A REPORT FROM THE FIFTH INTERNATIONAL AACFS CONFERENCE by Dr. Rosamund Vallings


A REPORT FROM THE FIFTH INTERNATIONAL AACFS CONFERENCE by Dr. Rosamund Vallings

From January 26-29, 2001, I was privileged to attend the AACFS 5th International conference for Chronic Fatigue Syndrome hosted by Sudhir Gupta, the President of AACFS. It was an exciting experience to once again learn of the great wealth of research currently taking place, and to meet with those researchers and clinicians who are at the cutting edge. On the first afternoon, there was a pre-conference symposium looking at optimization of the case definition. Then followed 2 intensive days of research and clinical presentations from all over the world, coupled with a display of posters representing many disciplines. I really enjoyed the opportunity to be part of the ever popular Clinician to Clinician session, and there was also a lively forum to discuss the possibility of name-change. We were also hosted to a fine banquet at which Professor Anthony Komaroff was awarded the Perpich Memorial Award, and gave a brilliant speech recounting his experiences with CFS.

In the following report, I have tried to sort the presentations into sections according to various disciplines, following the conference format as far as possible.

EPIDEMIOLOGY and NATURAL HISTORY

The conference opened with a presentation by L Steele (Kansas) who had looked to see if the case definition for CFS was useful in describing the health problems experienced by those suffering from Gulf War illness. She concluded that although CFS is more common in Gulf War veterans than in the general population, there were 6 distinct symptom groups and only 7% fitted the case definition for CFS.

R Nisenbaum (Atlanta) discussed the course of illness among 38 of the 82 patients who were diagnosed with CFS in Wichita, Kansas between 1997 and 1999. After 12 months, 68% had transitioned to other illness states, such as non-fatigued, less CFS symptoms or medical or psychiatric exclusionary conditions. Half the patients reported that reduced fatigue was the first symptom associated with improvement, followed by improved memory and concentration, reduced joint pain and better sleep. Most effective reported treatments were: traditional medical therapy, changes in diet, vitamins, herbal remedies and exercise. There was no association between illness improvement, type of onset or illness duration. Among a random sample of 18.675 respondents in Chicago, 32 were diagnosed as suffering from CFS. L Jason (Illinois) discussed the issue of then subtyping these individuals according to type of onset, symptoms etc. He concluded that subtype differences may account for the inconsistencies among CFS patients grouped into one category, and that subtyping may well lead to more appropriate treatment strategies.

P de Becker (Brussels) produced results of a factor analysis which determined 4 symptom groupings: general, cognitive, musculoskeletal and mood changes/psychiatric factors. The first 3 group scores fitted with both Holmes and Fukuda defined CFS patients, while the mood change/psychiatric factor score was not an important factor in determination of CFS. The musculoskeletal factor determined exercise ability.

The SF36 as a useful tool in determining outcome in patients with CFS and comparing with depression was discussed in 2 papers presented by S Schwarz (Tulsa). He concluded that admission scores on the physical component summary might be able to predict which CFS patients will worsen over time. Those who improved on the physical type scales tended to have higher mental type scores at admission and follow up. There were initial differences between CFS and depression, and CFS patients did not display the same improvement with treatment as seen in depression.

EPIDEMIOLOGY POSTERS

Epidemiological issues were addressed in 7 posters. R Taylor (Chicago) stressed the importance of distinctive diagnostic validity of 5 conditions: CFS, fibromyalgia, somatic depression, somatic anxiety and irritable bowel syndrome. P de Becker (Brussels) compared CFS patients fitting the Holmes and Fukuda definitions for CFS, and found that those fitting the Fukuda criteria were the less severely affected patients, which leads to an increase in clinical heterogeneity.

Factor analysis was also used by P Levine et al (washington DC) to detect subgroups in CFS and GWS. They concluded that this should be utilised in future to develop case definitions for CFS. Different pathogeneses and/or possible response to treatment may thus be identified. T Gerrity (Washington DC) suggested that Gulf War illness may be a demonstration of how fatiguing illnesses can assume different manifestations, but may still be mediated through similar neuroregulatory pathways.

J Alegre (Barcelona) had used the Fatigue Impact scale to evaluate 57 patients with CFS in Spain. High scores and the cognitive dimension parameters correlated with illness duration.

E Lindal (Reykjavik) presented the results of a mail survey to estimate the current prevalence of CFS in Iceland. The number estimated according to the Fukuda criteria was 2562. If these results were generalised to the US population, 2.5 million individuals would be apparently afflicted.

PHYSIOLOGY

In a presentation by P Soetekouw (Nijmegen), orthostatic intolerance was not shown to be increased in CFS heart rate and plasma epinephrine were increased in CFS, suggesting an activated pathoadrenal state. Sympathoadrenergic reactivity to head-up tilt was not altered in CFS patients. A Peckerman (New Jersey) presented results of a study supporting the hypothesis of altered baroreceptor control of blood pressure in CFS. This effect of the illness may mark patients with more severe illness. A greater suppression of the baroreceptor reflex in CFS during orthostatic stress, but not during mental stress, may reflect impaired ability to maintain cardiac output under conditions of decreased preload.

J Baraniuk (Washington) studied handgrip responses to determine sympathetic nervous system dysfunction, which was found in this preliminary study to be an integral part of CFS pathology.

P Englebienne (Brussels) explained how the interaction of RnaseL ankyrin domain with ABC transporters might explain pain and many of the physiological disorders of CFS. The study suggests that the possible dysregulations in ABC transporter function find an origin in their abnormal interaction with the small fragments of RnaseL containing ankyrin repeat motifs, released from a proteolytic cleavage of pathological origin.

PHYSIOLOGY POSTERS

As an accompaniment to the work presented by Englebienne et al several posters were also displayed clarifying the work of the Belgian team. The first indicated that the 37kDa LMW RnaseL fragment is produced by proteolytic cleavage of the native 80kDa monomeric protein. Calpain has been identified as one of the proteolytic enzymes involved in the cleavage. The 37kDa fragment could retain both the 2-5a binding and catalytic activities. S Roelens’ posters (Brussels), concluded that in peripheral blood mononuclear cells (PBMC) in CFS a correlation exists between the presence of 37kDa binding RnaseL protein and a 26kDa actin fragment. Some of the actin fragments seen in CFS patients are likely to be generated by apoptotic proteases. Also the amount of native actin in the serum correlates with the amount of RnaseL in the PBMC extracts of CFS patients. A further poster showed that the activation of RnaseL in the PBMC of CFS patients upregulates apoptotic activity in these cells, which is likely to be further downregulated by the large accumulation of its proteolytic cleavage products. This suggests that accumulation of LMW RnaseL fragments in the PBMC could exert a blockade in the apoptotic cascade, impairing the elimination of already damaged cells. RnaseL and G-actin fragments were retrieved in sorted CD14+cells, which suggests that the perturbed apoptotic process may play a role in the altered immunologic functioning in CFS.

