HHV6 association with CFS

One of the first reports of isolated post-infectious fatigue associated with encephalitis, lymph proliferation, and the presence of HHV-6 infection, was made by Buchwald et al. (1990). Daugherty et al. (1991) also reported a group of patients with profound fatigue lymphadenopathy and cognitive dysfunction associated with evidence of HHV-6 reactivation, although variant analysis was not available at that time.

Early studies of CFS patients demonstrated an increase in serum IgG and IgM for HHV-6 in a large number of patients compared with control subjects. However, increases in antibodies to other viruses, particularly other herpesviruses, were also detected. Serological measurements of IgG and IgM titers have limited ability to suggest active infection, because most adults have been infected with HHV-6. These immunoglobulins might only indicate exposure, but not active or persistent infection. Studies using molecular analysis (in subsequent years) generally showed higher prevalence of HHV-6 variant A in CFS patients than in control subjects.

Research performed by Knox et al. (1998) demonstrated active HHV-6 infection in 37% of CFS patients; this is significantly higher than in control subjects. Longitudinal observations from this study indicated that active HHV-6 infection was intermittent and the viral load variable. When patients with prominent CNS complaints were considered separately, 56% had evidence of active HHV-6 infection, suggesting that selection for CFS "with CNS involvement" co-selected for active HHV-6 infection. The cerebrospinal fluid examination of these patients demonstrated that 20% (7/35) were positive for HHV-6 DNA, and because the spinal fluid specimens were acellular, the presence of HHV-6 DNA suggested active CNS infection.

While Ablashi et al. (2000) found that 54% of CFS patients were positive for a specific HHV-6 IgM early antigen (p41/38) compared to just 8% of healthy controls, Patnaik et al. (1995) found that 77% of CFS patients were positive for HHV-6 IgG early antigen versus 12% of controls. Conversely, Wallace et al. (1999) and Reeves et al. (2000) found no greater incidence of HHV-6 infection in CFS patients compared with control patients using an enzyme immunoassay for seroreactivity and lymphocyte co-cultivation to detect HHV-6.

Ablashi et al. (2000) also reported that HHV-6 isolates from CFS patients were predominately variant A (70%), whereas the isolates from healthy controls were predominately variant B. Subsequently, Yalcin et al. (1994) and Di Luca et al. (1995) also reported that the HHV-6 isolates from CFS patients were predominately variant A. These findings support the suggestion that the A variant of HHV-6 plays a more dominant role in CFS than in other disease states.

In a review of HHV-6, Krueger and Ablashi (2003) underscored that the natural history of HHV-6 variant A infection is not known, because until recently, sero-logical testing, most often employed to detect HHV-6, could not differentiate variant A from variant B. A variant-specific serological testing for HHV-6 is not currently commercially available but is under development.

In another study of patients, who met the CDC criteria for CFS, 25% (20/81) were found to have active HHV-6 infection in peripheral blood leukocytes compared to 2% (1/55) of healthy control subjects (Knox et al., 1998). When cerebro-spinal fluids from CFS patients were analyzed for HHV-6, 9% were found to be positive. These studies again illustrate that while active HHV-6 is not found in the blood or spinal fluid of all CFS patients, it is found in a significantly higher proportion than in healthy immunocompetent adults. Several virologists (D. Ab-lashi, C. Knox, and D. Carrigan, personal communication) have also noted persistent positivity for HHV-6, both in peripheral samples and cerebrospinal fluid, for prolonged periods of up to 6 years. However, very few patients have been followed rigorously with variant-specific tests.

In a summary of 27 published studies on the association of HHV-6 with CFS, 15 studies employed detection methods that did not differentiate between active and latent HHV-6 infection. These methods of detecting HHV-6 can be particularly problematic given the ubiquitous nature of latent HHV-6 in adults. Of the 12 studies employing methods that did differentiate active from latent HHV-6 infection, 10 (83%) showed a positive and statistically significant association between active HHV-6 and CFS.

HHV-6 in CNS of CFS patients

Various studies have documented abnormalities in the brains of CFS patients, as evidenced by increased T2-weighted images in the high white matter tracts (Fig. 2), functional abnormalities, as demonstrated by an alteration of the hypothalamic pituitary-adrenal (HPA) axis, cognitive impairment as measured by psychometric testing, regional hypoperfusion as demonstrated by SPECT scanning (Fig. 3), and hypometabolism as demonstrated by PET scanning. Clinically, cognitive impairment, non-restorative sleep, and autonomic dysfunction are characteristic symptoms included in the CDC and Canadian consensus case definitions for CFS.

Owing to the prevalence of neurological complaints in a subset of patients, spinal fluid analysis was performed on 145 patients, of which 20% proved positive for viruses in the cerebrospinal fluid, predominantly HHV-6 variant A (DL Peterson, unpublished). In order to study and ultimately treat these patients, a clinical algorithm for CNS infection with HHV-6 variant A was designed (Fig. 4).

Fig. 2 Magnetic resonance image (MRI) showing increased T2-weighted images in the high white matter tracts.

Fig. 2 Magnetic resonance image (MRI) showing increased T2-weighted images in the high white matter tracts.

Fig. 3 Axial SPECT image showing multiple foci of decreased perfusion (arrows) in the brain. (for colour version: see colour section on page 358).

Patient meets Canadian Consensus case definition Prominent CNS symptoms Abnormal MRI/SPECT scan Abnormal cerebral spinal fluid

■ Increased opening pressure during lumbar puncture ■ Elevated total protein

HHV-6 positive spinal fluid

Fig. 4 Clinical algorithm to identify a subgroup of chronic fatigue syndrome patients suffering from HHV-6 infection in the central nervous system.

These selected patients displayed CNS symptoms, abnormal magnetic resonance image (MRI) and SPECT scans, and abnormal cerebrospinal fluid (increased opening pressure, increased total protein, and lymphocytosis). Challenges faced in the diagnosis of this subset of patients have included a great deal of laboratory variability, a costly algorithm, and small patient numbers.

Hall et al. (1998) reported on children who were examined after primary infection and noted persistence of HHV-6 variant A in the spinal fluid more frequently than in peripheral blood mononuclear cells (PBMCs) or saliva.

Buchwald et al. (1992) reported a cohort study of 259 patients with neurological symptoms, abnormal MRI findings, and lymphocyte phenotyping, suggesting chronic immunologically mediated inflammatory changes of the CNS. Additionally, active replication of HHV-6 (most likely representing reactivation of latent infection) was demonstrated in approximately 70% of the patients and only 20% of controls using monoclonal antibodies specific for HHV-6 and polymerase chain reaction (PCR).

There is persuasive evidence that the HHV-6 variant A infection in the CNS is a particularly serious condition. While HHV-6 presence in the blood is ubiquitous, and thus the relevance of a reactivated infection is of questionable clinical significance, HHV-6 in the CNS is relatively rare, and its presence there is often concurrent with MRI and SPECT changes in the brain, and neurocognitive dysfunction. As pointed out by Shor (2003), if a chronic HHV-6 variant A CNS infection is clearly identified, this subset of patients would no longer technically be diagnosed with CFS as currently defined by the CDC, because they would fall into the exclusionary category of "other chronically fatiguing illness.'' Again, defining subsets of CFS patients is of utmost importance because this HHV-6 variant A positive group could be a more homogenous subset for study and treatment protocols.

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