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European Review for Medical and Pharmacological Sciences 2003; 7: 107-109 Fatal during Epstein-Barr reactivation

B. CACOPARDO, G. NUNNARI, M.T. MUGHINI, S. TOSTO, F. BENANTI, L. NIGRO

Department of Internal Medicine and Medical Specialities, Unit of Infectious Diseases, University of Catania - Catania (Italy)

Abstract. – Fulminant hepatitis by Case Report Epstein-Barr virus is a rare event which is predominantly due to primary . We report a rare case of fatal hepatic failure due A 19-year-old male student was admitted to Epstein-Barr virus reactivation in a 19- to the Department of Infectious Diseases year-old boy who was taking oral steroids. (University of Catania) presenting with fa- Transaminase peak and the fulminant course of the disease began soon after steroid inter- tigue and jaundice. Past clinical history in- ruption. Epstein-Barr virus reactivation was cluded acute at the age of 7. At diagnosed on the basis of past clinical history the age of 14, had of heterophile-positive infectious mononucle- been diagnosed on the basis of prolonged osis, a high titer of IgG anti Epstein-Barr viro- fever, pharyngitis, splenomegaly and positive capsidic , slight elevation of anti-viro- Paul-Bunnel Davidson test. capsidic IgM, a high titer of anti-EA IgG anti- Two months before the onset of jaundice, bodies and elevated viral load in serum mea- sured by polymerase chain reaction. It is con- the patient complained of severe arthralgias cluded that Epstein-Barr virus should be con- with joint swelling and fever. A local practi- sidered as a possible etiological agent of ful- tioner diagnosed rheumatoid arthritis on minant hepatitis. clinical grounds. The patient began therapy Key Words: with methylprednisolone at a dosage of 40 mg/day orally and a prompt remission of Epstein-Barr virus, Reactivation, Steroids, Fulminant hepatitis. symptoms was achieved. Steroid treatment was scheduled as 40 mg/day for 20 days fol- lowed by 20 mg/day for a further 20 days. Thirty days after beginning steroid treat- ment, the patient developed fatigue, general Introduction malaise and became icteric. He did not pre- sent fever or sore throat. The liver and spleen were palpable at 6 cm and 4 cm below Infectious mononucleosis caused by the costal margin, respectively. No lym- Epstein-Barr virus (EBV) infection is usual- phadenopathy was found. Laboratory test re- ly accompanied by a mild, self-limiting he- sults revealed ALT 916 IU/L, total bilirubi- patic dysfunction. EBV-related liver failure naemia 14 mg/dl and prothrombin activity in previously healthy individuals is very rare 80%. Total white blood cell count was 9.700 although it has been reported in immuno- mm3 (neutrophils 38%, lymphocytes 32%, compromised patients during primary EBV monocytes 30%) and platelets were infection1,2. Cases of fulminant hepatic fail- 108.000/mm3. Serum immunoglobulins were ure (FHF) induced by primary EBV infec- normal. Rheumatoid factor was negative. tion have frequently been described in chil- CD4+ T cell count was 887/mm3 and CD8+ dren affected with the X-linked lymphopro- count was 1416/mm3. Abdominal ultrasound liferative syndrome2,3. We report a very rare scan showed mild hepatosplenomegaly with case of fulminant hepatitis induced by the no evident focal lesions. Serum HbsAg, anti- reactivation of EBV during immunosup- Hbc IgM and anti-HCV antibody were nega- pressive therapy. tive. Anti-; anti Coxsachie