Biochemical evidence presented by S Shetzline (Brussels) indicates that the origin of the 37kDa RnaseL in PBMC extracts is more complex than previously reported as analysis revealed peptide sequences equivalent to human 80kDa RnaseL.

D Bell (Lyndonville) showed how orthostatic testing can be safely done in the office setting by recording supine pulse and BP every 5 minutes for 10 minutes, followed by standing pulse and BP every 5 minutes for 30 minutes. Results were compared with measurements of erythrocyte mass and plasma volume and a clear relationship was shown between orthostatic intolerance and circulating blood volume.

Defective vasoconstriction was found in adolescents with POTS and CFS by J Stewart (New York). During tilt, defective vasoconstriction translates into enhanced pooling of dependent limbs. This may signify a redistribution of blood to the lower extremities even while supine, accounting for tachycardia through vagal withdrawal.

There were 2 posters from Japan: K Ohashi (Tokyo) demonstrated that strenuous exercise in CFS is associated with variability in circadian activity. Y Yamamoto (Tokyo) found that head-up tilt was associated with significant differences in heart rate variability between controls and CFS patients. This can be a useful test aiding diagnosis.

W Nix (Mainz) found that there was delayed recovery of muscle force in CFS, although the actual development of fatigue was similar in patients and controls. A combination of central and peripheral factors seem to be involved. In his second poster he evaluated muscle fatigue by single fibre EMG, and abnormal findings were not shown

P de Becker (Brussels) compared exercise capacity in healthy sedentary females with that in females with CFS. There was significant decreased capacity in those with CFS, and reaching the target heart rate seemed to be the limiting factor. Autonomic disturbances may be implicated. J VanNess (Philadelphia) also looked at cardiopulmonary exercise testing in CFS. Level of functional impairment can be assessed by use of VO2 max, which was low in the population tested. There was no control group, so it is unclear whether the results indicate effects of inactivity or pathology.

MICROBIOLOGY

The first paper in this session was presented on behalf of P Cheney (N Carolina). All chronic illnesses studied including GWS and CFS show prominent circulating plasma RNAs not observed in normal controls. Prominent RNA bands so far sequenced show homology with human genes which are noted for their tendency for gene rearrangement under severe physiologic stress. The sequences appear to be disease specific, varying by less than 1% between individuals with similar illness. Gene probes may therefore provide novel diagnostic and treatment possibilities.

C Snell (Philadelphia) concluded in his study that elevated levels of RnaseL are associated with reduced VO2max and exercise duration in those with CFS. The low tolerance for exercise maybe linked to abnormal oxidative metabolism, perhaps resulting from defective interferon responses. The results have implications for the testing of antiviral therapies in CFS, particularly those directed at the 2-5A synthetase/ribonuclease L pathway.

Assessment of the frequency of HHV6 in CFS was undertaken by the team at Columbia. D Ablashi showed that the majority of 24 patients studied from Incline Village, Nevada had HHV6 infection. HHV6 was detected in the plasma, CSF and PBMCs. The data suggests the presence of cell free infectious virus in the CSF. It was postulated that HHV6 invading the CNS may participate in the neurological manifestations of the disease. The potential for use of antiviral agents such as Foscarnet and Valciclovir was discussed, but some of the newer agents maybe more appropriate to determine whether HHV6 does play a role in CFS.

MICROBIOLOGY POSTERS

A poster also presented by Ablashi et al, showed good concordance between reactivation of HHV6 and presence of RnaseL. They could therefore be used together or separately in monitoring response to treatment. 2 patients were treated with ampligen, which inhibited HHV6 replication and upregulated the 2-5a synthetase/RnaseL pathway.

P de Becker (Brussels) presented data on 1546 CFS patients and 309 with chronic fatigue, showing that infectious agents, transfusion or hepatitis B vaccination may play an important role in the onset of CFS. Associated with these a number of stressors and consequent immunological and neuroendocrinological changes can contribute to the onset of the illness.

CFS patients with active HHV-6 infection were shown by J Brewer (Phoenix) to have activation of coagulation and are hypercoagulable. Hereditary thrombosis factors will increase the tendency. This maybe a significant factor in CFS contributing to symptoms.

C Jadin’s poster (S Africa) reflected on the importance of screening for rickettsia, chlamydia and mycoplasma in a number of diseases including CFS. This can provide valuable tools for treatment. That work was furthered also by P Bottero (Paris) who stated that these organisms may be implicated in CFS.

Low titres of antinuclear antibodies were found in 48% of those with CFS in a study of 68 patients in Barcelona by J Alegre et al. A small percentage of patients had markers of viral reactivation (EBV, CMV).

Lyme disease was addressed by M Cichon (Florida). 37 patients had been screened for Lyme disease as an exclusion in a study for CFS using ampligen. 14 of these patients had a positive test using the Lyme Urine Antigen test, which was found to be the most sensitive of all tests tried.

IMMUNOLOGY

K Maher et al (Miami) had found in preliminary studies that the intracellular content of NK cell lytic protein, perforin, correlates with the cytolytic potential of the cell. If perforin is removed in mice, the immune abnormalities are the same as in CFS and also as in a genetic disease of childhood (FHL) in which there is a mutation in the perforin gene causing impaired cytotoxic activity. Cytolytic protein granule protein concentrations were measured in CFS in an attempt to define the mechanism underlying the reported cytotoxic effects in CFS. Results showed that intracellular perforin was reduced in NK cells and in cytotoxic T cells in CFS patients. The findings substantiate the claims of an NK associated defect in CFS and suggest a molecular basis for reduced cytotoxicity.

