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Fulminant Epstein-Barr virus (EBV) hepatitis in a young immunocompetent subject
Médecine et maladies infectieuses 36 (2006) 396–398 http://france.elsevier.com/direct/MEDMAL/
Clinical case
Fulminant Epstein-Barr virus (EBV) hepatitis in a young immunocompetent subject Hépatite fulminante à virus Epstein-Barr (EBV) chez un jeune sujet immunocompétent F. Adera,*, D. Chatellierb, R. Le Berrec, P. Morandd, F. Fourriere a
Service universitaire de réanimation médicale et maladies infectieuses, hôpital Gustave-Dron, 135, rue du Président-Coty, CH de Tourcoing, 59208 Tourcoing cedex, France b Service de réanimation médicale, CHU de Poitiers, 86021 Poitiers cedex, France c Service des maladies infectieuses, CHU de la Cavale-Blanche, 29609 Brest cedex, France d Service de virologie, CHU de Grenoble, 38043 Grenoble cedex, France e Service de réanimation polyvalente, hôpital Roger-Salengro, CHU de Lille, 59031 Lille cedex, France Received 25 September 2005; accepted 1 March 2006
Abstract We report a case of fulminant hepatitis related to a primary Epstein-Barr virus (EBV) infection in an immunocompetent 15-year-old male patient. The main causes of fulminant hepatitis are viral infections, drugs, and autoimmune diseases. Primary Epstein-Barr virus infection is usually a benign, self-limited disease in pediatrics but can exceptionally be fatal. © 2006 Elsevier SAS. All rights reserved. Résumé Nous rapportons le cas d’une hépatite fulminante à virus Epstein-Barr (EBV) chez un jeune patient immunocompétent de 15 ans. Les causes principales d’hépatite fulminante sont les infections virales, les médicaments et les maladies auto-immunes. La primo-infection à EBV est généralement bénigne et spontanément régressive chez les enfants et adolescents mais peut exceptionnellement être fatale. © 2006 Elsevier SAS. All rights reserved. Keywords: Epstein-Barr virus; Infectious mononucleosis; Fulminant hepatitis Mots clés : Virus Epstein-Barr ; Mononucléose infectieuse ; Hépatite fulminante
1. Introduction Epstein-Barr virus (EBV), a member of the herpesvirus family (HHV-4), is one of the most common viruses, infecting more than 90% of humans and persisting throughout life. Its main characteristics are B lymphocytes tropism, latency, and a propensity to oncogenicity. Whereas most EBV primary
* Corresponding
author. E-mail address: [email protected] (F. Ader).
0399-077X/$ - see front matter © 2006 Elsevier SAS. All rights reserved. doi:10.1016/j.medmal.2006.03.002
infections of infants and children are asymptomatic or have nonspecific symptoms, infections of adolescents and young adults frequently result in symptomatic infectious mononucleosis with an EBV-induced polyclonal B-cell proliferation. More than 50% of these patients present with the triad of fever, generalized lymphadenopathy, and pharyngitis. Although a strong antibody response to EBV occurs, the infection is controlled by a vigorous, antigen-specific major histocompatibility complexrestricted cytotoxic T-cell response. Approximately 10% of symptomatic patients have splenomegaly, palatal petechiae, and hepatomegaly. Less commonly, severe complications
F. Ader et al. / Médecine et maladies infectieuses 36 (2006) 396–398
occur such as hemolytic anemia, myocarditis, hepatitis, spleenic rupture, hemophagocytic syndrome, Guillain-Barré syndrome, meningitis and encephalitis; these can be fatal in rare cases [1,2]. We report a case of fulminant hepatitis related to a primary EBV infection in an immunocompetent15-year-old male. 2. Case report A previously healthy 15-year-old male developed a flu-like syndrome. There was no family history of immunodeficiency or early death. His general practitioner prescribed aspirin (1 g daily). The following day, the patient presented with nausea and vomiting. Clarithromycin (500 mg daily) was added for sore throat after physical examination. Two days later, he developed jaundice and was admitted to a medical emergency ward. On admission, he was noted to be febrile (38.2 °C), weak, and icteric with