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The 2nd day of the conference focussed on research and the first session covered:
EPIDEMIOLOGY – the opening address was given by L Jason (Chicago IL) when he again emphasised the prevalence of fatigue. Many studies have been done looking at prevalence of CFS with wide variation ranging from 7.4 to 2600 per 100,000, but for those meeting the current research definition criteria 1-4 per thousand seems the most likely incidence Latinos represent the highest racial group with CFS in the USA, probably due to poorer health status. Of those with CFS, 41% meet the criteria for MCS, 16% for FM and 5% of those with GWI match the criteria for CFS. Most studies show a female predominance and paediatric prevalence ranges from 60 per thousand to 2%.
With so many studies showing different rates there needs to be a standardisation of diagnostic criteria.
W.Reeves (Atlanta GA) said that the research definition is now under review, including ambiguities associated with exclusionary and comorbid conditions, using standardised applicable international measuring instruments to measure intensity and disability associated with fatigue. Exclusions may be permanent or temporary. Temporary exclusions (until treated) may include sleep disorders, hypothyroidism, diabetes and morbid obesity with a BMI>40. Major depressive disorder with psychotic features and PH of anorexia/bulimia are not exclusionary if there has been resolution for 5 years.
Suitable measuring instruments:
Psychologica l - SCID or DIS
Fatigue – intensity - CIS or Chalder or Krupp severity scale
Somatic and psych health report - SPHERE - measures anxiety, depression and fatigue
Functional disability – SF36 or SIF
Sleep – Pittsburg sleep questionnaire, SAQ – to exclude apnoea and narcolepsy.
Memory and cognition – Cambridge neuro-psych test, RTB , CFI
Pain – SPHERE or McGill pain questionnaire.
Where there is a psychological condition in the differential diagnosis, the patient must have a structured interview with an experienced physician and SCID or DIS should be used.
The symptom list has been re-ordered:
The most prevalent symptom is non-refreshing sleep.
In summary, it is mandatory to use a standard definition and standard methods must be used for assessment. Publications must show how the definition was used and adequately describe the study subjects.
E Unger (Atlanta GA) confirmed that unrefreshing sleep is a defining symptom and the most frequent. This is a chicken and egg situation whereby the poor sleep aggravates the CFS, which in turn worsens the sleep. Formal studies such as all night poly-somnography including sleep latency measurement can be used.
T Chalder (London UK) presented her paper looking at the rate of CFS in childhood in a large (4240) London sample. She concluded that CFS was rare in this age group. 0.19% met the criteria for CFS. 0.4% parents thought their child had CFS, but there was no overlap between the child’s symptoms and parental labelling. It seems that parents and children have different perceptions of symptom experience. There was considerable overlap between fatigue and psychological disorders, and there was frequent maternal neuroticism.
K Busichio (Newark NJ) looked at physical impairment in CFS. Her group found that fatigue was only modestly associated with physical functioning in 102 women with CFS (average age 40). Pain was a better predictor of work impairment in CFS-only and FM/CFS patients.
R Suhadolnik (Temple Univ) gave an overview of the biochemistry and genetics of CFS, which he explained encompassed a huge overlap of all disciplines. He acknowledged the many people who had contributed to the many advances in the understanding of CFS. He then outlined the various biochemical processes which had been shown to be altered in CFS. Immune activation and NK cell decrease seem to be evident in most patients.
1. Oxidative stress - described using the peroxynitrite model, whereby elevated levels of various cytokines cause elevation of nitric oxide. This can decrease NK cell function, and also leads to mitochondrial dysfunction and HPA and other organ dysfunction causing fatigue and many other symptoms. He showed that there was an increase in markers of oxidative damage. The oxidative stress can thus damage muscles and the ATP generated system.
2. 2-5A/RNaseL abnormalities have been shown in CFS, particularly in the severely ill. 37kDa RNaseL is found in PBMCs in CFS in Suhadolnik’s and de Meirleir’s studies and not in healthy controls, depressed or FM patients. He stressed that there was no time lapse in the examination of the US samples, which W Behan has cited as a risk for false positives .
3. p68 kinase (PKR) – PKR mRNA expression has been shown to be increased in CFS leading to increased PKR protein activity.
4. Apoptosis – (programmed cell death) is evident in CFS
5. Skeletal muscle function and mitochondrial function - reduced intracellular concentration of ATP suggests a defect in oxidative metabolism with a resultant acceleration of glycolysis in the working skeletal muscles in CFS. There is also reduced oxidative muscle metabolism (shown by MRI), and muscle recovery is delayed. Elevated levels of RNaseL are associated with reduced VO2 max and exercise duration in patients.
There is evidence for changes in brain metabolism.
In addition to altered biochemical processes, there is evidence for some genetic predispositionto CFS, which coupled with a triggering event can lead to immune dysregulation. Ongoing twin studies are providing useful information. Vernon and Behan have both been using micro-arraying techniques for gene expression profiling.
