Crohn disease (CD) is a chronic inflammatory condition of the gastrointestinal tract characterized by segmental transmural inflammation. Immune modulators such as 6-mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are an important class of therapies used for the treatment of inflammatory bowel disease (IBD). Opportunistic infections can be difficult to recognize in these patients and can be associated with significant morbidity or mortality. Lymphoproliferative disorder (LPD) is a rare complication of viral infections in immunocompromised hosts, and typically consists of fever, constitutional symptoms, hepatosplenomegaly, liver function and coagulation abnormalities, and hypertriglyceridemia. Although LPDs have been associated with CD alone (1), a subset of patients treated with AZA or 6-MP may be at risk after acquisition of primary Epstein-Barr virus (EBV) infection.
Wilson disease is a rare autosomal recessive genetic disorder of copper metabolism, which results in accumulation of excess copper in the liver leading to cirrhosis. There does not appear to be an association between CD and Wilson disease. Additionally, there have been no case reports of LPD in patients with Wilson disease.
We report the case of a young girl diagnosed with both CD and Wilson disease who presented with a 1-month history of fever of unknown origin and was subsequently diagnosed as having LPD. We describe the association of primary EBV infection and LPD in a patient with CD and discuss possible risk factors for the disease as well as the effect of specific immunosuppressive therapy, with the goal to improve management and outcomes.
A 16-year-old girl with a medical history significant for CD and Wilson disease, characterized by cirrhosis and portal hypertension, presented with a 1-month history of fever of unknown origin. She reported fevers as high as 104°F approximately 2 of every 3 days, along with generalized malaise, fatigue, and occasional lower extremity muscles aches. When the fever began, she also had a mild sore throat and ear pain, which was treated with oral antibiotics, and her symptoms resolved. Two weeks later she was thought to have a urinary tract infection and treated with intramuscular ceftriaxone for 3 consecutive days. Once again, following this course of antibiotics she was afebrile for a brief period of time. She also complained of a minimally productive cough with reportedly blood-tinged mucus. Due to persistent fevers, however, she was admitted for inpatient evaluation. At the time of admission she denied any abdominal discomfort, diarrhea, rash, joint pain, headache, dizziness, neck stiffness, sore throat, or photophobia. There was no recent travel or exposure to animals. She did, however, report contact with a school friend who was diagnosed as having mononucleosis approximately 3 weeks before admission.
Her CD was diagnosed 5 years previously, and had been well controlled on mesalamine 2.4 g once daily, AZA 50 mg twice daily, and infliximab infusions, which started 6 months before admission. At the time of her initial IBD presentation she was found to have abnormal liver enzymes, and after a full workup, she was diagnosed as having Wilson disease. Her treatment consisted of ursodiol and trientene 500 mg twice daily and nadalol 20 mg daily for her portal hypertension.
On admission she was alert, appropriate, well nourished, and in no acute distress. She was febrile to 102°F; blood pressure 120/75; pulse 100 beats per minute, regular; respiratory rate at 22/min; and oxygen saturation 98% on room air. Head and neck examination was unremarkable other than small anterior cervical lymphadenopathy. She had a new 2/6 midsystolic murmur at the left sternal border, with no radiation to the axilla or neck. Her chest was clear to auscultation bilaterally. Her abdomen was soft, nontender, without guarding or rebound, no hepatomegaly, yet she had a palpable spleen. Her initial laboratory studies showed a hemoglobin 10.8 g/dL, mean cell volume 95 fL, white blood cells 2400/μL, absolute neutrophil count 1500, platelet count 53 000/μL, Na 137, K 3.7, Cl 98, CO2 27, Cr 0.7 mg/dL, blood urea nitrogen 7 mg/dL, alanine aminotransferase 16 U/L, aspartate aminotransferase 56 U/L, alkaline phosphatase 133 U/L, albumin 3.8 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.1 mg/dL, erythrocyte sedimentation rate 66 mm, and C-reactive protein 0.22 mg/L. Ceruloplasmin checked in January 2005 was 46 g/L (normal 0.2–0.5 g/L), and urine copper in October 2007 was 176 μg/24 h (upper limit of normal <40 μg/24 h). A peripheral blood smear showed generalized pancytopenia with normal morphology. AZA was discontinued on admission. Urinalysis was within normal limits, and a monospot was negative. Blood, stool, throat, and urine cultures were sent and were negative. EBV polymerase chain reaction (PCR) on admission was 243 copies; anti-EBV capsid antigen IgM was 7.832 REV (normal 0–0.9). Cytomegalovirus PCR, parvovirus B19 PCR, and HIV1/HIV2 antibody testing were negative. A chest x-ray was normal as was an echocardiogram. Three days into her hospitalization, cefipime was empirically started for high spiking fevers (104°F) and neutropenia (absolute neutrophil count 850). On hospital day 3, computed tomography (CT) of her sinuses was performed and showed a small amount of fluid with air fluid levels in the right sphenoid sinus, but they were otherwise clear.