Auto-immunity in CFS was reviewed by E Tan on behalf of a large international multicentre study. Low titres of antinuclear antibodies had previously been found in CFS patients, but although this could be a marker for CFS, it does not mean CFS is an auto-immune disease. This study was directed at extending initial observations showing the presence of autoantibodies to a cellular protein, expressed primarily in neuronal cells (MAP2). This is one of the most abundant proteins in neurons and is a marker for neuronal health. Disparities were observed in reactivity with MAP2 in CFS from the different centres and in normal controls. This may be a reflection of the heterogeneity of CFS patients from one centre to another. This may confirm the importance of subcategorising CFS studies according to issues such as type of onset, gender, illness duration etc. The disparities in controls remain unexplained. Preliminary evidence however, shows that other proteins beside MAP2 might also be target antigens in CFS autoimunity.

IMMUNOLOGY POSTERS

K de Meirleir (Brussels) found that the presence of an increased amount of LMW RnaseL correlates with higher levels of IFN gamma, which has antiviral properties. Normal NK cell numbers and high LMW/HMW RnaseL ratio correlate with higher IL-2 levels in CFS patients compared to controls.

Immunological studies on the blood of patients with Gulf War Syndrome were undertaken by A Vojdani (California). Results indicated that as with CFS, these sick veterans are suffering from neuro-immunological disorders.

A study using mice was presented by W Sheng (Minneapolis) and supported the hypothesis that cytokine expression in the CNS is involved in neurobehavioural responses to immunologic stimuli, coupled with reduction in activity. However psychological/physical stimuli such as swim-stress did not invoke upregulation of cytokine expression despite the resulting reduced physical activity.

GENETIC STUDIES

J Goldberg (Chicago) gave an overview of the role of genetic factors in CFS and the designs and methods that are used in genetic epidemiology and their use in CFS. One can study families looking at family history of disease and clusters of disease, or one can study fixed family clusters such as siblings, twin pairs etc. Family studies that involve DNA markers can be used to demonstrate genetic linkage to known marker loci.

A co-twin control study looking at psychiatric comorbidity in CFS was presented by R Herrell (Chicago). He found that lifetime PTSD, major depressive episode and panic disorder were more common in those with CFS than their unaffected co-twins. There is overlap in symptoms of CFS and depression (fatigue, poor cognition and sleep disorder) but this does not entirely account for the association.

Further twin studies were undertaken by N Afari (Seattle) and she had looked at the prevalence of chronic fatigue in the offspring of twins with and without CFS. She found that there was a substantial risk of having Chronic Fatigue for the offspring of both MZ and DZ twins where one twin had CFS. This is consistent with the possible familial nature of Chronic Fatigue. The offspring of the healthy member of the DZ pairs seem to be at greater risk than the offspring of the healthy member of MZ pairs. This suggests familial clustering of fatiguing illness in extended families with a member who has CF.

Comorbid clinical conditions in Chronic Fatigue using co-twin controls were undertaken by L Aaron (Seattle). She concluded that chronically fatiguing illnesses are associated with high rates of many clinical conditions. Prevalence of comorbid conditions was considerably higher in the fatigued twins than their non-fatigued co-twins. (e.g. fibromyalgia, irritable bowel syndrome, chronic pelvic pain, multiple chemical sensitivity and TMJ disorder). Regression analysis indicated that these associations could not be attributed solely to psychiatric illness.

D Lewis (Washington) used regional cerebral blood flow SPECT imaging to evaluate the relationship with CFS in monozygotic twins discordant for CFS. There was no evidence of distinctive patterns associated with CFS.

A further presentation by J Goldberg (Chicago) showed that the concordance rate for each definition of chronic fatigue is higher in MZ twins than DZ twins. This suggests that genes may play a role in the aetiology of CFS.

GENETIC STUDIES — POSTERS

However a study by Sabath et al (Seattle) found that the immune systems in discordant twin pairs were dissimilar and concluded that there was not a genetic basis. When looking at aerobic capacity in MZ twins discordant for CFS, R Schoene found that while exercise capacity was reduced in the CFS affected twins, both of the pairs of twins had strikingly suboptimal performances, suggesting familial susceptibility for low aerobic capacity. D Petersen (Nevada) found that 81 of 85 patients with CFS had deficient or absent levels of mannose-binding protein (an opsonin associated with various chronic diseases), giving credence to the theory of genetic predisposition.

BRAIN and NEUROLOGICAL ISSUES

R Mahurin (Seattle) opened this session by presenting research suggesting a potential means of identifying and quantifying neural substrates of task difficulty, cognitive effort and mental fatigue, using SPECT scanning. Unique features of cognitive impairment were identified, with those with CFS seeming to need to make more mental effort for cognitive tasks.

When looking for Chiari-1 malformations, D Clauw (Washington DC) did not find MRI evaluations of the cervical spine and posterior fossa differed in fibromyalgia subjects or controls.

G Moorkens (Antwerp) found there were specific neuro-endocrine differences after Hexarelin and GHRH administration between Fibromyalgia and CFS patients, suggesting different etiological mechanisms. GH, ACTH,TSH and prolactin responses were studied.

Two studies were presented by R Gracely (Washington DC). The first looked at the likelihood of a central defect in pain processing in fibromyalgia. Using MRI, activation of similar cerebral regions suggests cortical or subcortical amplification of pain in FM. A relative lack of response by the thalamus and caudate in patients is consistent with previous studies indicating reduced activity in these structures in chronic pain. The second controlled study, using ascending stimuli compared to random stimuli, suggested that expectancy effects do not account for the heightened pain sensitivity in FM.

BRAIN/NEUROLOGY POSTERS

A modified PASAT was used by G Lange et al ( NJ) to show that CFS patients, with objectively documented difficulties in auditory verbal information processing, demonstrated poorer performance during data acquisition. There was unique right hemisphere activation in the regions of the frontal gyrus, inferior parietal lobe and right post-central gyrus, as well as in the left posterior cingulate and right thalamus. These results are consistent with activations in healthy adults when task complexity is high or when performance is poor. Lange’s second poster had found that some CFS subjects had some enlargement in the body of the lateral ventricle. This maybe associated with white matter loss in the frontal and parietal lobes.

N McGregor et al (Newcastle, NSW) found that there was altered visual processing in CFS patients, and this was associated with evidence of altered connective tissue turnover and the accumulation of dietary trans-fatty acids.

B Evengard (Stockholm) concluded that there are different neurobiological profiles in CFS patients when compared with those with burnout and healthy controls. This suggests different underlying pathological processes.

INTERNATIONAL PERSPECTIVE — BELGIUM and THE NETHERLANDS

As a lot of research was going on in this part of the world, it was interesting to hear an overview of the developments in CFS in these regions.

