Published online April 3, 2006
PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1440-1443 (doi:10.1542/peds.2005-1559)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Krishnan, S.
Right arrow Articles by Dozor, A. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krishnan, S.
Right arrow Articles by Dozor, A. J.
Related Collections
Right arrow Respiratory Tract

EXPERIENCE AND REASON

Lung Lesions in Children With Crohn's Disease Presenting as Nonresolving Pneumonias and Response to Infliximab Therapy

Sankaran Krishnan, MDa, Agnes Banquet, MDa, Leonard Newman, MDb, Umadevi Katta, MDc, Asawari Patil, MDc and Allen J. Dozor, MDa

a Divisions of Pediatric Pulmonology
b Gastroenterology, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla, New York
c Department of Pathology, Westchester Medical Center, Valhalla, New York


   ABSTRACT
TOP
 ABSTRACT
CASE REPORTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Lung lesions in children with Crohn's disease are often difficult to diagnose and treat. We report here 3 children (aged 13, 14, and 17 years) on immunosuppressive therapy for previously diagnosed Crohn's disease who presented with nonresolving pneumonias. All 3 had unfavorable response to empiric antibiotics and had progression of lesions. Cultures of sputum and blood did not yield any organisms. Subsequent lung biopsies revealed noncaseating granulomas with giant cells in 2 subjects and bronchiolitis obliterans with organizing pneumonia in the third. All patients were treated with infliximab, a novel anti–tumor necrosis factor monoclonal antibody, and showed rapid clinical and radiologic response. We emphasize that a high index of suspicion for noninfectious etiologies needs to be maintained in patients with Crohn's disease who present with lung lesions to ensure timely intervention. Infliximab therapy seems to be effective and well tolerated in such patients.

Abbreviations: IBD, inflammatory bowel disease • CT, computed tomography


   CASE REPORTS
TOP
 ABSTRACT
 CASE REPORTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Case1.
C.H. was a 13-year-old female who presented in September 2003 with back pain, cough, and fever and chest radiograph features of a "round pneumonia" (Fig 1). She was diagnosed with Crohn's disease in 1999 at 9 years of age, and her inflammatory bowel disease (IBD) was stable on a maintenance regimen of oral prednisone 0.5 mg/kg on alternate days and 6-mercaptopurine for the past 3 years. Her condition had failed to respond to methotrexate and sulfasalazine previously. She had also been diagnosed with primary sclerosing cholangitis 2 years ago. The lung lesions showed no clinical or radiologic response to appropriate antibiotics. Instead, new lesions appeared sequentially over a 4-week period, and her clinical condition worsened with progressive hypoxemia. Several blood and sputum cultures were negative for bacteria, fungi, and mycobacteria. All tests for infections, thromboembolic phenomena, and rheumatologic or collagen vascular disorders were negative. Mantoux testing was negative. Her lung function, which was normal previously, showed a restrictive pattern (Table 1). A high-resolution chest computed tomography (CT) scan revealed multiple pleural and intraparenchymal infiltrates with no adenopathy or interstitial disease (Fig 1). Open lung biopsy confirmed that the lesions were nonnecrotic, noncaseating granulomas with giant cells (Fig 2). Cultures from the biopsy samples were negative. With the diagnosis of primary Crohn's lesions, her therapy was increased to prednisone 1 mg/kg twice daily, and 6-mercaptopurine was continued. Clinical symptoms, including fever and cough, persisted without radiologic improvement. She then was treated with infliximab at a dose of 5 mg/kg given as an intravenous infusion. There was an immediate clinical response, with complete resolution of her fever, cough, and hypoxemia. Her chest radiograph showed dramatic resolution of the granulomas within 2 weeks (Fig 1), and lung function improved rapidly. She received monthly infliximab infusions for 3 months and has been receiving this therapy every 4 to 6 weeks since then. There have been no adverse effects during or after infliximab infusions. She continues to receive 6-mercaptopurine. At the time of this writing, she remains symptom-free from a respiratory viewpoint (22 months).