The initial working diagnosis, given her fevers, myelosuppression, and initial PCR results, was primary EBV-related infection with secondary bone marrow suppression in an immunocompromised host. However, due to persistent high fevers despite antibiotic therapy she underwent a CT scan of her chest, abdomen, and pelvis to evaluate for lymphadenopathy and/or intraabdominal process. The CT scan (which was compared with a previous examination 16 months earlier) revealed a diffusely heterogeneous liver, unchanged splenomegaly, and multiple varices, as well as mildly enlarged abdominal lymph nodes that were unchanged. Given rising EBV titers and progressive pancytopenia, she underwent a bone marrow aspiration and biopsy on hospital day 7. It showed hypoplasia with the degree of peripheral pancytopenia out of proportion to the degree of hypoplasia, suggesting an element of hypersplenism. It also revealed scattered CD3-positive T cells and CD20-positive B cells, and in situ hybridization using an EBV-encoded RNA (EBER) probe showed rare EBER expression, thus confirming latent viral infection. No pathogens or malignant cells were noted. She continued to have daily high spiking fevers, and antibiotics were broadened to include piperacillin/tazobactam, doxycycline, fluconazole, and ganciclovir. She received 1 dose of intravenous immunoglobulin (IVIG) on day 13 with no improvement in symptoms or fever. By hospital day 14 her anemia (hemoglobin 5.6 g/dL) had progressed and she had severe menorrhagia necessitating multiple red blood cell transfusions.
At the end of the second week she had continued fevers and the cervical lymphadenopathy initially present on admission became more prominent. Because of a growing concern for an underlying malignancy, in particular, hepatosplenic T-cell lymphoma, a rare but aggressive non-Hodgkin lymphoma recently reported in patients with IBD receiving concomitant infliximab and AZA therapy (2), a PET scan was performed. This showed multiple areas of intense increased activity in the neck, supraclavicular, axillary, mediastinal, and inguinal regions corresponding to enlarged lymph nodes, along with an intensely active and enlarged spleen (Fig. 1). Given her ongoing coagulopathy, thrombocytopenia, and underlying liver condition, a liver biopsy was not done and instead she underwent a cervical lymph node biopsy on hospital day 16. The excisional biopsy showed a heterogeneous population of plasmocytoid cells. Immunostaining revealed polyclonal expression with many EBER-positive cells. The specimen was not supportive of a malignant lymphoma, but was rather consistent with immunosuppression-associated EBV LPD. Methylprednisolone was immediately started and she became afebrile within 24 hours. Shortly thereafter the antibiotics were discontinued. She also received 2 CytoGam infusions during her hospitalization with 2 subsequent infusions given as an outpatient. Her symptoms continued to resolve and she was discharged after 23 days of hospitalization. The patient is now doing well as an outpatient taking mesalamine and has not resumed AZA or infliximab. Her EBV PCR reverted to negative, but she continues to have a white blood cell count of 2.9, which is believed to be due to her ongoing hypersplenism.
CD affects various aspects of the immune system. Although increasing evidence points to an aberrant innate immune system in patients with IBD, the treatments with immunomodulators commonly used in IBD inherently compromise the patient's immune response to viral and bacterial infections. AZA is 1 of the most widely used immunosuppressive agents, and has been proven effective in corticosteroid-dependent, corticosteroid-refractory, and fistulizing CD (3–5).