J van der Meer presented figures suggesting a CFS prevalence of 451/100,000 in the Netherlands. He told us that 13% Dutch GPs never diagnose CFS, compared to 27% in 1993. The perceived problems by GPs were need for long consultations (89%), communication difficulties (43%) and poor co-operation (31%). 78% of cases are referred to specialists and 47% of cases are not diagnosed by GPs.

Assessment is multidimensional and includes a checklist for individual strengths, SIP, Beck, actometer, neuropsych and exercise testing. These instruments can then be used in clinical trials, such as using fluoxetine, nutritional supplements and CBT. Longitudinal assessments using these tools can also add to clinical judgement. Use of computer assisted diagnosis was also discussed. There was shown to be a discrepancy of 12% between computer and clinical assessment with computer diagnosis being stricter. Physicians generally find assessment of impairment in CFS difficult.

Regarding pathogenesis, a combination of predisposing factors and heterogeneous initiating factors are thought to combine with somatic and psychological perpetuating factors to produce ongoing symptoms. No evidence has been found in the Netherlands for a role of persisting pathogens such as mycoplasma, Bornavirus, CMV, HIV or Dengue fever. Immunologically, the cytokine changes do not correlate with illness severity.

Gijs Bleijenberg then reviewed studies of 3 groups of patients using CBT, group support and natural course of illness. Fatigue and functional impairment were measured, together with outcomes such as performance, psychological wellbeing and work rehabilitation. He pointed out that focusing on symptoms caused impairment and fatigue, coupled with loss of control, and the fact that physical attributions meant that fear of fatigue following exercise impaired exercise involvement. Those participating in CBT had 16 one hour sessions over 8 months, the support group had 11 one and half hour meetings over 8 months. All patients wore an aktometer for 2 weeks. 31% of the CBT group dropped out and were found to be those with more psychological co-morbidity. Those completing CBT had a definite positive outcome, while the support group and natural course groups experienced minimal improvement. There was significant improvement (up to 50%) both clinically and in Karnofsky scores in the CBT group. The therapists involved had no prior clinical experience of CFS and 82% agreed that those with CFS were more difficult to treat than psychiatric patients. Final conclusion was that CBT was more effective than attendance at support group, but was less effective in those who were passive rather than active. A protocol for the passive patients needs to be developed. He pointed out the importance for CFS patients of initially rehabilitating towards personal activities rather than work, because of the difficulties in getting a job after prolonged illness.

A further Dutch study had looked at fatigue in CFS compared to recovered breast cancer patients. Fatigue was rated as severe in 38% of the cancer patients, but fatigue impairment was worse on all parameters in CFS.

The Belgian perspective was covered by K de Meirleir and P Englebienne (Brussels) who pointed out that they headed a specialist hospital clinic where all patients were referred and tended to be the most severe. These patients therefore had a very thorough and specialised clinical workup. SPECT scans were found to be generally abnormal, the proliferation index of T lymphocytes was diminished.

Possible triggers were considered and 60% of patients were found to have an infection at onset. 50% had two onset factors. The increased sensitivity to alcohol experienced by most patients would point to an ion channelopathy. Symptoms were factor analysed and fell into 4 main groups: general, cognitive, musculoskeletal and mood change/psychiatric.

Much of the Belgian research focused on the abnormal enzyme pathways and 88% of patients tested positive to RnaseL, (as found by Suhadolnik). The 37Kda is produced by calpain cleavage, and the whole process affects the calcium and potassium channel mechanisms. RnaseL is a likely marker for CFS, and correlates with severity. (It is negative in AIDS). The ALT and the haematocrit are adversely affected by the abnormal RnaseL ratio and when the ratio is higher the serum calcium is low, which is consistent with a channelopathy. The channelopathy will lead to low body potassium because of loss, metabolic alkalosis and hyperventilation syndrome. Symptoms relating to CVS, abnormal hormone levels and abnormal exercise response follow. There is a secondary hypomagnesia, abnormal sodium retention and changed tryptophan uptake. The latter leads to depression. The CD4/CD8 ratio correlates with VO2 max. A very complex model was proposed, the mechanism leading to a Th1/Th2 shift with viral reactivation and intracellular opportunistic infections. 68.7% patients were infected with mycoplasma in Belgian studies with a predominance of M.hominis. Mycoplasma can lead to calpain cleavage. Mycoplasma can invade all tissues such as monocytes, muscle cells etc.

Therapeutic strategies were aimed at restoration of immune competence with normalisation of the Th1/Th2 ratio coupled with elimination/decrease in the load of micro-organisms. These are 2 completely different approaches, which need to be used together, and the reason some treatments fail maybe because of a unilateral approach. Ampligen has been found to be of great benefit though is still very expensive and difficult to access in most countries. Antibiotics such as azithromycin have been found to lead to 50% clinical recovery after a long course (often 6 months of treatment completely restored very young patients). Shorter courses often lead to relapse after completion. Specialised techniques such as PCR and gene tracking for mycoplasma have led to better outcomes.

CBT has been used in Belgium with some success, but the effects seem to be temporary, and long-term studies at 4 years show a tendency to relapse in most people. 8 year follow up of patients using the above de Meirleir protocol show 92% still have not relapsed.

CLINICAL STUDIES

Three different diagnostic labels (CFS, Nightingale Disease and ME) were used in an interesting study presented by L Jason to determine their effects on the attributions of medical trainees and undergraduates regarding CFS. Medical trainees viewed the CFS label as the most accurate based on the case history described, the ME label was associated with the poorest prognosis. When labelled ME, the undergraduates however were more likely to attribute a physiological cause to the illness coupled with decreased potential for organ donation.

The role of interpersonal violence history and PTSD diagnosis in Chronic Fatigue and CFS was discussed by R Taylor (Chicago). Although there was a higher prevalence of these conditions in the histories of those with different types of Chronic Fatigue, there is no greater incidence in those with CFS compared to other fatiguing conditions.

It is apparent that there is no relationship between the number of medically unexplained complaints such as chronic pelvic pain, chronic fatigue, back pain and tinnitus and psychopathology, according to a study presented by L Tiersky (NJ). The DIS was used to determine whether CFS patients had a psychiatric diagnosis following development of CFS as well as any lifetime history.

