http://www.meactionuk.org.uk/Question-for-Professors-van-Kuppeveld-and-van-=
der-Meer.htm
Questions for Professors Frank J M van Kuppeveld and Jos W M van der Meer
Margaret Williams 4th February 2012
Professors Frank J M van Kuppeveld and Jos W M van der Meer have recently
stated in plain terms that =93In the past, several infectious agents have
been associated with CFS but none of these could be confirmed in subsequent
studies=85.=94 (Lancet 4th February 2012: 379: 9814, e27 =96 e28
doi:10.1016/S0140-6736(11)60899).
Where is their evidence for the assertion that no infectious agent =93could
be confirmed in subsequent studies=94 in (ME)CFS patients?
Is their assertion correct? Did The Lancet=92s editorial team check the
authenticity of that assertion before publishing it?
Here is some evidence that Professors van Kuppeveld and van der Meer (and
The Lancet=92s editors) seem to have overlooked:
1983
=93Virological 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)=85.The group described
here are patients who have had this miserable illness=94 (BD Keighley, EJ
Bell. JRCP 1983:33:339-341).
1987
=93Recently associations have been found between Coxsackie B infection and =
a
more chronic multisystem illness=85.referred to as=85myalgic
encephalomyelitis=85140 patients presenting with symptoms suggesting a
postviral syndrome were entered into the study=85Coxsackie B antibody level=
s
were estimated in 100 control patients=85All the Coxsackie B virus antibody
tests were performed blind=85Of the 140 ill patients, 46% were found to be
Coxsackie B virus antibody positive=85This 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=94 (BD Calder et al. JRCGP 1987:37:11-14).
1988
=93These 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=85.Several studies have suggested that infection with enteroviruse=
s
is causally related to PVFS=85The association of detectable IgM complexes a=
nd
VP1 antigen in the serum of PVFS patients in our study was high=85This
suggests that enterovirus infection plays an important role in the
aetiology of PVFS=94 (GE Yousef, EJ Bell, JF Mowbray et al. Lancet January
23rd 1988:146-150).
1988
=93The 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=85These (chronic enteroviral
syndromes) affect a young, economically important age group and merit a
major investment in research=94 (EG Dowsett. Journal of Hospital Infection
1988:11:103-115).
1990
=93Skeletal 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)=85These data are the first demonstration of persistence of defective
virus in clinical samples from patients with CFS=85We are currently
investigating the effects of persistence of enteroviral RNA on cellular
gene expression leading to muscle dysfunction=94 (L Cunningham, RJM Lane, L=
C
Archard et al. Journal of General Virology 1990:71:6:1399-1402).
1990
=93Myalgic encephalomyelitis is a common disability but frequently
misinterpreted=85This illness is distinguished from a variety of other
post-viral states by a unique clinical and epidemiological pattern
characteristic of enteroviral infection=8533% had titres indicative and 17%
suggestive of recent CBV infection=85Subsequently=8531% had evidence of rec=
ent
active enteroviral infection=85There has been a failure to recognise the
unique epidemiological pattern of ME=85Coxsackie 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=85 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=94 (EG Dowsett, AM Ramsay et al. Postgraduat=
e
Medical Journal 1990:66:526-530).
1991
=93Persistent enteroviral infection of muscle may occur in some patients wi=
th
postviral fatigue syndrome and may have an aetiological role=85.The feature=
s
of this disorder suggest that the fatigue is caused by involvement of both
muscle and the central nervous system=85We used the polymerase chain reacti=
on
to search for the presence of enteroviral RNA sequences in a
well-characterised group of patients with the postviral fatigue
syndrome=8553% were positive for enteroviral RNA sequences in
muscle=85Statistical analysis shows that these results are highly
significant=85On the basis of this study=85there 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=94 (JW Gow et al. BMJ 1991:302:696-696).