Figure 1
View larger version (60K):
[in this window]
[in a new window]
  		FIGURE 1 Chest radiographs and CT scan for case 1. A, Initial chest radiograph. B, Initial chest CT. C, Chest radiograph 2 weeks after the first infliximab infusion.

 

View this table:
[in this window]
[in a new window]
  		TABLE 1 Lung-Function Tests

 

Figure 2
View larger version (130K):
[in this window]
[in a new window]
  		FIGURE 2 Histopathology of lung tissue obtained by thoracoscopic biopsy for case 1. At low magnification (original magnification: x40; hematoxylin and eosin staining), distinct areas of nodularity can be seen in the lung tissue.

 
Case2.
T.C. was a 14-year-old female diagnosed with Crohn's disease in 2001 at 11 years of age. She was treated with corticosteroids and mesalamine until remission and has been stable on daily mesalamine. She was diagnosed also with exercise-induced asthma and treated with albuterol pre-exercise and as needed. She presented in September 2004 with chest tightness, shortness of breath, and cough that did not respond to albuterol. A chest radiograph revealed an infiltrate in the left lower lobe of the lung (Fig 3), which did not respond to 2 weeks of appropriate antibiotic therapy. Mantoux testing was negative. Blood and sputum cultures were negative for bacteria, fungi, and mycobacteria. A high-resolution chest CT scan revealed multiple, scattered granulomatous lesions with no significant adenopathy (Fig 3). Rheumatological studies were negative. Open lung biopsy revealed nonnecrotic, noncaseating epitheloid cell granulomas with giant cells (Fig 4). Infliximab therapy was initiated as an intravenous infusion at 5 mg/kg. There was rapid improvement in the clinical features, and she was discharged from the hospital on mesalamine. Subsequent chest radiographs demonstrated complete resolution of her pulmonary infiltrates (Fig 3), and her lung function showed significant improvement (Table 1). She has subsequently received infliximab infusions every 8 weeks and has been stable on follow-up to the time of this writing (8 months). No adverse effects of infliximab infusion have occurred.


Figure 3
View larger version (55K):
[in this window]
[in a new window]
  		FIGURE 3 Chest radiographs and CT scan for case 2. A, Initial chest radiograph. B, Initial chest CT. C, Chest radiograph postinfliximab infusion.

 

Figure 4
View larger version (162K):
[in this window]
[in a new window]
  		FIGURE 4 Histopathology of lung tissue obtained by thoracoscopic biopsy for case 2. There is diffuse interstitial fibrosis. Some airspaces contain epitheloid granulomatous inflammation (A, fibroblasts; B, epitheloid cell), whereas some have fibrous plugs (C). Special stains for detecting acid-fast organisms and fungi were negative. (original magnification: x100; hematoxylin and eosin staining.)

 
Case3.
K.F. was a 17-year-old male diagnosed initially with ulcerative colitis in 2001 at the age of 13; his diagnosis was later revised to Crohn's disease. His baseline immunosuppressive therapy included mesalamine and 6-mercaptopurine. His past medical history is significant for seizure disorder, for which he is on phenytoin. He was also admitted at 16 years of age for pulmonary embolism possibly secondary to peripheral thrombophlebitis and treated with subcutaneous enoxaparin for 3 months. He presented in March 2005 with fever, chest pain, oral lesions, conjunctivitis, and dehydration. A chest radiograph revealed bilateral basal infiltrates and bilateral small-to-moderate pleural effusions (Fig 5). He had leukocytosis with a left shift. He was treated for bacterial pneumonia in the face of underlying immunosuppressive therapy with intravenous antibiotics. His oral lesions responded to acyclovir for suspected herpetic gingivitis. Fever and chest radiograph findings persisted for the next 3 weeks despite appropriate antibiotic regimens. Initial blood and sputum cultures were negative for bacteria, fungi, and mycobacteria. A thoracoscopic lung biopsy was then performed. Histopathology revealed classic features of bronchiolitis obliterans and organizing pneumonia. After poor response to 1 week of oral prednisone, therapy was initiated with infliximab as an intravenous infusion. There was rapid clinical and radiologic improvement after just 1 treatment. He continued to remain asymptomatic on outpatient follow-up (1 month) with plans to continue infliximab infusions monthly. Additional follow-up and pulmonary-function tests are planned.