107 B. Cacopardo, G. Nunnari, M.T. Mughini, S. Tosto, F. Benanti, L. Nigro virus A and B and anti-Toxoplasma IgG and serum immunoglobulin levels2; (3) post-trans- IgM antibodies were also negative. Serum plant lymphoproliferative disorders and non- HCV RNA was negative as determined by Hodgkin’s lymphoma2,3. polymerase chain reaction (PCR). HIV 1 The profile of the case presented does not serology was negative. Ceruloplasmin was fit any of the above mentioned conditions. normal and non-organ specific serum autoan- This was a case of fulminant hepatitis in a pa- tibodies were negative. Bone marrow aspi- tient who had no evidence of long-standing rate showed hypercellularity with an increase immunosuppression and was healthy before in atypical lymphoid cells, but with no evi- initiating corticosteroids. As far as we know, dence of histiocytic hyperplasia or prominent this is the first report of fulminant hepatitis haemophagocytosis. The titre of IgG anti- due to the reactivation of latent EBV. Past EBV viral antigen (VCA) antibodies clinical history of infectious mononucleosis, was 1/2560; IgM anti-EBV VCA and IgG an- the high titer of IgG anti-Epstein-Barr viro- tibodies against early antigen (EBV-EA) capsid antigen, the slight elevation of specific were positive at a titre of 1/320. Finally, EBV IgM and anti-EA IgG antibodies support the DNA was found both in unfractionated hypothesis of viral reactivation in this case5, whole blood and in serum using both qualita- which is further confirmed by the elevated vi- tive BamHI-W-repeat PCR and quantitative ral load in serum6. competitive PCR (viral load: 200,000 A peculiar clinical characteristic of this copies/ml). The day after admission, methyl- case was the absence of signs and symptoms prednisolone assumption was interrupted. typical of EBV infection such as lym- Three days later, both ALT and bilirubin lev- phadenopathy and pharyngitis. Overt hepati- els peaked at 4810 U/I and 24 mg/dl, respec- tis due to EBV in the absence of other signs tively. Prothrombin activity fell below 20%. of infection is uncommon in young patients, On day 7 following admission, ALT level de- whereas this is more commonly seen in pa- creased to 358 U/I and signs of hepatic en- tients older than 402,4. cephalopathy appeared. The patient was ad- The reactivation of EBV was probably in- mitted to the intensive care unit. He received duced by high-dose steroid treatment or, less intravenous acyclovir, fresh frozen plasma, probably however, due to autoimmune arthri- omeprazole, lactulose and oral neomycin. On tis. Autoimmune diseases, immunosuppres- day 10 of hospitalization, encephalopathy in- sive drugs, , CMV and HIV-1 have creased to grade 3 and the patient died be- been reported elsewhere as underlying causes fore liver transplant could be performed. of EBV reactivation7-10. In particular, steroids are a common cause of EBV reactivation from latency. It remains to be established whether steroids may reactivate EBV directly Discussion by promoting viral replication or alternative- ly by down-regulating the ability of the mem- Infectious mononucleosis is usually a be- ory T-cell response to control the latent virus. nign disease. Severe complications such as The immunopathogenic mechanisms respon- splenic rupture, encephalitis, , sible for liver damage in EBV infection are as and hepatitis are seen in fewer yet not clearly specified. EBV produces no than 1% of all cases and fatalities are even direct cytopathic effects in hepatocytes2, al- rarer4. Fulminant hepatitis may represent a though sporadic infection of hepatocytes by common cause of death in different types of EBV has been demonstrated11. EBV infec- EBV-induced disorders: (1) spontaneous fatal tion of T cells has been hypothesized to pre- infectious mononucleosis, whose clinical fea- cipitate autoaggressive cytotoxicity12. tures are related to primary EBV infection Moreover, a cytotoxic T-cell response against and characterized either by typical symptoms EBV- on infected B cells or hepato- and signs of infectious mononucleosis or by cytes has been put forward as being responsi- evidence of haemophagocytosis in bone mar- ble for liver necrosis in a pattern similar to row aspirate2,3; (2) X-linked lymphoprolifera- that reported for virus liver dam- tive disease which is a familial syndrome age2. In this case, the sudden withdrawal of mostly involving children with abnormal steroids could have played a triggering role

108 Fatal hepatitis during Epstein-Barr virus reactivation by inducing an immunologic rebound direct- 6) STEVENS SJ, VERVOORT MB, VAN DEN BRULE AJ, ed at EBV-infected cells. Studies of with- MEENHORST PL, MEJIER CJ, MIDDLEDORP JM. Monitoring of Epstein Barr DNA load in peripheral drawal from corticosteroids have, in fact, al- blood by quantitative competitive PCR. J Clin ready described episodes of hepatic decom- Microbiol 1999; 37: 2852-2857. pensation or worsening of hepatic histology 7) AALTO SM, LINNAVUORI K, PELTOLA H, et al. in patients with acute or chronic viral hepati- Immunoreactivation of Epstein-Barr virus due to tis13. The present study provides evidence Cytomegalovirus primary infection. J Med Virol that the use of steroids may favour the reacti- 1998; 56: 186-191. vation of EBV from a latent status. Finally, 8) RAHMAN MA, KINGSLEY LA, ATCHINSON RW, et al. EBV should be considered as a possible etio- Reactivation of Epstein-Barr virus during early in- logical agent of fulminant hepatitis also in the fection with immunodeficiency virus. J absence of the typical signs of infectious Clin Microbiol 1991; 29: 1215-1220. mononucleosis. 9) PALANDUZ A, YILDIMARK Y, T EHLAN L, et al. Fulminant hepatic failure and autoimmune hemolytic anemia associated with Epstein Barr virus infection. J Infect 2002; 45: 96-98.

10) OGAWA J, KOIKE R, SUGIHARA T, et al. An autopsied case of chronic active Epstein Barr virus infection References complicated in systemic lupus erythematous and antiphospholipid antibody syndrome. Nihon 1) Shaw N.J, Evans JHC. Liver failure and Epstein- Rinsho Meneki Gakkai Kaishi 2002; 25: 458-465. Barr virus infection. Arch Dis Child, 1988; 63: 432-445. 11) PAPATHEODORIDIS GV, DELLADETSIMA JK, KAVALLIEROU L, KAPRANOS N, TASSOPOULOS NC. Fulminant hepatitis 2) MARKIN RS. Manifestations of Epstein-Barr virus due to Epstein Barr virus infection. J Hepatol associated disorders in liver. Liver 1994; 14: 1-13. 1995; 23: 348-350. 3) WICK MJ, WORONZOFF-DASHKOFF KP, MCGLENNEN RC. 12) BAUMGARTEN E, HERBST H, SCHMITT M, SEEGER KH, The molecular characterization of fatal infectious SCHULTE-OVERBERG U, HENZE G. Life-threatening in- mononucleosis Am J Clin Pathol 2002; 117: 582- fectious mononucleosis: is it correlated with virus- 588 induced T-cell proliferation? Clin Infect Dis 1994; 4) COHEN JI. Epstein-Barr virus infection. N Engl J 19: 152-156. Med 2000; 343: 481-492. 13) HESS G, MANNS M, HUTTEROTH TH, MEYER ZUM 5) OBEL N, MADSEN MH, KANGRO H. Serological and BUSCHENFELDE KH. Discontinuation of immunosup- clinical findings in patients with serological evi- pressive therapy in hepatitis B surface antigen-pos- dence of reactivated Epstein-Barr virus infection. itive chronic hepatitis: effect on viral replication and APMIS 1996; 104: 424-428. on liver cell damage. Digestion 1987; 36: 47-54.

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