A Lyden (Washington DC) found a subset of individuals who began to experience CFS-like symptoms when they are not performing regular exercise. Baseline measures were taken before symptom development and there were differences in autonomic and HPA axis hypo- responsiveness, which are typically observed in those with established CFS. Symptoms developed following 7 days exercise cessation. This study may indicate that some individuals have a vulnerability to developing CFS according to their endocrine profiles.

P Fennell (NY) presented a study testing the validity of the Fennell Phase Inventory to measure the phases typically experienced by those with CFS. The phases are: crisis, stabilisation, resolution and integration. This instrument was found to accurately differentiate the phases of adaptation to the illness.

CLINICAL STUDIES — POSTERS

A plane crash in the area of Bijlmer resulted in a number of local people experiencing health problems. E Van Hoof (Brussels) presented data suggesting these complaints were similar to CFS and Gulf War illness. 67% were found to be infected with mycoplasma.

Type of onset was considered by D Cukor (NY) looking at whether those with sudden onset would have more psychopathology, somatic complaints and more circumscribed complaints that the gradual onset group. There was however no correlation and this study questions the utility of distinguishing CFS patients according to type of onset.

A Donnay had looked at whether carbon monoxide poisoning may play a role in the aetiology of CFS, FM and multiple chemical sensitivity. He found that those with these conditions did have an increase in end-tidal breath CO, which was enough to distinguish them from healthy controls, but not from each other. He therefore questioned the possibility that these patients may have been affected by exogenous CO. However he postulated that it is possible that the increased levels maybe due to endogenous CO derived from routine breakdown of heme proteins.

Functional status in CFS patients was assessed by K Busichio (NJ) using the community integration questionnaire (CIQ). This has provided valuable information regarding daily functioning in CFS. Those who are unemployed due to health problems demonstrate less community involvement and are generally less productive inside and outside the home than employed subjects. Physical rather than psychological factors contribute more to lower daily functioning.

J Baraniuk (Washington DC) showed a poster looking at Multiple Chemical Sensitivity (MCS) using a MCS questionnaire. 4 respiratory responses (cough, runny nose, shortness of breath and rhinitis) were found to have the power to predict positive responses and CFS status. 42% patients with CFS were found to suffer MCS compared to 3.8% controls. Clusters of substances most associated with the symptoms were: volatile organic compounds or fine particulate materials. Medication-related symptoms were common in women with CFS but not other groups.

Fibromyalgia patients and healthy controls were shown to have very consistent ratings for the whole range of pain perception in an ascending paradigm. The findings presented by R Gracely (Washington DC) do not support an exaggerated affective response in experimental pain in CFS.

PSYCHOLOGICAL ISSUES — POSTERS

35 Danish CFS patients were found to suffer severe social isolation,with none reporting a return to pre-morbid functioning after 5 years, in a poster presented by F Albrecht (Maryland). Two reported that they were performing close to normal work and social life. Most reported deterioration in social and familial contact and entertainment. These results do suggest that CFS produces severe functional impairment and substantial recovery is uncommon.

A Peckerman (NJ) confirmed that living with CFS is highly stressful, but results of the study are more equivocal regarding the view of CFS as a stress disorder. In CFS the stress is not attributable to inefficient coping skills and does not appear to affect symptoms adversely. However those who acquired the illness after Gulf War service do seem to have problematic coping strategies. Results suggest that learning more adaptive coping skills maybe a useful adjunct to management in both Gulf War Veterans with CFS.

Traumatic and negative life experiences at any time in one’s life leave one prone to attribute the illness to a psychological cause, according to a poster presented by K Busichio et al (NJ). It seems likely that the earlier life events can leave one vulnerable to psychological attributions. Different treatment approaches may therefore be needed for these patients, as this may impact on the progression of the illness. In a second poster by the same team, participants’ attributions about their illness paralleled the type of disability reported. Belief that the illness was physical in nature correlated with overall and specific decreases in physical functioning, while psychological attributions were related to issues such as motivation. Illness attributions can be an important issue in formulating a treatment plan. Their 3rd poster found that traumatic and negative life events do relate to dysfunction in CFS. Using the SF36, physical functioning correlated with the occurrence of any traumatic experiences and with negative life events during the onset of CFS. The Mental health Index correlated with negative life events during and after the onset of CFS. Pain index correlated with occurrence of any traumatic experience. The timing of events may relate to specific areas of future disability.

The group also looked at the issue of malingering, using measures to estimate whether in fact those with CFS had neuropsychological impairments as a result of lack of effort during testing or attempts to feign impairment for financial gain. No subjects were found to be performing sub-optimally on a measure of effort, however subjects who reported more cognitive difficulties performed worse on the test, showing that those with cognitive difficulties put less effort into testing – though this was not considered significant.

Psychiatric co-morbidity and symptoms in fatiguing illnesses was studied by E Axe (Los Angeles) and it was found that only 3 of 14 CFS-related symptoms were associated with psychiatric disorders such as major depression or a somatization disorder. These symptoms were cognitive complaints, sleep disturbance and headaches. Treating these symptoms therefore could have a positive effect for those patients who are depressed.

BIOCHEMISTRY — POSTERS

There were 2 posters by the team in Newcastle (NSW) presented by N McGregor. The first was an analysis of serum lipid changes associated with fatigue, muscle pain and different factor symptom groupings. Results suggested that each measure represents a distinct change in lipid chemistry. It was further suggested that investigation of lipid metabolism and low fat diets in the treatment of CFS patients is warranted. The 2nd poster also looked at symptom clusters. The different factor groupings were associated with changes in red cell oxidative marked parameters, suggesting that each measure represented a distinct change in chemistry.

P Soetekouw (Nijmegen) studied 25 patients and 25 controls to assess carnitine levels but found no significant differences in levels of total carnitine, free carnitine and 20 carnitine esters between CFS patients and controls.

Skeletal oxidative damage was observed in CFS patients by D Racciatti et al (Chieti, Italy). This was thought to be a consequence of imbalance between an abnormal production of reactive oxygen species (due to oxidative metabolism related to mitochondrial activity) and a disabled scavenger enzyme system. This data supports an organic origin of CFS.

CHILDREN and ADOLESCENTS

K Rowe (Melbourne) reviewed the symptom patterns occurring among 189 adolescents with CFS. Fatigue and headaches were found to be the most frequent symptoms, followed by sleep problems, cognitive difficulties and myalgia. 85% had had a viral or febrile onset. From the responses to a 38-item, well-validated symptom questionnaire, 3 subgroups could be identified on a severity basis. The most severe group had more pain and fatigue, the moderately severe group had more neuro-cognitive symptoms and the least severe group had more headache/nausea and abdominal pain.