Figure 5
View larger version (82K):
[in this window]
[in a new window]
  		FIGURE 5 Chest radiographs for case 3. A, Initial chest radiograph. B, Postinfliximab infusion.

 

   DISCUSSION
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
IBD including Crohn's disease has long been recognized to have extraintestinal manifestations ranging from skin to joint to ocular pathology.1,2 Primary lung involvement is rare and reported mostly as isolated cases in the literature. Respiratory disease associated with IBD in adults includes interstitial pneumonitis, tracheal stenosis, bronchiolitis, pulmonary vasculitis, bronchiolitis obliterans with organizing pneumonia, necrotic pulmonary nodules, serositis involving intrathoracic structures in the form of pleural effusions or pericarditis, and pulmonary infiltrates with eosinophilia.2–7 Pediatric reports remain sketchy8–11 and include isolated or diffuse lung granulomas. Pulmonary infiltrates in the setting of immunosuppression present a diagnostic dilemma, and definitive diagnosis often requires a lung biopsy. Frequently, as in our patients, possibility of noninfectious etiologies in this setting is often considered late after exhausting empiric antimicrobial options. We emphasize the need for maintaining a high index of suspicion for such lesions in patients with nonresolving pneumonias.

Treatment of lung lesions has usually involved increasing doses of corticosteroids as well as traditional therapies for Crohn's disease including mesalamine and other immunosuppressive agents. Most reported patients on such therapies have shown unsatisfactory responses. Our first patient was also treated initially with steroids, with poor results. Subsequently, there was a dramatic response to infliximab. In view of our experience with the first patient, we treated the subsequent 2 patients with infliximab early and obtained gratifying results.

Infliximab is a newer therapy for IBD. It is a monoclonal antibody to tumor necrosis factor {alpha}. There are several studies documenting efficacy and safety of infliximab in adults13,14 and children.15–20 Results have been mixed, with sustained remission of gastrointestinal symptoms ranging from 50%18 to 90%.17 However, none of these studies have addressed therapy for lung lesions. The largest pediatric trial of infliximab to date did not include any subjects with lung disease.20 Therapy for lung lesions associated with Crohn's disease in children using infliximab has not been reported previously. All 3 of our patients tolerated the infusions without adverse effects.


   CONCLUSIONS
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Noninfectious etiologies, including granulomas, should be considered in the differential diagnosis of children with Crohn's disease and nonresolving pneumonia. We have reported 3 children who presented with lung lesions that were unresponsive to antimicrobial therapies but responded quickly to infliximab therapy. Additional long-term trials are needed to determine the safety and efficacy of this approach.


   FOOTNOTES
 
Accepted Aug 26, 2005.

