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Journal of Crohn's and Colitis: 10 (10)


Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium


Published on behalf of

Crohn's disease with pulmonary manifestations in children: 2 case reports and review of the literature

Narendra B. Vadlamudi, Udayakumar Navaneethan, Kirk A. Thame, David R. Kelly, Reed A. Dimmitt, William T. Harris
DOI: http://dx.doi.org/10.1016/j.crohns.2012.05.007 e85-e92 First published online: 1 April 2013


Crohn's disease (CD) is a chronic granulomatous disease of unknown etiology that affects primarily the gastrointestinal system but can be associated with extraintestinal manifestations. Latent pulmonary involvement in children with CD has been described, but symptomatic pulmonary disease has rarely been reported in children. In this review, we report two pediatric cases, one with pleural effusion at the time of CD diagnosis and the other with bilateral cavitary lesions in a previously diagnosed CD patient. We review the current literature and summarize the diagnosis and management of pulmonary involvement in CD. Awareness of these pulmonary complications of CD in children may lead to more prompt diagnosis, guide appropriate therapy, and decrease morbidity.

  • Crohn's disease;
  • Granulomatous lung disease;
  • Children

1 Introduction

Crohn's disease (CD) is a complex, multifactorial disease characterized by chronic inflammation primarily involving the gastrointestinal system.1 It can affect any part of the gastrointestinal tract from the mouth to the anus. Up to 25–40% of patients with CD can have a variety of extraintestinal manifestations including erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, arthritis, hepatitis, sclerosing cholangitis, pancreatitis, nephrolithiasis, uveitis, and episcleritis.2 Pulmonary involvement in CD is often underappreciated, with the overall prevalence of bronchopulmonary manifestations previously estimated to be as low as 0.2%. This figure likely is misleadingly low as pulmonary involvement is commonly not considered as part of Crohn's routine care.3 Asymptomatic complications occurring during the course of CD are the most frequent and patients can have alteration in lung function tests and/or bronchoalveolar lavage (BAL) abnormalities.47 Although asymptomatic pulmonary involvement is well described, only a minority of patients have associated symptoms or overt signs. Respiratory manifestations often, but not always, follow the onset of bowel disease and may exacerbate during gastrointestinal disease relapses.8 Moreover, pulmonary symptoms in CD patients could also result from side effects of medications,9 opportunistic infections10 and also from some overlap syndromes including sarcoidosis,3134 thus creating diagnostic challenges and delays in initiation of appropriate therapy.

Since the first description of the association of pulmonary manifestations in patients with inflammatory bowel disease in 1976, several cases and case series have been reported in adults.11 In pediatric patients however, the association is less well described. An extensive English literature search revealed only 15 previously reported pediatric CD patients with symptomatic pulmonary disease. This article reports two additional pediatric CD patients presenting with pulmonary symptoms and also reviews the relevant characteristics of bronchopulmonary involvement in CD patients.

1.1 Case 1

An 11-year-old female with psoriasis was admitted to our hospital with a three-week history of worsening non-productive cough. She denied any history of shortness of breath, chest pain, fever or hemoptysis. A review of systems was negative for diarrhea, vomiting, hematochezia, joint pain and weight loss. Her past medical history was significant for poorly controlled psoriasis with frequent flares that were not responding to topical therapy. Physical examination on admission revealed a well appearing girl in no apparent distress. Her height and weight percentiles were appropriate for her age. She was afebrile and had normal vital signs. Chest findings included decreased air entry at the left base on auscultation. The remainder of the systemic examination was unremarkable except for the presence of a licheniform rash in the intertriginous regions of the axilla, inframammary, and scalp areas without suppuration or exudates.

Her initial laboratory investigations revealed a white blood count of 10,800/μL, hemoglobin of 10.3 g/dL, erythrocyte sedimentation rate of 22 mm/h, and C-reactive protein of 2.2 mg/dL (reference range < 1.00 mg/dL). Chest radiograph revealed a left sided consolidation and a pleural effusion. She was empirically started on intravenous cefotaxime for suspected pneumonia after obtaining blood and urine cultures. During the course of her hospital stay she developed progressive shortness of breath and worsening left-sided consolidation with increasing pleural effusion (Fig. 1 ) that mandated thoracentesis and chest tube placement.


