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Documented involvement of viruses in ME/CFS
Margaret Williams 30th December 2009
For decades it has been known and shown that viruses play a role in ME/CFS.
Now there is evidence of a direct association with a gamma retrovirus - XMRV
-- that disables the immune system in ME/CFS, thus allowing numerous latent
viruses to re-activate, which could result in the protean symptomatology.
As Professor Nancy Klimas said in her November 2009 lecture at the
University of Miami: "We've always thought something like that has to go on
in (ME)CFS because you all have some neuro-inflammation. Your brain has a
low grade level of inflammation. And you have some inflammation in the
tissues that make hormones, particularly in the hypothalamic- pituitary- axis.
And this is a virus that infects that type of tissue." (see below).
Latent viruses that have been particularly studied in relation to ME/CFS
include Coxsackie B virus (CBV), Epstein Barr virus (EBV) and human herpes
virus-6 (HHV-6), and illustrations are provided below.
However, advised by psychiatrists of the Wessely School, in the UK the NICE
Guideline of 2007 recommends limited serology testing for certain viruses
only, which excludes testing for Coxsackie B virus, for which there is the
most evidence (testing for Epstein Barr Virus, a particular interest of
Professor Peter White is, however, permitted).
Given that a classified synonym for ME/CFS is "post-viral fatigue syndrome"
(ICD-10 G93.3) and given that, like the MRC PACE Trial, the NICE Guideline
purports to apply to people with "CFS/ME", it is striking that the Guideline
states on page 141: "Serological testing should not be carried out unless
the history is indicative of an infection".
It is notable that the PACE Trial Investigators did not include virological
testing of participants in their trial that is based on their theory that
patients with "CFS/ME" are merely deconditioned, so it needs to be
ascertained what, exactly, do the Wessely School psychiatrists understand
the term "post-viral" to mean if not a history indicative of an infection?
The following are illustrations of viral involvement in ME/CFS:
Describing an outbreak of infection of the central nervous system
complicated by intense myalgia in late summer 1952 affecting nurses at the
Middlesex Hospital, London, the author (ED Acheson, who later became UK
Chief Medical Officer) reported the clinical features to be severe muscular
pain affecting the back, limbs, abdomen and chest, with evidence of mild
involvement of the central nervous system, diarrhoea, vomiting, respiratory
distress, paresis and brain stem involvement that included nystagmus, double
vision and difficulty in swallowing; additionally, bladder symptoms occurred
in more than half the patients. Acheson highlighted this small outbreak
because of the similarity to atypical poliomyelitis (ED Acheson. Lancet: Nov
20th 1954:1044-1048) . The label of "atypical poliomyelitis" was originally
given to ME (The Disease of a Thousand Names. David S Bell. Pollard
Publications, Lyndonville, New York, 1991). Many patients today experience
exactly the symptoms described by Acheson, but such symptoms are dismissed
by the Wessely School as somatisation and as hypervigilance to normal bodily
Acheson described and compared the outbreak at the Royal Free in 1955 with
the outbreak at The Middlesex in 1952, noting the relatively prolonged
active course of the disease, marked muscular pain and spasm, involvement of
the lymph nodes, liver and spleen, tenderness under the costal margins, and
ulcers in the mouth, all of which - if looked for and if not dismissed as
somatising -- are still to be found in "pure" ME today (ED Acheson. Lancet:
Aug 20th 1955:394-395) .
In his detailed review of numerous outbreaks of Benign Myalgic
Encephalomyelitis from 1934, Acheson described the common characteristics of
the disease and clinical picture, which included agonising muscular pain,
headache, nausea, sensory disturbances, stiffness of the neck and back,
dizziness, muscular twitching, tremor and in-coordination, localised
muscular weakness, emotional lability, problems with memory and
concentration, hyperacusis, somnolence and insomnia, with relapses being
almost inevitable, together with variability of symptoms. Signs included
hepatic enlargement, lymphadenopathy and evidence of CNS involvement,
nystagmus being "almost invariable" in some of the outbreaks. The question
of hysteria was addressed and discounted: "Final points against mass
hysteria as a major factor in the syndrome are the consistency of the course
of the illness and the similarities in the symptoms.The disorder is not a
manifestation of mass hysteria" and Acheson specifically warned that the
diagnosis of ME should be reserved for those with (virally induced) evidence
of CNS damage: "If not, the syndrome will become a convenient dumping ground
for non-specific illnesses characterised by fluctuating aches and pains,
fatigue and depression", exactly the situation that exists in the UK 50
years after Acheson's prophecy (ED Acheson. American Journal of Medicine,
April 1959:569-595) .
"The clinical picture was variable both in the time pattern of its
progression and the severity of the symptoms.It became clear early on in the
outbreak that there was organic involvement of the central nervous system
(and) there was objective evidence of involvement of the central nervous
system.The most characteristic symptom was the prolonged painful muscle
spasms.Bladder dysfunction occurred in more than 25% of all the
patients.Case to case contact between patients and their relatives also
occurred.McEvedy and Beard's conclusions (of mass hysteria) ignore the
objective findings of the staff of the hospital of fever, lymphadenopathy,
cranial nerve palsies and abnormal signs in the limbs.Objective evidence of
brain stem and spinal cord involvement was observed" (Nigel D Compston.
Postgraduate Medical Journal 1978:54:722- 724).
"Virological studies revealed that 76% of the patients with suspected
myalgic encephalomyelitis had elevated Coxsackie B neutralising titres (and
symptoms included) malaise, exhaustion on physical or mental effort, chest
pain, palpitations, tachycardia, polyarthralgia, muscle pains, back pain,
true vertigo, dizziness, tinnitus, nausea, diarrhoea, abdominal cramps,
epigastric pain, headaches, paraesthesiae, dysuria)..The group described
here are patients who have had this miserable illness. Most have lost many
weeks of employment or the enjoyment of their family (and) marriages have
been threatened." (BD Keighley, EJ Bell. JRCP 1983:33:339- 341).
".from an immunological point of view, patients with chronic active EBV
infection appear 'frozen' in a state typically found only briefly during
convalescence from acute EBV infection" (G Tosato, S Straus et al. The
Journal of Immunology 1985:134:5:3082- 3088. Note that "CFS" was then
thought to be caused by EBV).
"Epstein-Barr virus infection may have induced or augmented an
immunoregulatory disorder that persisted in these patients" (Stephen E
Straus et al. Ann Intern Med. 1985:102:7-16) .
