The Hummingbirds' Foundation for M.E.

The Hummingbirds' Foundation for M.E. (HFME) is fighting for the recognition of M.E.,
and for patients to be accorded the same basic human rights as those with similar
disabling and potentially fatal neurological diseases such as M.S.

Articles sorted by author: Dr Chia

An important note:

Before reading this research/advocacy information given in the links below, please be aware of the following facts:

1. Myalgic Encephalomyelitis and Chronic Fatigue Syndrome are not synonymous terms. The overwhelming majority of research on CFS or CFIDS or ME/CFS or CFS/ME or ICD-CFS does not involve M.E. patients and is not relevant in any way to M.E. patients. If the M.E. community were to reject all CFS labelled research as only relating to CFS patients (including research which describes those abnormalities/characteristics unique to M.E. patients), however, this would seem to support the myth that CFS is just a watered down definition of M.E. and that M.E. and CFS are virtually the same thing and share many characteristics.

A very small number of CFS studies refer in part to people with M.E. but it may not always be clear which parts refer to M.E. The
A warning on CFS and ME/CFS research and advocacy paper is recommended reading and includes a checklist to help readers assess the relevance of individual CFS studies to M.E. (if any) and explains some of the problems with this heterogeneous and skewed research.

In future, it is essential that M.E. research again be conducted using only M.E. defined patients and using only the term M.E. The bogus, financially-motivated disease category of CFS must be abandoned.

2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as CFS, ME/CFS, CFS/ME, CFIDS or Myalgic Encephalopathy and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used CFS propaganda, as explained in A warning on CFS and ME/CFS research and advocacy and in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.


Unfortunately the author featured on this page (Dr Chia) supports the flawed concept and terminology of 'ME/CFS.'

While terms such as 'CFS' and 'ME/CFS' are unfortunately used by Dr Chia, it is certain that at least part of his research relates to authentic M.E. patients. The evidence for enteroviral causation of M.E. is overwhelming.

It is important that readers are aware however that the HFME not only does not support the concept of 'ME/CFS' but is in fact actively involved in campaigning against such problematic concepts, for the benefit of all patient groups involved.

Articles by Dr Chia MD (and Dr Chia MD)

Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach John kai-sheng Chia 1* and Andrew Y Chia 11 EV Med Research, United States. To whom correspondence should be addressed.
E-mail:
chiasann@pol.net.

J Clin Pathol. Published Online First: 13 September 2007. doi:10.1136/jcp.2007.050054 Copyright 2007 by the BMJ Publishing Group Ltd & Association of Clinical Pathologists.

Abstract

Aims The aetiology for chronic fatigue syndrome remains elusive although enteroviruses have been implicated as one of the causes by a number of studies. Since most CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, we evaluated the presence of viral capsid protein 1(VP1), Enterovirus RNA and culturable virus in the stomach biopsies of CFS patients.

Methods165 consecutive CFS patients underwent upper GI endoscopies and antrum biopsies. Immunoperoxidase staining was performed using enterovirus-specific monoclonal antibody (mAb) or a control mAb specific for cytomegalovirus. RT-PCR ELISA was performed on RNA extracted from paraffin sections or samples preserved in RNA-later. Biopsies from normal stomach and other gastric diseases served as controls. 75 samples were cultured for enterovirus.

Results135/165 (82%) biopsies stained positive for VP1 within parietal cells, whereas 7/34 (20%) of the controls stained positive (P <0.000001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from 6 patients at the onset of the CFS/abdominal symptoms, and 2-8 years later demonstrated positive staining in the paired specimens. EV RNA was detected in 9/24 (37 %) paraffin-embedded biopsy samples, and 1/21 controls had detectable EV RNA (p<0.01). 1/3 patient had detectable EV RNA from two samples taken 4 years apart. 5 patient samples demonstrated transient growth of non-cytopathic enteroviruses.

Conclusion Enterovirus VP1, RNA and non-cytopathic viruses were detected in the stomach biopsies of CFS patients with chronic abdominal complaints. A significant subset of CFS patients may have chronic, disseminated, non-cytolytic form of enteroviral infection, which could be diagnosed by stomach biopsies.

Discussion:

"An estimated 80 - 90% of our 1400 CFS patients have recurring gastrointestinal symptoms of varying severity, and epigastric and/or lower quadrant tenderness by examination, compared to only 3/100 control subjects (authors unpublished observations). Finding enterovirus VP1 protein in 82% of stomach biopsy samples seems to correlate with the high percentage of CFS patients with GI complaints."

