Evans Syndrome Related to Hepatitis B Virus Infection: A Case that Responded Only to Lamivudine Therapy

Evans syndrome is characterized by simultaneous or sequential development of autoimmune thrombocytopenia (AITP) and autoimmune hemolytic anemia (AIHA) (1). Despite therapeutic interventions, most patients with Evans syndrome have a chronic and relapsing course that is associated with significant morbidity and mortality (2). The underlying problem in Evans syndrome is not exactly clear. Although some viral infections, especially Epstein Barr virus (EBV) (3), measles, rubella, mumps, and varicella viruses (4,5) can induce autoimmune hemolytic anemia, no relationship has been detected between Evans syndrome and viral infections. The association of hepatitis B virus (HBV) infection with aplastic anemia or thrombocytopenia has been reported in adult patients (6–10). We could not find any report of Evans syndrome related to HBV infection. Here, we present a case of Evans syndrome related to HBV infection, which was improved only with lamivudine therapy. CASE REPORT A 3-year-old boy presented with easy bruising and punctuated hemorrhages. On physical examination there was pallor, as well petechiae and ecchymoses, especially to the lower extremities. There was no other pathologic finding. The patient's history revealed that he was born from a third pregnancy at term via vaginal delivery with no event. The child was healthy until the present problems occurred. Anemia (hemoglobin: 5.3 g/dL), thrombocytopenia (platelet count: 3,000/mm3), reticulocytosis (14%), and positive results for direct Coombs test were detected by hematologic screening. On the bone marrow smear, megakaryocytes were increased, and there was no atypical cell. Transaminases were mildly elevated (alanine: 144 U/L, aspartate: 93 U/L; normal range, 0–40 U/L), and other liver function and renal function study results and electrolyte levels were within normal limits. Serum complement levels (C3 and C4) were normal. Rheumatoid factor, antinuclear antibody, and anti–DNA results were negative. Evans syndrome was the diagnosis. We were unable to study autoantibodies to red blood cells or platelets. Hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg), and hepatitis B core antibody (antiHBc) IgG results were positive. Anti–HBs, anti–HBe, anti–HBcAg IgM, and anti–hepatitis A virus (HAV) IgM and IgG results were negative and antibodies to hepatitis C and delta hepatitis were absent. Serologic studies for cytomegalovirus and EBV had negative results. Serologic studies for HBV, CMV, and EBV were performed by enzyme-linked immunosorbent assay (Abbott Axsym System: Abbott Laboratories, Abbott Park, IL; Organon Teknika, Durham, NC; and EBV–VCA IgM and IgG: DiaSorin, Saluggia, Italy, respectively). Abdominal ultrasonography revealed mildly increased echogenicity of the liver parenchyma. The serologic profile for HBV of the mother at delivery was unknown. The child had not been vaccinated against HBV. After the diagnosis of HBV infection, family members were screened for HBV. The mother and the father were positive for anti–HBs; however, the three siblings were negative for HBsAg, anti–HBs, and anti–HBc total, so they have been vaccinated against HBV. At first, 1 g/kg intravenous immunoglobulin was given as a single dose to control the activity of the autoimmune event. Thrombocytopenia (platelet count: 1,000/mm3) and positive Coombs test results did not improve. Gastrointestinal hemorrhage occurred at the end of the first week. Treatment with methylprednisolone (30 mg · kg−1 · d−1 for 7 days) platelet and H2-receptor antagonists was begun. Anemia was corrected with the transfusion of packed red blood cells. Gastrointestinal hemorrhage was controlled but platelet count reached only 15,000/mm3. Intravenous immunoglobulin and high-dose methylprednisolone were given again, but platelet count remained between 5,000/mm3 and 15,000/mm3 and Coombs test results were still positive. At 2 months after the initial diagnosis, pathologic findings were unchanged. α-Fetoprotein level was normal. Serum HBV DNA was assayed with the Digene hybrid-capture system HBV-DNA assay (Morex Diagnostics, Gaithersburg, MD, U.S.A.) and found to be 973 pg/mL. Liver biopsy was contraindicated because of