Summary of the Viruses in CFS conference, June 23-24th, 2008

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Summary of the Viruses in CFS conference, June 23-24th, 2008

 

 

By Anthony Komaroff, MD

 

 

The Viruses in Chronic Fatigue Syndrome & Post-Viral Fatigue Conference was

held in Baltimore, Maryland, on June 22-23, 2008. Investigators from around

the world examined evidence for the possible role of several different viruses

in initiating and perpetuating chronic fatigue syndrome (CFS).

 

 

Post-Infectious Fatigue Syndrome (PIFS)

 

For over 60 years, scientists have reported sporadic cases of a chronic

fatiguing illness developing in the wake of a well-documented infection.

Nevertheless, it is only in the last few years that scientists have

systematically

studied this PIFS. These studies have begun by identifying all cases of a

well-documented type of infection in a large group of people. Then, the

research

team carefully follows the patients for a long time thereafter, evaluating

symptoms, and performing physical examinations and laboratory testing.

 

In 2006, a landmark study of post-infectious fatigue syndrome that was

conducted in Dubbo, Australia, was published. The team studied people with each

of

three different kinds of infections—Epstein-Barr virus infection, Ross River

virus infection, and infection with a bacterium, Coxiella burnetii, the

cause of a disease called Q fever. The study showed that about 10% of patients

in

each of the three groups developed a post-infectious fatigue syndrome that

met the Centers for Disease Control and Prevention

(CDC) criteria for CFS.

 

 

At the Conference, the team reported in detail on this study. The chronic

illness was most likely to develop in those patients who were sickest at the

time of the initial infection: demographic, psychological and microbiological

factors did not predict who would develop PIFS. Although final results were

not presented, the team reported that the activity of a handful of genes

predicted who would become most severely ill with PIFS, and that genes were

plausible candidates to explain the symptoms of PIFS. In particular, the team

found

variations in the genes for two immune system chemicals that affect

inflammation

(cytokines)—interferon-y (gamma) and interleukin-10.

 

 

 

Human Herpesvirus-6 (HHV-6) and HHV-7

 

 

For almost 20 years, studies have found evidence associating HHV-6 with

chronic fatigue syndrome (CFS). Most human beings are permanently infected with

HHV-6, although the virus usually remains “asleep†(inactive) inside

certain

cells and is not making copies of itself. However, sometimes the virus “

reawakens†and begins to multiply—a condition called active infection.

 

Any human being with an inactive infection—which is to say, most human beings

—will have detectable antibodies against the virus in their blood. People

with active infections can be identified by tests of antibodies, virus

antigens, and viral nucleic acids in the blood. Most researchers who have

studied it

report that patients with CFS more often have active infection with HHV-6

than either healthy people or people with other illnesses than can cause

fatigue.

 

 

At the Barcelona Conference in 2006, a preliminary study reported that

patients with CFS and evidence of active infection with HHV-6 and/or a related

virus, Epstein-Barr virus, improved when treated with an antiviral drug,

valganciclovir (Valcyte®). However, that study did not give some patients the

antiviral drug and other patients a placebo (i.e., sugar pill), and so it could

not

prove that the treatment actually helped .

 

At the Baltimore Conference, the same group from Stanford University

reported on a randomized, placebo-controlled trial. The study had ended just

before

the conference began, and only a small amount of the data had been analyzed.

The patients who received the valganciclovir seemed to improve more than the

patients given placebo, but further analysis of the data is required to

determine the results of the study.

 

 

A team from Latvia reported that latent (inactive) infection with HHV-7 was

present more often in patients with CFS than in healthy control subjects. The

team also found that active infection with HHV-6 was present in many more

patients with CFS than in healthy control subjects.

 

 

 

Epstein-Barr Virus

 

 

In the mid-1980’s, some cases of (what came to be called) CFS were

associated with reactivated Epstein-Barr virus (EBV) infection.

 

At the Baltimore Conference, one team reported that a protein made by EBV

during active infection stimulates the production of several cytokines. These

cytokines can produce many of the symptoms of CFS. The team reported that the

mechanism by which EBV induces the production of these cytokines is through

triggering an immune system “master switch†called NF-kB (kappaB).

 

 

Parvovirus

 

PIFS following infection with parvovirus B19 has been reported for more than

a decade. A team from Japan followed over 200 patients immediately after

they had been infected with the virus. PIFS was not associated with continued

presence of viral DNA in the blood, but levels of complement—proteins

involved

in inflammation—were.

 

Another study found that people experiencing a lot of stress at the time

they developed a new infection with parvovirus were more likely to go on to

develop a PIFS that met criteria for CFS. In addition, as was found in the

Dubbo

study (above), patients whose immune system cells produced high levels of

inflammatory cytokines at the time of initial infection were also more likely

to

go on to develop a PIFS.

 

 

Enteroviruses

 

 

Enteroviruses include three families of human viruses: Coxsackievirus,

echovirus and poliovirus. These viruses can infect the cells of the brain and

spinal cord, respiratory tract, muscle and gut cells, and have been suspected

as

a possible cause of CFS for many decades.

