Wisconsin Viral Research Group, Ltd. Physician's Corner: CFIDS/ME

The chronic fatigue syndrome (CFS) is a debilitating illness associated with persistent severe fatigue and a variety of physical and neurological signs and symptoms. While the syndrome itself has been recognized for many years, its etiology and pathogenesis are poorly understood. The incidence of CFS, as diagnosed using the Centers for Disease Control and Prevention (CDC) criteria, is between 0.8% and 1.6% in the United States and could be higher. There is currently no definitive laboratory test for diagnosing CFS, and no effective therapy for CFS has been identified although numerous empiric approaches have been tried.

That members of the herpesvirus family can establish chronic or frequently reactivating infections in individuals with apparently intact immune systems is well established. This trait has been most clearly demonstrated for herpes simplex virus (HSV) which can cause chronic oral or genital infections. Our laboratory has been pursuing the hypothesis that a sizable subpopulation of patients with CFS actually have a disease syndrome caused by persistent or frequently recurring active infection of their tissues with human herpesvirus six (HHV-6), a virologic relative of HSV. With respect to this hypothesis, it is of interest that "infectious" signs and symptoms (e.g. fever, sore throat, swollen lymph nodes and sudden onset) are frequently seen in patients with CFS in contrast to normal, healthy individuals and patients with other diseases (such as major depression) having severe fatigue as a major component.

Virologic studies by several investigators have suggested that more than half of patients with CFS, as defined by the CDC clinical criteria, have active HHV-6 infections in their peripheral blood as compared to less than 10% of normal control individuals, a highly significant difference in rates of infection. 

The term HHV-6 actually encompasses two distinct variants of the virus, designated the A (HHV-6A) and B (HHV-6B) variants. Virtually all adults are infected with HHV-6B with the majority of these infections occurring prior to the age of two years. The rate of infection with HHV-6A is unknown. However, analyses of blood of adults have suggested that in Europe and the United States the prevalence of HHV-6A is much lower than that of HHV-6B. This conclusion has been confirmed by a more recent study in which HHV-6B was detected in 100% of blood samples from normal adults compared to the detection of HHV-6A in only 16% of the same specimens.

In summary, data in the scientific literature suggest that a portion of patients with CFS have an abnormal relationship with HHV-6. We propose that HHV-6 is the cause of CFS in some patients and that these patients are distinct from the other CFS patients with respect to the etiology of their disease. The ability of HHV-6 to induce high level production of proinflammatory cytokines, combined with its frequent infection of the brain and spinal cord and its ability to infect and destroy all types of lymphocytes (including NK cells whose function is known to be decreased in patients with CFS), can account for the range of clinical abnormalities that define CFS.

Recent experimental work from our laboratory offers strong support for the hypothesis stated above. In this study (which was presented at the Fourth International American Association for Chronic Fatigue Syndrome Conference), 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 cells 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.

The cross-sectional (one blood sample per patient) incidence of active HHV-6 infection was almost 40% 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 normal controls.

To assess the possibility that HHV-6 infections may be episodic or variable with respect to viral load in patients with CFS, several patients whose first blood sample was negative for active HHV-6 infection were retested at intervals ranging from 4 to 12 weeks after the initial sample was obtained. Over 40% of the patients 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 several patients with CFS over periods of time ranging from 1 to 5 months. The consecutive blood samples from the patients were found to be HHV-6 positive about 60% of the time with the positivity rates for the individual patients ranging from 40% to 70%. 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 40% 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.

In ongoing work, dual infections with both HHV-6 variants are indicated, but in some cases only HHV-6B appears to be involved. The fact that about 60% of the isolates involved HHV-6A offers some support for the idea of it playing a special role in CFS, however, HHV-6B frequently infects the brain, and patients with active HHV-6B infections in their brain can show a variety of clinical signs and symptoms including difficulty concentrating and decreased short term memory.

In summary, this recent work from our laboratory demonstrates that a sizable proportion of patients with CFS suffer from an active, persistent infection of HHV-6. We believe this infection can account for all or many of the clinical manifestations of their disease. This raises the possibility that CFS may be amenable to effective treatment with pharmacologic agents capable of suppressing the replication of HHV-6.

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