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Human herpesvirus 6-associated hemophagocytic syndrome in a healthy adult. (Dispatches).

Virus-associated hemophagocytic syndrome virus-associated he·mo·phag·o·cyt·ic syndrome
A syndrome that resembles malignant histiocytosis and follows infection with a herpes virus, such as Epstein-Barr virus.
 is a fulminant ful·mi·nant
Occurring suddenly, rapidly, and with great severity or intensity, usually of pain.

 disorder associated with systemic viral infection and characterized pathologically by multiple-organ infiltration of hemophagocytic histiocytes into the lymphoreticular lymphoreticular /lym·pho·re·tic·u·lar/ (-re-tik´u-ler) pertaining to the cells or tissues of both the lymphoid and reticuloendothelial systems.  tissues. This is the first report of a previously healthy adult in whom Human herpesvirus herpesvirus, any of the family (Herpesviridae) of common DNA-containing viruses, many of which are associated with human disease. See cytomegalovirus; Epstein-Barr virus; herpes simplex; herpes zoster.  6 reactivation induced this syndrome with severe hemodynamic he·mo·dy·nam·ics  
n. (used with a sing. verb)
The study of the forces involved in the circulation of blood.

 and respiratory distress.


Virus-associated hemophagocytic syndrome (VAHS VAHS Virus-associated hemophagocytic syndrome, see there ) 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 Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.

Mentioned in: Conjunctivitis

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 inguinal /in·gui·nal/ (in´gwi-n'l) pertaining to the groin.

1. Of or located in the groin.

, and supraclavicular lymphadenopathy lymphadenopathy /lym·phad·e·nop·a·thy/ (-op´ah-the) disease of the lymph nodes.

angioimmunoblastic lymphadenopathy , angioimmunoblastic lymphadenopathy with dysproteinemia
 and hepatosplenomegaly were observed. The leukocyte count was 14,590/[mm.sup.3], the hemoglobin concentration 13.9 g/dL, and platelet count 12.7x[10.sup.4]/[mm.sup.3]. Elevated liver enzymes (glutamate oxalacetic transaminase transaminase /trans·am·i·nase/ (-am´i-nas) aminotransferase.

See aminotransferase.
 155 U/L, glutamate pyruvate pyruvate /py·ru·vate/ (pi´roo-vat) a salt, ester, or anion of pyruvic acid. Pyruvate is the end product of glycolysis and may be metabolized to lactate or to acetyl CoA.

 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, the patient suddenly went into shock and severe respiratory distress developed, with Pa[O.sub.2] 45 mmHg and PaC[O.sub.2] 35 mmHg at Fi[O.sub.2] of 100%. Pancytopenia pancytopenia /pan·cy·to·pe·nia/ (-sit-ah-pe´ne-ah) abnormal depression of all the cellular elements of the blood.

 was evident, with a leukocyte count of 270/[mm.sup.3], hemoglobin of 9.1 g/dL, and platelet count of 9.7x[10.sup.4]/[mm.sup.3] (Figure 1). The patient's bone marrow was hypocellular, with a nucleated cell count of 1.6x[10.sup.4]/[mm.sup.3] (normal 13.7-23.1 x[10.sup.4]/[mm.sup.3]), and showed an increased number of histiocytes with hemophagocytosis and mature large granulolymphocytes. Elevated serum concentrations of tumor necrosis factor tumor necrosis factor
n. Abbr. TNF
A protein that is produced in the presence of an endotoxin, especially by monocytes and macrophages, is able to attack and destroy tumor cells, and exacerbates chronic inflammatory diseases.
 (TNF)-alpha (44 pg/mL; normal <15.6 pg/mL), interleukin (IL)-[1.sup.2] (129 pg/mL; normal <3.9 pg/mL), IL-6 (3,415 pg/mL; normal <3.1 pg/mL), IL-8 (15,598 pg/mL; normal <31.2 pg/mL), and granulocyte-colony stimulating factor (G-CSF G-CSF granulocyte colony-stimulating factor.


granulocyte-colony stimulating factor.

