HHV-6 Overview

HHV-6 in CFS

Is human herpesvirus-6 a trigger for chronic fatigue syndrome?

By Anthony L. Komaroff

Division of General Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School

*Note this article has been reproduced from it’s original publication in The Journal of Clinical Virology, Dec. 2006 with the permission of the author and publisher.

Chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a debilitating chronic illness of uncertain cause. The case definition of the illness, developed by the Centers for Disease Control (CDC), is summarized in Table 1 (Fukuda et al., 1994). The CDC case definition relies entirely on a combination of symptoms (not laboratory data), and on the exclusion of chronic active organic or psychiatric illnesses that can produce chronic fatigue. CFS occurs in men and women, in all age groups and in all ethnic, racial and socioeconomic groups (Buchwald et al., 1995; Jason et al., 1995; Dobbins et al., 1997; Steele et al., 1998; Jason et al., 1999; Reyes et al., 2003; Bierl et al., 2004; Jones et al., 2004).

The chronic illness often begins suddenly with a "flu-like" illness, although community-based surveys indicate that most cases have a more gradual onset (Reyes et al., 2003). Patients with CFS have markedly impaired functional status – similar to or worse than several major chronic illnesses, such as congestive heart failure, diabetes mellitus, and major depression (Komaroff et al., 1996; Buchwald et al., 1996; Hardt et al., 2001b; Hardt et al., 2001a; Solomon et al., 2003). In the community at large, independent of whether subjects have sought medical attention for the illness, between 1 and 8 in 1000 U.S. adults meet the CDC criteria for the syndrome (Reyes et al., 2003). The CDC estimates that 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 CFS. That is, the preponderance of published evidence finds that—in contrast to patients with depression, various fatiguing organic illnesses and healthy control subjects — patients with CFS have abnormal findings in the central and autonomic nervous systems, and evidence of chronic activation of various parts of the immune system.1.1. Neurologic studies in CFS

MRI studies. The majority of published imaging studies find specific abnormalities of the central nervous system more often in patients with CFS than in various disease and health control group subjects. Two magnetic resonance imaging (MRI) studies have found reduced grey matter volume in CFS (Okada et al., 2004; de Lange et al., 2005), and enlarged ventricular volumes (Lange et al., 2001). Many MRI studies have reported areas of high signal on T2-weighted images (Buchwald et al., 1992; Schwartz et al., 1994a; Natelson et al., 1993; Cook et al., 2001). Typically, these are small, punctate areas located in the subcortical white matter, and not periventricular plaques such as are typical of multiple sclerosis (MS). However, in some patients larger plaque-like areas are seen. Functional MRI has revealed characteristic abnormalities, as well (Tanaka et al., 2006).

Since brain tissue has only rarely been obtained from patients with CFS, the pathologic implications of the MRI findings are uncertain, but most likely represent inflammation and/or demyelination. In summary, patients with CFS and with MS share the symptom of profound fatigue, cognitive difficulties (particularly slowed processing speed), as well as white matter abnormalities and enlarged ventricular volume (Lange et al., 2001). A few patients with classic CFS (characterized by respiratory symptoms, fevers, adenopathy) for many years have subsequently developed full-blown MS (unpublished data from our clinical practice). Thus, there is a suggestion that — in at least some patients — CFS and MS may share a common etiologic agent.

SPECT and PET studies. Single-photon emission computed tomography (Ichise et al., 1992; Schwartz et al., 1994b; Schwartz et al., 1994a; Schmaling et al., 2003) and positron-emission tomography (Yamamoto et al., 2004) also have revealed abnormalities that could represent either hypoperfusion in the microcirculation and/or metabolic dysfunction of neuronal and glial cells.

Hypothalamic functional testing. Hypothalamic function is abnormal in many patients with CFS. There is hypofunction of CRH neurons in the hypothalamus (Demitrack et al., 1991), with evidence of a subtle hypocortisolism that is not in the Addisonian range (Dinan et al., 1997; Scott et al., 1998; Scott and Dinan, 1998; Scott et al., 1999; Cleare et al., 2001). This abnormality of the HPA axis is the opposite of what is seen in patients suffering from major depression. There also is disruption of both serotonergic and noradrenergic hypothalamic pathways (Demitrack et al., 1992; Bakheit et al., 1992; Cleare et al., 1995), and of growth hormone secretion (Mookens et al., 2000). Typically, these abnormalities are in patterns opposite to those seen in depression. Such hypothalamic dysfunction theoretically could produce many of the symptoms of CFS.

