Viral and immune interactions

Viral infections have long been suspected as the cause of CFS/ME, but no infectious agent has ever been identified. A related viewpoint is that a virus may trigger CFS/ME, but then an abnormal biochemical change perpetuates the illness. This has been referred to as the "hit-and-run theory." Ron Glaser (Ohio State University) examined another possibility, that latent viruses (or even parts of viruses) could be producing abnormal proteins within the cells of our patients, causing immune dysregulation, cytokine production, and inefficient T-cell or NK-cell function. Viruses (or parts of viruses) can induce cells to manufacture proteins and enzymes, some of which may be injurious to the call. Glaser's group injected into mice an enzyme (dUPTase) that is encoded by the EB virus. Immune function and behavior were then monitored. Lymphocytes in the injected mice were less able to replicate, and the treated animals lost weight, had elevated temperatures, and were slow-moving.

Glaser's group also elegantly demonstrated that stress and age affect latent virus activation. Geriatric patients, for example, had much higher titers of antibodies to Epstein-Barr Early Antigen (EA) and Capsid IgG (VCA-IgG) than young adults. And when antibody titers were measured in young students at various times during the school year, titers were noted to rise as much as four-fold during exam periods, and drop to more moderate levels during Summer vacation.

Comment: This is no surprise to anybody who has experienced the recurrence of herpetic mouth ulcers or recurrent shingles (zoster) following periods of stress. The point, however, is that latent viruses (like VZV, EBV, and HHV6) can reactivate during periods of stress, causing immune changes and even symptoms of illness. Since EBV is an oncogenic virus, Glaser raises concerns that such reactivation could conceivably cause B-cell lymphomas. To my knowledge the latter has not been confirmed in CFS/ME.

One question that arises frequently is, "Which test should we use to detect chronic reactivation of viruses such as HHV-6 and EBV?" Dharam Ablashi (HHV6 Foundation, Nevada) pointed out that viral reactivation is more closely associated with CFS/ME than just titers of latent antibodies. He examined several techniques for measuring viral presence. Qualitative PCR on whole blood did not differentiate between active and latent infection, and there was too little virus in serum to make this assay useful. Active infection can be inferred by quantitative PCR, serum nested PCR, and analysis of cytopathic effect, but these techniques are difficult, expensive, and not readily available to clinicians. On the other hand, Ablashi provided evidence that highly elevated titers (>1:320 or 1:640) of commercially available IFA assays for IgG can be used to identify patients suspected of having active infection.

Comment: Now we know that high titers of EBV or HHV-6 IgG are likely due to reactivation, and possibly amenable for antiviral therapy.

Susan Levine (private practice in NY City) and others measured IgG levels to HHV-6 and early antigen titers of EBV in persons with CFS/ME. 45% of PWCs had titers of >1:320 to EBV and 35% had titers of >1:320 to HHV-6, whereas none of 11 controls had such elevated titers. This suggests that a subset of PWCs suffer from chronic infections with EBV and/or HHV-6. Cytokines are immunologically-based chemicals that can cause viral symptoms such as fever, sore throat, swollen glands, achiness, etc. Brian Gurbaxani (CDC, Atlanta) described a simple but helpful study that demonstrated increased levels of one pro-inflammatory cytokine, Interleukin 6 (IL-6), in PWCs. His group demonstrated that increased levels of IL-6 were proportionate to CFS/ME symptom severity, but also correlated with waist-to-hip ratio (one measure of allosteric load, or "stress") and C-reactive protein (CRP), which is a marker of inflammation. This finding supports the hypothesis that an ongoing inflammatory process could be contributing to CFS symptoms.

John Chia (EV Med Research, California) reported on enterovirus infections in PWCs with GI distress. Enteroviruses (a genus of RNA viruses that includes echovirus, Coxsackie virus, and poliovirus) have been reported in CFS/ME patients by the British, but have not been explored much in the US. Chia obtained gastric biopsies on 108 PWCs with upper gastrointestinal complaints plus 12 normal healthy subjects and 9 subjects with other GI disorders. 100 of the patient biopsies revealed at least mild chronic inflammation, of which 5 demonstrated infection with H. pylori. Eighty-six (86/108=80%) were positive for the VP1 (enteroviral capsid protein), while only 2/21 (10%) of controls were positive. Enteroviral RNA was detected in 5 of the 15 biopsy specimens studied (33%). Thus enteroviral infections may play a role in a subset of PWCs with upper gastrointestinal complaints.

While the evidence is not as compelling as with other infectious organisms, Garth Nicholson (Institute for Molecular Medicine, Calfornia) and colleagues continue to report positive PCR results for Mycoplasma species in PWCs and Gulf War Syndrome victims.

Additional Posters

Tae Park (Seoul, South Korea) reported once again on his remarkable success in treating PWCs with one gram of intravenous gamma globulin weekly for 6 months. In addition Park attends to diet, sufficient salt and water intake, regular exercise, and sleep management. He reported on 50 patients (28M, 22F), all of who were severely ill and disabled with CFS/ME. Twenty-five of the 28 males improved enough to return to work (Karnofsky Performance Score from 40 to 90; Fatigue Impact Scale from 120 to 20-40). Eighteen of 22 females remarkably improved also (KPS 40 to 80; FIS 125 to 40-50).

Comment: Four major studies using IVGG for the treatment of CFS/ME have shown variable results— two were successful, two were not. Park has abundant and continued success with his regimen, but possibly his adjunctive therapy or regular IV fluid administration contributes to some of his success?

Lastly, Jacob Teitelbaum (Annapolis Research Center, Maryland) provided a poster on his most recent vogue, d-ribose. Ribose is a sugar (not at all like table sugar!) that is used by the cell and specifically by the mitochondria in the production of energy. Other studies have suggested that d-ribose supplementation may improve cellular energy in heart and skeletal muscles. Teitelbaum's pilot study included 41 PWCs who took 5 grams of d-ribose thrice daily for about two weeks. Using visual analog scales, 66% of the patients reported significant improvement during the study, with an average increase of 42% in energy and 30% in well-being.

Comment: If confirmed, this is great news! I am concerned, however, over the short treatment period, which is well within the placebo effect range. Also, subjective improvement is one thing, but do any objective parameters improve? Teitelbaum states that a randomized controlled trial is underway, so perhaps we will find out soon.