4 papers then followed relevant to Suhadolnik’s presentation.
S Vernon (Atlanta GA) discussed the utility of the blood for gene expression profiling and biomarkers in CFS, using micro-array. In her study, she had found that the results were successful in distinguishing CFS subjects from healthy controls. Gene activity differences were identified implicating some of the pathways involved in CFS. She noted that there could be age differences in this study and that in future there is need to control for all variables. She stressed that the more genes one can measure the better.
W Behan (Glasgow, Scotland) compared the muscle of patients with fatigue due to different chronic diseases using micro-array technology to establish whether or not there is a common profile of gene expression. She said age matching and gender was very important. Comparison between the groups identified a range of genes that were differentially expressed more than 3-fold. Symptoms of fatigue and myalgia in CFS are similar to that in other common conditions (COPD,CHF). Studies show profound deconditioning in all groups, but additional mechanisms must be going on. A large number of transcripts were identified in those deconditioned but absent in controls.
G Kennedy (Dundee, Scotland) provided further evidence for dysfunction in oxidative pathways in CFS. High levels of isoprostanes were found. 8-iso-PGF2α is a sensitive and reliable measure for oxidative stress in vitro. Viral infections increase isoprostanes, but the changes shown in the sample of CFS patients studied were not present in those with organo-phosphate poisoning or GWI, in which conditions the effects are due to anti-cholinergic effects. Isoprostanes are potent vasoconstrictors, and this may help to explain some of the symptoms in CFS.
D Racciati (Chieti, Italy) explained how oxidative stress may play a fundamental role in CFS pathology. The oxidative stress may be a result of elevated peroxynitrite, leading to a self-perpetuating viscious cylcle mechanism, producing a chronic pathological condition in response to a trigger such as a viral infection.
INFECTION and IMMUNOLOGY
John Hay (Buffalo NY) introduced this session with a presentation showing the evidence for infection and immunological changes in CFS.
INFECTIONS correlate with disease and fatigue and many CFS patients report an infectious episode at onset. More than 30 infectious agents have been investigated in the quest for a cause of this illness including picornaviruses, EBV and retroviruses. Some of the likely organisms leading to CFS-like illness include:
HHV6 and 7 – minimally found in CFS patients and probably not significant
Bornaviruses - ? involved in humans – but found in a small number of CFS patients.
Borrelia burg (Lyme disease) – those who are sero-positive are likely to have symptoms of CFS
Mycoplasma – Komaroff found no antibodies for these organisms, but Vojdani found 34% positives in CFS patients compared to 8% of controls.
Parvovirus B19 – a large percentage of people carrying this virus do have fatigue, but it cannot be diagnosed after the acute phase.
He concluded that there was no consistent pattern of infection and a number of organisms can lead to the CFS state.
IMMUNE DYSFUNCTION may be involved, as administration of cytokines gives rise to symptoms similar to CFS. eg parvovirus may cause dysregulation of cytokines (TNFα and IFNγ). Other cytokines such as IL -1β and IL-6 were studied. IL-6 was found to be increased following exercise in CFS.
NK cells showed low activity in 25% CFS patients compared with 7% in controls (Whiteside, 1998) but no differences were found in monozygotic twin studies (Sabath, 2002).
Suhadolnik and de Meirleir found up regulation of the RNaseL pathway in CFS while Gow et al had no significant evidence for this.
ALLERGY – many with CFS report atopy. IgE and CFS were found to correlate in 2 recent studies.
AUTO-IMMUNITY is an appealing potential link. Konstantinov (1996) found significantly increased ANA positives in CFS, but Skower (2002) had less promising results.
In conclusion Hay said that as yet there is no consensus for immune dysfunction in CFS. Patients need to be divided prior to any data analysis as there are many routes to this disease making research data potentially difficult to assess.
3 further papers were presented at this session.
K Maher (Miami,FL) discussed molecular defects associated with CFS, in particular determining the molecular mechanisms underlying decreased cytotoxicity. The cytotoxic armamentarium involves perforin, granzyme A and granzyme B and all are down in CFS. NK cells were also found to contain fewer molecules of CD11a and CD26, and the cytotoxic protein content of T6 cells was reduced. Cytotoxic effects may not therefore be NK specific but may encompass the cytotoxic T cell subset as well.
P McGaffney (Minneapolis,MN) found a significant difference in gene expression, detecting 166 genes. In particular the analysis revealed elevated expression of mRNA for IL-1 and the IL-1 receptor,type 2. IL-1 is a very potent inflammatory cytokine and these genes were dysregulated in almost all patients and none of the controls. This may give insight into the pathophysiology of CFS but there is still a long way to go.