Computed tomographic scan revealing left pleural effusion with consolidation of the left lower lobe.

The work-up including ANA, DsDNA, HLAB27, C3, C4, immunoglobulins, lymphocyte markers, uric acid, lactate dehydrogenase, thyroid profile, ferritin, celiac screen, HIV 1 and 2 antibodies, hepatitis panel, serology for Herpes simplex virus, Epstein–Barr virus and cytomegalovirus, Legionella antigen, and mycoplasma titers was all normal. Purified protein derivative (PPD) and QuantiFERON®-TB Gold In-Tube tests for tuberculosis were negative. Angiotensin converting enzyme and serum lysozyme for sarcoidosis were normal. All her blood and urine cultures for bacteria, virus and fungi were negative. She underwent bronchoscopy, which revealed thick tracheal secretions. Bronchoalveolar lavage (BAL) fluid analysis revealed a total cell count of 2719/μL with 93% neutrophils, 3% lymphocytes, 2% alveolar macrophages and 2% eosinophils. Pleural fluid analysis revealed 3% neutrophils, 83% lymphocytes and 14% monocytes. BAL and pleural fluid cultures for bacteria, virus, fungi and mycobacteria were negative. Due to the new onset of diarrhea on day 10 of admission and development of hypoalbuminemia, the gastroenterology team was consulted. Her stool calprotectin level was significantly elevated at 847 μg/g but stool studies for cultures, ova, parasites, Giardia and Cryptosporidiosis were negative. Stool was also tested for Clostridium difficile by using toxin assay and was negative. Biopsies from esophagogastroduodenoscopy revealed active chronic gastritis and duodenitis. Colonoscopy revealed erythematous mucosa in the terminal ileum and ileocecal valve. Terminal ileal and colonic biopsies revealed signs of chronic inflammation including neutrophil cryptitis, crypt abscesses and gland distortion along with inflammatory infiltrate in the lamina propria supporting a diagnosis of Crohn's disease. However, no granulomas were identified (Fig. 2). PROMETHEUS® IBD Serology 7 was also consistent with Crohn's disease. She consequently was initiated on Crohn's therapy with intravenous steroids and infliximab with significant improvement in her pulmonary status. Her diarrhea improved in 5 days and dyspnea and cough were resolved within 2 weeks. A chest radiograph obtained at 6 weeks after discharge showed complete resolution of the pulmonary changes (Fig. 3). She remained symptom free during close follow-up for 12 months after discharge and her CD is stable on maintenance therapy with infliximab.


Ileocecal valve showing active colitis with crypt abscess (hematoxylin and eosin, × 198).


Follow-up chest radiograph 6 weeks after discharge revealing a well expanded left lung.

This case is unique for the significant pleural effusion alongside bronchial pneumonia developing prior to the onset of clinical symptoms of CD, a feature that has not been reported in pediatric literature before.

1.2 Case 2

A 17-year-old African American female with a past medical history significant for Crohn's disease presented with a three-week history of progressive skin lesions on her right wrist, left shin, and labia. She was presumed to have cellulitis and was initially prescribed trimethoprim–sulfamethoxazole. With her skin lesions progressing on antibiotic therapy, she presented to an outside hospital, where she was prescribed intravenous piperacillin with tazobactam and vancomycin, but again experienced no clinical response. While being treated, she developed cough, shortness of breath and fever. Chest examination was significant for bilateral crepitations. A chest radiograph showed opacities in both lung fields concerning for pneumonia. Despite adding a new intravenous antibiotic to broaden the antimicrobial coverage, her symptoms and radiographic signs persisted. Computed tomography (CT) scan of the chest and abdomen revealed several bilateral cavitary lesions in the lung (Fig. 4 ) and two round dense lesions in the liver (Fig. 5 ), the larger of which measured 2 × 2 cm. Due to the complexity of multisystem involvement, she was referred to our hospital for further management. Her past medical history was notable for being diagnosed with Crohn's colitis in 2006 after presenting with diarrhea, hematochezia, abdominal pain and weight loss. Her esophagogastroduodenoscopy was normal at that time and colonoscopy revealed inflammatory mucosal changes with histology revealing chronic inflammatory changes with characteristic granulomas in the colon. Following her diagnosis with CD, she was prescribed azathioprine. However, she was non-compliant with therapy and had inconsistent follow-up with her primary gastroenterologist and had several relapses of intestinal disease.