In her second paper, Rowe had followed up 200 young people with CFS seen in a specialist clinic with illness duration from onset ranging from one to ten years. Average duration of illness at follow up was 38 months. The severity of illness had no effects on the duration of illness, but the most severe group had taken the longest to reach a diagnosis. Depression was linked to severity of illness and occurred in 7%. 76% had found professionals who took them seriously and provided management strategies, symptom relief and emotional support were helpful. Of the 70% who had tried alternative therapies, less than a third had found at least one therapy that had helped, and most thought these approaches a waste of money. 30% considered they were well with 60% able to function in full-time study or work. Early diagnosis, implementation of management strategies and flexible school arrangements eased many of the burdens of chronic illness. During recovery, the symptom that tended to go first was headache followed by fatigue.

D Bell (Lyndonville) had also followed up 35 children and adolescents with CFS thirteen years after illness onset. Average age at onset was 12 years and 77% had gradual onset. 13 (37%) of the children considered themselves resolved of illness, 15 (43%) were well but not resolved, 4 (11%) considered themselves chronically ill and 3 (8.6%) considered themselves worse. 8 (23%) had missed more than 2 years of school and 5 of these were still ill at follow up. The amount of school missed correlated with illness severity at follow up and perceived social impact of the illness. The time of resolution was between 1 and 9 years, and this was often a very gradual process. Those who missed the least school made the best recovery. There was no correlation between age of onset and level of recovery.

Work looking at vascular perturbations in CFS in adolescents in relation to chronic orthostatic intolerance was presented by J Stewart (NY). He found that leg circumference tends to be larger in CFS patients on standing, and resting venous pressure was higher in CFS than controls. Data also suggests that the threshold for oedema is lower and filtration is increased. These findings make CFS patients particularly vulnerable to dependent pooling and oedema. This may imply a redistribution of blood to the lower extremities even when supine, accounting for tachycardia through vagal withdrawal.

PAEDIATRIC POSTERS

M Scott Smith (Seattle) compared adolescents with CFS and migraine. Those with CFS were found to have far greater functional disability than adolescents with migraine or controls, but did not report higher levels of anxiety or depression. In both CFS and migraine, somatization scores were higher than in normal controls.

Adaptive coping styles do not seem to improve symptom severity or improve perceived self competence in adolescence, according to a study by D Bell et al (Lyndonville). Increased social support is helpful in the area of perceived self competence.

S Hoogveld (Nijmegen) found significant differences in personality profiles of adolescents with CFS compared to controls and this might indicate a higher vulnerability to internalising problems. These young people were described by parents as being more ego-controlled, more conscientious and less extrovert than controls. Emotional stability was often lower, but parents described their CFS children as more agreeable.

TREATMENT

The first presentation in this session was by D Williams (Washington DC). He had done a randomised controlled trial of CBT in fibromyalgia (FM). 2 groups were assigned: standard medical treatment coupled with aerobic fitness instruction or CBT plus standard medical care. CBT was given over 6 sessions. Of the CBT group, 25% achieved improvement in physical functioning at 12-month follow up, while 12% of those in the standard medical group achieved the same level of improvement. This represents a 48% improvement with the addition of CBT, and this finding supports the inclusion of CBT as an essential component in standard treatment procedures for FM.

The efficacy and safety of modafinil for the treatment of fatigue in Multiple Sclerosis (MS) was discussed by K Rammohan (Ohio). Modafinil is described as a wake-promoting agent shown to be effective in narcolepsy. 200mg daily was found to significantly improve fatigue and daytime sleepiness in a study of 72 MS patients. It was well tolerated, though side effects were more common at 400mg, and at this higher dose there was no extra improvement noted. This drug may be a useful addition to the pharmacological options available to treat fatigue associated with MS and other fatiguing conditions.

K Rowe (Melbourne) presented a 7-year follow up of 58 young people with CFS who were involved in an IV gammaglobulin trial. There was continued improvement in functioning with 75% able to work or study full-time. 17% still described themselves as disabled. A small percentage had relapsed or experienced exacerbation of symptoms, and the occurrence of other serious illnesses was not greater than could be expected by chance.

D Cox (London) described the inpatient occupational therapy intervention for CFS at Romford, Essex. The principles of CBT and graded activity were applied to this very ill group of patients. At 6 months there was no significant change in symptoms or ability level, but there was a significant effect on the patients’ perceived health, length of time tired and management of the illness, with 72% of the inpatient group, compared to 44% of the comparison group, stating that they felt better and felt the illness was being managed better. It was found wise to limit the hospital stay to no more than 6 weeks, as transition back to home would then prove more difficult. Age had no significant effects on outcome, although those who had been ill for less than 5 years did better.

A pilot study of tumour necrosis factor fusion protein, etanercept (a substance which blocks the interaction of TNF with its cell surface receptors) was done by K Lambrecht et al (Minneapolis). 6 CFS patients were given an 8 week trial of etanercept injections. Significant reductions were observed in the severity of fatigue, muscle pain, headache and lymphodynia. Exercise tolerance was improved. This lends support to the theory that proinflammatory cytokines maybe involved in the pathogenesis of CFS, and this should be further studied in a placebo-controlled trial.

A safety and feasibility study of immunomodulation using lymph node extraction, ex vivo cell culture and autologous cell reinfusion by N Klimas et al (Miami) found a lack of adverse effects, coupled with favourable clinical results. 13 patients were studied of which 2 had unsuitable nodes. The remaining 11 all underwent the procedure successfully with significant positive clinical outcome over 24 weeks. An improved cytokine shift correlated with clinical improvement, and this holds weight to the idea that increases in cytokines lead to symptoms. At 18 months, improvement is sustained. Further clinical trials seem warranted.

TREATMENT POSTERS

T Emms (Newcastle NSW) presented data suggesting that food intolerance as opposed to allergy may represent co-morbidity in a subgroup of CFS patients, and this could have implications for development of gastro-intestinal dysfunction. It was suggested that clinicians should trial a treatment protocol involving dietary history coupled with elimination diets.

Longterm nutritional supplementation was shown by K Dykman (Texas) to have some positive effect on the general functioning in FM/CFS patients. Glyconutritional products and phytogenins were used. Polynutrient supplements were also trialled by F Brouwers et al (Nijmegen) and no significant differences were found between placebo and experimental condition.