EBV infects >90% of the world's adult population (6). Primary EBV infection is often asymptomatic or causes infectious mononucleosis, which is usually a benign or self-limiting illness. After primary infection, EBV remains latent in circulating B lymphocytes. EBV can also induce lymphoproliferative histiocytosis, posttransplant lymphoproliferative disorder, and lymphoma in immunocompromised hosts. Recent guidelines published by the European Crohn's and Colitis Organisation regarding the recognition and treatment of EBV infection in patients with IBD do not recommend screening for latent or subclinical EBV infection or initiation of chemoprophylaxis before onset of immunomodulator therapy (7). During severe EBV infection, however, they recommend discontinuation of immunomodulatory therapy and prompt initiation of antiviral therapy. Acyclovir and ganciclovir have limited efficacy against EBV and have not been shown to be effective against its latent form (8). Preventive strategies may include active immunization with a future EBV vaccine (9,10) or passive immunization with IVIG, such as CytoGam, a cytomegalovirus hyperimmune globulin containing 10- to 100-fold greater anti-EBV antibody titers compared with standard IVIG (11). Attention to identifying risk factors is important to prevent the serious complications that can result from primary EBV infection in immunocompromised patients. A recent analysis in 100 patients with IBD showed that those taking AZA/6-MP alone have a 3 times greater chance of developing an opportunistic infection compared with controls (12). When 2 or 3 drugs were used in combination, the odds ratio increased dramatically to 14.5. Age older than 50 years was also associated with an increased risk of opportunistic infections. Although the vast majority of patients with IBD who develop these infections recover, 3 cases of fatal infectious mononucleosis after primary EBV infection associated with AZA therapy for CD have been reported (13–15). All of the patients were male, in their late teens/early 20s, and died of multiorgan failure, 2 related to a massive upper gastrointestinal bleed and the third following complications of E coli sepsis.
Recent results from a large French population-based CESAME (Cancers Et Surrisque Associe aux Maladies Inflammatoires Intestinales en France) study demonstrated that the risk of an LPD was 5 times greater in patients exposed to thiopurines than in those not previously exposed to those drugs (16). Furthermore, their findings strongly suggest that the additional risk of LPD seen in patients treated with thiopurines was more likely related to the immunosuppressive effects of the medication than to an over-representation of patients receiving thiopurines with uncontrolled chronic inflammation. Because most reported cases of LPD were associated with EBV, the ability of thiopurines to significantly decrease T-cell lymphocyte proliferation, thus preventing the clearance of EBV-immortalized B cells, may be the main mechanism of disease progression (16).
The risk of LPD in patients treated with immunosuppressive therapy for CD is low and the benefits of these medications for most patients outweigh the risks. Timely recognition of primary EBV infection in an immunocompromised population is critical so that prompt discontinuation of immunosuppression and commencement of other appropriate therapies such as methylprednisolone and antivirals can occur.
1. Bernstein CN, Blanchard JF, Kliewer E, et al
. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001; 91:854–862.
2. Mackey AC, Green L, Leptak C, et al
. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update. J Pediatr Gastroenterol Nutr 2009; 48:386–388.
3. Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease. Cochrane Database Syst Rev
4. Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev
5. Candy S, Wright J, Gerber M, et al
. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 1995; 37:674–678.
6. Niederman JC, Evans AS, Subrahmanyan L, et al
. Prevalence, incidence and persistence of EB virus antibody in young adults. N Engl J Med 1970; 282:361–365.
7. Rahier JF, Ben-Horin S, Chowers Y, et al
. European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohn's Colitis 2009; 3:47–91.
8. Lin JC, Smith MC, Pagano JS. Prolonged inhibitory effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine against replication of Epstein-Barr virus. J Virol 1984; 50:50–55.
9. Rees L, Tizard EJ, Morgan AJ, et al
. A phase I trial of Epstein-Barr virus gp350 vaccine for children with chronic kidney disease awaiting transplantation. Transplantation 2009; 88:1025–1029.
10. Lockey TD, Zhan X, Surman S, et al
. Epstein-Barr virus vaccine development: a lytic and latent protein cocktail. Front Biosci 2008; 13:5916–5927.
11. Green M, Michaels MG, Katz BZ, et al
. CMV-IVIG for prevention of Epstein-Barr virus disease and posttransplant lymphoproliferative disease in pediatric liver transplant recipients. Am J Transplant 2006; 6:1906–1912.
12. Toruner M, Loftus EV Jr, Harmsen WS, et al
. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134:929–936.
13. Posthuma EF, Westendorp RG, van der Sluys Veer A, et al
. Fatal infectious mononucleosis: a severe complication in the treatment of Crohn's disease with azathioprine. Gut 1995; 36:311–313.
14. N'Guyen Y, Andreoletti L, Patey M, et al
. Fatal Epstein-Barr virus primo infection in a 25-year-old man treated with azathioprine for Crohn's disease. J Clin Microbiol 2009; 47:1252–1254.
15. Garrido Serrano A, Pérez Martín F, Guerrero Igea FJ, et al
. Fatal infectious mononucleosis during azathioprine treatment in Crohn's disease. Gastroenterol Hepatol 2000; 23:7–8.
16. Beaugerie L, Brousse N, Bouvier AM, et al
. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374:1617–1625.