Hypothalamic dysfunction also can be caused by cytokines produced in response to a chronic infection of the central nervous system. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are associated with fatigue (Patarca, 2001; Gupta et al., 1999; Gupta et al., 1997) and with altered circadian production of cortisol and increased daytime sleepiness (Vgontzas et al., 2002). They also are associated with fatigue in patients with metastatic colorectal cancer (Rich et al., 2005).

Cognitive testing. Formal testing of cognition has, in most studies, revealed abnormalities in patients with CFS (Johnson et al., 1994; Krupp et al., 1994; Marcel et al., 1996; Tiersky et al., 1997; Daly et al., 2001; DeLuca et al., 2004; Naschitz et al., 2004). Patients with CFS often have abnormalities of information processing efficiency, memory and/or attention during timed tasks (Sandman et al., 1993; McDonald et al., 1993; DeLuca et al., 1993; Schmaling et al., 1994; DeLuca et al., 1995; Marcel et al., 1996; DeLuca et al., 1997; Michiels et al., 1998; Daly et al., 2001). While mood disorders alone can cause cognitive impairment, carefully controlled studies have not found that the cognitive impairment is explained by a coexisting depression (Marcel et al., 1996).

Abnormalities of autonomic nervous system function. The majority of studies of the autonomic nervous system find abnormalities of both sympathetic and parasympathetic function (Sisto et al., 1995; Bou-Holaigah et al., 1995; Freeman and Komaroff, 1997; Stewart et al., 1999; Stewart, 2000; Naschitz et al., 2001; Naschitz et al., 2002; Peckerman et al., 2002; Jones et al., 2005). The most frequently observed abnormalities are postural orthostatic tachycardia syndrome, neurally-mediated hypotension, and heart rate variability during head-up tilt testing.

Electroencephalographic studies. Several groups have reported motor cortex excitability in chronic fatigue syndrome (Gordon et al., 1999; Sacco et al., 1999; Starr et al., 2000). Our group used quantified electroencephalography (also called BEAM testing) to compare the brain waves of 57 patients with CFS to those of 50 with depression and 83 healthy controls. Spike waves and sharp waves were seen much more often in patients with CFS than in the two comparison groups (data not submitted for publication). Thus, the patients with CFS had electroencephalographic findings that were similar to, but milder than, that seen in seizure disorders.

Psychiatric studies. Since common psychiatric disorders — particularly depression — often cause fatigue, the role of psychiatric illness in CFS has been debated. Most studies find that patients with CFS often suffer from co-existing psychiatric disorders. However, most studies also find that in 30-50% of patients with CFS there is no co-existing psychiatric disorder, and that the great majority of those with a psychiatric disorder developed the disorder only after becoming ill with CFS (Taerk et al., 1987; Kruesi et al., 1989; Wessely and Powell, 1989; Hickie et al., 1990; Gold et al., 1990). Moreover, a careful controlled trial of fluoxetine (ProzacÒ) in patients with CFS failed to demonstrate an improvement in their fatigue, even in those with a concomitant major depression (Vercoulen et al., 1996).

1.2. Immunologic studies in CFS

The most commonly-reported immunologic findings involve impaired function of natural killer cells (Caligiuri et al., 1987; Aoki et al., 1987; Kibler et al., 1985; Klimas et al., 1990; Whiteside and Herberman, 1989), increased numbers of CD8+ cytotoxic T cells that bear antigenic markers of activation on their cell surface (Landay et al., 1991), and increased production of various pro-inflammatory cytokines (Patarca et al., 1994; Cannon et al., 1997; Swanink et al., 1996; Bennett et al., 1997; Cannon et al., 1999; Gupta et al., 1999; Patarca, 2001; Gupta et al., 1997) and type 2 cytokine-producing cells (Skowera et al., 2004). Many of these cytokines can produce symptoms characteristic of CFS: fatigue, fevers, adenopathy, myalgias, arthralgias, sleep disorders, cognitive impairment, and mood disorders. Two studies have reported increased production of IL-6 by peripheral mononuclear cells in patients with CFS (Gupta et al., 1999; Gupta et al., 1997). Studies of the 2-5A synthetase/RNase L enzymatic pathway in lymphocytes pathway (the “2-5A pathway”), which is induced by viral infection, find that this pathway is activated in CFS, and that a characteristic low molecular weight form of RNase L is often present (Suhadolnik et al., 1994; Suhadolnik et al., 1997; DeMeirleir et al., 2000).