1991
A major publication (Postviral Fatigue Syndrome. British Medical Bulletin
1991:47:4: 793-907, published by Churchill Livingstone for The British
Council) contains the following:
=93Molecular viral studies have recently proved to be extremely useful. Th=
ey
have confirmed the likely important role of enteroviral infections,
particularly with Coxsackie B virus=94 (Postviral fatigue syndrome: Current
neurobiological perspective. PGE Kennedy. BMB 1991:47:4:809-814)
=93We conclude that persistent enteroviral infection plays a role in the
pathogenesis of PVFS=85The strongest evidence implicates Coxsackie
viruses=85Patients with PVFS were 6.7 times more likely to have enteroviral
persistence in their muscles=94 (JW Gow and WMH Behan. BMB 1991:47:4:872-88=
5).
1992
=93We 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=85We have isolated
RNA from patients and probed this with large enterovirus probes=85detailed
studies...showed that the material was true virus=85Furthermore, 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=94 (Press
Release for the Albany Conference, Professor Peter O Behan, University of
Glasgow, October 1992).
1993
=93Samples 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=85We 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=94 (NE Bowles, RJM Lane, L
Cunningham and LC Archard. Journal of Medicine 1993:24:2&3:145-180).
1993
=93These data support the view that while there may commonly be asymptomati=
c
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=85Evidence derived from epidemiological,
serological, immunological, virological, molecular hybridisation and animal
experiments suggests that persistent enteroviral infection may be involved
in=85 PFS=94 (PO Behan et al. CFS: CIBA Foundation Symposium 173, 1993:146-=
159).
1994
=93Individuals with CFS have characteristic clinical and laboratory finding=
s
including=85evidence of viral reactivation=85The object of this study was t=
o
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=85The present work
confirms the finding of elevated bioactive 2-5A and RNase L activity in
CFS=85RNase 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=85displayed
baseline RNase L activity that was elevated above the control mean=94
(Robert J Suhadolnik, Daniel L Peterson, Paul Cheney et al. In Vivo
1994:8:599-604).
1994
In his Summary of the Viral Studies of CFS, Dr Dharam V Ablashi concluded:
=93The presentations and discussions at this meeting strongly supported the
hypothesis that CFS may be triggered by more than one viral agent=85Komarof=
f
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=94 (Clin Inf Dis 1994:18 (Suppl 1):S130-133).
1995
=93These results suggest there is persistence of enterovirus infection in
some CFS patients and indicate the presence of distinct novel enterovirus
sequences=85Several studies have shown that a significant proportion of
patients complaining of CFS have markers for enterovirus infection=85.It is
worth noting that the enteroviral sequences obtained from patients without
CFS were dissimilar to the sequences obtained from the CFS patients=85This
may provide corroborating evidence for the presence of a novel type of
enterovirus associated with CFS=94 (DN Galbraith, C Nairn and GB Clements.
Journal of General Virology 1995:76:1701-1707).
1995
=93In the CFS study group, 42% of patients were positive for enteroviral
sequences by PCR, compared to only 9% of the comparison group=85Enteroviral
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=94 (C Nairn et al. Journal of Medical Virology
1995:46:310-313).
1997
=93To 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)=85=94 (DN Galbraith et al.
Journal of General Virology 1997:78:307-312).
2001
=93Over 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)=85Because patients with CFS manifest a wid=
e
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=85It 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=94 (Susan
Levine. JCFS 2002:9:1/2:41-51).
2003
=93Differences in bacterial and/or viral infections in (ME)CFS patients
compared to controls were significant=85The 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=94 (Nicolson GL et al. APMIS
2003:111(5):557-566).
2003
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: =93There 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=94 (RJM Lane, LC
Archard et al. JNNP 2003:74:1382-1386).
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).
2006
=93Early 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
=85immune competence of the individual=85Infections are known to trigger an=
d
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)=85.Enteroviruses have bee=
n
reported to trigger approximately 20% of cases of (ME)CFS=85Antibodies 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 (ME)CFS=94 (LD Devanur, JR Kerr=
.
Journal of Clinical Virology 2006: 37(3):139-150).
2006
=93(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 =96 a neurotropic, gliotropic and
immunotropic virus =96 is present more often in patients with (ME)CFS than =
in
healthy control subjects=85Moreover, HHV-6 has been associated with many of
the neurological and immunological findings in patients with (ME)CFS=94
Anthony L Komaroff. Journal of Clinical Virology 2006:37:S1:S39-S46.