"The clinical, pathological, electrophysiologica l, immunological and
virological abnormalities in 50 patients with the postviral fatigue syndrome
are recorded. These findings confirm the organic nature of the disease
(and) suggest that it is associated with disordered regulation of the immune
system and persistent viral infection" (PO Behan, WMH Behan, EJ Bell.
Journal of Infection 1985:10:211- 222.
"Ninety percent of the patients tested had antibodies to Epstein-Barr virus
and 45% tested had antibodies to cytomegalovirus. if this fatigue syndrome is
triggered by an infectious agent, an abnormal immune response may be
involved" (TJ Marrie et al. Clinical Ecology 1987:V:1:5-10) .
"Recently associations have been found between Coxsackie B infection and a
more chronic multisystem illness. A similar illness.has been referred to as.
myalgic encephalomyelitis. 140 patients presenting with symptoms suggesting a
postviral syndrome were entered into the study.Coxsackie B antibody levels
were estimated in 100 control patients.All the Coxsackie B virus antibody
tests were performed blind.Of the 140 ill patients, 46% were found to be
Coxsackie B virus antibody positive.This study has confirmed our earlier
finding that there is a group of symptoms with evidence of Coxsackie B
infection. We have also shown that clinical improvement is slow and
recovery does not correlate with a fall in Coxsackie B virus antibody titre"
(BD Calder et al. JRCGP 1987:37:11-14) .
"The illness has an acute onset after a variety of infections and then
enters a chronic phase characterised by fatigue and numerous other
symptoms..Other findings include a sleep disorder, mild immunodeficiency,
slightly low complement, anti-DNA antibodies and elevated synthetase which
is an interferon-associat ed enzyme commonly increased in viral infections"
(Irving E Salit. Clinical Ecology 1987:V:3:103- 107).
"These results show that chronic infection with enteroviruses occurs in many
PVFS (post-viral fatigue syndrome, a classified synonym for ME/CFS) patients
and that detection of enterovirus antigen in the serum is a sensitive and
satisfactory method for investigating infection in these patients..Several
studies have suggested that infection with enteroviruses is causally related
to PVFS.The association of detectable IgM complexes and VP1 antigen in the
serum of PVFS patients in our study was high.This suggests that enterovirus
infection plays an important role in the aetiology of PVFS" (GE Yousef, EJ
Bell, JF Mowbray et al. Lancet January 23rd 1988:146-150) .
"Myalgic encephalomyelitis was thought for some time to be produced by a
less virulent strain of poliovirus.chronic, persistent viruses may often be
reactivated during this illness.once reactivated, do these viruses then go
on to produce many of the symptoms of the disease? And what reactivates
these endogenous viruses? Could it be environmental toxins? Could it be
infection with other, exogenous lymphotropic viruses?" (Anthony L Komaroff.
Journal of Virological Methods. 1988:21:3-10) .
(In the light of the discovery in 2009 of the XMRV retrovirus - see below --
this paper by Professor Komaroff 21 years in advance of that discovery
showed remarkable prescience).
"Postviral fatigue syndrome / myalgic encephalomyelitis. has attracted
increasing attention during the last five years.Its distinguishing
characteristic is severe muscle fatiguability made worse by exercise.The
chief organ affected is skeletal muscle, and the severe fatiguability, with
or without myalgia, is the main symptom. The results of biochemical,
electrophysiologica l and pathological studies support the view that muscle
metabolism is disturbed, but there is no doubt that other systems, such as
nervous, cardiovascular and immune are also affected.Recognitio n of the
large number of patients affected.indicates that a review of this intriguing
disorder is merited..The true syndrome is always associated with an
infection.Viral infections in muscle can indeed be associated with a variety
of enzyme abnormalities. (Electrophysiolo gical results) are important in
showing the organic nature of the illness and suggesting that muscle
abnormalities persist after the acute infection.there is good evidence that
Coxsackie B virus is present in the affected muscle in some cases" (PO
Behan, WMH Behan. CRC Crit Rev Neurobiol 1988:4:2:157- 178).
"The main features (of ME) are: prolonged fatigue following muscular
exercise or mental strain, an extended relapsing course; an association with
neurological, cardiac, and other characteristic enteroviral complications.
Coxsackie B neutralisation tests show high titres in 41% of cases compared
with 4% of normal adults.These (chronic enteroviral syndromes) affect a
young, economically important age group and merit a major investment in
research" (EG Dowsett. Journal of Hospital Infection 1988:11:103- 115).
"Ten patients with post-viral fatigue syndrome and abnormal serological,
viral, immunological and histological studies were examined by single fibre
electromyographic technique..The findings confirm the organic nature of the
disease. A muscle membrane disorder.is the likely mechanism for the fatigue
and the single-fibre EMG abnormalities. This muscle membrane defect may be
due to the effects of a persistent viral infection.There seems to be
evidence of a persistent viral infection and/or a viral-induced disorder of
the immune system.The infected cells may not be killed but become unable to
carry out differentiated or specialised function" (Goran A Jamal, Stig
Hansen. Euro Neurol 1989:29:273- 276).
"Skeletal samples were obtained by needle biopsy from patients diagnosed
clinically as having CFS (and) most patients fulfilled the criteria of the
Centres for Disease Control for the diagnosis of CFS (Holmes et al
1988).These data are the first demonstration of persistence of defective
virus in clinical samples from patients with CFS.We are currently
investigating the effects of persistence of enteroviral RNA on cellular gene
expression leading to muscle dysfunction" (L Cunningham, RJM Lane, LC
Archard et al. Journal of General Virology 1990:71:6:1399- 1402).
