This is a summary of the talk given to our Society at the Annual General Meeting on November 23rd, 1996. The speaker was Associate Professor Andrew Lloyd, MD, FRACP, a member of the internationally recognised CFS research team at The Prince Henry Hospital and University of NSW in Sydney. In October 1996 Professor Lloyd attended the American Association for CFS Conference in San Francisco and here he summarises some of the research findings presented at the conference.

Professor Lloyd began studying CFS in 1987 at The Prince Henry Hospital in Sydney. He was awarded his doctorate in medicine (MD) for his work, which spanned more than three years and made a significant contribution to the understanding and the nature of CFS. In the early 1990s Professor Lloyd spent three years at the Laboratory of Molecular Immunoregulation, National Cancer Institute, Maryland, USA. Professor Lloyd is currently staff specialist in infectious diseases and director of the AIDS Unit at the Prince Henry Hospital, and director of the Inflammation Research Unit at the University of NSW.

Epidemiology of fatigue

Epidemiology is the study of patterns of illness, in particular illness patterns in the community. In order to understand the epidemiology of any pattern of illness, researchers need to define the phenomenon that they are studying. In the past a great deal of research has focused on trying to develop a fatigue test as a means of measuring fatigue. To summarise a century of attempts at this, it is very clear that the sort of fatigue felt by patients with CFS cannot be measured objectively. Therefore researchers are dependent on subjective recordings.

To scientists, subjective recordings have grey boundaries and are not easy to compartmentalise. This is a key issue in CFS since the boundaries surrounding the disorder are grey and it is reasonably clear that CFS is not a uniform disorder within those grey boundaries. In most human diseases, a dichotomy can be found; something that clearly defines ill health from health. Unfortunately that sort of division is not found in CFS. It is therefore difficult to determine the associations of chronic fatigue and CFS.


Bias

Professor Lloyd described many patients who present to their doctors explaining that they began feeling sick six months earlier after they had what seemed to be a viral illness. Such descriptions make sometimes invalid assumptions that the virus is the cause and bring in the issue of bias, in particular, recall bias. For instance, it is known that in young children, on average six or eight viral illnesses occur per year while adults will develop half this number. These statistics immediately say, just by random variation, that there is quite a significant likelihood that any chronic illness will be attributed back to a viral illness at onset, maybe because they simply happened to occur at the same time. Cause and effect is not necessarily clear. There is also a strong tendency, if you are looking retrospectively, to link things that may not necessarily be linked.

Professor Lloyd also noted that two thirds of patients presenting with major depression attribute the onset of their disorder to a viral illness. It is possible that the viral illness did actually cause their major depression, or precipitate it, but it does not help researchers support the argument that CFS is a biological illness rather than depression.


Selection bias - gender and presentation

So-called selection biases are statements of reality, that women present more commonly to medical practice for any given illness. Professor Lloyd explained that women may have better insights into their illness, and may be more determined to get it resolved. This is particularly true for controversial illnesses.


Confounding biases

Confounding biases can also give false impressions of illness patterns and a good example of this is the herpes viruses. A decade or so ago, there was a lot of interest in whether infections such as Epstein Barr virus (EBV), which is the cause of glandular fever, were the cause of CFS. In fact, for a period of time, CFS was called Chronic EBV. In retrospect it is very clear that for the great majority of patients labelled as having Chronic EBV, their illness had nothing whatsoever to do with EBV. The link was being made mostly because minor alterations in the immune status of patients were making their immune system produce more antibodies against EBV infection. However, EBV is a virus that we retain for life after we have been infected, usually at a young age and hence antibodies against the virus are found often at high levels throughout the lifespan.


Incidence of CFS

Given the uncertainties about how CFS is categorised, a very important issue is how common it is. One thing that is very clear that was discussed at length at the conference is the fact that the broad ball-park of the estimated prevalence of CFS is moving upwards. The more good quality surveys there are, the clearer it is that The Prince Henry's team's estimate of one in 2,500 is likely to be the minimum prevalence estimate. It seems quite likely that CFS is considerably more common than that, perhaps in the order of 200 cases per 100,000 of the population.


