Primary Epstein-Barr virus hepatitis complicated by ascites with epstein-barr virus reactivation during primary cytomegalovirus infection.

Abstract

The severity of Epstein-Barr virus (EBV) infection depends on the age of acquisition and immune status of the host. In early childhood, EBV infection is common and usually associated with few or no symptoms. Primary infection occurring in adolescence or early adulthood, however, is typically associated with acute infectious mononucleosis or ‘glandular fever’ (1). Infectious mononucleosis is characterized by fever in almost all cases, lymphadenopathy in 90%, splenomegaly in 50%, hepatomegaly in up to 20% and jaundice in 5% of cases. Although elevated aminotransferase enzymes (up to five times normal) are detected in up to 80% of cases, hepatitis is usually mild and complete recovery is usual (1,2). Ascites is an unusual complication of EBV hepatitis, and in previously reported cases other factors may have contributed to ascites (3–10). We report an unusual case of EBV hepatitis with ascites, and subsequent EBV reactivation during primary cytomegalovirus infection, and review the previously reported cases linking EBV with ascites. CASE HISTORY A previously healthy 11-year-old Asian female presented with a 10-day history of intermittent fever and transient periorbital edema, occasional vomiting, and abdominal pain. On the day of admission, she had developed abdominal distension and jaundice. There were no known risk factors for parenteral acquisition of infection and no foreign travel. She had not received any medication before admission. She was born in the UK to consanguineous parents. She was fully immunized including BCG. Her weight was 31.7 kg (< 25%) and her height was 145.4 cm (50-75%). Her temperature was 38.8°C and she was jaundiced. There was no lymphadenopathy, periorbital or pedal edema, and no stigmata of chronic liver disease. There was dullness to percussion with symmetrical reduction in air entry in both lower lung fields. Her abdomen was distended with firm, smooth hepatomegaly, palpable 2 cm below the costal margin in the right mid-clavicular line and the spleen tip was just palpable. There was shifting dullness. Ophthalmology assessment did not reveal Kayser-Fleischer rings. A chest radiograph confirmed bilateral pleural effusions and an abdominal ultrasound demonstrated an enlarged liver of patchy echogenicity with a contracted thick-walled gall bladder, splenomegaly (14 cm), and moderate ascites. There was no biliary tract dilatation. Doppler studies of the hepatic vessels were normal. Initial investigations revealed mild anemia with lymphocytic leucocytosis (Hb 10.6 g/dl, WBC 24.5 × 109/1, Lymphocyte count 18.19 × 109/ 1). Blood film demonstrated abnormal lymphoid morphology and numerous target cells. Coagulation was prolonged (INR 1.6). Serum creatinine, urea and electrolytes were normal. Serum bilirubin 115 (μol/l (normal,3-15 (μol/l), ALT 97 IU/L (normal,0-35 IU/L), Gamma GT 329 IU/L (normal, 8-48 IU/L), Serum albumin 25 g/L (normal, 39-51 g/L), Alkaline phosphatase 2276 IU/L (normal, 160-625 IU/L). Microbiologic investigations revealed no evidence of infection with hepatitis A, B or C; influenza A, B; adenovirus; parvovirus; coxsackie B; mycoplasma; psittacosis; Q fever; leptospira; brucella; malaria; Mycobacterium tuberculosis. There was no serological evidence of CMV infection (absent IgM & IgG antibodies). Recent EBV infection was ascertained by detection of IgM antibody to EBV viral capsid antigen (VCA) and absent IgG antibody to EBV nuclear antigen (EBNA). The following investigations were normal: serum lipids, alpha fetoprotein, alpha-1-antitrypsin phenotype, ceruloplasmin, 24-hour urinary copper pre and post penicillamine, immunoglobulins, IgG subclasses, autoantibodies (including nuclear, smooth muscle, gastric parietal, mitochondrial, liver/kidney microsomal, endomysial antibodies), complement, blood and urine cultures, urinary metabolic screen. The ascites was managed by infusion of 20% albumin and diuretic therapy. She was afebrile by day 10. Her pleural effusions and ascites had resolved, so she was discharged. In view of her unusual presentation, a liver biopsy was performed on day 33 to exclude underlying chronic liver disease. By then she had made a complete clinical recovery; her liver function tests had improved (ALT 91 