"Finding enteroviral protein in some of the control subjects could be explained by the high prevalence of enterovirus infections throughout the year, affecting as many as 50 million Americans per year, or 17-25% of the population.4 Viral shedding in stool can persist for weeks after acute infections. It is probable that the control subjects had an asymptomatic or self-limited enterovirus infection within the preceding months. More careful screening of the control subjects may increase the specificity of this test in future studies."

"Enterovirus infection initiated the GI symptoms and CFS, and the persistence of the virus years later likely was responsible for the patients symptoms."

"Endomyocardial biopsy taken from patients with viral myocarditis demonstrated persistence of enteroviral genome in almost one-third of the samples 1 year after acute infection.31 Muscle biopsy specimens taken from CFS patients, and postmortem examination of brain tissues from one CFS patient, years after the initial infection, also demonstrated the persistence of enteroviral genome.69 32 Collectively, these findings clearly support the concept of viral persistence in human tissues."

"Taken together, the findings of enteroviral protein, RNA and the growth of non-cytopathic viruses in the stomach tissue of CFS patients, years after initial infection, suggest a strong association between enteroviral persistence/infection and CFS."

"By inference, a significant subset of CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection, which can lead to diffuse symptomatology without true organ damage. If confirmed, stomach biopsies could be used as a test to document viral persistence, and serve as an objective means to follow the response to antiviral therapy, in addition to quantitation of subjective complaints."


Journal of Clinical Pathology 2005;58:1126-1132; doi:10.1136/jcp.2004.020255 © 2005 by BMJ Publishing Group Ltd & Association of Clinical Pathologists

REVIEW The role of enterovirus in chronic fatigue syndrome J K S Chia Correspondence to: Dr J K S Chia CEI Research Center, 23560 Crenshaw Blvd 101, Torrance, CA 90505, USA; Chiasann@pol.net

PDF

ABSTRACT Two and a half decades after coining of the term chronic fatigue syndrome (CFS), the diagnosis of this illness is still symptom based and the aetiology remains elusive. Enteroviruses are well known causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles, and heart. Initial reports of chronic enteroviral infections causing debilitating symptoms in patients with CFS were met with skeptism, and had been largely forgotten for the past decade. 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 CFS. Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA through antiviral treatment. This review summarises the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.

DISCUSSION
Taken together, these data suggest that enterovirus can initiate and perpetuate the immunological response often seen in patients with CFS. Smouldering viral infection of various cells of the body with continuous expression of double stranded RNA and viral antigens could result in a chronic inflammatory state in the local tissues and account for the diverse symptoms reported by these patients.

The mechanism of viral persistence reconciles the two seemingly opposing observations of the past two decades: absence of live virion in chronically infected patients and animals and the finding of enteroviral RNA in the blood or other tissues. The finding of double stranded RNA is consistent with the clinical symptoms of patients with CFS. Without forming double stranded RNA, our patients with HIV or hepatitis B/C infections are usually not symptomatic, even though the measurable viraemia often exceeds 104–106/ml. In contrast, patients with CFS and the presence of viral RNA in peripheral blood leucocytes or in tissues, but without true viraemia, have debilitating symptoms; the severity of the symptoms correlated with the frequency of finding enteroviral RNA in the peripheral blood leucocytes (J Chia and A Chia. Detection of double-stranded RNA in the peripheral blood leukocytes of patients with the chronic fatigue syndrome. Abstract T-101. In: Program of the 104th General Meeting for the American Society of Microbiology. New Orleans: Louisiana, 2004). In most of the patients with CFS, the cyclic nature of low grade febrile illness and severe exacerbation after physical activity would be consistent with a cyclical pattern in the viral replicative activity.

It is probable that viral RNA found inside cells, in a stable double stranded form, can dissociate and replicate using viral RNA replicase; some of the positive strands, although restricted in replication,51 are translated to viral proteins during active metabolic states (for instance, exercise), which subsequently perpetuates the immunological response, including but not limited to synthesis of specific neutralising antibody. Consistent with this hypothesis, a recent study on Sjögren’s syndrome clearly detected enteroviral RNA and VP1 protein in minor salivary gland biopsies from these patients, but not in controls.52 From the available data in the literature, however, it is not possible to exclude with complete certainty the possibility that a few virions are actually formed and sequestered in membrane vesicles within the infected human cells.