The relationship between chronic fatigue and psychological health

Professor Lloyd stressed that we cannot say that all CFS is simply a straightforward, biological, immunological illness that has no social, psychological or other perspectives. There is no illness like that. However, that is what understandably the patient in the general community is wanting researchers to say. To give such a simple message would give sufferers mistaken perspectives on how best to understand and manage their illness. One aspect of Professor Lloyd's research has shown that individuals who have this sort of simplistic notion of their illness are far less likely to improve than individuals who take a broader perspective. It needs to be recognised that all chronic illness has biological, social and psychological components and that treatment approaches trying to address all of those things are more likely to be successful.


Post-infective fatigue

Non-specific viral illness

A study by Dr Simon Wessely in the UK was based on about 2,500 general practice registrants who were ultimately divided into two groups. One group of patients had what the GP diagnosed as a non-specific viral illness. These individuals were matched with a control group who had not had a viral illness. Over six and twelve month periods, Dr Wessely looked at what proportion of those two groups developed CFS. Results showed that patients who had experienced a non-specific viral illness were no more likely than the control group to develop a chronic fatiguing illness. This study raises the suggestion that non-specific and mild viral illnesses are not likely to be a key factor in the development of CFS.


Specific viral illness

Professor Lloyd referred to various retrospective studies where researchers have followed up small numbers of individuals who at one point in time where shown to have a specific infection such as Ross River virus or influenza. In each of those illnesses, and in many more, there are reports suggesting that CFS can follow an acute infective illness.


* Infectious Mononucleosis

Dr Peter White in the UK recruited approximately 200 individuals in the midst of an acute episode of what was thought to be glandular fever. Of those individuals, blood tests confirmed that 180 patients did have glandular fever (caused by EBV). A second group of the patients had an illness clinically similar to glandular fever but it could not be confirmed by blood tests. The remaining small group had other more common viral illnesses. All of these individuals were followed over time and their condition observed. The open-ended study was designed to look at whether people got better completely or whether they did not. Results showed that 10% of individuals who had glandular fever developed an illness that was characterised by chronic fatigue, and had all of the symptom patterns typical of CFS.


* Q Fever

Research by Professor Barrie Marmion, a microbiologist in Adelaide, shows that Q fever appears to be an important precipitant for a form of CFS that he calls QFS. His study followed up meat workers and individuals who had acute Q fever and found that about a quarter of them had persistent symptoms in the form of a fatigue syndrome, marked by muscle pain, unrefreshing sleep and concentration and memory difficulties. He reported that these patients also had very prominent drenching night sweats.


* Ross River Virus

Professor Lloyd stated that one of the things that is of particular interest in relation to Ross River Virus (RRV) is that it does not have any neurotropism; ie. the virus is not known to infect the brain. There are many other viruses that cause chronic fatigue syndromes, like EBV, which are known to be able to infect brain tissue. It is Professor Lloyd's belief that the site where CFS is predominantly located is within the brain. Therefore, RRV is an interesting virus to study in trying to understand CFS because a recent study shows - and this fits with Professor Lloyd's observations - that CFS can follow from RRV infection.


Epidemiological studies

Professor Lloyd's research group is in the process of developing three models where they are recruiting individuals with acute, recent onset glandular fever, RRV or Q fever. These individuals will be followed over time to see whether they recover or have persisting symptoms, notably fatigue. The researchers will seek to define the issues that separate those who recover promptly from those who do not. They are testing immunological hypotheses by analysing patients' blood samples and are secondly asking the question of whether psychological health prior to the onset of the infection, or the development of psychological ill-health during the illness, means that patients are less likely to recover. They are also investigating whether other factors such as the doctor/patient relationship has an impact on recovery. While Professor Lloyd admits this is an ambitious study, he hopes it will be one that can answer a lot of questions about CFS.