CT scan of the chest revealing cavitary lesions (arrow) in the left lung.


CT scan of the abdomen revealing a dense lesion (arrow) of the right lobe of the liver.

A review of systems was significant for the presence of fever, cough, dyspnea, fatigue and a weight loss of 20 lb over the last 3 weeks. She also reported intermittent abdominal pain, which did not limit her daily activities, and a two-week history of intermittent non-bloody diarrhea. Her family history was negative for inflammatory bowel diseases, autoimmune disorders or recurrent infections.

Physical examination revealed a well appearing female with mild respiratory distress. Vital signs included a temperature of 97.7 °F, pulse of 76/min, respiratory rate of 24/min and blood pressure of 110/67 mm Hg. Her weight and height were appropriate for her age. She had a 5 cm ulcerated lesion on the back of the right hand with surrounding erythema, an 8 cm ulcerated lesion on the right shin (Fig. 6 ), and a 2 cm ulcerated lesion on the left labia majora. She appeared to be in moderate pain when touching her right hand and right shin. The rest of the systemic examination was unremarkable.


Healing skin lesion over the right leg at the time of discharge.

Her complete blood count at presentation revealed a WBC — 12.51 with 76% segmented neutrophils, 20% lymphocytes, 2% monocytes and 2% myelocytes. No peripheral eosinophils were identified. Comprehensive metabolic panel, erythrocyte sedimentation rate, CRP, LDH and uric acid were all normal. Bronchoalveolar lavage (BAL) showed numerous macrophages and neutrophils, but the BAL fluid was negative for bacteria, fungus, pneumocystis, and mycobacterium. Flow cytometry was negative for malignant cells. A CT-guided liver biopsy showed chronic inflammation with focal necrosis. MRI of the leg was negative for osteomyelitis. All cultures, including blood, urine, wound, sputum, bronchial wash and liver tissue, were negative for bacteria, fungi and mycobacteria. An immune work-up revealed normal immunoglobulin and complement levels and normal distribution of lymphocytes on the lymphocyte marker study. Neutrophil burst for chronic granulomatous disease (CGD) was normal. Test results for mycoplasma, histoplasmosis, aspergillosis and blastomycosis were negative. QuantiFERON®-TB Gold In-Tube and PPD for tuberculosis were negative. An ANCA panel for vasculitis was negative. Angiotensin converting enzyme level and serum lysozyme level for sarcoidosis were normal. Stools were occult blood-positive, and stool calprotectin was significantly high, indicating ongoing intestinal inflammation. PROMETHEUS® IBD Serology 7 showed a pattern consistent with Crohn's disease. Her CT abdomen also revealed bowel wall thickening in the ascending colon, concerning for active colitis. Her 6-MP metabolite levels drawn at admission were significantly low, suggestive of non-compliance. Skin biopsy of her right leg showed ulceration with granulomatous inflammation and dermal fibrosis with a mixed inflammatory infiltrate, interpreted as consistent with Crohn's disease of the skin.

Antibiotic therapy was discontinued once all her microbial cultures came back negative, and further immune modulatory therapy with infliximab to treat her CD was initiated. After the administration of infliximab, her systemic symptoms improved over the following 5 days with resolution of the skin lesions and an improved chest radiograph at a 6 week follow-up.

We report this clinical case for several reasons. First, the misinterpretation of the multiple CD-associated skin lesions for abscesses underscores the importance of emphasizing the extra-intestinal manifestations of CD. Second, to our knowledge, this is the first description of a CD-associated cavitary lung lesion in a pediatric patient.