"Myalgic encephalomyelitis is a common disability but frequently
misinterpreted. This illness is distinguished from a variety of other
post-viral states by a unique clinical and epidemiological pattern
characteristic of enteroviral infection.33% had titres indicative and 17%
suggestive of recent CBV infection.Subsequen tly.31% had evidence of recent
active enteroviral infection.There has been a failure to recognise the
unique epidemiological pattern of ME.Coxsackie viruses are
characteristically myotropic and enteroviral genomic sequences have been
detected in muscle biopsies from patients with ME. Exercise related
abnormalities of function have been demonstrated by nuclear magnetic
resonance and single-fibre electromyography including a failure to
coordinate oxidative metabolism with anaerobic glycolysis causing abnormal
early intracellular acidosis, consistent with the early fatiguability and
the slow recovery from exercise in ME. Coxsackie viruses can initiate
non-cytolytic persistent infection in human cells. Animal models demonstrate
similar enteroviral persistence in neurological disease. and the deleterious
effect of forced exercise on persistently infected muscles. These studies
elucidate the exercise-related morbidity and the chronic relapsing nature of
ME" (EG Dowsett, AM Ramsay et al. Postgraduate Medical Journal
A paper reporting the discovery of a retrovirus associated with (ME)CFS
(Retroviral sequences related to human T-lymphotropic virus type II in
patients with chronic fatigue immune dysfunction syndrome. Elaine
DeFreitas, Paul R Cheney, David S Bell et al. Proc Natl Acad Sci USA
1991:88:2922- 2926) is addressed in detail in the section "The role of
Viruses in ME/CFS".
"Persistent enteroviral infection of muscle may occur in some patients with
postviral fatigue syndrome and may have an aetiological role..The features
of this disorder suggest that the fatigue is caused by involvement of both
muscle and the central nervous system.We used the polymerase chain reaction
to search for the presence of enteroviral RNA sequences in a
well-characterised group of patients with the postviral fatigue syndrome.53%
were positive for enteroviral RNA sequences in muscle.Statistical analysis
shows that these results are highly significant. On the basis of this
study.there is persistent enteroviral infection in the muscle of some
patients with the postviral fatigue syndrome and this interferes with cell
metabolism and is causally related to the fatigue" (JW Gow et al. BMJ
"The findings described here provide the first evidence that postviral
fatigue syndrome may be due to a mitochondrial disorder precipitated by a
virus infection.Evidence of mitochondrial abnormalities was present in 80%
of the cases with the commonest change (seen in 70%) being branching and
fusion of cristae, producing 'compartmentalisati on'. Mitochondrial
pleomorphism, size variation and occasional focal vacuolation were
detectable in 64%.Vacuolation of mitochondria was frequent.In some cases
there was swelling of the whole mitochondrion with rupture of the outer
membranes.prominent secondary lysosomes were common in some of the worst
affected cases.The pleomorphism of the mitochondria in the patients' muscle
biopsies was in clear contrast to the findings in normal control
biopsies.Diffuse or focal atrophy of type II fibres has been reported, and
this does indicate muscle damage and not just muscle disuse" (WMH Behan et
al. Acta Neuropathologica 1991:83:61-65) .
Considerations in the Design of Studies of Chronic Fatigue Syndrome.
Reviews of Infectious Diseases. Volume 13, Supplement 1: S1 - S140.
University of Chicago Press. Contributing authors included Anthony L
Komaroff, David S Bell, Daniel L Peterson, Sandra Daugherty and Sheila
Bastien, whose work has been referred to in other parts of this document.
Postviral Fatigue Syndrome. British Medical Bulletin 1991:47:4: 793-907.
This major publication, published by Churchill Livingstone for The British
Council, includes papers by the Wessely School considered by some to be
misrepresentative of ME/CFS (for example: "History of postviral fatigue
syndrome" by S Wessely; "Postviral fatigue syndrome and psychiatry" by AS
David -- in which David, a co-author of the Oxford criteria, confirmed
that "British investigators have put forward an alternative, less strict,
operational definition which is essentially chronic.fatigue in the absence
of neurological signs, (with) psychiatric symptoms.as common associated
features" (AS David; BMB 1991:47:4:966- 988) and "Psychiatric management of
PVFS" by M Sharpe) but also contains the following:
"Molecular viral studies have recently proved to be extremely useful. They
have confirmed the likely important role of enteroviral infections,
particularly with Coxsackie B virus" (Postviral fatigue syndrome: Current
neurobiological perspective. PGE Kennedy. BMB 1991:47:4:809- 814)
"Our focus will be on the ability of certain viruses to interfere subtly
with the cell's ability to produce specific differentiated products as
hormones, neurotransmitters, cytokines and immunoglobulins etc in the
absence of their ability to lyse the cell they infect. By this means
viruses can replicate in histologically normal appearing cells and
tissues.Viruses by this means likely underlie a wide variety of clinical
illnesses, currently of unknown aetiology, that affect the endocrine,
immune, nervous and other .systems" (JC de la Torre, P Borrow, MBA Oldstone.
BMB 1991:47:4:838- 851).
"We conclude that persistent enteroviral infection plays a role in the
pathogenesis of PVFS.The strongest evidence implicates Coxsackie
viruses.Patients with PVFS were 6.7 times more likely to have enteroviral
peristence in their muscles" (JW Gow and WMH Behan. BMB 1991:47:4:872- 885).
"The postviral fatigue syndrome (PVFS), with profound muscle fatigue on
exertion and slow recovery from exhaustion seems to be related specifically
to enteroviral infection. The form seen with chronic reactivated EBV
infection is superficially similar, but without the profound muscle fatigue
on exercise" (JF Mowbray, GE Yousef. BMB 1991:47:4:886- 894).
"We will report at the First International Research Conference on Chronic
Fatigue Syndrome to be held at Albany, New York, 2-4 October 1992, our new
findings relating particularly to enteroviral infection.We have isolated RNA
from patients and probed this with large enterovirus probes.detailed
studies...showed that the material was true virus.Furthermore, this virus
was shown to be replicating normally at the level of transcription. Sequence
analysis of this isolated material showed that it had 80% homology with
Coxsackie B viruses and 76% homology with poliomyelitis virus, demonstrating
beyond any doubt that the material was enterovirus" (Press Release for the
Albany Conference, Professor Peter O Behan, University of Glasgow, October
"Samples from 25.9% of the PFS (postviral fatigue syndrome) were positive
for the presence of enteroviral RNA, compared with only 1.3% of the
controls.We propose that in PFS patients, a mutation affecting control of
viral RNA synthesis occurs during the initial phase of active virus
infection and allows persistence of replication defective virus which no
longer attracts a cellular immune response" (NE Bowles, RJM Lane, L
Cunningham and LC Archard. Journal of Medicine 1993:24:2&3: 145-180).
"These data support the view that while there may commonly be asyptomatic
enterovirus infections of peripheral blood, it is the presence of persistent
virus in muscle which is abnormal and this is associated with postviral
fatigue syndrome.Evidence derived from epidemiological, serological,
immunological, virological, molecular hybridisation and animal experiments
suggests that persistent enteroviral infection may be involved in. PFS" (PO
Behan et al. CFS: CIBA Foundation Symposium 173, 1993:146-159) .