At the conference, researchers from the University of Newcastle presented results of their study which looked at various levels of organochlorines in the blood of CFS patients and another group of CFS patients who had specifically been exposed to pesticides. A group of control subjects was also studied, but these subjects were unfortunately unable to be matched by environmental exposure. Results show a mild elevation in the level of some of the organochlorines. Professor Lloyd's perspective of this is that it is an interesting observation that needs to be pursued further.

Professor Lloyd also mentioned a series of studies that have been co-ordinated at the Centers for Disease Control in the USA. There has been a lot of controversy in the United States about so-called Gulf War Syndrome, and about whether veterans returning from the Gulf may actually have an increased prevalence of CFS. One study has found that there was an increased prevalence of CFS in those that had been deployed, but it was not specific to the Gulf (ie. it also occurred in individuals who were deployed in Bosnia). This study raises issues about Post Traumatic Stress Disorder and whether people who come back from war have ill-health because of the stress of their experiences. It is also possible that there are things about service itself, ie. food or immunisations that might have in some way put people at increased risk.


Neurobiology

To summarise the discussion on neurally mediated hypotension (NMH) at the conference, various groups of researchers agree that classical NMH is rare in people with CFS. It is estimated that only between 1 % and 5 % of an unselected group of patients with CFS would have NMH. Autonomic dysfunction - minor alterations in physiological responses to standing upright - occurs commonly with CFS patients. Researchers believe that such occurrences may be part of an explanation for the symptoms of light-headedness and presyncope that some people with CFS experience. Fludrocortisone (Florinef) is one potential treatment of NMH, however results of a recent double-blinded placebo-controlled trial of fludrocortisone showed no difference between CFS patients and control subjects (not yet published).


Newcastle research

Researchers at the University of Newcastle are hoping to gain insight into CFS by screening the urine of patients and control subjects by looking for abnormal metabolites. To achieve such insight into the disease process of CFS, or a diagnostic test, researchers need a result where every CFS patient has the urine abnormality, and every control subject does not. In this and every other investigation into CFS, there are not such clear cut results. A series of proteins and so-called 'profiles', or patterns, of proteins have been found but none of those patterns or the individual proteins are unique to CFS, and they differ only in broad prevalence and potentially in quality. Professor Lloyd stressed that the conservative scientific view needs to be that these studies are only a potential starting point for further investigation.


Concentration and memory difficulty

Various researchers at the conference presented results of studies where patients had undergone extensive cognitive performance tests. These tests have reproducibly shown that for people with CFS, intellectual tasks take longer to get efficiently performed. But unfortunately, these results are non-specific.

Professor Lloyd's colleague, Dr Ute Vollmer-Conna, conducted a study where she matched a group of people with CFS, a group who had acute viral illnesses, and a group with classic depressive illness with healthy control subjects. Results showed that patients with CFS, patients with depression and patients with acute viral illness all have impaired reaction times and performance in comparison to healthy control subjects.

Another study measured the cognitive function of CFS patients before prolonged aerobic exercise on a treadmill, and then afterwards at four and 24 hour intervals. Results showed a performance decrement in these patients in comparison to a group of healthy controls who did the same exercise but had no deterioration in cognitive performance. Professor Lloyd said that these results fit with what his patients tell him, that fatiguing exercise will not only make them more physically fatigued but will also affect their concentration and memory. Again, these results do not give real insights into how CFS is produced but they do further suggest that the brain is being affected in some way by physical tasks.

Professor Lloyd said that he was impressed by the quality of science at the conference, and by the number of researchers from around the world presenting results of their studies. The overall consensus at the conference was that there is no effective treatment that alters the natural history of CFS.

Ed: Thanks to Professor Lloyd for reviewing this summary before publication.

Reprinted from Emerge, Autumn 1997.