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Virus - what virus?

Dr Elizabeth Dowsett discusses the evidence both for and against the theory that ME is caused by the family of viruses known as enteroviruses - those which live in the bowel and among which are the viruses which cause polio. With an introduction by Jane Colby, author of ME - The New Plague.

Introduction

Virus? What virus?

Many people with ME are not just "normally" ill (if one can use such a contradictory phrase!). They do not just have normal symptoms of an infection such as sore throats and swollen glands, but they feel more ill than they have ever felt in their lives.

Without having experienced such an illness it is difficult to imagine. The feeling is that one has become seriously poisoned by toxins such as those which really nasty bugs can produce. But if you developed ME in the 1990s you may have been diagnosed as having "Chronic Fatigue Syndrome." This name (CFS for short) is increasingly being recognised as unsatisfactory because many cases diagnosed as CFS do not follow the course or symptom pattern of what we might call "true" ME. Therefore we may see yet a new name arising, along with the recognition that ME proper is not the same as CFS, which is coming to be seen more as an umbrella term for several different types of illness causing fatigue.

Most cases of true ME are known to follow a viral infection, either a serious one or one which seemed at the time to be relatively mild. It may be that if every case of ME were diagnosed early enough, all of them would be seen to fall into this category. Often it is many months or even years before a diagnosis is made. Whether or not the ME was originally triggered by a virus, especially if the infection appeared to be mild at the time, is by then lost in the mists of time.

Perhaps it isn't surprising, therefore, that there are so many confusing theories about the causes of ME. It is very often simply not possible to isolate the exact time at which the disease began, and to remember whether or not there was an infection shortly before it. Some infections can even take place subclinically - that is, they cause no immediate symptoms, though they may lead to complications later if a chronic effect is triggered.

Not everyone reacts to viruses in the same way, and so what we call "host factors" come into play, and here there is also great scope for confusion. If you get an infection, you are playing "host" to it. What reaction will your body have to that? Many different things can affect someone's "host response".

In the case of ME, one of the many contributory factors to the illness, or even one of the many effects of it, can become isolated from the whole picture and put under the microscope on its own. Then we feel very wise and point at it and say - "Aha." We think we have found the cause.

One subject which caused a great deal of "Aha" in the past was stress. Was the patient very stressed at the time of the ME taking hold? Aha, ME must be a stress-induced disease. This has since been seen to be an unsatisfactory explanation on its own.

But does all this have anything to do with infection? Interestingly, if a person is very stressed at the time of an infection, this is not good news. If our lifestyle is very demanding or we are under great stress from work demands or personal trauma or accident (all factors which are known to undermine immune response) we can have a much worse reaction to what might otherwise be a trivial infection. If we do something very physically demanding in the early days of an infection, such as playing squash or working at a very physical job, this can also affect how our body deals with a foreign invasion - which is what an infection is. If we have a vaccination, which demands the attention of our immune system to deal with it, this will distract the immune system from infections that we are exposed to at the same time.

If we do not have the necessary antibodies to cope with a particular bug, this is also bad news. ME often follows a foreign holiday. It is one of the known risk factors, especially where polluted beaches are concerned. Did we meet with viruses that we had never met before and against which we had built up no natural immunity? The list of possible links with infection goes on and on.

In the following article, Dr Elizabeth Dowsett, an award-winning microbiologist with 30 years' experience of ME, dissects the case for and against one particular group of viruses which has long been suspected of being the villain in the piece. Not one of the accessories to the crime, but the villain itself. How likely is this to be true?

Is ME/CFS caused by a persistent enterovirus infection?

By Dr Elizabeth Dowsett
MB, ChB, Dip. Bact.
Honorary Consultant Microbiologist South Essex Health Trust

Evidence for persistent enterovirus infection in chronic medical conditions in humans has been presented by MUIR and ARCHARD in the UK [1] and evidence against by MELCHERS et al in the Netherlands [2]. However, the Dutch team does not rule out an autoimmune reaction to enterovirus infection - that is, a misdirected attack by the host's immune system upon normal host tissues which bear a close biochemical resemblance to components of a virus already cleared from the system. New technical methods for detecting minute fragments of virus genetic material are now coming into general use and may resolve these two, apparently contradictory views.

We have much to learn from history and even more to lose from ignorance leading to prejudice against persons suffering from ME/CFS. The study of minute human parasites was initiated by a Dutch spectacle maker who invented the light microscope in 1609, but this technical innovation was initially greeted with general ridicule at the idea of "animalcules" (little animals) seen spinning round in material scraped from human teeth, like tadpoles in a pond.

In France and Germany some 250 years later, the pioneers of bacteriology (Louis Pasteur and Robert Koch) using microscopes capable of higher magnification, demonstrated a clear relationship between bacteria and the medical scourges of those days (TB, cholera and syphilis) as well as to commercial disasters such as the bankruptcy of the wine industry due to problems with fermentation. Infections such as gastro-enteritis were ascribed solely to bacteria or were classed as "cause unknown" if bacteria could not be seen on culture.