Downregulation of Th2 cytokine production with a shift to Th1 cytokine expression was suggested as a useful intervention in CFS by R Partarco (Miami). Past approaches have been based on the use of Staphylococcus vaccine, influenza and/or rubella vaccines and autologous reinfusion of expanded lymph cells. Further studies are needed to allow elucidation of factors that mediate Th2-type cytokine expression predominance and maintenance.

G Whalen (Washington DC) considered the issue of autonomic dysfunction in CFS, and compared immune and cardiac responsiveness to beta-adrenergic agonist infusion (using isoproterenol) in CFS patients and controls. No differences were found, suggesting that there are no differences in afferent sensitivity to beta-adrenergic receptor occupation in this illness.

C Van der Eb (Illinois) designed a college course experience for students and their partners with CFS. Field work involved one-to-one support by the student with a person with CFS (a buddy system). The students were involved in a community-based learning programme educating them about the realities and personal costs of such an illness. This provided much needed, individualised support for those with CFS.

The use of ampligen in CFS by C Snell (Philadelphia) in 2 women with CFS led to some improvement in quality of life , decreased pain, enhanced energy levels and improved cognition. Ampligen intervention was also looked at from the economic point of view by A Shillington (Illinois). A pharmacoeconomic analysis was performed on data collected from 92 patients with severe CFS, who were randomised to a double blind, placebo-controlled trial of ampligen. A twice weekly infusion of 400mg ampligen over 24 weeks was found to significantly reduce the consumption of valuable health resources, and thereby reduce the costs of treating CFS. The therapy was well tolerated. A poster by D Strayer (Philadelphia) also showed considerable benefit from the use of ampligen as measured by Karnofsky scores and cognitive function data. 41 severely debilitated CFS patients were treated with the majority continuing treatment beyond 24 weeks. In his 2nd poster, he compared twice weekly with thrice weekly dosing with ampligen , and found that the thrice weekly dosing offered no advantages.

Midodrine (a peripheral alpha-antagonist) was used with some improvement in adolescents with orthostatic intolerance and CFS by M Alexander (Boston). Serious side effects seem uncommon and this drug can be a useful adjunct for management. If fludrocortisone is used concurrently, there is a small risk of hypertension.

Group CBT for 31 patients with CFS was compared to a waiting list control group of 35 CFS patients by G Bleijenberg (Nijmegen). It was found that CBT had a positive effect on fatigue when compared to the control group, but differences on outcomes concerning functional impairment were opposite to what was expected, in that those in the control group improved while those on CBT remained the same.

On the final afternoon of the conference, the current state of our knowledge and various aspects of underlying pathology, diagnosis and management were summarised:

BIOLOGICAL ASPECTS OF CFS AND FIBROMYALGIA (A Komaroff, D Clauw)

The issue of pain in fibromyalgia (FM) was considered. Many syndromes are associated with FM such as irritable bowel syndrome, and the generalised pain threshold is low. Patients have an increased sensitivity to noxious stimuli, but normal detection threshold to touch. Likely mechanisms are: expectancy, hypervigilance or central changes in nociceptive processing, which is more physiological. Physiological mechanisms seem to be more prominent than psychological. The problem seems to be at the level of the cord or brain and not at the skin. Levels of substance P are 3-4 times higher in the spinal fluid in FM, and MRI studies show changes when the patient is experiencing pain. i.e. we are looking at a sensory processing defect.

Various types of brainscanning were reviewed. On MRI there are small areas of high signal in the white matter, and although many of these are seen in healthy controls, all studies have shown an increased number in those with CFS/FM. (80% in patients, 20% in controls). SPECT scans are more physiologic and show a “tattered” signal in CFS. A functional MRI gives a better picture of the physiology. The brain appears to be working harder than in a healthy person doing the same task. Other parts of the brain seem to be brought in to “help”.

Abnormalities have been found in both the parasympathetic and sympathetic nervous systems. In the neuro-endocrine system, the hypothalamus is disordered, with disruption of ACTH stimulation and abnormalities in prolactin and growth hormone.

DIAGNOSTIC STRATEGIES IN CFS (K de Meirleir)

History taking is an important part of making a diagnosis of these disorders. One needs to consider whether the illness occurred as a result of an infectious on non-infectious event. History of all the following need to be considered: blood transfusion, surgery, febrile illness, toxic exposure, bites or stings, stress, trauma, foreign travel, STDs, sleep patterns, dental problems, ownership of pets or birds, immunisations, pregnancy, bleeding gums, sinus and respiratory infections, TM joint dysfunction etc.

First level of testing should include: full blood picture, IgE, intracellular RBC magnesium and serology, ECG including an exercise test. (The U+T wave is often big, and may look like a prolonged UT segment), chest Xray, abdominal ultrasound and further tests depending on specific symptoms e.g. panoramic Xray of dental roots, pulmonary function testing.

Second level of testing, much of which could only be done in a specialised laboratories (such as in Brussels) would include: LMW RnaseL/actin fragments, swabs to check for toxin producing coag uve staph aureus, immunophenotyping (total lymphocytes, activated T cells, CD4/CD8 ratio, NK subsets etc), antithyroid antibodies, immunoglobulins, Th1/Th2 profile, TNFalpha, interleukin 1, PCR for mycoplasma, chlamydia etc., hypoglycaemia test ( looking at ACTH, GH, cortisol, prolactin after injection of insulin), polysomnography in males over 35 (for sleep apnoea), neuropsychiatric evaluation. It was pointed out that many physicians would not have access to these specialised tests, and also much time would be needed, particularly for tests such as a full neuropsychological investigation, which could take 3 hours.

DIAGNOSIS OF FIBROMYALGIA (L Calabrese)

10% of the population have widespread pain, females more so than males. The prevalence of FM is 2%. There is no diagnostic test. The more tender points, the greater the distress. The more constant the pain, the more likely the diagnosis is to be FM. The pain is achy and generalised, and waxes and wanes. 30% patients reviewed recently had an active mood disorder. Patients usually feel drained with a poor sleep pattern, headaches and concurrent irritable bowel is common.