R.Suhadolnok (Temple Univ) enlarged further on the biochemistry and clinical differences. His team studied 3 groups: CFS patients, healthy controls and those with depression. He had again found a close association between the upregulated 2-5A/RNaseL immune defence pathway and the clinical presentation of CFS. These markers can be used together with clinical parameters to identify CFS patients and to identify homogenous subsets within the population. This would thus prove useful in studying treatment methodologies for various subsets.
B Natelson (New Jersey) introducing this session explained the trials and tribulations of drug research in CFS. One could compare an assortment of biological functions between patients and healthy controls, or one could use a trial of a specific pharmacological agent. Such a trial may give a clue as to cause.
3 trials using phenelzine, selegiline and ambrotose only showed minor statistical improvement. He reported on a larger trial using Modafinil, a drug used to combat fatigue and sleepiness in conditions such as narcolepsy and MS. It was thought it could have a role in CFS. A double blind, placebo-controlled trial in moderately ill patients was performed. The trial lasted 4 weeks and the dose was increased from 100mg daily to 200mg over the first few days. Drop out rate was 20% mainly due to adverse effects such as headache and nausea. The trial was conducted in 6 sites and many measures were studied. No significant improvements were seen. There was a tendency for slight improvement on the drug and in 2 sites there was an amazing placebo effect! The subtle therapeutic effects were not backed up by research.
A number of factors deemed to be important for future research emerged from this study:
1. Choose only those reporting sudden onset consistent with viral illness
2. Psychiatric diagnoses should be excluded.
3. Those with MCS or FM should be excluded as they have higher levels of comorbid psychopathology.
This will ensure a more homogenous sample. It may also be preferable to use only one site.
O Zachrisson (Goteborg,Sweden) presented a randomised controlled studyon the use of staphylococcus toxoid in FM/CFS. His group found that over 6 months there was significant improvement. There was good tolerability with only 10% dropout. 65% of the CFS group improved significantly, but there was worsening of symptoms on withdrawal. The symptoms that improved were: fatigue, sleep, cognition, sadness and irritability. The antibody response was related to the clinical response. Maintenance treatment is needed to prevent relapse and this agent is no longer on the market as it contains a preservative which breaks down to mercury and salicylate.
D Clauw (Washington DC) had studied the effectiveness of aerobic exercise and CBT in 1000+ Gulf War veterans with chronic multisystem illnesses. Patients were excluded if they already had an exercise plan. 4 groups were studied: usual care, exercise alone, CBT alone and a CBT+exercise group. Physical functioning was not significantly improved in any of the 4 treatment groups. However both exercise alone and CBT+exercise improved fatigue, cognition, distress and mental health functioning. Affective pain was improved with CBT alone and CBT+exercise, but 3 other pain measures were not improved.
C Lennartson (Stockholm, Sweden) studied the effects of low intensity interval training in 30 women with CFS. 20 were in the training group, which involved walking (15-30 min), stretching and relaxation. 10 were controls. Rest periods were included. 5 dropped out of the training group. This type of light intensity training was found significantly to be useful for those with CFS, and this exercise did not appear to exacerbate symptoms, so that patients could continue the programme without fear of relapse.
T Chalder (London,UK) introduced this session and gave an over view of her thoughts on Chronic Fatigue. She described labelling difficulties with medically unexplained illnesses. eg psychosomatic, somatization, hysteria, conversion disorder etc. She preferred to divide these illnesses in terms of:
She suggested we should try to study the physiological mechanisms alongside cognitive and behavioural factors. Precipitating factors such as life events, social support, lack of fitness and coping ability are determinants in the level of fatigue. She has used several different questionnaires to determine the level of fatigue, and found that the perceived lack of practical rather than emotional support was predictive of fatigue level. She noted that CBT could target the cognitive and emotional effects.
T Giesecke (Washington DC) had looked at the roles played by biological, psychological and cognitive factors in subsets of patients with FM. 3 groups were identified: a) Those with FM with extreme tenderness and no identifiable psych/cognitive contribution. b) Those who are moderately tender with normal mood and c) those where mood and cognitive factors contribute considerably to tenderness.
R Taylor (Chicago IL) evaluated the effects of an empowerment orientated rehabilitation programme on QOL and outcomes related to symptoms and disability. These programmes which were consumer driven were found to be effective. Patients set their own goals and determined steps. They also took primary control over evaluation.
D Williams (Michigan MI) had worked with Gulf War vets with chronic multi-system illness. The aim was to improve symptoms and physical functioning using 12 weeks of aerobic exercise and CBT alone or in combination. Results had been less than expected despite some improvement. Results were more specifically analysed looking at functional status, mental health, pain, fatigue and memory. Sex, mood disorders, personality disorders, disablility issues and dolorimeter threshold were all associated with negative changes in outcome. Tender point count was predictive of positive outcome in both exercise and CBT.
A Peckerman (New Jersey NJ) found
that PTSD contributes to disregulation of cardiovascular responses to mental and
orthostatic stress, leading to more physical symptoms in Gulf War vets with CSF/ICF.
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