Chronic fatigue syndrome (CFS) is a debilitating chronic illness [Fukuda et al., 1994] that often begins suddenly with a “flu-like” illness. Patients with CFS have great functional impairment [Komaroff et al., 1996]. The cost to the U.S. economy from lost productivity alone (not including medical care costs) is $9 billion annually [Reynolds et al., 2004].
While the pathogenesis of CFS is unknown, there is abundant evidence of an underlying biological process. In comparison to various health and disease control groups, patients with CFS have abnormal findings in the CNS and autonomic nervous system, evidence of chronic activation of various parts of the immune system, and disordered energy metabolism.
CNS abnormalities have been found using MRI [Buchwald et al., 1992; Schwartz et al., 1994a; Lange et al., 2001; de Lange et al., 2005], functional MRI [Tanaka et al., 2006], SPECT [Schwartz et al., 1994b; Schmaling et al., 2003], and positron-emission tomography (PET) [Yamamoto et al., 2004]. Neuroendocrine studies reveal hypofunction of corticotropin releasing hormone (CRH) neurons in the hypothalamus [Demitrack et al., 1991], disruption of both serotonergic and noradrenergic hypothalamic pathways [Demitrack et al., 1992; Cleare et al., 1995], and of growth hormone secretion [Moorkens et al., 2000]. Typically, these abnormalities are in patterns opposite to those seen in major depression. Cognitive testing has revealed abnormalities [Tiersky et al., 1997; Daly et al., 2001; Deluca et al., 2004] that are not explained by concomitant mood disorders [Marcel et al., 1996]. Autonomic nervous system testing has found abnormalities—particularly postural orthostatic tachycardia syndrome, neurally mediated hypotension, and heart rate variability during head-up tilt testing [Bou-Holaigah et al., 1995; Freeman and Komaroff, 1997; Stewart, 2000; Naschitz et al., 2002].
The immunological findings described most commonly in CFS are impaired function of natural killer cells, increased numbers of CD8+ cytotoxic T cells that bear antigenic markers of activation on their cell surface, and increased production of various pro-inflammatory and TH2 cytokines [Komaroff, 2006]. Many of these cytokines can produce symptoms characteristic of CFS: fatigue, fevers, adenopathy, myalgias, arthralgias, sleep disorders, cognitive impairment, and mood disorders.
Many recent studies of patients with CFS have identified disorders of energy metabolism [Myhill et al., 2009], increased allostatic load [Maloney et al., 2009], and increased oxidative and nitrosative stress [Maes and Leunis, 2008].
Cases of CFS can follow in the wake of well-documented infection with several infectious agents, and may be more likely when the symptoms of acute infection were most severe [Hickie et al., 2006]. The first large study on the possible role of HHV-6 in CFS included 259 patients with a “CFS-like” illness (the case definition had not yet been developed) and age- and gender-matched healthy control subjects. Primary culture of lymphocytes showed active replication of HHV-6 in 70% of the patients versus 20% of the control subjects (P < 10 −8) [Buchwald et al., 1992].
Some subsequent studies have employed only serological techniques that do not distinguish active from latent infection. The results have been mixed: a slight preponderance has showed an association between CFS and HHV-6 infection [Ablashi et al., 2000; Reeves et al., 2000; Hickie et al., 2006].
In contrast, other studies have employed assays that can detect active infection: PCR of serum or plasma, IgM early antigen antibodies, and primary cell culture. Most of these studies have shown an association between CFS and active HHV-6 infection [Patnaik et al., 1995; Secchiero et al., 1995; Wagner et al., 1996; Zorzenon et al., 1996; Ablashi et al., 2000; Nicolson et al., 2003], whereas a few have not [Koelle et al., 2002; Reeves et al., 2000]. The number of patients in the studies that have found an association between CFS and active HHV-6 infection (N = 717) is much larger than the number in studies that have failed to find an association (N = 48).
Several observations, summarized above, together suggest that active infection with HHV-6 may cause some cases of CFS. First, active infection with HHV-6 is present in a substantial fraction of patients with CFS. Second, HHV-6 is tropic for the nervous system and immune system cells, and CFS is characterized by neurological and immunological abnormalities. Clinical studies with antiviral drugs that have in vitro activity against HHV-6 could provide strong evidence in favor of, or against, the hypothesis that HHV-6 may trigger and perpetuate some cases of CFS.
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Source: Yao K, Crawford JR, Komaroff AL, Ablashi DV, Jacobson S. Review part 2: Human herpesvirus-6 in central nervous system diseases.J Med Virol. 2010 Oct;82(10):1669-78. doi: 10.1002/jmv.21861. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758195/ (Full article)