2007
=93Research 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=85and neuroendocrine dysfunction=85.Various viruses have been s=
hown
to play a triggering or perpetuating role, or both, in this complex
disease=85.The role of enterovirus infection as a trigger and perpetuating
factor in CFS/ME has been recognised for decades=94 (Jonathan R Kerr.
Editorial. J Clin Pathol 14th September 2007. Epub ahead of print).
2007
=93Since 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=85Our recent analysis of 200 patient=
s
suggests that=85 enteroviruses may be the causative agents in more than hal=
f
of the patients=85At the time of oesophagogastroduodenoscopy, the majority =
of
patients had mild, focal inflammation in the antrum=8595% of biopsy specime=
ns
had microscopic evidence of mild chronic inflammation=8582% of biopsy
specimens stained positive for VP1 within parietal cells, whereas 20% of
the controls stained positive=85An 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=85Finding
enterovirus protein in 82% of stomach biopsy samples seems to correlate
with the high percentage of (ME)CFS patients with GI
complaints=85Interestingly, the intensity of VP1 staining of the stomach
biopsy correlated inversely with functional capacity=85A 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=94 (Chia JK, Chia AY. J Clin Pathol 13th September 2007 Epub
ahead of print).
2009
Dr John Chia, an infectious diseases specialist from Torrance, California,
who specialises in ME/CFS, is on record: =93I believe that the main reason
(ME)CFS patients are symptomatic is due to continuing inflammatory response
toward viruses living within the cells, enteroviruses in most of the cases
I see. We have clearly documented certain enterovirus infections
triggering autoimmune responses in some patients=94 (
http://aboutmecfs.org/blog/?p=3D865).
These few illustrations from the many available serve to illustrate that
Professors van Kuppeveld and van der Meer=92s assertion that: =93In the pas=
t,
several infectious agents have been associated with CFS but none of these
could be confirmed in subsequent studies=85.=94 is demonstrably incorrect.
The ignoring of the evidence-base of infection in ME/CFS is all the more
disturbing given that Frank van Kuppeveld is Associate Professor (Infection
and Inflammation) in the Department of Medical Microbiology, Radboud
University Nijmegen Medical Centre and his research focuses on
enteroviruses, and Jos van der Meer is Professor of Internal Medicine and
Chairman of the Division of General Internal Medicine at Radboud University
Nijmegen Medical Centre who also works in the Nijmegen Institute for
Infection, Inflammation and Immunity.
Do Professors van Kuppeveld and van der Meer have no concern for accuracy?
Another article in which Professor van der Meer was a co-author appeared to
show a similar lack of attention to the existing biomedical evidence-base:
(A controversial consensus =96 comment on article by Broderick et al=94:
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02468.x/pdf).
Professor van der Meer accuses the International Consensus Panel of bias
towards the biomedical construct: =93the authors seek to discard the findin=
gs
in published studies that have applied the existing international criteria,
if the result do not fit with their notions of causation=85.In a 21st centu=
ry
consensus document, accounting in a balanced fashion for the strength of
the evidence is an essential element=94, yet he does exactly the same by
ignoring the biomedical evidence in his own articles.
From his two latest articles, one must question whether Professor van der
Meer contributes to scientific progress in what everyone agrees is a
controversial condition.
Equally, do editors of medical journals no longer see the need to adhere to
elementary rules of procedure by assuring themselves that what they publish
represents a potentially useful and original development of knowledge, and
that any contribution is squarely built on the foundations of existing
knowledge?
By publishing items that disregard the pre-existing body of knowledge,
authors and editors fail in their duty to provide readers with information
that can be relied upon and which can serve as a dependable basis for
future work.
Investigators are not free to declare established knowledge disproven
simply by ignoring the data on which that knowledge is predicated.
Merely ignoring and/or denying the existing knowledge-base, as Professors
van Kuppeveld and van der Meer appear to have done, serves no scientific
purpose but may actively delay the advancement of science and thus prolong
the incalculable suffering of people with ME/CFS.
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