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Effects of simultaneous rhG‐CSF and methylprednisolone “pulse” therapy on hepatitis A virus‐associated haemophagocytic syndrome

To the Editor: We describe a patient with hepatitis A (HA)-virus associated haemophagocytic syndrome successfully treated with simultaneous rhG-CSF and methylprednisolone. A 49-year-old woman was admitted because of fever and icterus. Liver dysfunction was evident with elevated serum bilirubin and various enzymes (Fig. la). Serology for hepatitis A virus (IgM) was positive; for hepatitis B and C, CMV, herpes zoster, herpes simplex, adenovirus, and human immunodeficiency virus all negative; and for EBV (IgG) positive, EBV (IgM) negative. Acute hepatitis due to HA virus was diagnosed, although marked splenomegaly was unexampled. She was given supportive treatment followed by amelioration of liver function tests, although pyrexia continued and skin rashes appeared over her trunk with progression of pancytopenia (Fig. lb). A blood test on March 30 revealed that the haemoglobin concentration was 5.9 g/dl, leukocyte count 0.5 x 109/1, comprised of 0% neutrophils, and platelet count 32 x 109/l. Bone marrow examination was compatible with VAHS, showing hypopcellularity of haematopoietic components with hyperplasia of reticulum cells (reticulum cells, 50% of nucleated cell) exhibiting haemophagocytosis (Fig. 2a, 2b). Further investigations showed that both serum ferritin and sIL2R level were high (Fig. la). VAHS was diagnosed and rhG-CSF and methylprednisolone “pulse” therapy was initiated. Pancytopenia was ameliorated shortly after initiation of the treatment. Bone marrow examination after discontinuation of the treatment showed normal maturation of haematopoietic components and disappearance of reticulum cells. Since the original description of VAHS (l), laboratory studies have shown evidence of acute viral infection in most patients who have been thoroughly evaluated for various viral disease (2). To our knowledge, there has been only one reported case of VAHS due to hepatitis A virus (3) in which the patient was an immunocompromised host. The patient presented in the present report represents the first case of hepatitis A-associated VAH S in an immunocompetent subject. This patient showed good evidence of hepatitis A infection with no positive serology for any other acute viral or bacterial infections. Unusually for hepatitis A, her spleen was markedly enlarged, and this was presumably due to infiltration with histiocytes. It has been suggested (4) that there is an alteration of T-cell function in VAHS, with uncontrolled T cells producing large amounts of cytokines. Secondary activation of macrophages may then result in haemophagocytosis followed by hyperferritinaemia. Good correlations between serum levels of ferritin and of sIL2R and the clinical course were observed in our patient (Fig. la). Although IFN-)I, TNF and IL-lP were not increased, that may be explained by the mild disease state. Aplastic anaemia is a usual cause of pancytopenia after viral hepatitis. There is increasing evidence that a variety of infectious agents alter haematopoiesis through effects on the microenvironment (5). One of the major causes of haematopoietic aplasia after hepatitis virus infection may be due not to the stem cell defect, but to the microenvironment disturbance. The present report substantiates that VAHS is an important cause of the myelosuppressive state after viral hepatitis and suggests that precise histological evaluations are needed. Management of VAHS has usually been anticipatory with supportive measures. However, the considerable reported mortality rate ( 6 ) and severe neutropenic conditions in our patient prompted us to use methylprednisolone “pulse” with rhG-CSF regimes. The dramatic haematopoietic recovery with this regime might be due to up-modulation of IL-1R expression on haematopoietic cells by synergetic ac-