EBV hepatitis in a young Crohn's disease patient on prolonged remission with azathioprine

To the Editor:

With the increased and wide use of immunosuppressive agents and biological therapies in the treatment of inflammatory bowel diseases (IBD), it has become clear from both clinical studies and postmarketing surveillance that these agents may increase susceptibility to infections.¹

Like other members of the herpesvirus family, Epstein-Barr Virus (EBV) infects more than 90% of the world's adult population, regardless of geographical location. EBV seropositivity increases with age and after primary infection EBV remains latent in circulating B lymphocytes for life.² Nonetheless, according to recent guidelines from European Organization for Crohn's and Colitis (ECCO), screening for latent or subclinical EBV infection or chemoprophylaxis before onset of immunomodulator therapy is not recommended [EL2a, RG B].³ Only two cases of fatal infectious mononucleosis after primary EBV infection associated with azathioprine (AZA) therapy in patients with Crohn's disease (CD) have been reported.^4,5

Here we report the case of a 31-year-old, non smoker, CD patient who developed EBV hepatitis requiring hospitalization while on prolonged remission with AZA. Diagnosis of CD was made when he was 14-years-old by ileocolonoscopy with biopsies and entero-computed tomography (CT), performed because of persistent diarrhea, abdominal pain, weight loss, and anemia. According to the Montreal Classification the disease was classifiable at diagnosis as A1 L1 B2 and treated by mesalazine 2.4 g/day. Relapses of symptoms were treated by systemic steroids (2 cycles/year) until December 2003. At that time the patient presented an intestinal obstruction requiring intestinal resection. The histological examination of the surgical specimen revealed the presence of entero-enteric fistulae. The postoperative course was complicated 7 days after resection by the appearance of intermittent fever due to a small abdominal perianastomotic abscess, successfully treated by ciprofloxacin and metronidazole. Mesalazine at standard dosage (2.4 g/day) was started for the prevention of postoperative recurrence. Six months after resection an endoscopic recurrence occurred (grade i4 according to Rutgeerts classification of postoperative recurrence, with narrowing of the neoterminal ileum and ulcers documented by ileocolonoscopy), as well as a clinical one, mainly consisting of persistent abdominal pain. The patient was referred to our GI Unit and AZA (2 mg/kg/day) together with a cycle of budesonide (9 mg/day to taper) were started on July 2004. From this point to 2009 the patient was in good health. Ileocolonoscopy and small intestine contrastographic ultrasound (SICUS) showed a regression of the lesions in the neoterminal ileum. The patient remained asymptomatic and laboratory tests were negative. Just 5 years after starting AZA, in May 2009, the patient developed fever up to 39.5°C, resistant to antipyretic and empirical antibiotic treatment. The fever required hospitalization, during which increased values of transaminases (×8 normal values) and C-reactive protein (62.5 g/L, with normal values <5 g/L) were reported. No alcohol use and/or abuse and no drug exposure, except those for CD, were reported by the patient. A search for hepatitis B and C viruses was negative. Serological tests for EBV and cytomegalovirus (CMV) antibodies demonstrated positivity of IgM for both viruses. However, a search for CMV by polymerase chain reaction (PCR) was negative. Upper abdominal ultrasound scan, as well as a CT upper abdominal scan, showed a normal appearance of the liver and portal system, with marked splenomegaly (bipolar diameter of 16.5 cm). No relapse of CD symptoms occurred and AZA was maintained during the hospitalization. The patient was discharged with a diagnosis of acute EBV hepatitis. Two months later the patient was in good health, and transaminases and C-reactive protein were normal. Even if screening for EBV or chemoprophylaxis are not recommended in all IBD patients, due to the low frequency of clinically significant infection and/or reactivation of infection, some cases as reported in the literature may occur and should be recognized early and managed by a multidisciplinary team.