IU/L, alkaline phosphatase 866 IU/L, gamma GT 79 IU/L, bilirubin 20 (μol/L) and EBV serology demonstrated IgG and IgM antibodies to VCA. The liver biopsy (Fig. 1a and 1b) showed normal architecture. There was very mild portal tract lymphocytic infiltrate with occasional plasma cells but no interface hepatitis. The dominant abnormality was in the parenchyma, where there was a marked increase in sinusoidal B lymphocytes associated with mild cholestasis and Kupffer cell hyperplasia, but no hepatocyte ballooning. The features were characteristic of EBV hepatitis, and did not suggest autoimmune hepatitis. EBV antigens could not be demonstrated in the sinusoidal lymphocytes by either LMP1 or EBER techniques, perhaps because of the late timing of the biopsy in the course of the illness.FIG. 1.: (A) Liver biopsy showing prominent increase in sinusoidal cellularity, with mild portal inflammation (magnification × 100). (B) High magnification to show small lymphocytes without atypia, within sinusoids (× 400).She remained well, with normal liver enzymes until 5 months after her original presentation, when she was readmitted with frontal headache, fever, vomiting, and listlessness. She was febrile (39.5°C) and had cervical lymphadenopathy but her tonsils were normal. Her abdomen was distended with hepatosplenomegaly and ascites. She had a petechial rash on her limbs and palate. She had developed a lymphocytosis again. Her INR was normal but albumin was low and liver enzymes were abnormal (ALT 88 IU/L; bilirubin 17 (μol/L; albumin 28 g/L; alkaline phosphatase 1859 IU/L). Abdominal ultrasound confirmed the clinical findings. Viral studies showed further evidence of active EBV infection (Monospot positive, EBV-VCA IgG positive, EBV PCR on blood positive-18,000 DNA copies/mL) but also primary CMV infection (CMV IgM positive, CMV PCR on blood-positive). She now had mildly elevated immunoglobulins: Serum IgG 18.8 g/L (normal, 5.4-16.1), Serum IgA 2.73 g/L (normal, 0.70-2.50), Serum IgM 3.79 g/L (normal, 0.50-1.80); positive antinuclear antibodies and elevated double stranded DNA antibodies 165 IU/L (0–100). However, liver/kidney microsomal and smooth muscle antibodies were absent. T cell subsets and functions were normal. With conservative management, her fever resolved after 8 days and her hepatosplenomegaly and liver enzymes gradually normalized by 5 weeks after her second admission (ALT 32 IU/L, bilirubin 6 (μol/L, albumin 42 g/L). She now had positive EBV-VCA IgG and EBNA IgG antibodies. CMV PCR was negative after 1 month, while EBV PCR showed decreasing viral copies and it was negative at 10 months after the second illness. She remains well 12 months later, with normal biochemistry. Her autoantibodies have resolved but her IgG remains mildly elevated (IgG 18.5 g/L, IgA 2.06 g/L, IgM 0.86 g/L). DISCUSSION Hepatic dysfunction due to Epstein-Barr virus infection is usually mild and resolves completely. Jaundice is seen in only 5% of cases of infectious mononucleosis (1,2). Severe hepatic dysfunction and fulminant liver failure due to EBV infection occurs mainly in immunocompromised patients. The association of ascites and EBV hepatitis had been reported previously (3–10). However, most of these cases had other complicating factors, which may have contributed to hepatic dysfunction. The first report of ascites associated with EBV infection was in a 36-year-old female with latent familial hemochromatosis who developed ascites and bilateral pleural effusions with an intercurrent EBV infection (3). Subsequently Chang et al. (4), reported an adult with fulminant hepatic failure secondary to infectious mononucleosis with ascites noted on post-mortem examination. Provisor et al. (5) described two male maternal cousins aged 5 months and 6 years respectively, who presented with clinical features of severe EBV infection including ascites. Both had lymphocytosis and positive EBV serology. One month after the illness the 5-monthold developed agammaglobulinemia. His cousin died during the acute illness. The cousin's 16-year-old brother also developed agammaglobulinemia after EBV infection, suggesting an inherited immune defect. Colebunders et al. (6) reported a 15-year-old female with marked right-sided pleural effusion, hepatosplenomegaly, and ascites in association with EBV infection. However, she had a history of hepatitis at 10 