Human herpesvirus-6-associated acute lymphadenitis in immunocompetent adults

Abstract

In contrast to other causes of herpetic lymphadenitis, the histological features associated with human herpesvirus-6 (HHV-6) infection have remained elusive since its discovery in 1986. We describe the histologic and phenotypic changes associated with acute HHV-6 lymphadenitis in two immunocompetent adults who presented with fever, fatigue, generalized lymphadenopathy, and elevated liver enzymes. Serologic tests for human immunodeficiency virus, acute Epstein-Barr virus, and cytomegalovirus infection were negative. Lymph node biopsies were consistent with viral lymphadenitis. Intranuclear and cytoplasmic inclusions were identified in CD4-positive T lymphocytes in expanded paracortical areas. Immunohistochemical staining with monoclonal antibody to the HHV-6 gp60/110 kDa envelope glycoprotein showed that the inclusions were positive for viral antigen. Electron microscopy demonstrated numerous viral particles in the cytoplasm and nucleus, characteristic of Herpesviridae family. Clustering of viral particles was observed, which has previously been reported only in infected tissue culture cells. PCR followed by sequencing of DNA extracted from the lymph nodes identified the virus as HHV-6, type B. This is the first report that documents distinctive histologic features of HHV-6 lymphadenitis and demonstrates that the cells harboring the virus in vivo are CD4-positive T lymphocytes.

Figure 1

Histological and immunohistochemical findings. (a) and (b) HE-stained sections of the cervical lymph node from the Case no. 1 with markedly expanded paracortical areas containing a polymorphous population of atypical cells of varying sizes. Many of the cells contain large, eosinophilic, nuclear, and/or cytoplasmic inclusions, suggesting viral etiology. (c) Immunostaining for HHV-6 revels numerous positive atypical cells. Cytoplasmic inclusions are positive; however, antibody does not stain nuclear inclusions. (d) and (e). Immunohistochemical stains reveal that atypical cells, including cells with inclusions (arrows), are positive for CD3 (d) and CD4 (e) and negative for CD8 (not shown). (f) H&E-stained section of the liver biopsy from the Case No 2 demonstrating viral inclusions.

Figure 2

Transmission electron microscopy (TEM) micrographs of infected cervical lymph node. (a) Naked nucleocapsids are present in the nucleus (solid arrows). Nuleocapsids surrounded by a thick fuzzy coat (tegument) are present in the cytoplasm (arrowheads). Some of the tegumented nucleocapsids in the cytoplasm are also surrounded by an outer envelope with spikes (open arrows). Mature virions composed of the nucleocapsid, the tegument and the envelope with spikes are shown in the inset. Bar equals 1 μm. (b) Several clusters of mature virions in membrane-bound vacuoles (endosomes) are present in the cytoplasm of this cell. Bar equals 0.5 μm.