4. Discussion
This was an open-label study of valganciclovir (VGCV) in 12 patients with CFS and elevated antibody titers to both HHV-6 and EBV. VGCV treatment was associated with reduction in antibody titers in most patients. A majority of the treated patients also had dramatic improvement in activity level, although three did not. Obviously, a placebo effect is always possible in open-label studies. Many previous treatments had been tried in these 12 patients, without any benefit, suggesting that they were not placebo responders. Moreover, patients with CFS appear to be less likely than patients with other diseases to experience a placebo effect (Cho et al., 2005). Nevertheless, large randomized trials are essential before VGCV therapy is given routinely in patients with CFS and elevated antibody titers to HHV-6 or EBV. Based on our experience, such studies should probably be restricted to CFS patients whose illness began with an acute flu-like illness, which may be a minority of patients with CFS in the community at large (Solomon and Reeves, 2004).
Since HHV-6 is typically acquired by the age of two and EBV is generally acquired in early childhood or as a young adult, we interpreted the elevated titers as a sign of reactivated rather than primary infection. The antibody titers of the patients were considerably higher than those in 12 healthy controls, tested in the same laboratory. However, reference values for antibody titers against HHV-6 and EBV do vary by laboratory and variations of 1-2 dilutions in results on tests run on the same sample are considered common in most commercial laboratories. Focus Diagnostics, the laboratory used by Stanford for the EBV, HHV-6 and CMV serological tests, has a reference range that is higher than what has been reported in the literature (Savoldo et al., 2002; Straus et al., 1985; Tobi et al., 1982). At our request, Focus Diagnostics tested 12 healthy controls and the median titers were 1:80 for HHV-6 IgG and 1:320 for EBV VCA IgG. When fifty laboratory workers were tested at Focus, median values were slightly higher: 1:160 for HHV-6, and 1:640 for EBV VCA.
Although EBV EA antibodies dropped in three responders, it did not drop in the others, which was contrary to our expectations. Since antibody levels fall slowly over time, these results may understate the full extent of the drop. Antibody measures cannot determine whether a patient has an active viral reactivation. However, the fact that we observed falling EBV and HHV-6 titers concurrent with clinical recovery is significant. Larger studies and standardized assays are necessary to determine how useful these serological assays can be in identifying prospects for treatment. Molecular assays available in clinical laboratories were not informative. None of the responding patients was positive for HHV-6 or EBV DNA using an assay capable of detecting as few as 200 copies/ml. DNA of these viruses is typically detected only during a primary or acute infection. Better biomarkers are needed to identify reactivation of chronic disease and assess response to treatment.
Both HHV-6 and EBV can reactivate in a healthy person in response to an acute illness and normal controls can be found with elevated antibody titers to HHV-6 and EBV, especially in those under the age of thirty who are more likely to have had a recent primary infecton. This makes the assessment more complex and underscores the necessity of a careful evaluation by an experienced clinician, in order to differentiate between transient reactivation due to other illness, asymptomatic elevation of viral titers, and a chronic reactivated viral infection which would deserve treatment.
Clinical evaluation and a history suggestive of a viral etiology must remain the primary determinant for treatment. Treatment cannot be based solely on antibody levels or detection of viral DNA. In cases where humoral immune response is impaired, antibody levels may not be elevated at all or only slightly elevated above the mean. Also, there may be persistent viral infection in the CNS tissue with no trace in the peripheral blood. A prospective placebo controlled trial of valganciclovir is necessary to determine whether a subset of CFS patients would benefit from treatment. The fact that antibody titers to either HHV-6 or EBV dropped four-fold or more in several of these patients suggests (a) some if not all of these patients had active infections and (b) elevated antibody levels can be useful to confirm a suspicion of a chronic infecion that has reactivated.
In this study, treatment with oral VGCV did not produce any serious adverse effects, but it was not without some difficulties. As noted above, all of the responding patients reported some degree of worsening of their condition during their inital month of treatment. This worsening resembled a Jarisch Herxheimer-like reaction and included several days of myalgias, chills, headache, worsening of the "brain fog" and fatigue, and skin rash in some patients. The pathology of this response is unclear, but may be mediated by an immune response to transiently increased circulating viral antigen(s).
Adverse events for patients using VGCV is far higher for immunocompromised patients including those with AIDS-associated CMV retinitis and solid organ transplants with CMV disease. Neutropenia was reported to be 27% for retinitis patients (Roche Valcyte product information: (http://www.rocheusa.com/products/valcyte/) and 8% in solid organ transplants (Paya et al., 2004). In this small study, none of our patients experienced any hematological adverse effects or untoward reactions requiring the discontinuation of the VGCV.
Several other limitations of this study need to be acknowledged. We did not test for HHV-7 or distinguish between the HHV-6 A and B subtypes. Also, despite the fact that the improvements in physical activity and cognitive functions were dramatic and impressive, they were self-reported and not objective measurements. We are planning a double-blind placebo controlled trial with more comprehensive evaluation of the functional status of subjects, using established and validated instruments as well as better documentation of viral activity.