years of age and investigations for other underlying liver diseases were not reported. Marano et al. (7) reported a 22-year-old male with exudative ascites complicating infectious mononucleosis. However, he had been an intravenous drug abuser 6 months before admission and also had a history of heavy drinking. Investigations for underlying liver disease were extensive and included a liver biopsy, which showed features in keeping with EBV hepatitis and no evidence of underlying chronic liver disease. Van der Laan et al. (8) reported a young woman with peritonitis, ascites, and hepatitis, and concomitant infection with EBV and Chlamydia trachomatis, but C. trachomatis alone is known to cause ascites. Devereaux et al. (9) described a 37-year-old immunocompetent male with ascites and severe hepatitis complicating EBV infection. The potential complicating factors included treatment with paracetamol and erythromycin before identification of liver dysfunction and the presence of markedly raised ferritin and alpha-fetoprotein. A liver biopsy was not performed (9). Kojima et al. (10) reported a 73-year-old male with EBV infection, lymphadenopathy, rash, pleural effusion, and ascites. His ESR, IgG levels, and autoantibodies were significantly raised with granulocytopenia and thrombocytopenia. A liver biopsy showed expanded portal zones with inflammatory infiltrate, piecemeal necrotic foci, and portal-portal bridging fibrosis consistent with chronic hepatitis. He would fulfill the International Hepatitis Group criteria for diagnosis of probable autoimmune hepatitis and he did improve with prednisolone therapy. Our case is unusual as it not only describes a clear association of acute hepatitis and ascites with EBV infection alone, but also demonstrates subsequent reactivation of EBV infection giving rise to similar clinical features. In this case, the diagnosis of EBV hepatitis with ascites during the first admission was confirmed by demonstrating IgM antibody to viral capsid antigen and typical histology on the liver biopsy. Investigations excluded both an alternative infective etiology and chronic liver disease. On follow-up review after the first admission (5 months) clinical examination as well as liver function tests were normal demonstrating full recovery with supportive management. The reactivation of EBV infection occurred simultaneously with primary cytomegalovirus (CMV) infection. During the second admission, CMV IgM antibody and viral detection by PCR in the peripheral blood confirmed acute CMV infection. Increased copies of EBV on PCR testing were in keeping with a reactivation of EBV infection. The clinical features of hepatitis with ascites during the second admission can either be explained by reactivation of EBV infection or primary CMV infection. Detailed immunologic investigations demonstrated normal humoral and cellular immunity. Our patient was not investigated for X-linked lymphoproliferative disease, a rare familial disorder resulting in selective immunodeficiency to EBV. It is characterized by uncontrolled proliferation of EBV infected lymphocytes resulting in a fatal lymphoproliferative disorder. Diagnosis can be confirmed by SAP gene mutations. However this was unlikely in our patient because of her sex and because her symptoms resolved very quickly in each episode of the illness. Reactivation of latent EBV has been reported in immunocompetent subjects during psychosocial, physical or academic stress. However these subjects were asymptomatic and reactivation was proved either by raised antibody titre or isolating EBV DNA in saliva (11,12). Serological immunoreactivation of EBV by primary CMV infection has also been demonstrated in immunocompetent patients (13). Antinuclear antibodies and double stranded DNA antibodies were noted during the second admission. They were most likely a nonspecific response to the acute viral infection, as they promptly resolved on follow up. In addition, the occurrence of hypergammaglobulinemia is a well-reported feature of EBV infection. This case demonstrates that Epstein-Barr virus associated hepatitis may be complicated by ascites in an immunocompetent host and subsequent symptomatic reactivation can occur secondary to primary cytomegalovirus infection. Only supportive treatment is needed and recovery without sequelae appears to be the expected long term outcome.