Human Herpesvirus 6-Associated Hemophagocytic Syndrome in a Healthy Adult

Virus-associated hemophagocytic syndrome is a fulminant disorder associated with systemic viral infection and characterized pathologically by multiple-organ infiltration of hemophagocytic histiocytes into the lymphoreticular tissues. This is the first report of a previously healthy adult in whom Human herpesvirus 6 reactivation induced this syndrome with severe hemodynamic and respiratory distress.

Virus-associated hemophagocytic syndrome is a fulminant disorder associated with systemic viral infection and characterized pathologically by multiple-organ infiltration of hemophagocytic histiocytes into the lymphoreticular tissues. This is the first report of a previously healthy adult in whom Human herpesvirus 6 reactivation induced this syndrome with severe hemodynamic and respiratory distress.
irus-associated hemophagocytic syndrome (VAHS) is a fulminant disorder associated with systemic viral infection and characterized pathologically by multiple-organ infiltration of hemophagocytic histiocytes into the lymphoreticular tissues. VAHS has been associated with Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus, and Herpes simplex virus (HSV), as well as with a variety of nonviral infections (1). There have been several reports of VAHS in children caused by Human herpesvirus 6 (HHV-6) infection. We report what may be the first record of reactivated HHV-6 causing VAHS with severe hemodynamic and respiratory distress in a previously healthy adult.

Case Report
A healthy 22-year-old man with a high fever lost consciousness and was admitted to our hospital. On admission, a skin rash covered his whole body; cervical, axial, inguinal, and supraclavicular lymphadenopathy and hepatosplenomegaly were observed. The leukocyte count was 14,590/mm 3 , the hemoglobin concentration 13.9 g/dL, and platelet count 12.7x10 4 /mm 3 . Elevated liver enzymes (glutamate oxalacetic transaminase 155 U/L, glutamate pyruvate transaminase 379 U/L) were found, along with elevated lactate dehydrogenase 911 U/L (normal 130-290 U/L) and C-reactive protein 4.9 mg/ dL (normal <0.2 mg/dL). Serum antibody tests for CMV and HSV were negative, but a serum antibody test for EBV was positive (1:640) on day 2 after admission. Infectious mononucleosis was suspected, and the case was managed conservatively without antibiotics for 13 days after admission.
On day 14 after admission, at the onset of pancytopenia, subcutaneous administration of recombinant human G-CSF (Lenograstim; Chugai Pharmaceutical Co. LTD., Tokyo, Japan) was started at 2 µg/kg. Improvement in hematologic parameters was apparent 8 days after the start of G-CSF, and Osaka University Medical School, Osaka, Japan

DISPATCHES
there were no further complications (Figure 1). With mechanical ventilation and fluid resuscitation with catecholamine, the respiratory and hemodynamic status improved. HHV-6B was not isolated from PBMC on day 32 after admission. The symptoms and signs of VAHS disappeared completely, and the patient was discharged 44 days after admission.

Conclusions
VAHS is characterized by prominent phagocytosis of erythrocytes and nucleated blood cells in the bone marrow and lymph nodes. The general symptoms are fever and hepatosplenomegaly. Some cases have been been associated with hypercytokinemia by TNF-alpha, IL-1-beta, and interferon (IFNgamma), resulting in severe hemodynamic collapse and acute lung injury (3). Lymphocyte activation induces excessive production of IFN-gamma, which acts on a variety of cells, resulting in macrophage activation and tissue damage. In keeping with this proposed injury mechanism, successful treatment with cyclosporin A has been documented (3). We administered G-CSF alone, although the serum G-CSF concentration was markedly increased when VAHS was diagnosed, suggesting remarkable up-regulation. HHV-6 is a lymphotropic virus that grows in PBMC. It is widespread in the normal population; >80% of the general population in Japan is seropositive. Exanthema subitum has been considered a manifestation of primary infection with HHV-6 (2). There have been several reports of VAHS in children caused by HHV-6 infection (4,5). The few adults who escape HHV-6 infection during childhood and acquire primary HHV-6 infection as young adults have a selflimited, febrile illness, usually associated with lymphadenopathy and resembling infectious mononucleosis (6). To our knowledge, this is the first report of a healthy adult in whom HHV-6 reactivation induced VAHS with severe hemodynamic and respiratory distress.
Dr. Tanaka is a trauma surgeon at the Department of Traumatology and Acute Critical Care Medicine of the Osaka University Medical School, Osaka, Japan. His current interest is leukocyte function in patients with severe trauma. Guidelines for Dispatches. These brief articles are updates on infectious disease trends and research. The articles include descriptions of new methods for detecting, characterizing, or subtyping new or reemerging pathogens. Developments in antimicrobial drugs, vaccines, or infectious disease prevention or elimination programs are appropriate. Case reports are also welcome. Dispatches (1,000 to 1,500 words) need not be divided into sections. Provide a short abstract (50 words); references, not to exceed 10; figures or illustrations, not to exceed two; and a brief biographical sketch.