a role for herpes simplex virus in the aetiology of chronic fatigue syndrome and related disorders

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r Medical Hypotheses mid rrypDthaa (1993) 40,3ol-3ca 0 LongmanGroup UK Ltd 1953 A Role for Herpes Simplex Virus in the Aetiology of Chronic Fatigue Syndrome and Related Disorders P. A. BOND 737 Sheerstock, Haddenham, Aylesbury, Bucks HP17 8EY, UK Introduction 1. Immnne dysfunction. Chronic fatigue syndrome (CFS) is one of the most recent and widely accepted names for a condition which has caused much controversy over recent years. Efforts to define CFS, at least for research purposes, have produced reports which should be useful guides to future work (1.2). Bxplanations of CFS have been very varied, from its being due to mass hysteria (3). disuse atrophy (4), a formof depression (5), hyperven- tilation (6). an enterovirus (7). Epstein Barr virus (8). human herpes virus-6 (HHV-6) (9). to a recently de- scribed retrovhus (10). The confusion could be all the greater because Cl% may be part of a spectrum of disorder, sharing a common aetiology and with no clear boundaries. The hypothesis, which I shall put forward, shows how a single agent could account for the major symp- toms of CFS and a group of mlated disorders. I shall also attempt to show that other explanations are either less tenable, or am compatible with the present hypo- thesis. 2. Primsry infection or reactivation of herpes viruses, especially herpes simplex virus (HSV). To illustrate how this may operate, I will draw an analogy with AIDS, The primary event in AIDS is infection with HIV, which then leads to impabment of immunity due to the specific loss of T cells bearing tbe CD4 madcer. As a secondary consequence, the patient becomes susceptible to certain tumours and a variety of infections. It is these sequelae that result in the symptoms. Unlike AIDS, there is no one agent that brings about the immune dysfunction in CFS. It could result from infection with a retrovirus (lo), herpes viruses, such as EBV, parasites, such as Toxopkw~ gondii or it may be the direct result of stress. ‘Ihe symptoms of CFS, on the other hand, I suggest am mainly caused by primary infection with, or reactiva- tion of a single agent - this being HSV. The immune system in CFS Hypothesis It is suggested that the development of CFS occurs in two maiu stages: A variety of abnormalities of the immune system have been reported in CF’S. These include impaired func- tion of T lymphocytes (11). deficiencies in natural killer cells (12,13), T lymphocytes (14,15) and vari- Date received 10 September 1992 Date accepted 16 October 1992 301

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Page 1: A role for herpes simplex virus in the aetiology of chronic fatigue syndrome and related disorders

r Medical Hypotheses mid rrypDthaa (1993) 40,3ol-3ca 0 LongmanGroup UK Ltd 1953

A Role for Herpes Simplex Virus in the Aetiology of Chronic Fatigue Syndrome and Related Disorders

P. A. BOND

737 Sheerstock, Haddenham, Aylesbury, Bucks HP17 8EY, UK

Introduction 1. Immnne dysfunction.

Chronic fatigue syndrome (CFS) is one of the most recent and widely accepted names for a condition which has caused much controversy over recent years. Efforts to define CFS, at least for research purposes, have produced reports which should be useful guides to future work (1.2). Bxplanations of CFS have been very varied, from its being due to mass hysteria (3). disuse atrophy (4), a form of depression (5), hyperven- tilation (6). an enterovirus (7). Epstein Barr virus (8). human herpes virus-6 (HHV-6) (9). to a recently de- scribed retrovhus (10).

The confusion could be all the greater because Cl% may be part of a spectrum of disorder, sharing a common aetiology and with no clear boundaries.

The hypothesis, which I shall put forward, shows how a single agent could account for the major symp- toms of CFS and a group of mlated disorders. I shall also attempt to show that other explanations are either less tenable, or am compatible with the present hypo- thesis.