Address correspondence to Sankaran Krishnan, MD, Department of Pediatrics, Division of Pediatric Pulmonology, New York Medical College, 106 Munger Pavilion, Valhalla, NY 10595. E-mail: sankaran_krishnan{at}nymc.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Feldman M, Scharschmidt BF, Sleisenger MH, Fordtran JS, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed, 2002:2005 –2038
  2. Levine JB, Lukawski-Trubish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterol Clin North Am. 1995;24 :633 –646[ISI][Medline]
  3. Lucero PF, Frey WC, Shaffer RT, Morris MJ. Granulomatous lung masses in an elderly patient with inactive Crohn's disease. Inflamm Bowel Dis. 2001;7 :256 –259[CrossRef][Medline]
  4. Kraft SC, Earle RH, Roesler M, Esterly JR. Unexplained bronchopulmonary disease with inflammatory bowel disease. Arch Intern Med. 1976;136 :454 –459[Abstract]
  5. Omori H, Asahi H, Inoue Y, Irinoda T, Saito K. Pulmonary involvement in Crohn's disease report of a case and review of the literature. Inflamm Bowel Dis. 2004;10 :129 –134[CrossRef][ISI][Medline]
  6. Faller M, Gasser B, Massard G, Pauli G, Quoix E. Pulmonary migratory infiltrates and pachypleuritis in a patient with Crohn's disease. Respiration. 2000;67 :459 –463[CrossRef][ISI][Medline]
  7. Golpe R, Mateos A, Perez-Valcarcel J, Lapena JA, Garcia-Figueiras R, Blanco J. Multiple pulmonary nodules in a patient with Crohn's disease. Respiration. 2003;70 :306 –309[CrossRef][ISI][Medline]
  8. Al-Binali AM, Scott B, Al-Garni A, Montgomery M, Robertson M. Granulomatous pulmonary disease in a child: an unusual presentation of Crohn's disease. Pediatr Pulmonol. 2003;36 :76 –80[CrossRef][Medline]
  9. Bentur L, Lachter J, Koren I, et al. Severe pulmonary disease in association with Crohn's disease in a 13-year-old girl. Pediatr Pulmonol. 2000;29 :151 –154[CrossRef][ISI][Medline]
  10. Calder CJ, Lacy D, Raafat F, Weller PH, Booth IW. Crohn's disease with pulmonary involvement in a 3 year old boy. Gut. 1993;34 :1636 –1638[Abstract/Free Full Text]
  11. Puntis JW, Tarlow MJ, Raafat F, Booth IW. Crohn's disease of the lung. Arch Dis Child. 1990;65 :1270 –1271[Abstract]
  12. Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience with infliximab therapy in 100 patients with Crohn's disease. Am J Gastroenterol. 2000;95 :3490 –3497[CrossRef][Medline]
  13. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology. 1999;117 :761 –769[CrossRef][ISI][Medline]
  14. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn's disease in children and adolescents. J Pediatr. 2000;137 :192 –196[CrossRef][Medline]
  15. Kugathasan S, Werlin SL, Martinez A, Rivera MT, Heikenen JB, Binion DG. Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease. Am J Gastroenterol. 2000;95 :3189 –3194[Medline]
  16. Stephens MC, Shepanski MA, Mamula P, Markowitz JE, Brown KA, Baldassano RN. Safety and steroid-sparing experience using infliximab for Crohn's disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol. 2003;98 :104 –111[Medline]
  17. Cezard JP, Nouaili N, Talbotec C, et al. A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (remicade) in severe pediatric Crohn's disease. J Pediatr Gastroenterol Nutr. 2003;36 :632 –636[CrossRef][Medline]
  18. Baldassano R, Braegger CP, Escher JC, et al. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn's disease. Am J Gastroenterol. 2003;98 :833 –838[CrossRef][Medline]
  19. Diamanti A, Papadatou B, Knafelz D, Gambarara M, Ferretti F, Castro M. Clinical outcome and safety of periodic infliximab therapy in children and adolescents with Crohn's disease. J Pediatr Gastroenterol Nutr. 2004;39 :302 –303[Medline]
  20. Lamireau T, Cezard JP, Dabadie A, et al. Efficacy and tolerance of infliximab in children and adolescents with Crohn's disease. Inflamm Bowel Dis. 2004;10 :745 –750[Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 ChestHome page
H. Black, M. Mendoza, and S. Murin
Thoracic Manifestations of Inflammatory Bowel Disease
Chest, February 1, 2007; 131(2): 524 - 532.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Krishnan, S.
Right arrow Articles by Dozor, A. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krishnan, S.
Right arrow Articles by Dozor, A. J.
Related Collections
Right arrow Respiratory Tract