"Individuals with CFS have characteristic clinical and laboratory findings
including.evidence of viral reactivation. The object of this study was to
evaluate the status of key parameters of the 2-5A synthetase/RNase L
antiviral pathway in individuals with CFS who participated in a
placebo-controlled, double-blind, multi-centre trial.The present work
confirms the finding of elevated bioactive 2-5A and RNase L activity in
CFS.RNase L, a 2-5A-dependent enzyme, is the terminal effector of an
enzymatic pathway that is stimulated by either virus infection or exposure
to exogenous lymphokines. Almost two-thirds of the subjects.displayed
baseline RNase L activity that was elevated above the control mean" (Robert
J Suhadolnik, Daniel L Peterson, Paul Cheney et al. In Vivo 1994:8:599-604) .
A note on the significance of this paper
Viral infections of cells results in the production and secretion of
cytokines, including the interferons. Interferons control the way that
cells respond to a virus by means of a group of inter-related enzymes that
comprise an anti-viral pathway. This pathway is known as the
2',-5'-oligoadenyla te synthetase/RNase L pathway.
RNase L (ribonuclease latent) is the key enzyme in the antiviral pathway
and is designed to degrade viral RNA. It has to be "turned on" by a small
molecule, 2-5 A. Binding of 2-5A to RNase L changes the enzyme from its
latent (inactive) state to its active state. When active, RNase L inhibits
viral protein synthesis and thereby prevents viral replication.
Several critical parts of the anti-viral pathway are not functioning
correctly in ME/CFS.
The level of RNase L enzyme activity has been demonstrated to be upregulated
(ie. increased) by as much as 1,500 times above normal levels, and
researchers at Temple University School of Medicine, Philadelphia, have
shown that not only is the activity of the RNase L enzyme significantly
higher in patients with (ME)CFS than in controls, but also that there is a
significant increase in the level of 2-5A (the molecule that converts RNase
L from its latent to its active state) and in the level of 2-5A synthetase
(the enzyme that synthesises the 2-5A activator molecule).
The most striking finding in patients with (ME)CFS is, however, that they
have a unique form of the RNase L enzyme. The size of the RNase L protein is
normally 80 kDa (kiloDaltons) , but in many people with (ME)CFS, this 80 kDa
enzyme is either scarce or missing altogether. Instead, a unique low
molecular weight (LMW) form of RNase L is observed (30 kDa). Besides its
smaller size, the LMW RNase L seen in (ME)CFS patients has other biochemical
differences from the 80 kDa RNase L. The LMW RNase L binds its activator
more tightly and is more potent than the 80 kDa form of RNase L.
Studies have revealed several connections between the RNase L pathway and
the clinical status of (ME)CFS patients, demonstrating that the increased
activity of the RNase L pathway is an indication of a lower state of health
and that all three measurements of the pathway are abnormal in (ME)CFS.
Studies carried out in various countries apart from the US (including
Australia, Belgium, France and Germany) have all confirmed the presence of
the LMW RNase L in (ME)CFS; moreover, two different methods using different
probes to detect RNase L accurately identified (ME)CFS patients.
Importantly, the RNase L ratio also distinguished individuals with (ME)CFS
from those with fibromyalgia or depression.
In addition, studies have shown that the presence of LMW RNase L is
independent of the duration of (ME)CFS symptoms: the LMW RNase L was
detected in individuals who had (ME)CFS symptoms for as long as 19 years.
The presence of the LMW RNase L identifies a group of people with (ME)CFS
who have an abnormally elevated anti-viral response, and the anti-viral
RNase L protein level and enzyme activity are potentially powerful
diagnostic tools for (ME)CFS (with grateful acknowledgement to Nancy
Reichenbach, associate scientist in the Department of Biochemistry at Temple
University School of Medicine, and to the CFIDS Association of America:
Although these important abnormalities were known about in 1994, and despite
the evidence of the reliability and reproducibility of RNase L testing that
was presented in 1999 at the Second World Congress on (ME)CFS in Brussels,
in the UK there has been continued opposition to such testing, not only by
the Wessely School (who consistently advise that only limited investigations
should be carried out), but also by the ME Association.
For example, the Medical Director of the ME Association, Dr Charles
Shepherd, apparently intended to inform readers of the ME Association' s
Newsletter (Perspectives) that his view of the international work on RNase L
was that it "may involve what I and many of my colleagues regard as
over-investigation for highly speculative abnormalities in antiviral pathway
activity", which seemed to echo Professor Anthony Pinching's view that
"over-investigation can (cause patients) to seek abnormal test results to
validate their illness" (Prescribers' Journal 2000: 40:2:99-106) . The Spring
2001 Issue of the ME Association' s Medical and Welfare Bulletin stated (on
page 9) about RNase L testing: "Having discussed the possible value of this
type of blood test with members of the MEA's Scientific and Medical Advisory
Panel, there is general agreement that insufficient evidence exists to
recommend that this test should be carried out for either diagnostic or
management purposes" (members of the SMAP included Professor Peter Behan,
Professor Leslie Findley, Dr John Gow, Professor Anthony Pinching and Dr
The ME Association did, however, co-fund with The Linbury Trust studies
examining RNase L activity: blood from patients attending the Fatigue
Service at St Bartholomew' s Hospital and from Romford, Essex, was sent to Dr
John Gow, who was working with Professors Peter and Wilhelmina Behan and Dr
Abhijit Chaudhuri, all then at the University of Glasgow. Gow et al's work
on a total of 22 patients with CFS was published in Clinical Infectious
Diseases (2001:33:12: 2080-2081) , the conclusion being that "patients with
CFS showed no significant activation" of either part of the RNase L pathway,
and that "assay of antiviral pathway activation is unlikely to form a
rational basis for a diagnostic test for CFS".
Professors Suhadolnik and De Meirleir robustly showed that Gow et al's study
was fundamentally flawed. Pointing out that "Over the years, our teams have
repeatedly observed an activation at the enzymatic level of the antiviral
pathway in subsets of CFS patients", they noted that Gow et al had (1)
misunderstood the established knowledge of the IFN pathway, (2) did not
confirm their observations of genetic expression at the transcriptional
level (which would have clarified their results), (3) used the terms
"genetic expression" and "activity" interchangeably, when they are not
necessarily synonymous (particularly when the research involves enzymes).