2 Methods

The goal of this systematic search was to identify and review published articles describing pulmonary involvement in pediatric patients under 18 years of age with Crohn's disease. The literature review focused primarily on pulmonary involvement in children with CD described in the English language. The US National Library of Medicine database (MEDLINE), Excerpta Medica database (EMBASE) and PUBMED were searched in April 2011 for published articles using the key words “granulomatous” OR “inflammatory”, “pulmonary” OR “Lung” OR “Airway” OR “tracheobronchial” OR “bronchopulmonary”, “Crohn's” OR “Crohn's disease” OR “CD” OR “Inflammatory bowel disease” and “children” OR “adolescent” or “pediatric”. Full articles of all potentially relevant articles were retrieved, and reference lists of all identified studies were checked. Only case reports in children under 18 years of age were included. Non-English papers were excluded.

3 Results

A review of the English literature identified 15 pediatric cases (Table 1). Age ranged from 3 to 17 years with no significant gender discordance (7 males and 8 females). Pulmonary symptoms preceded the onset of bowel symptoms in four patients, simultaneously in three patients, and following CD diagnosis in eight patients. Among the patients with a prior diagnosis, CD was stable in five patients, was poorly controlled in two patients, and one patient had respiratory disease manifested 4 years after colectomy. All patients had colonic involvement at initial diagnosis, and in five patients the disease was limited to the colon. Other extraintestinal manifestations were noted in six patients including primary sclerosing cholangitis (two patients), arthralgia (two patients), finger clubbing (two patients), pancreatitis (one patient) and erythema nodosum (one patient). The most frequent respiratory symptoms were cough and shortness of breath. The majority of patients (seven of eight cases) had a restrictive lung pattern on pulmonary function tests. Radiologically, patients had varied presentations with basal infiltrates, patchy dense lesions, reticulonodular lesions and lobar pneumonia. An infectious etiology was vigorously excluded in all patients, and sarcoidosis was excluded in seven patients. All the patients had chronic granulomatous inflammation, and all but two cases showed characteristic noncaseating granulomas in open lung or bronchial biopsies. All but one patient had complete resolution of symptoms with (11) or without (3) therapy.

View this table:
Table 1

Summary of reported cases of pulmonary manifestations in children with Crohn's disease.

AuthorAgeLocationH/O CDaCD locationbSZP/5 ASAcPFTPPDBALLung lesion/granulomaTreatment
Ahmed129, FTracheaNoColonNoUnclearUnclearUnclearHemorrhagic tracheitis/yesUnclear
Bentur1313, FUnclearYesColon + SBSZPRestrictiveNegLPInterstitial/yesSteroids
Krishnan1413, FBilateralYesUnclearSZPRestrictiveNegUnclearConsolidation/yesaTNF
14, FBilateralYesUnclear5-ASARestrictiveNegUnclearInterstitial/yesaTNF
17, MBilateralYesUnclear5-ASAUnclearNegUnclearInterstitial/unclearaTNF
Levenbrown1515, FBilateralNoColon + SBNoRestrictiveNegUnclearBilateral nodular/yesSteroids + MTx
Kayser1612, MBilateralYesColon + SBNoRestrictiveNegUnclearInterstitial/yesSteroids + Aza
Puntis1715, MLeft lower lobeYesColon5-ASAUnclearNegUnclearPatchy consolidation/yesSpontaneous resolution
Shah1813, MBilateralNoColonNoUnclearNegUnclearDiffuse reticulo nodular/yesSpontaneous resolution
Calder193, MRight middle lobeNoMouth, colonNoUnclearNegUnclearDense lesions/yesUnclear
Ari Silbermintz2013, FBilateralYesColon + SBSZPRestrictiveNegUnclearConsolidation/yesaTNF
Minic2115, FRight middle lobeNoColon + SBNoUnclearNegLPDense lesion/yesSteroids
Mahgoub229, MBilateralYesColon + SBSZPUnclearNegUnclearInterstitial/yesNo response
Al-Binali2311, MBilateralNoColon + SBNoRestrictiveNegMPNodular/yesSpontaneous resolution
Valletta246, FLeft lower lobeNoColonSZPNormalNegLPDense lesions/noSteroids
Our case 111, FLeft lower lobeNoColonNoNot availableNegMild LPConsolidation and effusion/–aTNF
Our case 217, FBilateralYesColonYesNot availableNegMacrophages + neutrophilsCavitary lesions/–aTNF
  • Abbreviations: M = male, F = female, SZP — sulfasalazine, 5 ASA — 5-aminosalicylic acid, PFT: pulmonary function testing, PPD — purified protein derivative, BAL — broncho-alveolar lavage, SB — small bowel, Neg — negative, LP — lymphocyte predominance, MP — macrophage predominance, Aza = azathioprine, MTx = methotrexate and, aTNF = antitumor necrosis factor alpha.