thrombocytopenia. Antiviral therapy was begun; the patient received lamivudine 4 mg · kg−1 · d−1 orally instead of interferon because of the risk of lowering the platelet count to a hazardous level. Thrombocytopenia improved (platelet count: 200,000/mm3), transaminase levels decreased, and direct Coombs test results were negative at the end of the first month of treatment. Transaminases were within the normal limits at the second month. HBV serology revealed HBeAg seroconversion (negative HBeAg and positive anti–HBe); thereafter we obtained a serology report monthly. HBV DNA was assayed at 3 months and was negative (<4 pg/mL) at the third month of therapy. HBsAg was negative at the sixth month of lamivudine treatment and anti–HBs results were positive (>100 IU/mL) 1 month later. Complete blood count and transaminase levels were normal, direct Coombs, HBsAg, and HBV DNA results were negative and anti–HBs results were positive at the ninth month of the lamivudine therapy. Treatment with the drug was then stopped; clinical and laboratory investigations showed normal results 6 months after the cessation of lamivudine. DISCUSSION Several reports suggest that Mycoplasma pneumonia infections (11), EBV (3), measles, rubella, mumps, and varicella (4,5) can trigger autoimmune hemolytic anemia. However, Evans syndrome is usually associated with primary immunodeficiencies, collagen vascular diseases, lymphoproliferative disorders, and autoimmune lymphoproliferative syndrome (12). To our knowledge this is the first report of an association between this syndrome and HBV infection. Few cases of aplastic anemia or thrombocytopenia have been reported in adult patients with hepatitis B (6–10). Immunosuppressive agents are generally used to treat Evans syndrome but are not satisfactory (13). Splenectomy is not useful as in chronic immune thrombocytopenic purpura or autoimmune hemolytic anemia (14,15). Our patient did not respond to intravenous immunoglobulin or high-dose methylprednisolone, and thrombocytopenia and positive direct Coombs test results persisted. Although we had planned to treat for HBV infection, we could not perform a liver biopsy because of thrombocytopenia. Interferon is the only drug that has been the subject of research in recent years for the treatment of chronic hepatitis B in children (16) but we did not use interferon because of the risk of worsening the thrombocytopenia that already existed in the patient (17). Lamivudine is a dideoxynucleoside analogue used in the treatment of HBV infection (18). Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivudine 5´-triphosphate, the active anabolite that prevents HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA-chain extension. Lamivudine therapy is effective and safe in the adult population, but there are few reports on its safety in children (19). In our case, clinical and laboratory findings of Evans syndrome rapidly improved only after lamivudine therapy; thrombocytopenia and anemia did not recur after cessation of therapy. Liver function abnormality began to improve at the end of the first month and anti–HBs positivity was achieved at the seventh month of lamivudine therapy. Acute autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura usually respond to corticosteroid or immunoglobulin therapy in the first few days. A response can be expected for up to 4 weeks in patients with idiopathic thrombocytopenic purpura (20,21). Conversely, corticosteroid therapy has no effect on chronic HBV infection. In our case, Evans syndrome and HBV infection were resolved synchronously with lamivudine therapy, suggesting that the improvement could only be attributed to the lamivudine. Although corticosteroid therapy may aggravate the course of chronic HBV, a short course of steroid therapy before interferon use does not aggravate the disease (22). We did not observe any disease aggravation with high-dose methylprednisolone. There is no report on the relation between high-dose methylprednisolone and HBV infection. In conclusion, Evans syndrome can occur in patients with HBV infection and should be treated with effective antiviral therapy rather than therapy directed against the autoimmune process.

Topic: Blood groups and transfusion
Subfield: Hematology
Field: Medicine
Domain: Health Sciences