They also noted that confusion in the mind of Gow et al about these issues
led them to misquote their articles: "On the basis of their limited
observations, Gow et al challenge our observations and further deny any
rational basis to our proposal regarding the use of 37-kDa RNase L detection
as a biological marker for CFS. In our study, which they clearly misquoted,
we did not measure the enzymatic activity of the fragment and, hence, the
2-5A pathway activation as Gow and colleagues claimed. Instead, we limited
our study to the quantitative detection of the 37-kDa truncated enzyme.We
observed a significant increase in the 37-kDa RNase L level in patients with
CFS compared with that observed in healthy control subjects, patients with
fibromyalgia, and patients with depression.. Consequently, this does not
support the claim that the presence of the 37-kDa RNase L in CFS could only
be imparted to non-specific increases in the antiviral pathway
activation.Our data demonstrate that there is a more comprehensive
downstream cellular role for the signal transduction by IFN than what Gow
and colleagues pretend to present to the readers of Clinical Infectious
Diseases" (Clin Inf Dis 2002:34:1420- 1421).
The ME Association and its medical advisors, however, remained convinced
that Gow et al were correct: "A very important conclusion from this study is
that costly investigations such as the RNase L test, which assess the amount
of antiviral activity in ME/CFS, are unlikely to provide the basis for a
diagnostic test. Such tests are therefore of very questionable value in the
assessment of people with ME/CFS" (MEA Medical and Welfare Bulletin, Spring
2002, Issue No 6, page 10).
At the AACFS International Research Conference in 2003 held in Washington,
Wilhelmina Behan, as co-author of the Gow et al study, was publicly
challenged by Professor Suhadolnik to defend it, but was unable to do so.
Notwithstanding, on the basis of the Gow / Behan results, the ME
Association' s Medical Advisor remains of the view that "the presence of
.abnormalities in antiviral pathways has been assessed in research studies
funded by the ME Association" and that the results of these tests are not
"of proven value" (ME/CFS/PVFS: An exploration of the key clinical issues.
Dr Charles Shepherd and Dr Abhijit Chaudhuri, for The ME Association, 2007).
In contrast to such UK views about the significance of RNase L, in 2000
Professor Anthony Komaroff from Harvard had written about Professor De
Meirleir's work on RNase L in an Editorial in the American Journal of
Medicine: "What is this research telling us? It is another piece of
evidence that the immune system is affected in chronic fatigue syndrome and
it reproduces and extends the work of another investigator (Professor
Suhadolnik from the US), lending credibility to the result" (Am J Med
It is worth noting that elevated levels of RNase L are associated with
reduced maximal oxygen consumption (VO2 max) and exercise duration in ME/CFS
patients; Snell et al found that both abnormal RNase L activity and low
oxygen consumption were observed in most (ME)CFS patients, findings that
demonstrate that patients' extremely low tolerance for physical activity is
likely to be linked to abnormal oxidative metabolism, perhaps resulting from
defective interferon responses (Comparison of maximal oxygen consumption and
RNase L enzyme in patients with CFS. C Snell et al. AACFS Fifth
International Research and Clinical Conference, Seattle, January 2001;
It is also worth noting that the 37 kDa LMW RNase L fragment found in ME/CFS
patients is produced by cleavage of calpain (an apoptotic enzyme), and the
whole process affects the calcium and potassium ion channels, a
channelopathy that will lead to low body potassium (a known finding in
ME-CFS patients --Burnett et al found that total body potassium (TBK) was
lower in patients with (ME)CFS and suggest that abnormal potassium handling
by muscle in the context of low overall body potassium may contribute to
fatigue in (ME)CFS (Medical Journal of Australia, 1996:164:6:384) .
It is also important to note that patients who express the low molecular
weight RNase L may have problems with enzymatic detoxification pathways,
particularly in the liver. This is significant because of the resultant
adverse effect on thyroid function.
It has long been noted by practitioners that ME/CFS patients are often
clinically hypothyroid even though biochemically euthyroid. Evidence
suggests that such patients may not really be euthyroid, especially at the
tissue level. (Chopra IJ. J Clin Endocrinol Metab 1997:82(2):329- 334), so
particular attention needs to be paid to investigating the bioavailablity of
T3 because in ME/CFS, T3 levels are often low (or at the low end of the
normal range). Consequently, selenium levels need to be investigated in
patients with ME/CFS who have reduced T3 levels: this is because selenium
(as selenocysteine) is an integral component of two important enzymes,
glutathione peroxidase and iodothryonine deiodinase; it is expressed in the
liver and it regulates the conversion of thyroxine (T4) to the active and
more potent T3. Individuals who have a deficiency of 5' deiodinase cannot
produce T3 from T4, thus it is necessary to establish baseline levels of
selenium in ME/CFS patients whose T3 levels are low.
In the UK, the NICE Guideline does not recommend such testing.
In relation to RNase L, a recent literature review of the immunological
similarities between cancer and (ME)CFS pointed out:
"Cancer and CFS are both characterised by fatigue and severe disability
(and) certain aspects of immune dysfunctions appear to be present in both
illnesses.A literature review of overlapping immune dysfunctions in CFS and
cancer is provided. Abnormalities in ribonuclease (RNase L) and
hyperactivation of nuclear factor kappa-beta (NF-kappab) are present in CFS
and in prostate cancer. Malfunctioning of natural killer (NK) cells has
long been recognised as an important factor in the development and
recurrence of cancer, and has been documented repeatedly in CFS patients.
The dysregulation of the RNase L pathway, hyperactive NF-kappab leading to
disturbed apoptotic mechanisms and oxidative stress or excessive nitric
oxide, and low NK activity may play a role in the two diseases (and). are
present in both diseases. These anomalies may be part of the
physiopathology of some of the common complaints, such as fatigue" (Meeus M
et al. Anticancer Res 2009:29(11): 4717-4726) .
It seems that, even if not a specific biomarker for ME/CFS, the significance
of the abnormal RNase L anti-viral pathway in ME/CFS patients cannot be
sufficiently emphasised, but through the undoubted influence of the Wessely
School, ME/CFS sufferers in the UK are not permitted to have their
anti-viral pathway status investigated.