  • a H/O CD while presenting with respiratory symptoms.

  • b Location of CD at diagnosis.

  • c Exposure to SZP or 5 ASA treatment before presentation.

4 Discussion

CD predominantly affects the gastrointestinal system but may be associated with an extensive list of extraintestinal manifestations involving almost every organ system. Pulmonary involvement is rarely reported in pediatric patients. As demonstrated by these case reports, recognition of the extraintestinal manifestations of CD is important to avoid unnecessary and potentially harmful treatments and to improve management of the entire CD complex.

The prevalence and the pathogenesis of lung involvement in CD are poorly understood. In a case control study of 22 adult patients with CD, latent pulmonary involvement was observed in 54% of patients without clinical and radiological pulmonary abnormalities as evidenced by increased alveolar lymphocytosis.7 This phenomenon of latent pulmonary disease was later confirmed in pediatric patients with Crohn's disease.25 This study showed a significantly impaired lung transfer factor for carbon monoxide (DLCO) in patients with active disease, suggesting an interstitial process. In another case–control study of 14 children with CD and no clinical or radiological evidence of pulmonary disease, 71% of patients had bronchial hyper responsiveness (BHR) indicating involvement of major airways.26 In these patients however, BHR was not influenced by activity or duration of the CD. Several theories have been proposed indicating pulmonary damage by circulating immune complexes and inflammatory mediators27,28; however, further clinical studies failed to show a significant correlation.6,29 It has been hypothesized that the high frequency of pulmonary involvement may reflect an immune dysregulation common to all mucosal surfaces,30 in which lymphocytes sensitized to antigens at one mucosal site may circulate and preferentially localize in the same or different mucosal sites and initiate inflammatory reaction. This theory may explain the involvement of the lung at various levels leading to airway disease and recruitment of alveolar lymphocytes leading to interstitial lung disease. Also, both the colonic and respiratory epithelia share a common embryonic origin from the primitive gut and contain a submucosal lymphoid tissue which plays a crucial role in mucosal defense mechanism. This similarity in mucosal immune system may explain the same pathologic changes observed in both organ systems. Though pulmonary involvement in CD was first described a few decades ago, the exact mechanism behind the inflammatory changes in the lungs remains unclear. With the recent advances in the understanding of CD pathogenesis and cellular abnormalities, future investigation may further advance the understanding of pulmonary involvement in CD.

Symptomatic pulmonary disease is very rare in children and depending on the location of the inflammation, the manifestations can be broadly categorized into airway disease and interstitial lung disease. These manifestations usually follow the onset of CD and often exacerbate during relapses; however, pulmonary symptoms may precede the development of gastrointestinal disease. Among the fifteen patients reported, one patient had large airway disease, and the remaining fourteen had interstitial lung disease.

Patients with airway disease can have significant airway inflammation, which could potentially lead to airway narrowing. The most common presenting symptoms include cough, stridor, and fever. Chest radiographs are often non-specific and pulmonary function testing may reveal non-reversible airflow obstruction. CT scan of the chest may rarely show airway involvement but the definitive test would be endobronchial biopsies which may reveal noncaseating granulomas, characteristic of CD. In children, only one case of large airway disease has been reported in a 9-year-old previously healthy female who presented with a two-week history of intermittent stridor. Bronchoscopic evaluation revealed tracheal inflammation with significant airway narrowing that necessitated urgent tracheostomy. She was subsequently positive for CD in both serological tests and colonic biopsy specimens.12

Interstitial lung disease is the predominant form of lung injury observed in patients with CD and the usual presenting symptoms include dyspnea and cough. Of the fourteen cases reported, diffuse bilateral interstitial inflammation was noted in majority of patients (n = 10) and localized to a single lobe in four patients. It is notable that the severity of the radiological and clinical findings is often discordant.19 Pulmonary function tests, when abnormal, typically revealed a restrictive lung disease pattern.1315,19,22 BAL fluid showed a lymphocytic20,23 and mixed cellular22 infiltrate. Among the 14 pediatric patients reviewed, seven patients had bronchiolitis obliterans with organizing pneumonia (BOOP),1217,21 two had interstitial fibrosis,13,15 and the remaining patient had non-specific granulomatous inflammation.13,1820,22 All but two biopsy specimens also demonstrated characteristic noncaseating granulomas.

