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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.
Presented at the Fourth International American Association for Chronic Fatigue
Syndrome Conference October 12-14, 1998
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