Chronic Fatigue Syndrome: Current Concepts. Clinical Infectious Diseases
1994: Volume 18: Supplement 1: S1 - S167. Ed. Paul H Levine. University of
Chicago Press. Contributing authors include: Paul H Levine, Alexis
Shelokov, Anthony L Komaroff, David S Bell, Paul R Cheney, Leonard H
Calabrese, Leonard A Jason, Seymour Grufferman, Hirohiko Kuratsune, Charles
Bombadier, Nancy G Klimas, Mary Ann Fletcher, Roberto Patarca-Montero,
Benjamin H Natelson, Robert J Suhadolnik, Daniel L Peterson, Dharam V
Ablashi, Fred Friedberg, Jay A Levy, Peter O Behan, Wilhelmina MH Behan and
Mark O Loveless.
In his Summary of the Viral Studies of CFS, Dr Dharam V Ablashi concluded:
"The presentations and discussions at this meeting strongly supported the
hypothesis that CFS may be triggered by more than one viral agent.Komaroff
suggests that, once reactivated, these viruses contribute directly to the
morbidity of CFS by damaging certain tissues and indirectly by eliciting an
on-going immune response" (Clin Inf Dis 1994:18 (Suppl 1):S130-133) . It is
recommended that the entire 167-page Journal be read to show how ill-founded
is the Wessely School's "CBT model" of ME/CFS.
In their Closing Remarks, Professors Komaroff and Klimas said: "Few studies
by psychiatrists are presented in this supplement. Many investigators who
have argued that CFS is primarily a psychiatric disorder chose not to
present their work" (Clin Inf Dis 1994:18:(Suppl 1):S166-167) .
"These results suggest there is persistence of enterovirus infection in some
CFS patients and indicate the presence of distinct novel enterovirus
sequences.Several studies have shown that a significant proportion of
patients complaining of CFS have markers for enterovirus infection..From the
data presented here.the CFS sequences may indicate the presence of novel
enteroviruses. It is worth noting that the enteroviral sequences obtained
from patients without CFS were dissimilar to the sequences obtained from the
CFS patients.This may provide corroborating evidence for the presence of a
novel type of enterovirus associated with CFS" (DN Galbraith, C Nairn and
GB Clements. Journal of General Virology 1995:76:1701- 1707).
"In the CFS study group, 42% of patients were positive for enteroviral
sequences by PCR, compared to only 9% of the comparison group.Enteroviral
PCR does, however, if positive, provide evidence for circulating viral
sequences, and has been used to show that enteroviral specific sequences are
present in a significantly greater proportion of CFS patients than other
comparison groups" (C Nairn et al. Journal of Medical Virology
"To prove formally that persistence rather than re-infection is occurring,
it is necessary to identify a unique feature retained by serial viral
isolates from one individual. We present here for the first time evidence
for enteroviral persistence (in humans with CFS)." (DN Galbraith et al.
Journal of General Virology 1997:78:307- 312).
"Recent developments in molecular biology.have revealed a hitherto
unrecognised association between enteroviruses and some of the most
disabling, chronic and disheartening neurological, cardiac and endocrine
diseases.Persistent infection (by enteroviruses) is associated with
ME/CFS.The difficulty of making a differential diagnosis between ME/CFS and
post-polio sequelae cannot be over-emphasised. (EG Doswett. Commissioned for
the BASEM meeting at the RCGP, 26th April 1998:1-10).
An important paper by Ablashi and Peterson et al suggested that in both
multiple sclerosis (MS) and (ME)CFS, HHV-6 reactivation plays a role in the
"Two disorders of significant importance, MS and CFS, appear to be
associated with HHV-6 infection.the data presented here show that both MS
and CFS patients tend to carry a higher rate of HHV-6 infection or
reactivation compared to normal controls. This immunological and virological
data supports a role of HHV-6 in the symptomatology of these diseases.Based
on biological, immunological and molecular analysis, the data show that
HHV-6 isolates from 70% of CFS patients were Variant A.Interestingly, the
majority of HHV-6 isolates from MS patients were Variant B.These data
demonstrate that the CFS patients exhibited HHV-6 specific immune
responses.Seventy percent of the HHV-6 isolates from CFS patients were
Variant A, similar to those reported in AIDS.It has already been shown that
active HHV-6 infection in HIV-infected patients enhanced the AIDS disease
process. We suspect that the same scenario is occurring in the pathogenesis
of MS and CFS.The immunological data presented here clearly shows a
significantly high frequency of HHV-6 reactivation in CFS and MS patients.
We postulate that active HHV-6 infection is a major contributory factor in
the aetiologies of MS and CFS" (DV Ablashi, DL Peterson et al. Journal of
Clinical Virology 2000:16:179- 191).
(HHV-6 is one of eight known members of the human herpesvirus family. It has
two variants [A and B]; the A strain is much more pathogenic and infects the
immune and central nervous systems. Reactivation in adults has been
associated with glandular fever, autoimmune disorders and diseases of the
nervous system. Active HHV-6 infections are not found in healthy people
without disease associations and reactivation can result in suppression of
bone marrow function and inflammation, and can cause damage in tissues such
as brain, liver or lungs. HHV-6 has been specifically linked to MS, AIDS and
(ME)CFS [Co-Cure MED: 2nd March 2002]. HHV-6 used to be called human
B-lymphotropic virus (HBLV); it was discovered in 1986 from the blood of
patients with AIDS. HHV-6 also correlates with 37kDa - the low molecular
weight form of RNase L that is known to exist as part of a dysregulated
antiviral pathway in ME/CFS patients).
"Over the last decade a wide variety of infectious agents has been
associated with CFS by researchers from all over the world. Many of these
agents are neurotrophic and have been linked to other diseases involving the
central nervous system (CNS).Because patients with CFS manifest a wide range
of symptoms involving the CNS as shown by abnormalities on brain MRIs, SPECT
scans of the brain and results of tilt-table testing, we sought to determine
the prevalence of HHV-6, HHV-8, EBV, CMV, Mycoplasma species, Chlamydia
species and Coxsackie virus in the spinal fluid of a group of patients with
CFS. Although we intended to search mainly for evidence of actively
replicating HHV-6, a virus that has been associated by several researchers
with this disorder, we found evidence of HHV-8, Chlamydia species, CMV and
Coxsackie virus in (50% of patient) samples.It was also surprising to obtain
such a relatively high yield of infectious agents on cell free specimens of
spinal fluid that had not been centrifuged" (Susan Levine. JCFS
(HHV-8 is associated with Kaposi's sarcoma which is found in HIV AIDS and
with some B-cell lymphomas).