In a CD patient, the differential diagnosis of respiratory disease can be extensive and includes infectious and noninfectious causes. It is essential to rule out infection in every patient given the risk of immunosuppression from medications, with tuberculosis being a primary concern. Sarcoidosis and CD also share several common features. Both are chronic inflammatory disorders of unknown origin, characterized by noncaseating granulomas, and both can be associated with clinical manifestations like uveitis, erythema nodosum, arthritis and episcleritis. The clinical pictures of these two diseases traditionally are differentiated based on the topography of the disease. Sarcoidosis mainly involves the mediastinal lymph nodes and lung, while CD is primarily a gastrointestinal disease. However, it can become difficult to differentiate these two conditions especially when sarcoidosis manifests gastrointestinal involvement and/or CD has pulmonary involvement.3133 Though subclinical gastrointestinal sarcoidosis is common, symptomatic intestinal disease is rarer with an incidence of 0.1–0.9%.34

Sulfasalazine and mesalamine, the first line therapies for CD have been well documented to cause interstitial lung disease.35 Due to histologic feature overlap, drug induced interstitial lung disease cannot be completely excluded in patients exposed to these medications. The diagnosis is suggested by temporal association of pulmonary symptoms with medications and confirmed by resolution of symptoms with discontinuation of therapy. Eight patients in the present study were exposed to either sulfasalazine or mesalamine prior to the onset of respiratory symptoms.12,13,16,19,21,23 In four patients symptoms progressed despite the stopping therapy. It was unclear in the remaining patients however whether these drugs were withdrawn once the respiratory symptoms began.

Furthermore, chronic granulomatous disease (CGD)36 and Wegner's granulomatosis (WG)37 can also involve both pulmonary and gastrointestinal systems but are relatively rare especially in children. CGD can be excluded by a negative Nitroblue tetrazolium test. The diagnosis of WG involves a combination of histopathological evidence of vasculitis with granulomatous inflammation and necrosis along with laboratory evidence of positive c-ANCA.

Management of CD-associated pulmonary disease can be challenging and usually requires systemic steroids with or without additional therapies like azathioprine or methotrexate for adequate control of symptoms; however, spontaneous resolution has been reported.16,17,22 Half of the patients in this review responded to conventional therapy with steroids alone or steroids with azathioprine. Refractory cases have been shown to respond to infliximab, as reported in four patients.13,19

In summary, Crohn's disease is a systemic disorder that is not limited to the gastrointestinal system. Pulmonary involvement in CD may be more common in children than what was clinically suspected and previously reported. Often symptoms are limited to derangements in pulmonary function testing, but sometimes CD can be associated with significant lung disease in association with other systemic manifestations. Pulmonary manifestations may be independent of bowel disease activity and can manifest before, during or after the diagnosis of CD. This could possibly be due to derangement in the mucosal immunity of both lung and bowel, affected by similar antigenic stimuli. Our cases demonstrate previously unreported pulmonary involvement of CD that continued to progress until appropriate immunomodulatory therapy was initiated. This review emphasizes the importance of understanding various pulmonary manifestations in children with CD and awareness of these potential complications may lead to prompt diagnosis, guide appropriate therapy and decrease morbidity.

Statement of authorship

Narendra Vadlamudi carried out the study design, acquisition and analysis of data, and writing of the manuscript. Udayakumar Navaneethan, Kirk Thame, David Kelly, Reed Dimmitt and Tom Harris carried out the study design and critical analysis of the data and the manuscript. All authors read and approved the final manuscript.

Conflict of interest

No financial conflict of interest for all authors.


  • These cases were presented as a poster presentation at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Conference on October 20–23, 2011.

Crohn's disease
Inflammatory bowel disease
5-Amino-salicylic acid.


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