2. Primsry infection or reactivation of herpes viruses, especially herpes simplex virus (HSV).

To illustrate how this may operate, I will draw an analogy with AIDS, The primary event in AIDS is infection with HIV, which then leads to impabment of immunity due to the specific loss of T cells bearing tbe CD4 madcer. As a secondary consequence, the patient becomes susceptible to certain tumours and a variety of infections. It is these sequelae that result in the symptoms. Unlike AIDS, there is no one agent that brings about the immune dysfunction in CFS. It could result from infection with a retrovirus (lo), herpes viruses, such as EBV, parasites, such as Toxopkw~ gondii or it may be the direct result of stress. ‘Ihe symptoms of CFS, on the other hand, I suggest am mainly caused by primary infection with, or reactiva- tion of a single agent - this being HSV.

The immune system in CFS

Hypothesis

It is suggested that the development of CFS occurs in two maiu stages:

A variety of abnormalities of the immune system have been reported in CF’S. These include impaired func- tion of T lymphocytes (11). deficiencies in natural killer cells (12,13), T lymphocytes (14,15) and vari-

Date received 10 September 1992 Date accepted 16 October 1992 301

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ous T cell subsets (13, 15). all pointing to an abnor- mality in cell-mediated immunity. However, because of the criteria laid down for the diagnosis of CFS (e.g. 1,2), such changes are those which are still present 6 months or mom after the onset of the condition. The critical period, during which I suggest that the primary infection or reactivation of HSV occurs, will be much earlier, probably during the first few days of illness or even before symptoms appear. The events which allow HSV to infect or reactivate, may only be transi- tory. In mice just such a transient immunosuppression occurs following infection with HSV and this allows previously resistant animals to become infected with Coxsackie virus (16). The changes wrought by vimses may also be very subtle (17), such as the reciprocal interaction between cytomegalovirus and human im- munodeficiency virus (HIV), where infection of a cell with one facilitates the entry into that cell of the other (18) and the activation of HIV by HSV-1 (19) or cytomegalovirus (20), which appears to involve only the genes.

Most of the herpes viruses, including HSV, are able to cause changes in the immune system similar to those reported in CFS (21. 22), so that, after 6 months of illness, these may be the only detectable signs of abnormality.

MED1cALHYPoTliEsEs

there could well be production of interferon. Alternatively, interferon itself could cause the reac-

tivation of HSV. It was found that, when patients undergoing microvascular decompression for trigemi- nal neuralgia were given interferon before the surgery, significantly more (9 1%) experienced reactivation of HSV than in the placebo group (57%) (30). This paradoxical reactivation of HSV by interferon could account for its central side effects and the variety of infections, all having in common the ability to provoke the production of interferon, which can precede CFS. Interferon could also be involved in the maintenance of persistent infection by HSV, such as that reported in mouse macrophages (3 1).

primary genital herpes infection does not result ex- clusively in local symptoms. Acute systemic effects are often observed, which include headache, malaise and myalgias (32.33). Interestingly these occur with greater frequency in females than males, as is the case in most studies of CFS.

CFS patients exhibit a variety of other symptoms (l), often transient and of varying frequency. Apart from eliciting interferon production in the brain, HSV could cause symptoms in other ways. Infection of neuroglial cells does not always occur without dam- age, it can, in mice, result in substantial destruction (34). Such destructive infection could lead to the anaestbesia and paraesthesia sometimes reported in CFS (35). The activity of HSV is often considered to be confined to the nervous system, but them is evi- dence that extraneural sites of infection can exist in both animals (36) and man (37). The majority of people were found to harbour the virus in the tissue around the teeth (37). Such extraneural sites could reflect routes by which virus is shed other than through cold sores. Asymptomatic shedding in fact seems to be amore frequent occurrence than herpes labialis (38) or genital herpes (39). Symptoms could arise from the hnmune response to virus in these surface tissues. Nasal, oral, gastrointestinal and ocular tissues could be so affected.