Examination reveals the typical tender points, with no evidence of muscle or joint disease. (NB if the thumb nail blanches, one is applying adequate pressure). Lab investigations show normal acute phase reactants (ESR,CRP), muscle enzymes and thyroid function. Treatable disease must be excluded, such as sleep disorder, subclinical hypothyroidism, ankylosing spondylitis. One cannot rely solely on the tenderpoint examination and FM can co-exist with other conditions. FM does not respond to prednisone, so benefit from this may indicate a condition such as polymyalgia.

REVIEW OF TREATMENT OF CFS

We are looking at a heterogeneous population with lack of objective diagnosis. Few treatment trials have been done, and there is an absence of objective response markers. Newly diagnosed cases may be quite different from long-standing cases. For correct management a diagnosis is vital. Many hypotheses for therapeutic intervention exist, and a wide range of drugs have been tried such as: calcium channel blockers, psychoactive agents, opium antagonists, immune modifiers, antidepressants, stimulants etc.

Various treatments were reviewed:

Sleep impairment is an important area of treatment and may respond to tricyclics or clonazepam. Antidepressants do appear generally beneficial. Cortisol has been shown to have no benefit and may cause adrenal suppression. A trial with low dose hydrocortisone showed some mild benefit, but this is not generally recommended. For those suffering neurally mediated hypotension, treatment maybe helpful. In a study using of galantamine, an acetylcholinesterase inhibitor, there was no significant benefit. Growth hormone showed minimal help. CBT has been found to be better than just standard practice. Most people who have tried NADH have not been helped, though a small percentage did improve in one study. Neither treatment for allergies or use of antifungals have been found to be helpful. Some studies have shown evening primrose oil to be useful, but echinacea is of no help. Surgery for Chiari syndrome is rarely of use. There is some evidence that some antivirals can be of use, when viral pathology is implicated.

REVIEW OF TREATMENT OF FIBROMYALGIA (D Clauw)

There is often maladaptive illness behaviour with psychiatric co-morbidity, issues of secondary gain, general distress etc. as opposed to physiologic factors, but the greater the physiologic factors, the more likely the behavioural problems will develop.

Some drugs will raise the concentration of anti-nociceptive compounds. a) descending pathways: tricyclics, SSRIs, new MAOs. b) opioids c) GABA d) cytokines (no suitable drug) e) CRH. We know of no drugs to lower the concentration of pro-nociceptors, except possibly dextromethorphan.

Treatment approaches should include: education, pharmacology (tricyclics for sleep, symptom based therapy such as tramadol for pain etc.), aerobic exercise (which should begin after pharmacological approach to reduce pain), CBT to reduce maladaptive behaviours in a stepped approach and some complementary therapies (acupuncture, biofeedback/relaxation, physical modalities).

RESEARCH and REHABILITATION PANEL DISCUSSION (Chair: P Levine)

A 4 phase model of CFS was outlined by P Fennell using the Fennell Phase Inventory: crisis, stabilisation, resolution and integration. During each phase, 3 domains were important: physical/behavioural, psychological and social/interactive. For each domain in each phase, medical assessment and intervention and phase assessment and intervention were discussed. A very useful protocol was provided in a handout, which would be important for physicians, psychologists, social workers and other professionals dealing with CFS. D Uslan enlarged on some of the detail, and much discussion ensued regarding this important multi-dimensional approach to management.

Education of physicians was considered really important for the benefit of all CFS patients and a co-ordinated team approach seems the ideal.

CASE DEFINITION — considerations for revising the 1994 criteria (Chair: W Reeves)

(CDC and prevention planning session)

An open forum discussed this issue before the conference officially began. The actual definition of fatigue was covered. There are many parameters of fatigue (e.g. the fatigue in cancer is quite different to that in CFS) and the question was asked “Is fatigue the right way to identify these patients?”. One needs to be able to qualify and quantify fatigue. As yet there is no “perfect” definition of fatigue.

N Klimas pointed out that we should not refer to the definition as the CDC definition but the International Consensus definition. There is confusion between the research and clinical definition, and the current definition refers to the research case definition. She went on to say that fatigue has much ambiguity, such as physical and mental, frequency, duration and level etc., and the exclusion criteria are vague, e.g. obesity, depression.

L Jason talked of the standardisation/operation of the classification instruments. CFS patients are more functionally impaired than, for example those with diabetes. One needs questionnaires on various aspects of the illness. There are also a number of overlapping syndromes. Useful measures are the sickness impact scale, medical outcome scale, sleep assessment questionnaire, fatigue severity scale, Beck depression inventory, scale of fatigue (Australia) and SCID and DIS for assessment of psychiatric co-morbidity. Onset, severity and phases of illness need to be established.

Study design was discussed by S Vernon (CDC). There is often a lack of the number of symptoms at particular times in the illness, and this may relate to its waxing and waning character. There are problems in the absence of a specific lesion. Systemic blood needs to be used in the hope to find molecular markers.

W Reeves said that as the current definition was developed by consensus we need to empirically define CFS, The 1994 guidelines are driven by “fatigue”. There is no single marker for CFS, so it is necessary to decide which symptom complex best defines CFS.

Data was collected in a population based study in Wichita looking at the whole community of 27,000. 3500 were found to be fatigued for more than one month, and 46 had CFS. A dichotomous factor analysis of the symptom complexes was performed. Chronic fatigue, weakness and non-refreshing sleep were the factors not differentiating patients and controls. There was some overlap between those who were chronically unwell and those with CFS. These findings were similar to what was found in Gulf War Illness. Very few minority groups were seen.

In summary important conclusions were that patients with symptoms of fatigue need an intensive medical workup, and we cannot do research properly until we have a workable case definition.

NAME CHANGE WORKGROUP OPEN FORUM (N Klimas, C Lapp, L Jason)

This was a lively discussion in which the possibility of name change was addressed by a number of health professionals and CFS patients looking at the issue from many points of view. Names describing underlying pathology such as myalgic neuro-asthenia, neuro-endocrine immune disorder and myo-encephalopathy were suggested, as were names of people who had suffered the illness or researched it, such as Nightingale disease or Shelokov syndrome. Incorporation of place names seemed too specific to particular epidemics: Royal Free disease, Incline village syndrome, Icelandic disease.

General consensus seemed to come down in favour of getting away from Chronic Fatigue Syndrome, and concentrating on the underlying pathogenesis, while retaining something familiar, such as the term ME, which is still widely used in a number of countries. Myo-encephalopathy did fit the bill, but obviously any decision for name change needs to be international and taken with great care to avoid need for further change, which eventually only confuses the issue further and does not work in patients’ best interests.

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