Question for Professors van Kuppeveld & van der Meer -ME/CFS

[Guest guest]

Questions for Professors

J M van Kuppeveld

and Jos W M van der Meer

Margaret

4th February 2012

Professors J M van Kuppeveld and Jos W M van der

Meer have recently stated in plain terms that

*In the past, several infectious agents have been associated

with CFS but none of these could be confirmed in

subsequent studies….*

(Lancet 4th February 2012: 379: 9814, e27 –

e28doi:10.1016/S0140-6736(11)60899).

Where is their evidence for the assertion that no infectious

agent *could be confirmed in subsequent studies* in

(ME)CFS patients?

Is their assertion correct? Did The Lancet’s 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’s editors) seem to have

overlooked:

1983

*Virological studies revealed that 76% of the patients

with suspected myalgic encephalomyelitis had elevated

sackie 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*

(BD Keighley, EJ Bell. JRCP 1983:33:339-341).

1987

*Recently associations have been found between sackie

B infection and a more chronic multisystem illness....

referred to as... myalgic encephalomyelitis… 140 patients

presenting with symptoms suggesting a postviral syndrome

were entered into the study... sackie B antibody levels

were estimated in 100 control patients... All the sackie

B virus antibody tests were performed blind... Of the 140

ill patients, 46% were found to be sackie B virus

antibody positive...

This study has confirmed our earlier finding that there is

a group of symptoms with evidence of sackie B

infection. We have also shown that clinical improvement

is slow and recovery does not correlate with a fall in

sackie B virus antibody titre*

(BD Calder et al. JRCGP 1987:37:11-14).

1988

*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).

1988

*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.

sackie 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).

1990

*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).

1990

*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... Subsequently...

31% had evidence of recent active enteroviral

infection... There has been a failure to recognise the

unique epidemiological pattern of ME...

sackie 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.

sackie 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 1990:66:526-530).

1991

*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 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:

*Molecular viral studies have recently proved to be

extremely useful. They have confirmed the likely

important role of enteroviral infections, particularly with

sackie B virus*

(Postviral fatigue syndrome: Current neurobiological

perspective. PGE Kennedy. BMB 1991:47:4:809-814)

*We conclude that persistent enteroviral infection plays a

role in the pathogenesis of PVFS... The strongest evidence

implicates sackie viruses...

Patients with PVFS were 6.7 times more likely to have

enteroviral persistence in their muscles*

(JW Gow and WMH Behan. BMB 1991:47:4:872-885).

1992

*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

sackie B viruses and 76% homology with poliomyelitis

virus, demonstrating beyond any doubt that the material

was enterovirus*

(Press Release for the Albany Conference, Professor

O Behan, University of Glasgow, October 1992).

1993

*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).

1993

*These data support the view that while there may

commonly be asymptomatic 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).

1994

*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*

( J Suhadolnik, L , Cheney et al.

In Vivo 1994:8:599-604).

1994

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).

1995

*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....

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).

1995

*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 1995:46:310-313).

1997

*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).

2001

*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 sackie 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

sackie 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*

( Levine. JCFS 2002:9:1/2:41-51).

2003

*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 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:

*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).

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

*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...

Infections 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 of (ME)CFS... Antibodies to

sackie 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*

(LD Devanur, JR Kerr. Journal of Clinical Virology 2006:

37(3):139-150).

2006

*(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*

L Komaroff. Journal of Clinical Virology

2006:37:S1:S39-S46.

2007

*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*

( R Kerr. Editorial. J Clin Pathol 14th September

2007. Epub ahead of print).

2007

*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 oesophagogastroduodenoscopy, 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...

Interestingly, 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).

2009

Dr Chia, an infectious diseases specialist from

Torrance, California, who specialises in ME/CFS, is on

record:

*I 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*

(http://aboutmecfs.org/blog/?p=865).

````

These few illustrations from the many available serve to

illustrate that Professors van Kuppeveld and van der Meer’s

assertion that:

*In the past, several infectious agents have been

associated with CFS but none of these could be

confirmed in subsequent studies... .*

is demonstrably incorrect.

The ignoring of the evidence-base of infection in ME/CFS is

all the more disturbing given that 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 – comment on article by

Broderick et al*: (http://bit.ly/zBrZCZ).

Professor van der Meer accuses the International

Consensus Panel of bias towards the biomedical construct:

*the authors seek to discard the findings in published

studies that have applied the existing international criteria, if

the result do not fit with their notions of causation.... In a

21st century consensus document, accounting in a

balanced fashion for the strength of the evidence is an

essential element*,

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.