Persistent Active Human Herpesvirus Six (Hhv-6) Infections In Patients With Chronic Fatigue Syndrome.

Konstance K Knox, Ph.D.¹; Joseph H. Brewer, M.D.² and Donald R. Carrigan, Ph.D.¹ Institute for Viral Pathogenesis and Wisconsin Viral Research Group; Milwaukee, Wisconsin1 and St. Luke's Hospital; Kansas City, Missouri².

OBJECTIVE: Data from a number of laboratories have suggested a role for HHV-6 in the pathogenesis of chronic fatigue syndrome (CFS). In the studies described here we sought to explicitly test the hypothesis that a portion of patients with CFS have persistent, active HHV-6 infections.

METHODS: Blood samples from patients with CFS were evaluated by a rapid HHV-6 culture procedure. This technique diagnoses active HHV-6 infections by detecting transfer of the virus from the patient's blood leukocytes to a target human cell line. CFS patients from two CFS oriented clinics, a large infectious disease practice, and blood samples from CFS patients submitted to our laboratory from physicians and clinics around the United States were studied. Clinical characteristics of and multiple blood samples from a group of CFS patients from the infectious disease practice were evaluated in detail.

RESULTS: The cross-sectional (one blood sample per patient) incidence of active HHV-6 infection was 37% (128/349) in the CFS patients with the incidence being similar at all four sources of samples (range 25% to 47%). This incidence of active HHV-6 infection was significantly higher than the 0% seen in 26 normal controls (p<0.05).

To assess the possibility that HHV-6 infections may be episodic or variable with respect to viral load in patients with CFS, seven patients whose first blood samples were negative for active HHV-6 infection were retested at intervals ranging from 4 to 12 weeks after the initial sample was obtained. Three of the seven patients (43%) were found to be positive for active HHV-6 infection with the second sample. This finding suggested that active HHV-6 infections may be intermittently detectable in patients with CFS. This possibility was examined by testing at least four blood samples from each of four patients with CFS over periods of time ranging from 1 to 5 months. The consecutive blood samples from the four patients were found to be HHV-6 positive 58% (22/38) of the time with the positivity rates for the individual patients ranging from 40% (4/10) to 69% (9/13). These observations suggest that the active HHV-6 infections in patients with CFS are either intermittent or variable with respect to their viral load. Thus, an individual patient's HHV-6 infection status must be assessed using multiple blood samples obtained over a period of weeks or months. Also, the 37% estimate of the incidence of active HHV-6 infections in patients with CFS should be held as a minimal value since the true incidence may be higher (60% to 70%).

In the course of these studies it was observed that many HHV-6 positive CFS patients had central nervous system (CNS) involvement in their disease. To formally address this, 25 patients with CNS disease (abnormal SPECT or MRI scans, sensory abnormalities, cognitive defects, etc.) seen in the infectious disease practice were evaluated for active HHV-6 infections. Fourteen of the 25 patients (56%) were HHV-6 positive. This incidence of HHV-6 infection was higher (p < 0.08) than that seen in total population of unselected CFS patients (37%) suggesting that the selection for CFS with CNS involvement coselected for active HHV-6 infections. Confirmation of CNS infection with HHV-6 in some patients with CFS was obtained by the detection of HHV-6 DNA in the cerebrospinal fluid (CSF) of 20% (7/35) of the CFS patients studied.

CONCLUSION: These studies demonstrate that a sizable proportion (30% to 70%) of patients with CFS suffer from an active persistent infection with HHV-6 which may account for all or many of the clinical manifestations of their disease. Active HHV-6 infections may be especially prevalent in CFS patients with CNS involvement, consistent with the highly neuroinvasive nature of HHV-6.