hepatosplenomegaly. The serum glutamic oxaloacetic transaminase level was 19,000 U/L (normal range, 4–40 U/L) and glutamic pyruvic transaminase level was 8,700 U/L (normal range, 4–40 U/L) suggesting an acute cytolytic hepatitis. The platelet count in peripheral blood was 44,000 platelets/mm3. Abdominal ultrasound revealed hepatosplenomegaly without biliary obstruction. The next day a liver biopsy was performed, revealing a massive hepatic necrosis (up to 85%) with portal inflammatory infiltrates, predominantly with mononuclear cells. The massive necrosis did not allow polymerase chain reaction (PCR) extraction on liver parenchyma. Bone marrow was not assessed. The patient was transferred to the intensive care unit a few hours later because of loss of consciousness associated with anuric renal failure and severe hemostatic dysfunction indicating a rapidly progressing hepatic encephalopathy. Mechanical ventilation and extra-renal support were urgently applied and the electroencephalogram was continuously monitored. He was put on a liver transplant waiting list with absolute priority. Unfortunately, his condition rapidly deteriorated and evolved to coma and cerebral death with massive gastrointestinal hemorrhage and several cardiac arrests. The patient’s family did not allow autopsy. Blood cultures were sterile. Results of blood tests for hepatitis A, B, C, and E viruses were not indicative of prior or current infection. An HIV serum ELISA antibody test was non-reactive, and quantitative HIV RNA test was negative. The results of Leptospirosis, Toxoplasma, Coxiella, parvovirus B19, and HTLV1 antibody tests were negative. Other blood tests such as Cytomegalovirus, Herpes simplex virus I and II, and VZV revealed prior immunization with moderate titers of IgG antibodies without IgM. Concerning Epstein-Barr virus, the serum EBV capsid antigen IgM antibody titer was highly positive (> 1:10), the results of ELISA for EBV capsid antigen IgG antibody were positive, the EBV nuclear antigen antibody titer was undetectable (< 1:10) which suggested recent primary EBV infection. EBV DNA load was detected and quantified by real-time polymerase chain reaction in peripheral mononuclear cells (PBMCs) with a rate of copies over 30,000/1,5.105 PBMCs, and in a plasma sample with a rate of 7,125 copies/
397
ml (Light Cycler PCR, Roche Molecular Biochemicals, Indianapolis, IN) [3]. Tests for antinuclear, anti-smooth muscle, antimitochondrial, and liver-kidney microsome antibodies were negative. 3. Discussion In our case, it seems highly probable that fulminant hepatitis was related to EBV primary infection. Although EBV research on liver tissue inflammatory infiltrates could not be performed, serological pattern was consistent with an EBV primary infection, with detection of intra-cellular (PBMCs) and cell-free EBV virus DNA in serum showing a high viral load. It is known that the concentration of EBV DNA in plasma correlates well with the clinical status of patients with primary infection. In Yamamoto’s study, the number of virus DNA copies in plasma samples from patients with fatal IM was more than 100 times higher than the average copy number in patients with nonfatal IM, suggesting that far more virus replication occurred in patients with fatal IM [4]. Sporadic cases of acute liver failure caused by primary EBV infection have been reported in the literature, with an overall mortality of 87% [5,6]. Among immunocompetent individuals with infectious mononucleosis, nearly half of the patients exhibit an increased level of liver enzymes. Hepatic dysfunction leading to death occurs most of the time when EBV is associated with a lymphoproliferative disease in patients with congenital or acquired immunodeficiency. These include recipients of organ or bone marrow transplants, AIDS patients, and patients with severe combined immunodeficiency, including the recently known X-linked lymphoproliferative disease (XLP or Purtilo syndrome or Duncan disease), a rare and almost always fatal complication of EBV primary infection [7]. In this case the median age of patients