1.3 The role of infection in CFS

The sudden onset of CFS in some patients with an "infectious-like" illness, the nature of some of the symptoms, and the state of chronic immune activation, have made plausible the possibility that the illness can be triggered and perpetuated by an infectious agent, at least in some patients with CFS. No single infectious agent has been identified as the cause of CFS, but CFS has been described following in the wake of a variety of acute infections (Benjamin and Hoyt, 1945; Imboden et al., 1961; Lawton et al., 1970; Leventhal et al., 1991; Rosene et al., 1982; Cluff et al., 1959; Imboden et al., 1959; Salit, 1985). Fatigue states following infection with Epstein-Barr virus (EBV) have been described (Komaroff, 1987; Straus, 1988; Isaacs, 1948). Fatigue states following acute infectious mononucleosis, an illness typically caused by EBV, also have recently been well documented (Bryant and Norman, 1980; White et al., 1995; White et al., 1998; Katon et al., 1999; White et al., 2001). A condition very similar to CFS has been described following Q fever (Ayres et al., 1996; Marmion et al., 1996; Wildman et al., 2002). CFS also has been found in patients with proven Lyme disease who have received adequate antibacterial treatment, and in whom the cardinal manifestations of Lyme disease (e.g., arthritis, carditis) have resolved (Coyle and Krupp, 1990). Most investigators have reported enteroviral involvement in CFS (Cunningham et al., 1990; Gow et al., 1991; Bowles et al., 1993; Clements et al., 1995; Richardson, 1995; Soteriou et al., 1996; Gow et al., 1996), but others have not (Swanink et al., 1994; Lindh et al., 1996). Finally, a number of studies suggest that parvovirus infection can produce CFS (Kerr et al., 1996; Kerr et al., 2001; Matano et al., 2003).

A meticulously-conducted recent prospective observational study recently has confirmed the existence of a post-infectious fatigue syndrome, and provided clues as to its etiology. Hickie and colleagues identified all cases of acute infection with Epstein-Barr virus (a DNA virus), Ross River virus (an RNA virus), and Coxiella burnetii (the intracellular bacterium that causes Q fever) in one township in rural Australia (Hickie et al., 2006). The study involved 253 patients, and found that post-infectious fatigue syndrome was present in 12% of the patients six months after their acute infection. Virtually all the patients met the CDC criteria for CFS. The syndrome had a stereotyped progression and regression of symptoms, regardless of the infectious agent. It was more likely to occur in patients with more severe acute infectious symptoms, but was not predicted by pre-morbid psychological or demographic factors.

Finally, the possibility that infectious agents might trigger and perpetuate symptoms of CFS is suggested by several different gene expression studies using microarray technology. These studies — from different laboratories, studying different groups of patients — all find gene expression changes consistent with a state of chronic activation of the immune system (Vernon et al., 2002; Powell et al., 2003; Steinau et al., 2004; Kaushik et al., 2005; Vernon et al., 2006a). Gene expression studies also find mitochondrial dysfunction in cases of post-infectious fatigue caused by Epstein-Barr virus (Vernon et al., 2006b).

2. Human herpesvirus-6 in chronic fatigue syndrome

2.1 Diseases Associated with HHV-6

When it was discovered in 1986, human herpesvirus-6 (HHV-6) was a virus without a clear disease association. As reported in other publications in this issue, and in recent reviews (Krueger and Ablashi, 2003; Zerr, 2006), there are now a number of illnesses that have been associated with HHV-6, including several neurological illnesses in immunocompetent as well as immunocompromised subjects. In particular, HHV-6 may play an etiologic role in some cases of encephalitis in immunosuppressed patients (Zerr et al., 2005) and immunocompetent patients (Isaacson et al., 2005), multiple sclerosis (Challoner et al., 1995; Soldan et al., 1997; Ablashi et al., 2000) and seizure disorders (Enoki et al., 2006). In post-transplant patients, HHV-6 in the CNS causes cognitive dysfunction and fatigue that is similar to that reported by patients with CFS (Zerr et al., 2005).