The symptoms of CFS

The symptoms of CFS are many and varied but only a few of these am almost invariably seen. By definition, fatigue must be present, but impaired memory and concentration ate consistently found. Interferon, used to treat malignancy or virus infection, frequently causes ‘psychiatric’ symptoms. These, which include fatigue, loss of interest, lack of concentration, anxiety and depression (23). are strikingly similar to the ‘core’ symptoms of CFS. During the use of interferon to treat hepatitis B infection, it was noted that the ‘psychiatric’ symptoms occurred mainly in the 40% of patients who were HIV positive. The authors questioned whether a virus needed to be present in the CNS for the effects of interferon to occur. HSV could act in just such a way to cause the ‘core’ symptoms of CFS, as it is known to be a good inducer of interferon (24) and seems to reach the brains of animals and man with facility (25,26). In the brain, it is able to spread via neurons (27) or at a very slow pace (1 mm per day) in the neuroglial cells (28), for which HSV seems to have an affinity (29). The passage of HSV along the neu- roglial cells adjoining the rabbit optic nerve (28), is associated with a small area of Wammation where

HSV infection

HSV exists as two serotypes, designated 1 and 2. The majority of mankind is infected, though the frequency is influenced by geographic location, age and so- cioeconomic status. In developing countries serocon- version occurs early in life (40), while amongst American university students only 30% may possess neutralising antibodies (41). This suggests that, al- though most people are continuously exposed to HSV,

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HERPES SJhWLEX VIRUS IN THE AF!TlOLoGY OF CT’S

it is possible to resist the infection for many years. Primary infection seems to occur at an increasingly advanced age in industrialised societies and a potential host may need to be immunocompromised for this to happen. Stress, either physical or mental is known to cause both reactivation of HSV and relapse in CFS. Stress, such as that experienced by medical students at examination times, has been shown to cause reduc- tions in IgA concentrations and alteration in lympho- cyte subpopulations (42). as well as increased herpes virus antibody titres (43). Not only were antibodies to HSV elevated, but also those to EBV and cytomega- lovirus and perhaps to other herpes viruses had they beensought

HSV is able to remain iu the body for a lifetime. Reactivation may occur in response to a variety of stimuli (44), which are strikingly similar to those which cause relapse in CFS (45).

CFS could result when primary infection with HSV occurs later in life, as it does increasingly in indus- trialised societies. Individuals could be especially sus- ceptible when living in close proximity in institutions and at times of stress.

303

CFS, HSV and the brain

The question as to whether the symptoms of CFS are of central or peripheral origin is still unresolved. However, significant changes in mean latencies of the cognitive potential and reaction time have been re- ported in a group of 37 patients (46). Application of non-invasive brain imaging techniques (47, 48) and neuropsychological testing (49). all point to a deficit in the temporal lobe in the majority of CFS patients. However, more studies are required, especially of the normal population, before such methods cau be ap- plied diagnostically.

In human HSV encephalitis the most common site involved is the temporal lobe (50). By transneuronal transfer, HSV can pass from peripheral nerves to cor- tex and brainstem and it can also replicate in the recipient neurons (27). HSV- 1 nucleic acid sequences have been detected in the brains of apparently healthy mice, innoculated 24 weeks previously with the virus (25). They were also found in the brains of elderly patients who had died with psychiatric illness (25). a patient with psychotic depression (51) as well as the majority of normal subjects (26). In a minority of cases of multiple sclerosis, evidence of HSV-2 infec- tion has been found (52), which involved mainly glial cell nuclei within or near lesions that were selectively demyelinated.

It seems that HSV can reach the brains of animals and mau, via the neurons, with facility. Once there, it can move slowly in the neuroglial cells, either causing no apparent damage (28) or extensive destruction (34).

A spectrum of disease caused by HSV?

The diagnosis of CFS has proved controversial and it was not until recently that a concerted attempt was made to produce a concensus definition which would put research into this condition on a sounder footing (1). This diagnostic procedure sets out two major and eleven minor criteria, the second major criterion being a long list of exclusions, the most significant of these being ‘chronic psychiatric disease, either newly diag- nosed or by history’. The effect of this is to eliminate the great majority of patients presenting with chronic fatigue and where comparison was made between the 19% who satisfied the criteria and those that did not, no difference was found (53).