at death, is generally inferior to 5 years, and there is often a family maternal related history of early death in male individuals. The gene involved in XLP disease was recently identified and codes for proteins (SAP and SH2D1A) that might serve as a “brake” to prevent over activation of T-cell response to EBV infection [8]. Defective SAP/SH2D1A results in uncontrolled B and T-cell response causing severe damage mainly to the liver and bone marrow. Beside this vulnerable condition, sporadic fatal infectious mononucleosis can also occur. Acute liver necrosis is directly responsible for death in 50% of the cases. The median age at the time of contracting a fatal EBV infection is around 10 years. Regarding liver damage, EBV receptors have been found on B-lymphocytes but not on hepatocytes, although the expression of EBV-RNA in hepatocytes was detected in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease [9]. So far, no direct EBV cytopathic effect has been proven on hepatocytes. T-cells and natural killer cells, found in liver parenchyma in such cases, may be implicated in liver cell necrosis. Drug-induced cross hepatotoxicity is also possible resulting in hepatocyte necrosis. Many drugs cause a hepatotoxic reaction without a dose-
398
F. Ader et al. / Médecine et maladies infectieuses 36 (2006) 396–398
related pattern including aspirin and clarithromycin which was ingested by the patient a few days before hospitalization. Therapeutic issues in fulminant EBV hepatitis are scarce. Curative immunoglobulin infusions, corticosteroid, aciclovir, or interferon do not prevent a fatal evolution of infection. A few patients were cured by bone marrow transplantation or cord-blood stem cells transplantation which is exceptionally possible. A survivor case was reported, after treatment with an association of emergency orthotopic liver transplantation and low-dose immunosuppression, a pooled gammaglobulin preparation containing anti-EBV antibodies, and anti-viral therapy [10]. 4. Conclusion We report the case of a young patient who developed fulminant hepatitis immediately following EBV primary infection. In addition to common blood tests, the detection of EBV DNA by quantitative PCR assay must be considered in any young boy developing an acute onset of hepatitis after a flu-like syndrome, without obvious toxic or auto-immune cause. Taking into account of the possibility of XLP disease in young male individuals, it is suggested to suggest a genetic inquiry in the family especially if there is a maternal related history of males dying at an early age.
References [1] Cohen JI. Epstein-Barr virus infection. N Engl J Med 2000;343(7):481– 92. [2] Papatheodoridis GV, Delladestima JK, Kavallierou L, Kapranos N, Tassopoulos NC. Fulminant hepatitis due to Epstein-Barr virus infection. J Hepatol 1995;23:348–50. [3] Brengel-Pesce K, Morand P, Schmuck A, Bourgeat MJ, Buisson M, Barguès G, et al. Routine use of real-time quantitative PCR for laboratory diagnosis of Epstein-Barr virus infections. J Med Virol 2002;66:360–9. [4] Yamamoto M, Kimura H, Hironaka T, Hirai K, Hasegawa S, Kuzushima K, et al. Detection and quantification of virus DNA in plasma of patients with Epstein-Barr virus-associated diseases. J Clin Microbiol 1995;3(7): 1765–8. [5] Pavese P, et al. Infection mortelle à EBV avec agranulocytose. Med Mal Infect 2001;53:4475. [6] Stahl JP. Infections aiguës graves à EBV. Réanimation 2005;14:245–7. [7] Markin RS, Linder J, Zuerlein K, Mroczek E, Grierson HL, Brichacek B, et al. Hepatitis in fatal infectious mononucleosis. Gastroenterology 1987; 93:1210–7. [8] Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998;20:103–4. [9] Randhawa PS, Jaffe R, Demetris AJ, Nalesnik M, Starzl TE, Chen YY, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with posttransplantation lymphoproliferative disease. N Engl J Med 1992;327: 1710–4. [10] Ferenchak AP, Tyson RW, Narkewicz MR, Karrer FM, Sokol RJ. Fulminant Epstein-Barr viral hepatitis: orthoptic liver transplantation and review of the literature. Liver Transpl Surg 1998;4(6):469–76.