HHV-6 could produce neurologic symptoms in several ways. First, infection of microglial cells in the CNS by this gliotropic virus could stimulate the production of cytokines that then cause fatigue and other symptoms. HHV-6 is a potent inducer of TNF-α and IL-1B (Flamand et al., 1991), and possibly IL-6 (Enoki et al., 2006; Krueger et al., 1994; Arena et al., 1996; Go and Nakamura, 2002). Second, HHV-6-infected peripheral dendritic cells might traverse the blood-brain barrier, leading to the production of inflammatory cytokines in the CNS. Third, peripherally produced cytokines might traverse the blood-brain barrier to produce alterations in neurochemistry.

2.2 Association of Active HHV-6 Infection with CFS

Because it causes life-long, ineradicable infection, and because of its broad tissue tropism, it has been reasonable to speculate that HHV-6 might be a trigger and perpetuating factor for CFS. The similarities between CFS and several neurologic illnesses that have been associated with HHV-6 have reinforced that speculation.

The first large study of this hypothesis 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 vs. 20% of the control subjects (P< 10-8) (Buchwald et al., 1992). Another paper also involving primary culture of lymphocytes have produced mixed results (Zorzenon et al., 1996). Studies employing only serological techniques that could not distinguish active from latent infection have been mixed (Koelle et al., 2001; Ablashi et al., 2000; Naschitz et al., 2006; Reeves et al., 2001; Wallace et al., 1999; Wilborn et al., 1994; Yalcin et al., 1994; Hickie et al., 2006; Gupta and Vayuvegula, 1991), with a slight preponderance showing an association between CFS and HHV-6 infection.

On the other hand, other studies have employed assays that can detect active infection: PCR of serum or plasma, IgM early antigen antibodies, and primary cell culture. The clear majority of these studies have shown an association between CFS and active HHV-6 infection (Buchwald et al., 1992; Josephs et al., 1991; Secchiero et al., 1995; Zorzenon et al., 1996; Patnaik et al., 1995; Wagner et al., 1996; Ablashi et al., 2000; Nicolson et al., 2003; Koelle et al., 2001) whereas a much smaller number of studies have failed to find such an association (Reeves et al., 2001; Koelle et al., 2001). Moreover, the number of patients in the studies that have found an association between CFS and active HHV-6 infection (717) is much larger than the number in studies that have failed to find an association (48).

Several treatment studies provide indirect evidence that HHV-6 may play an etiologic role in CFS. The therapeutic agent Poly(I).poly(C12U) (AmpligenÒ) has in vitro efficacy against HHV-6 (Ablashi et al., 1994) and has improved both symptoms and functional capacity in a randomized, controlled trial (Strayer et al., 1994). Elsewhere in this issue, Montoya reports a small open-label study of valganciclovir in patients with CFS and evidence of active HHV-6 or EBV infection, demonstrating an impressive reduction in both viral load and symptoms. (A five week trial of acyclovir showed no efficacy in CFS (Straus et al., 1988), but acyclovir has little in vitro activity against HHV-6.)

3. Concluding remarks

The hypothesis that active infection with HHV-6 may cause some cases of CFS rests on several general observations. First, the great preponderance of the evidence indicates that patients with CFS have abnormalities of the central and autonomic nervous systems, and a state of chronic immune activation. Second, there is also considerable evidence that active infection with HHV-6 is present in a substantial fraction of patients with CFS. Third, the tissue tropism of HHV-6 makes it one plausible candidate (among several) to produce an illness characterized by neurological and immunological abnormalities. Fourth, the association of HHV-6 infection with encephalitis, multiple sclerosis and seizure disorders — each of which has clinical features that overlap with those of CFS—is consistent with the hypothesis. Clinical studies with antiviral drugs that have in vitro activity against HHV-6 could provide strong evidence in favor of, or against, this hypothesis. If controlled studies demonstrate that such drugs simultaneously eradicate active HHV-6 infection in vivo, and improve the symptoms of CFS, an etiologic role for the virus in some patients with this illness would be strongly suggested.