Most studies agree that psychiatric symptoms occur in the majority of CES patients. Major depression is the commonest, being found in about half the patients. A study which compared patients with unexplained chronic ‘postviral’ fatigue with those with fatiguing neuromuscular diseases and inpatients with major de- pression, found that 72% of the CFS patients were cases of psychiatric disorder, compared with 36% in the neuromuscular group (5). There was difficulty in distinguishing CFS and affective patients. Kendell (54) points out that when patients with chronic fatigue are assessed psychiatrically, 50-80% fulfil the criteria for psychiatric disorder. Most have major depression, while others have anxiety or somatisation disorders. He argues that many, perhaps the majority of patients, diagnosed as CFS, are suffering from depression or other psychiatric illness. Several studies have found a link between HSV and depressive illness, but of par- ticular interest was the demonstration that the in- cidence and antibody titres to HSV were significantly higher in psychotic depression compared to controls. Furthe~ore. the cell-mediated immunity to HSV in psychotic depression was similar to that observed after acute HSV infection or recurrence (55).

Fibromyalgia is a form of non-articular rheumatism, characterised by diffuse myalgias and arthralgias ac- companied by exaggerated tenderness at specific areas. It shares many features with CFS (56,57) and some have suggested that they am indeed the same condition. Neuropsychiauic symptoms, especially depression are common in both, while similar cogni- tive changes are described by patients. Similar immu-

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304 MED1cAL.HYPoTHEsPs

nological abnormalities have been described, of spe- cial interest being reports of decreased levels and functional activity of natural killer cells in the two syndromes (12,13,58).

Irritable bowel syndrome (IBS) is the commonest gastrointestinal disorder encountered by primary care physicians and gastroenterologists. Despite this high prevalence, in common with CPS, there is incomplete agreement on its definition and its status as a valid diagnostic entity. In CPS, patients report numerous symptoms other than fatigue and in IBS those other than gastrointestinal are frequent. Many of these are also common in mood and anxiety disorders and in- clude: weakness, fatigue, palpitation, nervousness, dizziness, headache, hand tremor, back pain, sleep disturbance and symptoms of sexual dysfunction (59). Irritable bowel patients are generally more psycho- logically disturbed than the general population, the most frequent symptoms being anxiety, depression, hysteria and somatoform disorder (60).

Cluster headache shares with CPS the distinction of having a large number of names, which in itself usually indicates some confusion over definition. It has been suggested that cluster headaches may be associated with HSV infection. Initially, an association was noted between herpes labialis and the headaches (61), subsequently a case was described in which herpes labialis preceded attacks by about a week (62). In this patient, following acyclovir in doses insufficient to affect herpes viruses such as cytomegalorivus, EBV and human herpes virus-6, the headaches ceased with- in two days of medication. Patients with cluster hea- dache were also found to have lower natural killer cell function (63) and when a division was made into those with and without a recent history of clinical HSV infection, the HSV group were even lower. Similar deficits in natural killer cell number and function have also been reported in CPS and fibromyalgia (12, 13, 58) and these cells are of central importance in the containment of viral infections, especially those of the herpes group.

Idiopathic chronic headaches are commonly classi- fied as migraine or muscle contraction headaches. However, it has been suggested that these represent a continuum, rather than distinct clinical entities (64). New daily persistent headaches occur mainly in young adults with no known headache precipitant& such as trauma or psychological stress. In a group of patients with new daily persistent headache, 84% had evidence of active Epstein Barr virus (EBV) infection, com- pared to 25% of controls. All the patients had symp- toms other than headache. These included fatigue, depression,nausea,paraesthesias,deficientconcentra-

tion, tinnitus and defective vision. In only 4 out of 3 1 patients was fatigue not listed as a symptom, while almost all the other symptoms are those commonly described in CFS (65). In view of the fact that herpes viruses can be reactivated under similar conditions (43). and that only EBV was sought, it seems likely that HSV would be reactivated in many of these pa- tients.