Nicolson et al showed that multiple co-infections (Mycoplasma, Chlamydia,
HHV-6) in blood of chronic fatigue syndrome patients are associated with
signs and symptoms: "Differences in bacterial and/or viral infections in
(ME)CFS patients compared to controls were significant. The results indicate
that a large subset of (ME)CFS patients show evidence of bacterial and/or
viral infection(s) , and these infections may contribute to the severity of
signs and symptoms found in these patients" (Nicolson GL et al. APMIS
Seeking to detect and characterise enterovirus RNA in skeletal muscle from
patients with (ME)CFS and to compare efficiency of muscle metabolism in
enterovirus positive and negative (ME)CFS patients, Lane et al obtained
quadriceps biopsy samples from 48 patients with (ME)CFS. Muscle biopsy
samples from 20.8% of patients were positive, while 100% of the controls
were negative for enterovirus sequences. Lane et al concluded: "There is an
association between abnormal lactate response to exercise, reflecting
impaired muscle energy metabolism, and the presence of enterovirus sequences
in muscle in a proportion of (ME)CFS patients" (RJM Lane, LC Archard et al.
JNNP 2003:74:1382- 1386).
In their presentation to the US Assembly Committee, Drs Dharam Ablashi and
Kristin Loomis said:
"Reasons to suspect viruses as a cause of CFS and MS: In CFS, symptoms wax
and wane; antiviral pathways are activated; symptoms are similar to many
viral conditions; geographic outbreaks have been reported; gene expression
profiling found genetic variants that reduce antiviral defences. In MS,
antiviral pathways are activated; geographic outbreaks have been reported;
all demyelinating disorders with known aetiology have been caused by
viruses; symptoms wax and wane and worsen with viral infections.
"Evidence of central nervous system abnormalities in (ME)CFS are similar to
those in MS: reduced grey matter volume in bilateral prefrontal cortex;
abnormal uptake of acetyl-L carnitine in the prefrontal cortex; enlarged
ventricle volumes; increased small punctate lesions on MRI in MS and in a
subset of (ME)CFS; fatigue is present in more than 85% of people with MS and
in 100% of people with (ME)CFS; reduced information processing speed; memory
and cognitive problems".
Ablashi and Loomis pointed out that an analysis of studies of HHV-6 in
(ME)CFS differentiated between active and latent virus, with 83% being
positive (Assessment and Implications of Viruses in Debilitating Fatigue in
CFS and MS Patients. Dharam V Ablashi et al. HHV-6 Foundation, Santa
Barbara, USA. Submission to Assembly Committee/Ways & Means, Exhibit B1-20,
submitted by Annette Whittemore 1st June 2005).
In a review of the role of enteroviruses in (ME)CFS, Chia noted that initial
reports of chronic enteroviral infections causing debilitating symptoms in
(ME)CFS patients were met with scepticism and largely forgotten, but
observations from in vitro experiments and from animal models clearly
established a state of chronic persistence through the formation of double
stranded RNA, similar to findings reported in muscle biopsies of patients
with (ME)CFS. Recent evidence not only confirmed the earlier studies, but
also clarified the pathogenic role of viral RNA (JKS Chia. Journal of
Clinical Pathology 2005:58:1126- 1132).
"We now recognise that the immune system plays a crucial role in the
pathogenesis of (ME)CFS.A disruption of the HPA axis has been implicated in
the pathogenesis of (ME)CFS.A link between the immune system and the HPA
axis has long been established. it is likely that HPA axis dysfunction is not
the cause of (ME)CFS, but that it is secondary to the primary pathogenesis.
However, once invoked, HPA axis dysfunction may contribute towards the
perpetuation of the illness.Stress is known to have a significant modulating
effect on the pathogenesis of viral infection (and) the principal means by
which this influence occurs is likely to be via the HPA axis.Early beliefs
that (ME)CFS may be triggered or caused by a single virus have been shown to
be unsubstantiated (and) it is likely that different viruses affect
different individuals differently, dependent upon the .immune competence of
the individual.Infectio ns are known to trigger and perpetuate the disease in
many cases. Therefore, one valuable approach that has not been widely
adopted in the management of (ME)CFS patients is to exhaustively investigate
such patients in the hope of identifying evidence for a specific persistent
infection (but in the UK, NICE specifically does not permit such
investigations) ..Enteroviruses have been reported to trigger approximately
20% of cases if (ME)CFS.Antibodies to Coxsackie B virus are frequently
detected in (ME)CFS patients, and enterovirus protein and RNA occur in the
muscle and blood of (ME)CFS patients and their presence has been associated
with altered metabolism in the muscle upon exercise in the context of
Kerr et al then go on to provide evidence of other triggers of (ME)CFS which
include Parvovirus; C. pneumoniae; C. burnetti; toxin exposure and
vaccination including MMR, pneumovax, influenza, hepatitis B, tetanus,
typhoid and poliovirus (LD Devanur, JR Kerr. Journal of Clinical Virology
2006: 37(3):139-150) .
Having carried out a prospective cohort study of post-infective and chronic
fatigue syndromes precipitated by viral and non-viral pathogens, the authors
concluded: "The syndrome was predicted largely by the severity of the acute
illness rather than by demographic, psychological or microbiological
factors.Importantly , premorbid and intercurrent psychiatric disorder did not
show predictive power for post-infective fatigue at any time point.We
propose that .neurobiological mechanisms triggered during the severe, acute
illness.underpin the persistent symptoms domains of post-infective fatigue
syndrome" (Ian Hickie et al. BMJ 2006: 333:575).
"CFS is a poorly-defined medical condition.which, besides severe chronic
fatigue as the hallmark symptom, involves inflammatory and immune
activation.The type I interferon antiviral pathway has been repeatedly shown
to be activated in peripheral blood mononuclear cells of the most severely
afflicted patients.Recently, the levels of this abnormal protein have been
significantly correlated to the extent of inflammatory symptoms displayed by
(ME)CFS patients. We report here that active double-stranded RNA-dependent
kinase (PKR) is expressed and activated in parallel to the presence of the
37 kDa RNase L and to an increase in nitric oxide production by immune
cells.These results suggest that chronic inflammation due to excess nitric
oxide production plays a role in (ME)CFS and that the normal resolution of
the inflammatory process by NFK-b activation and apoptotic induction is
impaired" (Marc Fremont, Kenny De Meirleir et al. JCFS 2006:13:4:17- 28).
