J Rheumatol 2003;30:305–7. 61. Ceyhan B. Inflammatory bowel disease and lung. Tuberk Toraks 2006;54:292–8. 62. Sargent D, Sessions J, Fairman P. Pulmonary vasculitis complicating ulcerative colitis. South Med J 1985;78:624–5. 63. Papa A, Scaldaferri F, Danese S, Guglielmo S, Roberto I, Bonizzi M, et al. Vascular involvement in inflammatory bowel disease: pathogenesis and clinical aspects. Dig Dis 2008;26:149–55. 64. van Bodegraven AA. Haemostasis in inflammatory bowel diseases: clinical relevance. Scand J Gastroenterol Suppl 2003:51–62. 65. Ha C, Magowan S, Accortt NA, Chen J, Stone CD. Risk of arterial thrombotic events in inflammatory bowel disease. Am J Gastroenterol 2009;104:1445–51. 66. Koutroubakis IE. Therapy insight: Vascular complications in patients with inflammatory bowel disease. Nat Clin Pract Gastroenterol Hepatol 2005;2:266–72. 67. Bernstein CN, Nabalamba A. Hospitalization-based major comorbidity of inflammatory bowel disease in Canada. Can J Gastroenterol 2007;21:507–11.

389 68. Bargen JA, Barker NW. Extensive arterial and venous thrombosis complicating chronic ulcerative colitis. Arch Intern Med 1936;58:17–31. 69. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001;85:430–4. 70. Talbot RW, Heppel J, Dozois RR, Beart RW. Vascular complications of inflammatory bowel disease. Mayo Clin Proc 1986;61: 140–5. 71. Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ. Venous thromboembolism in inflammatory bowel disease. Am J Gastroenterol 2004;99:97–101. 72. Novacek G, Miehsler W, Kapiotis S, Katzenschlager R, Speiser W, Vogelsang H. Thromboembolism and resistance to activated protein C in patients with inflammatory bowel disease. Am J Gastroenterol 1999;94:685–90. 73. Oldenburg B, Fijnheer R, van der Griend R, vanBerge-Henegouwen GP, Koningsberger JC. Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications? Am J Gastroenterol 74. Oldenburg B, Van Tuyl BA, van der Griend R, Fijnheer R, van Berge Henegouwen GP. Risk factors for thromboembolic complications in inflammatory bowel disease: the role of hyperhomocysteinaemia. Dig Dis Sci 2005;50:235–40. 75. Spira A, Grossman R, Balter M. Large airway disease associated with inflammatory bowel disease. Chest 1998;113:1723–6. 76. Ward H, Fisher KL, Waghray R, Wright JL, Card SE, Cockcroft DW. Constrictive bronchiolitis and ulcerative colitis. Can Respir J 1999;6:197–200. 77. Raj AA, Birring SS, Green R, Grant A, de Caestecker J, Pavord ID. Prevalence of inflammatory bowel disease in patients with airways disease. Respir Med 2008;102:780–5. 78. Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 2005;129:827–36. 79. Mahadeva R, Walsh G, Flower CD, Shneerson JM. Clinical and radiological characteristics of lung disease in inflammatory bowel disease. Eur Resp J 2000;15:41–8. 80. Wener CM, Muse VV, Mrk EJ. Case 33-2008: a 63 year old woman with dyspnea on exertion. NEJM 2008;339:1823–32. 81. Cellins J. CT signs and patterns of lung disease. Radiol Clin North America 2001;39:1115–35. 82. Costabel U, Uzaslan E, Guzman J. Bronchoalveolar lavage in drug-induced lung disease. Clin Chest Med 2004;25:637–49. 83. Mennink-Kersten MA, Verweij PE. Non-culture based diagnostics for opportunistic fungi. Infect Dis Clin North America 2006;20: 711–27. 84. Kafkas NV, Beboneras CC, Babalis DK. Massive pulmonary embolism and ulcerative colitis. Hellenic J Cardiol 2008;49: 365–70. 85. Respaldiza N, Montes-Cano MA, Friaza V. Uselfuness of oropharyngeal washings for identifying Pneumocystis jirovecii carriers. J Eukaryot Microbiol 2006;53:100S–1S. 86. Wissmann G, Varela JM, Calderon EJ. Prevention of Pneumocystis pneumonia in patients with inflammatory bowel disease based on the detection of Pneumocystis colonization. Inflamm Bowel Dis 2008;14:1751–2.