In 1955, when the study of virus infections was moderately advanced, the later infamous psychiatric partnership of McEvedy and Beard declared The Royal Free Hospital outbreak of ME/CFS, affecting 292 members of staff, to be evidence of mass hysteria despite the fact that they were writing in 1970 and had never seen a single patient so affected. One member of this partnership later went on to describe an epidemic of Winter Vomiting Disease, in a different institution, as a further example of this phenomenon.

Shortly after the end of World War II, highly sophisticated electron microscopes, made in Germany, came into use in UK laboratories. Their resolving power was capable of photographing the smallest virus and the cause of many infections, previously unknown, was revealed. These included infantile gastro-enteritis, water and milk borne diarrhoea of humans and animals, institutional food poisoning and "Winter Vomiting Disease", now known to be caused by the Norwalk virus which can be seen by electron microscopy of patients' discharges but which cannot yet be grown in culture.

Until recently, viruses have been described as sub-cellular entities (that is, obliged to make use of host cell facilities for replication and sustenance) which cause distinct forms of tissue destruction and infiltration by immune cells as recognised by light microscopy. The study of such viruses has dominated the first hundred years of virology and has undoubtedly led to the suggestion that the name "Myalgic encephalomyelitis" should be changed to "myalgic encphalomyelopathy" (that is, muscle pain and disturbance of brain and spinal cord of no specific cause) because no tissue destruction or inflammatory immune response can be seen under the microscope.

However, over the past 40 years, a different mechanism by which viruses may cause tissue disturbance has been described by research workers in the USA of whom OLDSTONE, whose seminal paper "Viral alteration of cell function" (published in "The Scientific American" 1989; 261:34) is the best known. He explains in more recent publications (1996/97)[3] that the main problem any sucessful virus has to solve is how to live symbiotically with the host cell for a lifetime. A practical solution demands the avoidance of gross cell damage which will attract inflammatory cells from the immune system.

As a result of such short-sighted abuse of the host, viruses causing visible tissue destruction must continually seek new cells and then new hosts to infect, drawing even more attention to their activities. Such careless and unsuccessful viruses have, until now, been the major focus of our attention because they are easily detected by old fashioned and conventional techniques.

On the other hand, successful viruses adapted to persistence are careful to avoid recognition by the host's immune response as well as any interference with the host cell's genetic make-up which might affect structure, cell membrane or its ability to provide life-long board and lodging for the parasitic virus. Unless this partnership, which involved adaptation on both sides, is perfectly equal, the host cell will have to pay a price for its continued survival. This usually means loss of some of the cell's specialised functions (e.g. the production of enzymes, hormone, neurotransmitters etc) while retaining the essential "housekeeping" functions which sustain and support both cell and virus.

Using traditions methods of light microscopy, such adapted and persistent viruses are undetected and the diseases they cause are said to be of "unknown cause". However, techniques such as PCR (the polymerase chain reaction) which amplifies minute fragments of virus genetic material can, in skilled hands, produce positive results in studies of brain, spinal cord, cardiac and skeletal muscle, blood serum, bowel, liver and other tissues in patients with proven enteroviral infections leading to neurological disturbance.

Viral persistence (without any evidence of inflammation) has been described in recent papers published by Oldstone and colleagues [4] which is capable of altering the transmission of nerve impulses essential for forming and changing memory and other cognitive networks in the brain.

Defects in memory and problems with learning are amongst the most specific, long lasting and troublesome disabilities suffered by patients with ME/CFS and this research is of vital importance to doctors, patients and teachers. Oldstone's team concludes that a number of current diseases affecting differentiated systems such as the nervous, endocrine, immune and cardio-skeletal muscle functions (such as ME/CFS) are likely to be caused by infectious agents which have evolved to persist and replicate in differentiated cells without causing visible damage or immune response. These studies in 12 widely differing groups of viruses, including enteroviruses, indicate that research into virus persistence (a common phenomenon) is likely to dominate virology in the 21st century.

Based on our knowledge of the incidence, both geographical and seasonal, the age, gender, occupational predisposition and other epidemiological characteristics of ME/CFS world-wide, it seems just as likely that, within the next few years, a persistent enteroviral cause and a means of prevention for this tragic disabling disease will emerge [5].

References

[1] MUIR P, ARCHARD LC. There is evidence for persistent Enterovirus infections in chronic medical conditions in humans.
Reviews in Medical Virology 1994; 4: 245-250

[2] MELCHERS W et al. There is no evidence for persistent Enterovirus infections in chronic medical conditions in humans.
Reviews in Medical Virology 1994; 4: 235 243

[3] de la TORRE JC, OLDSTONE MBA. Anatomy of viral persistence: Mechanisms of persistence and associated disease.
Advances in virus Research 1996; 46: 311-343

[4] de la TORRE JC et al. Viral persistence in neurons alters synaptic plasticity and cognitive functions without destruction of brain cells.
Virology 1996; 220: 508-515

[5] TYRRELL D. Unveiling hidden virus infections. The Lancet 1995; 346: 650

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