Human Herpesvirus Six and Multiple Sclerosis:

Systemic Active Infections in Patients with Early Disease.

 

Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR.

 

Clinical Infectious Diseases, October 2000

The results of a breakthrough investigation published in the October issue of the journal Clinical Infectious Diseases demonstrate that central nervous system (CNS), lymphoid, and peripheral blood samples from patients with clinically definite multiple sclerosis (MS) were found to have a significantly greater incidence of active human herpesvirus six (HHV-6) infection compared to controls. With respect to type of MS disease (relapsing remitting or progressive), no significant difference was found between HHV-6 viremia positive and HHV-6 viremia negative MS patients. In contrast, the patients with active HHV-6 infection were significantly younger and had a shorter duration of disease than those who did not have active infection with HHV-6.

CNS tissue, gathered at autopsy from 11 patients with clinically definite MS, was used in this investigation. Approximately half of these patients had relapsing remitting MS (RRMS) while the remainder had progressive MS (PMS). Control CNS tissue consisted of biopsy and autopsy derived samples from 28 subjects without MS. In addition, lymph node tissues from 9 patients with clinically definite MS were obtained and compared to lymph node tissue samples from 7 normal controls. All samples were immunohistochemically stained.

The results of immunohistochemical staining of CNS tissues from the MS patients are summarized in Table 1. Almost three-fourths of the MS patients (8/11) with CNS samples were actively infected with HHV-6. Importantly, 90% (17/19) of tissue sections showing active demyelination were positive for HHV-6 infection. In contrast, only 13% (3/23) tissue sections free of active disease were positive for HHV-6 infection. This association between active CNS disease and active HHV-6 viremia was highly significant (p < 0.0001).

Patients with MS experienced significantly higher incidence of active HHV-6 infection than the control patients with non-MS inflammatory, demyelinative diseases (8/11 (73%) versus 2/21 (10%); p < 0.001).

1 The two HHV-6 positive other demyelinating disease controls were diagnosed as having HHV-6 leukoencephalitis. 2 Calculated by means of two-sided Fisher’s Exact Test 3 Compared to results with MS patients

In an effort to find out of HHV-6 infection in MS patients was systemic or restricted to the CNS, lymphoid tissues from 9 patients with clinically definite MS were evaluated and compared to lymphoid tissue samples from 7 healthy subjects. Active HHV-6 infections were found in 67% (6/9) of the patients with MS while none of the control subjects had active HHV-6 infection (p < 0.015).

Such results suggested HHV-6 active infection might also be present in peripheral blood of MS patients. Samples of peripheral blood were analyzed using a rapid HHV-6 culture assay. The blood samples of 41 clinically definite MS patients were analyzed and compared to samples from 61 control subjects.

Detection of Active HHV-6 Infections in the Peripheral Blood Leukocytes of Patients with MS:

1 Determined by rapid culture assay 2 Determined by two sided Fisher’s Exact Test 3 Expressed as mean value +/- one standard deviation 4 Determined by Mann-Whitney Test 5 Relapsing/remitting disease 6 Progressive disease; either primary or secondary progressive at the time of testing

Blood samples from 22 (54%) of 41 patients with definite MS were found to contain active HHV-6 infections, compared with 0 of 61 normal controls (p<.0001) While no significant differences were observed between HHV-6 positive and HHV-6 negative patients with respect to gender or type of disease, HHV-6 positive patients were significantly younger (41.5 years vs 49.6 years) and had significantly shorter duration of disease (<12 years) than the HHV-6 negative patients.

The incidence of positive HHV-6 infection in patients with disease duration of less than 12 years (18/24 or 75%) was dramatically higher than that seen in patients with longer durations of disease (4/17 or 24%).

These results are clinically relevant because using the techniques described in this study, active HHV-6 infection can be identified relatively non-invasively in patients with MS. For example, the therapeutic effectiveness and sensitivity of antiviral drug therapy on the suppression of active HHV-6 infection in patients with MS could be monitored using blood specimens rather than tissue biopsies or cerebrospinal fluid (CSF) specimens. In addition, the findings presented suggest that a change in the pathogenic mechanisms involved in MS may occur over time concurrent with a change in the level of active HHV-6 infection in the peripheral blood and maybe even the CNS.

These results were recently published in the October 2000 issue of Clinical Infectious Diseases.