Comment; Chronic Fatigue comes from a variety of complex chronic illnesses. Viruses and subviral particles can cause these infections and be very difficult to diagnose, empiric treatment with antiviral therapy–which covers human herpesvirus-6 (HH-6) as well as other viruses makes sense to curtail or erradicate the infection & restore health & recovery.
Abstract
There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV‐6) and Epstein–Barr virus (EBV) have been proposed as infectious triggers. Thirty CFS patients with elevated IgG antibody titers against HHV‐6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double‐blind, placebo‐controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI‐20) and Fatigue Severity Scale (FSS) scores, self‐reported cognitive function, and physician‐determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels. VGCV patients experienced a greater improvement by MFI‐20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI‐20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1‐profile (P < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted. J. Med. Virol. 85:2101–2109, 2013.
DISCUSSION
Antiviral therapy for patients with CFS is widely viewed as unnecessary and is unsupported by clinical trials with rigorous study designs. Straus et al. [1988] reported that acyclovir lacked efficacy for the treatment of CFS patients in a randomized placebo‐controlled trial. However, acyclovir administration duration was only 5 weeks, and the possibility of HHV‐6 infection (a virus known to be essentially unaffected in vitro by acyclovir) was not investigated. Since then, several investigators have reported potential benefit of various antivirals used for longer periods in open‐label observations [Kogelnik et al., 2006; Lerner et al., 2010].
Findings in this study suggest that VGCV may have a clinical benefit, independent from placebo in that subset of patients with CFS who have serological evidence of reactivated EBV and/or HHV‐6 infection. With regard to the physical (i.e., FSS score) and mental fatigue (i.e., MFI‐20 mental fatigue subscore, self‐reported cognitive function) outcomes, these findings consistently indicated larger improvements in the VGCV arm. Most notable was the difference in proportion of responders between the arms: all but 2 of the 15 responders were in the VGCV arm.
While differences between arms in the originally chosen primary endpoint (i.e., change in MFI‐20 at month 9 compared to baseline assessed by ANOVA) were not found, compelling differences were found in the trajectories of MFI‐20 and FSS scores by MEL regression analysis. While these findings may seem contradictory, they are not. The primary endpoint investigated the effect of treatment on change in outcomes at a specific time point (9 months), whereas MEL regression analysis evaluated the effect of treatment on an entire trajectory of the particular outcome over time. CFS is characterized by a highly fluctuating clinical course; symptoms vary significantly on a daily, weekly, and monthly basis. Therefore, MEL regression models that make use of all data points appear to be more suitable to determine drug effect over placebo in CFS patients.
Patients in the VGCV and placebo arms experienced an initial worsening of their symptoms that has been previously reported by the Stanford CFS group and in a recent clinical trial [Kogelnik et al., 2006; Fluge et al., 2011]. It is possible that the worsening in the placebo arm was due to placebo effect and/or the additional physical/emotional load of frequent visits to the clinical research center. In the VGCV arm, in addition to the factors present in the placebo group, a drug effect may have taken place as well. The pathogenesis of this initial worsening is unclear but it may resemble a Jarisch–Herxheimer‐like reaction that has been observed during the initial treatment of certain infections and may be mediated by an immune response to transiently increased circulating microbial antigen(s) [Bryceson, 1976].
In addition, these results suggest possible mechanisms for the clinical benefit observed in the VGCV arm. Monocytopenia, neutrophilia, and differences in Th1‐related cytokines over time were associated with the use of VGCV. In immunocompromised patients, ganciclovir (the active drug in VGCV) is a commonly used antiviral against herpesviruses and appears to work by interfering with viral DNA chain elongation [Montoya, 2007; Razonable, 2011]. In immunocompromised patients, ganciclovir frequently contributes to leukopenia and neutropenia and it is not known to cause monocytopenia or neutrophilia. Monocytes are known to be targeted by HHV‐6 [Kondo et al., 2002; Janelle and Flamand, 2006] and can be infected by EBV [Savard et al., 2000; Tugizov et al., 2007; Walling et al., 2007]. Thus, it is possible that in CFS patients HHV‐6 and EBV are circulating in peripheral blood within monocytes. Since monocytes are transformed into macrophages in tissues, including the central nervous system, by lowering monocytes in peripheral blood, VGCV may be indirectly decreasing the viral HHV‐6/EBV burden in the tissues of CFS patients. In addition, by decreasing influx of infected monocytes (with the capacity of triggering inflammation) into affected tissues, VGCV may be contributing towards the restoration of a more effective and healthier local immune response.” The neutrophilic response observed in the VGCV arm was unexpected but was also validated by the increase of ENA‐78, a known neutrophil chemoattractant [Liu et al., 2009]. The antiviral role of neutrophils is becoming increasingly appreciated [Butler et al., 2011] and should not come as a surprise given the tendency of several viruses to cause leukopenia. The trend towards a Th1 cytokine profile in the VGCV arm would reverse the Th2 predominance that has been reported by Broderick et al. in CFS patients [Broderick et al., 2010; Brenu et al., 2011]. Significant declines in the HHV‐6 or EBV antibody titers at 6 months were not observed, suggesting that their decline requires longer periods of VGCV administration and/or that VGCV primarily works through immunomodulatory properties in CFS patients. Alternatively, it is possible that HHV‐6 and EBV antigens were circulating forming immune complexes resulting in artificially depressed levels of antibodies; thus, when VGCV reduced load of circulating Ag, antibody levels may have risen because less antibodies were bound in the immune complexes.
A study by Fluge et al. [2011] suggested that use of rituximab was associated with significant clinical benefit. Monocytopenia in this study and depletion of B cells in theirs, would suggest that excesses or abnormalities in antigen presentation might be a key underlying mechanism in CFS.
This study has several limitations including the small sample size and testing of numerous exploratory hypotheses. However, the randomized, double‐blind, placebo‐controlled, study design permits that these findings be worthy of further exploration. A limitation, against a stronger VGCV benefit, was that three patients in the placebo arm had detectable ganciclovir levels. Upon thorough and careful questioning, these patients reported no usage of VGCV or ganciclovir outside the study setting.
Findings in this study suggest that clinical trials using longer courses of VGCV and a larger sample size are warranted. They also suggest that outcomes be analyzed by MEL regression models (or similar methods) and that MFI‐20 scores/subscores and the FSS score be used among clinical endpoints. Results in this study also support the view that CFS is a real disease that necessitates sound translational research and that can be amenable to medical interventions.
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