Clinical case
Fulminant Epstein-Barr virus (EBV) hepatitis in a young immunocompetent subject Hépatite fulminante à virus Epstein-Barr (EBV) chez un jeune sujet immunocompétent F. Adera,*, D. Chatellierb, R. Le Berrec, P. Morandd, F. Fourriere a
Service universitaire de réanimation médicale et maladies infectieuses, hôpital Gustave-Dron, 135, rue du Président-Coty, CH de Tourcoing, 59208 Tourcoing cedex, France b Service de réanimation médicale, CHU de Poitiers, 86021 Poitiers cedex, France c Service des maladies infectieuses, CHU de la Cavale-Blanche, 29609 Brest cedex, France d Service de virologie, CHU de Grenoble, 38043 Grenoble cedex, France e Service de réanimation polyvalente, hôpital Roger-Salengro, CHU de Lille, 59031 Lille cedex, France Received 25 September 2005; accepted 1 March 2006
Abstract We report a case of fulminant hepatitis related to a primary Epstein-Barr virus (EBV) infection in an immunocompetent 15-year-old male patient. The main causes of fulminant hepatitis are viral infections, drugs, and autoimmune diseases. Primary Epstein-Barr virus infection is usually a benign, self-limited disease in pediatrics but can exceptionally be fatal. © 2006 Elsevier SAS. All rights reserved. Résumé Nous rapportons le cas d’une hépatite fulminante à virus Epstein-Barr (EBV) chez un jeune patient immunocompétent de 15 ans. Les causes principales d’hépatite fulminante sont les infections virales, les médicaments et les maladies auto-immunes. La primo-infection à EBV est généralement bénigne et spontanément régressive chez les enfants et adolescents mais peut exceptionnellement être fatale. © 2006 Elsevier SAS. All rights reserved. Keywords: Epstein-Barr virus; Infectious mononucleosis; Fulminant hepatitis Mots clés : Virus Epstein-Barr ; Mononucléose infectieuse ; Hépatite fulminante
1. Introduction Epstein-Barr virus (EBV), a member of the herpesvirus family (HHV-4), is one of the most common viruses, infecting more than 90% of humans and persisting throughout life. Its main characteristics are B lymphocytes tropism, latency, and a propensity to oncogenicity. Whereas most EBV primary
* Corresponding
author. E-mail address: [email protected] (F. Ader).
0399-077X/$ - see front matter © 2006 Elsevier SAS. All rights reserved. doi:10.1016/j.medmal.2006.03.002
infections of infants and children are asymptomatic or have nonspecific symptoms, infections of adolescents and young adults frequently result in symptomatic infectious mononucleosis with an EBV-induced polyclonal B-cell proliferation. More than 50% of these patients present with the triad of fever, generalized lymphadenopathy, and pharyngitis. Although a strong antibody response to EBV occurs, the infection is controlled by a vigorous, antigen-specific major histocompatibility complexrestricted cytotoxic T-cell response. Approximately 10% of symptomatic patients have splenomegaly, palatal petechiae, and hepatomegaly. Less commonly, severe complications
F. Ader et al. / Médecine et maladies infectieuses 36 (2006) 396–398
occur such as hemolytic anemia, myocarditis, hepatitis, spleenic rupture, hemophagocytic syndrome, Guillain-Barré syndrome, meningitis and encephalitis; these can be fatal in rare cases [1,2]. We report a case of fulminant hepatitis related to a primary EBV infection in an immunocompetent15-year-old male. 2. Case report A previously healthy 15-year-old male developed a flu-like syndrome. There was no family history of immunodeficiency or early death. His general practitioner prescribed aspirin (1 g daily). The following day, the patient presented with nausea and vomiting. Clarithromycin (500 mg daily) was added for sore throat after physical examination. Two days later, he developed jaundice and was admitted to a medical emergency ward. On admission, he was noted to be febrile (38.2 °C), weak, and icteric with hepatosplenomegaly. The serum glutamic oxaloacetic transaminase level was 19,000 U/L (normal range, 4–40 U/L) and glutamic pyruvic transaminase level was 8,700 U/L (normal range, 4–40 U/L) suggesting an acute cytolytic hepatitis. The platelet count in peripheral blood was 44,000 platelets/mm3. Abdominal ultrasound revealed hepatosplenomegaly without biliary obstruction. The next day a liver biopsy was performed, revealing a massive hepatic necrosis (up to 85%) with portal inflammatory infiltrates, predominantly with mononuclear cells. The massive necrosis did not allow polymerase chain reaction (PCR) extraction on liver parenchyma. Bone marrow was not assessed. The patient was transferred to the intensive care unit a few hours later because of loss of consciousness associated with anuric renal failure and severe hemostatic dysfunction indicating a rapidly progressing hepatic encephalopathy. Mechanical ventilation and extra-renal support were urgently applied and the electroencephalogram was continuously monitored. He was put on a liver transplant waiting list with absolute priority. Unfortunately, his condition rapidly deteriorated and evolved to coma and cerebral death with massive gastrointestinal hemorrhage and several cardiac arrests. The patient’s family did not allow autopsy. Blood cultures were sterile. Results of blood tests for hepatitis A, B, C, and E viruses were not indicative of prior or current infection. An HIV serum ELISA antibody test was non-reactive, and quantitative HIV RNA test was negative. The results of Leptospirosis, Toxoplasma, Coxiella, parvovirus B19, and HTLV1 antibody tests were negative. Other blood tests such as Cytomegalovirus, Herpes simplex virus I and II, and VZV revealed prior immunization with moderate titers of IgG antibodies without IgM. Concerning Epstein-Barr virus, the serum EBV capsid antigen IgM antibody titer was highly positive (> 1:10), the results of ELISA for EBV capsid antigen IgG antibody were positive, the EBV nuclear antigen antibody titer was undetectable (< 1:10) which suggested recent primary EBV infection. EBV DNA load was detected and quantified by real-time polymerase chain reaction in peripheral mononuclear cells (PBMCs) with a rate of copies over 30,000/1,5.105 PBMCs, and in a plasma sample with a rate of 7,125 copies/
397
ml (Light Cycler PCR, Roche Molecular Biochemicals, Indianapolis, IN) [3]. Tests for antinuclear, anti-smooth muscle, antimitochondrial, and liver-kidney microsome antibodies were negative. 3. Discussion In our case, it seems highly probable that fulminant hepatitis was related to EBV primary infection. Although EBV research on liver tissue inflammatory infiltrates could not be performed, serological pattern was consistent with an EBV primary infection, with detection of intra-cellular (PBMCs) and cell-free EBV virus DNA in serum showing a high viral load. It is known that the concentration of EBV DNA in plasma correlates well with the clinical status of patients with primary infection. In Yamamoto’s study, the number of virus DNA copies in plasma samples from patients with fatal IM was more than 100 times higher than the average copy number in patients with nonfatal IM, suggesting that far more virus replication occurred in patients with fatal IM [4]. Sporadic cases of acute liver failure caused by primary EBV infection have been reported in the literature, with an overall mortality of 87% [5,6]. Among immunocompetent individuals with infectious mononucleosis, nearly half of the patients exhibit an increased level of liver enzymes. Hepatic dysfunction leading to death occurs most of the time when EBV is associated with a lymphoproliferative disease in patients with congenital or acquired immunodeficiency. These include recipients of organ or bone marrow transplants, AIDS patients, and patients with severe combined immunodeficiency, including the recently known X-linked lymphoproliferative disease (XLP or Purtilo syndrome or Duncan disease), a rare and almost always fatal complication of EBV primary infection [7]. In this case the median age of patients at death, is generally inferior to 5 years, and there is often a family