Discussion

The present theory suggests that CPS arises in two stages:

1. Immunosuppression which can result from a variety of causes.

2. Primary infection or reactivation of HSV, resulting in the symptoms.

CPS is known to follow a variety of acute infections due to protozoa, bacteria and viruses, though in no study has one infectious agent been implicated in all cases. Interferon has been reported to cause paradox- ical reactivation of HSV (30), so that any symptoms stemming from an infection which elicits interferon production could in fact be due to HSV. Many viruses are also able to cause immunosuppression (21) and could therefore participate in the early stages of CPS. The retrovirus recently described in CPS patients (lo), could play a part via either or both of these mechan- isms. Later on, once HSV has established a primary infection or reactivated, its ability to cause transient immunosuppression could result in infection by Cox- sackie viruses (18). An aetiological role has been proposed for these viruses in CFS (7) and enteroviral RNA can persist in muscle (66). It is therefore possible that some of the symptoms of CPS, especially muscular, could be caused by Coxsackie viruses.

Several of the herpes viruses, especially EBV (8) and HHV-6 (9), have been suggested as aetiological agents in CPS, but it seems likely that the many aspects of their behaviour which run parallel to those of HSV, have led to confusion. It has been found that, while antibodies to EBV are indeed raised in CPS patients, those to other viruses, including HSV, am similarly elevated (43).

An important part of the argument against a viral cause for CPS rests on the dearth of physical signs and histopathological changes. However, it is becoming increasingly clearthatmany viruses, without inducing cytopathology, are able to profoundly change the me-

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HERPES SlMPLFZX VIRUS IN THE AETIOLOGY OF CFS 305

tabolism of the affected cell (17). This can involve disruption in the production of lymphokines, neuro- transmitters and other hormones. Herpes, influenza and measles viruses are prominent in this area.

Another explanation of CFS is that it is a manifesta- tion of mass hysteria (3). This explanation founders on the fact that epidemic and sporadic cases of CFS usually occur together. For example, between April and November 1955, 8 cases of ‘encephalomyelitis simulating poliomyelitis’ were referred to the infec- tious diseases department of the Royal Free Hospital (67). None of the patients had been in contact with each other. Between July and November, 292 mem- bers of staff at the Royal Free Hospital were affected by a similar illness (35). Also, the first plank in the argumeut of McEvedy and Beard (3) was that the condition was more common in females than males. They used figtries from the staff report of the Royal Free outbreak (35) as support, whilst ignoring the fact that the highest strike rate of 20% was amongst mules iu residence. The whole picture was distorted by there being 840 females in residence to only 20 males, Such figures would support the idea of an infectious agent, rather than mass hysteria.

The present theory would suggest that epidemics of CFS could be caused either by a distinct strain of HSV (68) or by an agent, such as the recently reported retrovirus (lo), which might affect the latency of her- pes viruses. Parvoviruses, such as B19, which can cause outbreaks of infection in schools, are able, apart from suppressing reticulocytes, to affect cell-mediated immunity (21).

A further contentious issue is whether CFS is just a form of depression. Some authors have indeed found it difficult to distinguish the two (5). while others have argued convincingly as to the distinction (69). Much of this problem stems from the inadequacy of the current systems for the diagnosis of both conditions. However, I would suggest that the confusion could arise from CFS and some forms of depression being part of the wider spectrum of HSV induced disorder, That depression in CFS represents au understandable reaction to experiencing au illness which is disabling, disruptive and with no clear treatment, is plausible. However, comparison of two groups of multiple scle- rosis patients, with and without temporal lobe lesions (detected by MRI), but with similar disability, showed that depression was associated with temporal lobe lesions (70).