G-CSF Granulocyte colony-stimulating factor Molecular therapeutics A biological response modifier, the recombinant DNA form of
) (165,000 pg/mL; normal <39.1 pg/mL) were observed. Blood and organ bacteria cultures were negative. The CD4/CD8 ratio (0.73; normal 0.88-1.84) was low, and complete suppression of immunoglobulin was observed, with decreased immunoglobulin (Ig) A (30 mg/dL; normal 115-440 mg/dL), IgG (620 mg/dL; normal 1,000-2,060 mg/ dL), and CD19 (1.1%; normal 9.7-17.3 %). Serum antibody tests for HHV-6 were positive (1:80 on day 7 and 1:280 on day 30 after admission), suggesting that this was a case of HHV-6 reactivation. HHV-6B was isolated as previously described (2) from peripheral blood mononuclear cells (PBMC) on day 5 after admission (Figure 2), suggesting VAHS induced by HHV-6.


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 [micro]g/kg. Improvement in hematologic hematological, hematologic

pertaining to or emanating from blood cells.

hematological tests
total and differential white cell counts, hematocrit estimation, erythrocyte count.
 parameters was apparent 8 days after the start of G-CSF, and there were no further complications (Figure 1). With mechanical ventilation and fluid resuscitation with catecholamine catecholamine (kăt'əkôl`əmēn), any of several compounds occurring naturally in the body that serve as hormones or as neutrotransmitters in the sympathetic nervous system. , 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.


VAHS is characterized by prominent phagocytosis phagocytosis: see endocytosis.

A mechanism by which single cells of the animal kingdom, such as smaller protozoa, engulf and carry particles into the cytoplasm.
 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 (IFN-gamma), 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 self-limited, 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.

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.

Dr. Tanaka is a trauma surgeon at the Department of Traumatology traumatology /trau·ma·tol·o·gy/ (-tol´o-je) the branch of surgery dealing with wounds and disability from injuries.

 and Acute Critical Care Medicine of the Osaka University Medical School, Osaka, Japan. His current interest is leukocyte function in patients with severe trauma.


(1.) Risdall R J, McKenna RW, Nesbit ME, Krivit W, Balfour HH, Simmons RD. Virus associated hemophagocytic syndrome. Cancer 1979;44:993-1002.

(2.) Yamanishi K, Okuno T, Shirake K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem exanthem /ex·an·them/ (eg-zan´them)
1. any eruptive disease or fever.

2. an eruption characterizing an eruptive fever.
 subitum. Lancet 1988; 1:1065-7.

(3.) Oyama Y, Amano T, Hirakawa S, Hironaka K, Suzuki S, Ota Z. Haemophagocytic syndrome treated with cyclosporin A: a t-cell disorder. Br J Haematol 1989;73:276-8.

(4.) Huang LM, Lee CY, Lin KH, Chuu WM, Lee PI, Chen RL, et al. Human herpesvirus-6 associated with fatal haemophagocytic syndrome [letter]. Lancet 1990;2:60-1.

(5.) Takagi M, Maruyama T, Kaneko K, Obinata K. Human herpesvirus-6 (HHV-6)-associated hemophagocytic syndrome. Pediatr Hematol Oncol 1996;13:451-6.

(6.) Niederman JC, Liu CR, Kaplan MH, Brown NA. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet 1988;2:817-9.

Hiroshi Tanaka, Tetsuo Nishimura, Mikko Hakui, Hisashi Sugimoto, Keiko Tanaka-Taya, and Koichi Yamanishi

Osaka University Medical School, Osaka, Japan

Address for correspondence: Hiroshi Tanaka, Department of Traumatology, Osaka University Medical School, 2-15, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan; fax: 81-6-6879-5720; e-mail:
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Author:Yamanishi, Koichi
Publication:Emerging Infectious Diseases
Geographic Code:9JAPA
Date:Jan 1, 2002
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