maternal related history of early death in male individuals. The gene involved in XLP disease was recently identified and codes for proteins (SAP and SH2D1A) that might serve as a “brake” to prevent over activation of T-cell response to EBV infection [8]. Defective SAP/SH2D1A results in uncontrolled B and T-cell response causing severe damage mainly to the liver and bone marrow. Beside this vulnerable condition, sporadic fatal infectious mononucleosis can also occur. Acute liver necrosis is directly responsible for death in 50% of the cases. The median age at the time of contracting a fatal EBV infection is around 10 years. Regarding liver damage, EBV receptors have been found on B-lymphocytes but not on hepatocytes, although the expression of EBV-RNA in hepatocytes was detected in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease [9]. So far, no direct EBV cytopathic effect has been proven on hepatocytes. T-cells and natural killer cells, found in liver parenchyma in such cases, may be implicated in liver cell necrosis. Drug-induced cross hepatotoxicity is also possible resulting in hepatocyte necrosis. Many drugs cause a hepatotoxic reaction without a dose-
398
F. Ader et al. / Médecine et maladies infectieuses 36 (2006) 396–398
related pattern including aspirin and clarithromycin which was ingested by the patient a few days before hospitalization. Therapeutic issues in fulminant EBV hepatitis are scarce. Curative immunoglobulin infusions, corticosteroid, aciclovir, or interferon do not prevent a fatal evolution of infection. A few patients were cured by bone marrow transplantation or cord-blood stem cells transplantation which is exceptionally possible. A survivor case was reported, after treatment with an association of emergency orthotopic liver transplantation and low-dose immunosuppression, a pooled gammaglobulin preparation containing anti-EBV antibodies, and anti-viral therapy [10]. 4. Conclusion We report the case of a young patient who developed fulminant hepatitis immediately following EBV primary infection. In addition to common blood tests, the detection of EBV DNA by quantitative PCR assay must be considered in any young boy developing an acute onset of hepatitis after a flu-like syndrome, without obvious toxic or auto-immune cause. Taking into account of the possibility of XLP disease in young male individuals, it is suggested to suggest a genetic inquiry in the family especially if there is a maternal related history of males dying at an early age.
References [1] Cohen JI. Epstein-Barr virus infection. N Engl J Med 2000;343(7):481– 92. [2] Papatheodoridis GV, Delladestima JK, Kavallierou L, Kapranos N, Tassopoulos NC. Fulminant hepatitis due to Epstein-Barr virus infection. J Hepatol 1995;23:348–50. [3] Brengel-Pesce K, Morand P, Schmuck A, Bourgeat MJ, Buisson M, Barguès G, et al. Routine use of real-time quantitative PCR for laboratory diagnosis of Epstein-Barr virus infections. J Med Virol 2002;66:360–9. [4] Yamamoto M, Kimura H, Hironaka T, Hirai K, Hasegawa S, Kuzushima K, et al. Detection and quantification of virus DNA in plasma of patients with Epstein-Barr virus-associated diseases. J Clin Microbiol 1995;3(7): 1765–8. [5] Pavese P, et al. Infection mortelle à EBV avec agranulocytose. Med Mal Infect 2001;53:4475. [6] Stahl JP. Infections aiguës graves à EBV. Réanimation 2005;14:245–7. [7] Markin RS, Linder J, Zuerlein K, Mroczek E, Grierson HL, Brichacek B, et al. Hepatitis in fatal infectious mononucleosis. Gastroenterology 1987; 93:1210–7. [8] Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998;20:103–4. [9] Randhawa PS, Jaffe R, Demetris AJ, Nalesnik M, Starzl TE, Chen YY, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with posttransplantation lymphoproliferative disease. N Engl J Med 1992;327: 1710–4. [10] Ferenchak AP, Tyson RW, Narkewicz MR, Karrer FM, Sokol RJ. Fulminant Epstein-Barr viral hepatitis: orthoptic liver transplantation and review of the literature. Liver Transpl Surg 1998;4(6):469–76.