Among other immunostimulatory effects, double stranded RNA is a potent inducer of interferon synthesis, which activates intracellular RNase, with resultant degradation of excessive single stranded RNA. The finding of a higher level of RNase L activity in the mononuclear cells of patients with CFS is consistent with this paradigm.53,54 However, enough positive and negative strands probably recombine to form stable double stranded RNAs, which are resistant to RNAse L inactivation, and the life cycle will start again when the pressure of the immune response decreases. Ironically, the continuing inflammatory response towards persistently infected cells/tissues to halt viral infection may be partially responsible for the difficulty in finding viral genomes in these patients, and may also be responsible for the symptoms.

Take home messages

  • A severe flu-like illness occurs in most cases of chronic fatigue syndrome (CFS), suggesting that an infection triggers and possibly perpetuates this syndrome

     

  • Common viral infections and unusual causes of CFS could be diagnosed based on the details of the initial flu-like illness, if present, epidemiological history, and early virological testing

     

  • Different laboratories from Europe and recently from the USA have found enteroviral RNA in the tissues, including peripheral blood mononuclear cells and muscles, of patients with CFS

     

  • Viral persistence through the formation of stable double stranded RNA reconciles the two opposing observations of the past two decades: (1) the absence of live virion in chronically infected patients and animals and (2) the presence of enteroviral RNA in the blood or other tissues

     

  • Smouldering viral infection of various cells with continuous expression of double stranded RNA and viral antigens could result in a chronic inflammatory state in the local tissues, accounting for the diverse symptoms

     

  • Interferon {alpha} and {gamma} act synergistically against enterovirus in vitro, and preliminary studies suggest that this combination may be an effective treatment for patients with chronic enteroviral infection

     

Self replicating double stranded RNA molecules (replicons) have been well studied and are currently used as vectors for DNA vaccines and drug susceptibility assays.55,56 Double stranded RNAs can be extremely potent adjuvants for immune responses or, alternatively, these molecules with certain sequences may silence our genes by blocking our mRNA,57 although the evidence for this last mechanism is not yet available for CFS.

"Ironically, the continuing inflammatory response towards persistently infected cells/tissues to halt viral infection may be partially responsible for the difficulty in finding viral genomes in these patients, and may also be responsible for the symptoms"

The paradox remains, however, that despite an ongoing immune response, these viral RNA infected cells are not eradicated. It is possible that viruses hide in long living, immunologically privileged cells, including but not limited to, macrophages, muscles, myocardial cells, and neurones,28–37 although these cells are unable to produce much live viruses, perhaps, in part, because of the pressure from local interferon and high concentrations of neutralising antibody—a form of cryptic infection. Viral antigen has been identified in tissues by virus specific monoclonal antibodies but positive staining did not allow the differentiation between membrane bound viral proteins and sequestered virions.58,59 Persistent infection of B cells and monocytes/macrophages, the cells initially responsible for the uptake/transport of virus, has been well described for other intracellular pathogens.60 Recently, we have found enteroviral RNA in the bone marrow samples of two patients with CFS and cyclic neutropenia (JK Chia, unpublished observation, 2004), suggesting that stem cells in the bone marrow could be a source of ongoing viral infection, as reported in animal models of enteroviral infection.59

Thus, renewed interest is needed to study further the role of enterovirus as the causative agent of CFS. Many aspects of this research need to be addressed but there are three urgent priorities.

(1) To overcome the technical difficulties associated with the enteroviral RNA detection assay, because a reliable and reproducible measurement of cell associated viral RNA will provide a marker for antiviral treatment and provide conclusive evidence of chronic infection.

(2) To perform a proof of concept, randomised, double blinded, placebo controlled clinical trial investigating the efficacy of the combination of interferon {alpha} and {gamma}.

(3) To develop inhibitors for viral RNA replicase, the main mechanism for RNA replication, which allows the persistence of the viral genome in infected cells. In the future, a well designed, randomised, controlled trial of antiviral treatment will ultimately provide crucial information on the pathogenic role of enterovirus in patients with CFS and other chronic diseases.

ACKNOWLEDGEMENTS
The laboratory work was supported by the Chu-Lee Tu memorial research fund.

© 2005 by BMJ Publishing Group Ltd & Association of Clinical Pathologists


From IiME

'Dr Chia is an infectious disease specialist practicing in Torrance, California, USA and has published research recently (Chronic fatigue syndrome  associated with chronic enterovirus infection of the stomach) on the role of enteroviruses in the aetiolgy of ME/CFS – an area which has been implicated as one of the causes by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS.  By analyzing samples of stomach tissue from 165 patients with CFS, Dr. Chia's team discovered that 82% of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS.'

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The book 'Caring For The M.E. Patient' by Jodi Bassett includes a Foreword by international M.E. expert Dr Byron Hyde.

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