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Prospective Study of Human Herpesvirus Six in Multiple Sclerosis

Final Progress Report

January 30, 2000

Lorri J. Lobeck, M.D.
Department of Neurology
Medical College of Wisconsin
Milwaukee, Wisconsin

Konstance K. Knox, Ph.D. and Donald R. Carrigan, Ph.D.
Institute for Viral Pathogenesis
Milwaukee, Wisconsin

Scientific Summary of Research Progress

The purpose of this study was to validate the use of peripheral blood specimens in detecting active human herpesvirus six (HHV-6) infections in patients with Multiple Sclerosis (MS). Prior to this study, central nervous system and lymphoid tissues had been assessed and confirmed the presence of active HHV-6. Use of these tissues for routine study has limitations because of the need for invasive procedures to obtain tissue. We have been successful in determining the presence of active virus in samples of blood from individuals with MS.

Forty patients, with MS, had blood samples drawn at the time of a clinical relapse. A second specimen was to be drawn four to six weeks later. Cross sectional data is available on 37 patients. Paired specimen data is available on 30 patients. These data include patients with two specimens that were either positive or negative for the presence of active virus on both specimens. Seven patients do not have paired sample data, as they either had indeterminate specimens or failed to return for the second blood sample to be obtained. Indeterminate samples were those which were lost due to culture toxicity. The remaining three patients had either two indeterminate specimens or had one indeterminate specimen and failed to return for the second blood sample. The conclusions reviewed below include the cross sectional data and paired specimen data.

Figure 1

The cross sectional study of the incidence of HHV-6 viremia is illustrated in Figure 1. Data from normal control subjects includes 50 healthy blood donors from the Kansas City Blood Bank and 11 healthy laboratory donors. The current study population is indicated as patients seen at the Medical College of Wisconsin Multiple Sclerosis Clinic. Another group of patients has been assessed in St. Luke’s Medical Center in Kansas City, Missouri. The findings confirm the presence of active virus in the peripheral blood of patients with MS.

The clinical features of patients participating in the study are reviewed in Figure 2. This cross-sectional data incorporates the patients’ viral status at the time of the first blood sample only. Some patients began immunomodulator therapy after the first sample was obtained, but prior to the second. No significant clinical differences were evident between the patients who tested positive or negative for the virus on the first blood sample.

Figure 3 illustrates data from paired specimens. A significant number of patients who were viremic at the time of a clinical relapse demonstrated a lack of viremia when tested 6 to 10 weeks later. Future investigations, to include more frequent samples, would provide insight into the timing and pattern of the HHV-6 viremia.

Figure 2

Figure 3

Figure 4 illustrates the change in clinical status between the time of the first and second blood sample in those patients with paired specimen data. As would be expected, patients with relapsing MS often experience improvement in their symptoms, although not always a return to the pre-relapse condition.

The profile of HHV-6 viremia in paired specimens is further illustrated in Figure 5. The majority of those patients testing positive on the first sample, tested negative on the second, while those negative on the first were most often negative on the second sample.

While the original proposal was to obtain samples 4 to 6 weeks apart, some samples were delayed. This delay led to a fortuitous observation that, as illustrated by Figure 6, more closely spaced samples tended to test alike, and those separated by more time were more likely to be different. This observation raises further questions about the episodic nature of HHV-6 viremia in patients with MS. More frequent and consistent sampling of individuals with MS should define the pattern of viremia.

 Figure 4

Figure 5

In conclusion, this project has been successful in demonstrating the presence of active HHV-6 infection in the blood samples of individuals with Multiple Sclerosis at the time of clinical relapse. The virus was not detected in blood samples of normal controls. In addition, several observations are described that suggest viremia is episodic and variable in patients with MS. As a result, we feel additional studies into the pattern of viremia are necessary to gain further understanding of these observations. Further, we feel the use of viral culture for HHV-6 should be incorporated into trials of anti-viral agents for patients with MS as the presence or absence of virus in peripheral blood may provide insight to which patients are most likely to respond to treatment.

Figure 6

Release for the Public

Researchers at the Medical College of Wisconsin and the Institute for Viral Pathogenesis have demonstrated the presence of active human herpesvirus-6 infections, as measured by viral cultures, in patients with Multiple Sclerosis coincident with new clinical relapses. Prior to this study, the active virus infection had been detected in specimens of brain or lymphoid tissue in some patients. The invasive nature of these techniques led to the search to find other ways to identify the active virus infection. These findings will hopefully lead to other studies investigating the role of this virus in Multiple Sclerosis.