In summary, the results of this preliminary study suggest that a subset of patients with CFS and elevated antibody levels to HHV-6 and EBV may have an illness that is caused by reactivation of these viruses, and that is responsive to VGCV antiviral therapy. Further definition of this subset of patients with better and more standardized viral assays is required, as are large randomized controlled trials with long-term follow-up to confirm the possible value of antiviral therapy in patients with CNS dysfunction and symptoms of sustained fatigue. In addition, we propose a new medical term for the syndrome that may best describe our patient cohort: Virus Induced CNS Dysfunction. It may be applied to the subset of CFS patients who have elevated HHV-6 and EBV titers and clinical symptoms of a viral syndrome with neurocognitive complaints and sustained fatigue. Other viruses may also play a role in defining additional CFS patient sets.
References
Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, et al. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol 2000;16:179-91.
Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160:221-36.
Ambinder RF. Epstein-Barr virus-associated lymphoproliferative disor- ders. Rev Clin Exp Hematol 2003;7:362-74.
Ambinder RF, Lin L. Mononucleosis in the laboratory. J Infect Dis 2005; 192:1503-4.
Bertram G, Dreiner N, Krueger GR, Ramon A, Ablashi DV, Salahuddin SZ, et al. Frequent double infection with Epstein-Barr virus and human herpesvirus-6 in patients with acute infectious mononucleosis. In Vivo 1991;5:271-9.
Buchwald D, Ashley RL, Pearlman T, Kith P, Komaroff AL. Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. J Med Virol 1996;50:25-30.
Cermelli C, Cenacchi V, Beretti F, Pezzini F, Luca DD, Blasi E. Human herpesvirus-6 dysregulates monocyte-mediated anticryptococcal defences. J Med Microbiol 2006;55:695-702.
Cho HJ, Hotopf M, Wessely S. The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis. Psychosom Med 2005;67:301-13.
Cuomo L, Trivedi P, De Grazia U, Calogero A, D'Onofrio M, Yang W, et al. Upregulation of Epstein-Barr virus-encoded latent membrane protein by human herpesvirus 6 superinfection of EBV-carrying Burkitt lymphoma cells. J Med Virol 1998;55:219-26.
Flamand L, Stefanescu I, Ablashi DV, Menezes J. Activation of the Epstein-Barr virus replicative cycle by human herpesvirus 6. J Virol 1993;67:6768-77.
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953-9.
Gao SZ, Chaparro SV, Perlroth M, Montoya JG, Miller JL, DiMiceli S, et al. Post-transplantation lymphoproliferative disease in heart and heart-lung transplant recipients: 30-year experience at Stanford University. J Heart Lung Transplant 2003;22:505-14.
Glaser R, Litsky ML, Padgett DA, Baiocchi RA, Yang EV, Chen M, et al. EBV- encoded dUTPase induces immune dysregulation: Implications for the pathophysiology of EBV-associated disease. Virology 2006;346: 205-18.
Hollsberg P, Kusk M, Bech E, Hansen HJ, Jakobsen J, Haahr S. Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity. Acta Neurol Scand 2005;112:395-402.
Horwitz CA, Henle W, Henle G, Rudnick H, Latts E. Long-term serological follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis. J Infect Dis 1985;151:1150-3.
Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19- associated chronic fatigue syndrome. Clin Infect Dis 2003;36:e100-6.
Krueger GR, Ablashi DV. Human herpesvirus-6: a short review of its biological behavior. Intervirology 2003;46:257-69.
Manian FA. Simultaneous measurement of antibodies to Epstein-Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response? Clin Infect Dis 1994;19:448-53.
Montoya JG. Successes and limitations of antimicrobial interventions in the setting of organ transplantation. Curr Opin Infect Dis 2004;17:341-5.
Montoya JG, Giraldo LF, Efron B, Stinson EB, Gamberg P, Hunt S, et al. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 2001;33:629-40.
Natelson BH, Ye N, Moul DE, Jenkins FJ, Oren DA, Tapp WN, et al. High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness. J Med Virol 1994;42:42-6.
Patnaik M, Komaroff AL, Conley E, Ojo-Amaize EA, Peter JB. Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J Infect Dis 1995;172:1364-7.
Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004;4:611-20.
Sairenji T, Yamanishi K, Tachibana Y, Bertoni G, Kurata T. Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Intervirology 1995;38:269-73.
Sauce D, Larsen M, Curnow SJ, Leese AM, Moss PA, Hislop AD, et al. EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15. Blood 2006;108:11-8.
Savoldo B, Huls MH, Liu Z, Okamura T, Volk HD, Reinke P, et al. Autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood 2002;100:4059-66.
Smith AP, Paolucci C, Di Lullo G, Burastero SE, Santoro F, Lusso P. Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6. J Virol 2005;79: 2807-13.
Solomon L, Reeves WC. Factors influencing the diagnosis of chronic fatigue syndrome. Arch Intern Med 2004;164:2241-5.
Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985;102:7-16.
Tobi M, Morag A, Ravid Z, Chowers I, Feldman-Weiss V, Michaeli Y, et al. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1982;1:61-4.
Yoshikawa T, Asano Y, Akimoto S, Ozaki T, Iwasaki T, Kurata T, et al. Latent infection of human herpesvirus 6 in astrocytoma cell line and alteration of cytokine synthesis. J Med Virol 2002;66:497-505.
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