"(ME)CFS is associated with objective underlying biological abnormalities,
particularly involving the nervous and immune system. Most studies have
found that active infection with HHV-6 - a neurotropic, gliotropic and
immunotropic virus - is present more often in patients with (ME)CFS than in
healthy control subjects.Moreover, HHV-6 has been associated with many of
the neurological and immunological findings in patients with (ME)CFS"
Anthony L Komaroff. Journal of Clinical Virology 2006:37:S1:S39- S46.
"Research studies have identified various features relevant to the
pathogenesis of CFS/ME such as viral infection, immune abnormalities and
immune activation, exposure to toxins, chemicals and pesticides, stress,
hypotension. and neuroendocrine dysfunction. .Various viruses have been shown
to play a triggering or perpetuating role, or both, in this complex
disease..The role of enterovirus infection as a trigger and perpetuating
factor in CFS/ME has been recognised for decades.The importance of
gastrointestinal symptoms in CFS/ME and the known ability of enteroviruses
to cause gastrointestinal infections led John and Andrew Chia to study the
role of enterovirus infection in the stomach of CFS/ME patients.They
describe a systematic study of enterovirus infection in the stomach of 165
CFS/ME patients, demonstrating a detection rate of enterovirus VP1 protein
in 82% of patients.the possibility of an EV outbreak.seems unlikely, as
these patients developed their diseases at different times over a 20 year
period" (Jonathan R Kerr. Editorial. J Clin Pathol 14th September 2007.
Epub ahead of print).
"Since most (ME)CFS patients have persistent or intermittent
gastrointestinal (GI) symptoms, the presence of viral capsid protein 1
(VP1), enterovirus RNA and culturable virus in the stomach biopsy specimens
of patients with (ME)CFS was evaluated.Our recent analysis of 200 patients
suggests that. enteroviruses may be the causative agents in more than half
of the patients.At the time of oesophagogastroduod enoscopy, the majority of
patients had mild, focal inflammation in the antrum.95% of biopsy specimens
had microscopic evidence of mild chronic inflammation. 82% of biopsy
specimens stained positive for VP1 within parietal cells, whereas 20% of the
controls stained positive.An estimated 80-90% of our 1,400 (ME)CFS patients
have recurring gastrointestinal symptoms of varying severity, and epigastric
and/or lower quadrant tenderness by examination. Finding enterovirus protein
in 82% of stomach biopsy samples seems to correlate with the high percentage
of (ME)CFS patients with GI complaints.Interest ingly, the intensity of VP1
staining of the stomach biopsy correlated inversely with functional
capacity.A significant subset of (ME)CFS patients may have a chronic,
disseminated, non-cytolytic form of enteroviral infection which can lead to
diffuse symptomatology without true organ damage" (Chia JK, Chia AY. J Clin
Pathol 13th September 2007 Epub ahead of print).
As mentioned elsewhere, researchers from the Enterovirus Research
Laboratory, Department of Pathology and Microbiology, University of Nebraska
Medical Centre wrote a specially-commissio ned explanatory article for the UK
charity Invest in ME, in which they stated that human enteroviruses were not
generally thought to persist in the host after an acute infection, but they
had discovered that Coxsackie B viruses can naturally delete sequence from
the 5' end of the RNA genome, and that this results in long-term viral
persistence, and that "This previously unknown and unsuspected aspect of
enterovirus replication provides an explanation for previous reports of
enteroviral RNA detected in diseased tissue in the apparent absence of
infectious virus particles" (S Tracy and NM Chapman. Journal of IiME
In her lecture in November 2009 at the University of Miami, Professor Nancy
Klimas said about viruses and ME/CFS that much of the research at Miami and
internationally found that the viruses studied all have several things in
common: they infect cells of the immune system and the neurological system;
they are capable of causing latent infections and they can reactivate under
She also said that their early work at Miami in the late 1980s (published in
the Journal of Clinical Microbiology in 1989) showed that ME/CFS patients
had immune activation and poor anti-viral cell function. She then went on to
discuss the importance of the findings of the retrovirus XMRV (evidence of
which was published in Science on 8th October 2009), saying that it was
"very impressive work". She continued: "This Science paper was amazing for
a number of reasons. First, this team had put together such strong science
that they could go for a Science paper. Science is like the Mecca of
publication. If you get your stuff in Science, that's the best place you
could possibly (get it published). And they don't take just anything and
they sure, sure, sure don't take anything unless it's extremely well done,
validated and tested out. So they took this paper - they not only took it,
they put it in Science Express. They thought it was so important, they
published on a very fast track.The way (the researchers at the Whittemore
Peterson Institute) looked is very sophisticated. They then tried to find
(the virus) in all these other ways.they looked from a whole different
angle. Still found it. Backed up and looked from another angle. Still
found it.they had five different kinds of ways they looked for this virus.
And they were able to find the virus. That's why Science was so
impressed.It is a virus that can infect tissues that aren't white blood
cells.We've always thought something like that has to go on in (ME)CFS
because you all have some neuro-inflammation. Your brain has a low grade
level of inflammation. And you have some inflammation in the tissues that
make hormones, particularly in the hypothalamic- pituitary- axis. And this is
a virus that infects that type of tissue.It's pretty impressive that out of
101 (ME)CFS cases defined by clinical case definition or a research case
definition that they found 99 with the virus.And, oh, by the way, we have a
biomarker. Not a small deal. A biomarker - the virus itself. No better
biomarker than something that's clearly, tightly associated with an
illness.So the conclusion, it really is a big thing. It's a big thing.That
work we were already doing plays right into this. All the genomics work and
all the immunology work. This is all critical to the better understanding
of this illness and how this virus plays into it" (with grateful
acknowledgement to PANDORA and
The Whittemore-Peterson Institute's study that found the new human
retrovirus XMRV was listed as one of the top 100 scientific discoveries in
2009 in Discovery magazine's January 2010 issue (Co-Cure NOT: 30th December
There can be no dismissing the evidence of viral involvement in ME/CFS, much
of which pre-dated the PACE Trial.
The Trial Investigators, the MRC Data Monitoring and Ethics Committee, the
Trial Steering Committee and the Trial Management Group surely have a duty
to provide a convincing explanation for their decision not to inform Trial
participants of this fundamental evidence as, without it, participants may
not have been in a position to provide fully informed consent before
agreeing to enter the Trial.
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