It has been argued that CFS is due to disuse atrophy (4). but, in a study of cardiac function in CFS, an opposite effect was observed to that expected if CFS was due to deconditioning (71). Others have con-

eluded that the weakness, complained of by CFS suf- ferers, cannot be ascribed to impairment of muscle power (72). Furthermore. in the more severe cases, apart from the inability to carry out the task, the patient may experience a severe relapse following even the mildest of exertion and this may last several days or even weeks.

Some have suggested that hyperventilation under- lies CFS (6), but others have failed to 6nd evidence of this (73.74). Further work is obviously needed before the merits of this hypothesis can be properly judged.

If the present theory is correct, CFS could emerge as part of a spectrum of HSV induced disorder. The interrelationships between CFS, irritable bowel syn- drome (60), fibromyalgia (56,57) and depression (5) support this concept. These disorders have several features in common. They are of unknown aetiology, they all have symptoms other than the primary ones and it is difficult to diagnose them with certainty. Furthermore, in making the diagnosis, an arbitrary cut-off point in the scale of severity is usually estab- lished. The symptoms of these conditious are seen, either individually or in various combinations, in a high proportion of the general population. Headache, for example, is a frequent symptom in CFS, IBS, fibromyalgia aud depression. In one study of physical symptoms in depression, headaches were reported in 76.5% of patients but also in 39% of controls (75). while in CFS, IBS and fibromyalgia they are reported by over 80% of patients.

Apart from their sharing many symptoms, CFS, tibromyalgia, IBS and depression overlap very consid- erably. The diagnostic distinction between CFS and fibromyalgia is increasingly blurred, with many con- sidering them to be the same disorder, while IBS is included by some as a symptom of fibromyalgia (57). Depression and CFS can be almost impossible to dis- tinguish (5). and other studies have suggested that 54-1001 of patients with IBS may have associated psychiatric illness (59). Particularly prominent in IBS aremood, anxiety and somatisation disorders, precise- ly those that am encountered in CFS.

Recent reports of affective spectrum disorder have revealed a close similarity to the spectrum of HSV induced disorder which I propose. Affective spectrum disorder was initially discovered by scanning the lit- erature for conditions that responded to 3 or more classes of antidepressants (76). The list included major depression, bulimia, panic disorder, obsessive compulsive disorder, attention deficit disorder with hyperactivity, cataplexy, migraine and IBS. This was later extended to include several obviously related conditions (77). such as CFS, fibromyalgia, narcolep-

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sy, Tourettes disorder and kleptomania. Although this list is more extensive than that which I put forward for the spectrum of HSV-induced disorder, I have been deliberately conservative in my claims and I suspect the two groups could prove to be the same, despite their completely different derivations. I would agree with the authors that our spectrum disorders ‘represent one of the most prevalent diseases in the population’.

A rational approach to therapy is opened up for the whole of the HSV-induced spectrum of disorders, with both antiviral agents and those that augment the im- mune system, playing their part Acyclovir therapy in CFS has produced conflicting claims. Anecdotal m- ports have suggested its usefulness, though the only well-documented double blind trial found no benefit (78). However, in this trial the patient group was narrowly defined (1) and thedrug is known to be active against the rapidly multiplying virus. Despite this, in controlled trials, acyclovir was shown to be often effective in postviral fatigue of short duration (79). This drug may prove to be effective against HSV in extraneural sites of infection though it would not be expected to be active against the virus when it is multiplying slowly in glial cells or neurons. The suc- cess claimed for agents that augment the immune system (80, 81) certainly support the idea of a viral cause. The beneficial effect in CFS of high doses of essential fatty acids, contained in oil of evening prim- rose (Efamol Marine), in a double blind, placcbo- controlled trial (82). again suggest viral activity, be- cause they am not only potent inactivators of en- veloped viruses, including HSV (83). but their metabolism to prostaglandins may be necessary for the action of interferon (84). It is likely that a combination of antiviral and immune stimulant drugs could be synergistic.

While there seems little hope at present of eliminat- ing a virus in the latent state, the main realistic objec- tive would be to develop a vaccine to prevent the primary infection or subsequent reactivation.

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