 

A research team reported finding enterovirus RNA (viral genetic material)

and high levels of antibodies against enteroviruses more often in patients with

CFS than in healthy control subjects. Stomach biopsies were performed in

some patients with CFS who had abdominal symptoms: enterovirus antigens were

found much more often in their stomach tissue than in stomach tissue from

patients who had biopsies for reasons other than CFS (like possible stomach

ulcers). In patients with enterovirus antigens in the stomach, enterovirus RNA

was

also found.

 

 

Borna disease virus

 

Borna disease virus has long been recognized to infect animals that are in

close contact with humans—horses, cattle, dogs and cats. It causes infection

of the brain, particularly the limbic system, which is involved in emotion,

behavior, and long-term memory. A team from Germany reported the latest

research from its laboratory indicating that the virus also can infect humans,

and

may cause various mood disorders.

 

 

The team reported that it had isolated Borna disease virus from the blood of

a U.S. patient with CFS. In the test tube, they found that the virus was

killed by an antiviral drug called amantadine. They then found that a German

patient with CFS and evidence of Borna disease virus infection improved

clinically with amantadine treatment.

 

A team from Japan reported finding evidence of Borna disease virus in about

10% of patients with CFS.

 

 

Endogenous retroviruses

 

Nested among each of our genes are sequences of DNA that may make viruses

called endogenous retroviruses. These DNA segments have been inherited from our

parents, and entered the human genome millions of years ago. Most of them

are thought to be unable to actually make retroviruses.

 

One research team reported that a particular endogenous retrovirus called

human endogenous retrovirus-K18 (HERV-K18) can be induced to make viruses when

a cell is infected with Epstein-Barr virus or stimulated by a chemical called

interferon-a

(which is both a natural chemical and a drug used to treat various

diseases). Three different variants of HERV-K18 exist. The team reported that

one

variant, K18.3, is found more often in patients with CFS.

 

The possibility that HERV-K18 might trigger CFS in some people is plausible:

HERV-K18 makes a protein called a “superantigen†that triggers a strong

immune response and dysregulates the immune system. Such a response could

theoretically trigger the symptoms of CFS. This research is preliminary, but

intriguing.

 

 

Immunological and genetic studies

 

Gene polymorphisms.

 

Contemporary biology allows scientists to do something that was impossible

only 30 years ago: to easily identify gene variations. Some genes exist in

several subtly different forms, called polymorphisms. The polymorphisms were

caused by a mutation, typically one that occurred in a distant ancestor and was

passed on to future generations. Tiny mutations in a gene can change the

function of the protein made by the gene, and that can lead to disease.

 

A team using genetic data collected by the CDC reported that several

polymorphisms in genes that are part of the brain hormone system

(“neuroendocrine systemâ€) are found much more often in people with CFS. It

is well known that the brain hormone system “talks†to the immune system,

through various chemical signals. The team showed that the communication between

these two systems was quite different in patients with CFS than in healthy

control subjects.

 

 

Gene expression studies.

 

Contemporary biology also allows scientists to do something else that was

impossible only 20 years ago: to identify every gene in a cell, and determine

if it is turned on or off. Genes that are turned on are said to be

“expressedâ€

: they are making the protein that they were built to make. For example,

scientists can take a group of cells—like white blood cells in patients with

a

particular disease, or diseased tissue

(such as a particular type of cancer)—and see which of the roughly 22,000

human genes are being expressed, and which are not: a “gene expression

fingerprintâ€.

 

A research team from England reported that 88 genes (out of the

approximately 22,000 human genes) were uniquely expressed in the white blood

cells of

patients with CFS: 85 genes were turned on, and 3 were turned off. The 88 genes

typically involved biological functions that are central to the immune

response to infection—which is consistent with the idea that CFS can be

triggered

and/or perpetuated by certain infections.

 

 

Immunological abnormalities and symptoms.

 

One presentation summarized the immunological measurements that distinguish

patients with CFS from healthy controls, including: increased numbers of

activated T cells (a type of white blood cell); impaired function of T cells

and

natural killer cells (NK cells), another type of white blood cell; TH2

cytokine shift (a change in the type of cytokines produced); increased levels

and

production of inflammatory cytokines; reduced amounts of a molecule called

soluble CD26; and increased amounts of a molecule called NPY. But did these

measurable abnormalities have any connection to the symptoms that patients with

CFS were experiencing? Data were presented indicating that diminished T cell

and NK cell function correlate with cognitive impairment and reduced level of

function.

 

 

Summary

 

 

CFS was named and defined only 20 years ago, although a similar illness had

been described in the medical literature for hundreds of years. The

possibility that CFS is often triggered by infectious agents has been widely

discussed

and debated. Few scientists have argued that a single novel infectious agent

is responsible for CFS, in the way that HIV is the central and necessary

cause of AIDS. Indeed, most illnesses caused by infectious agents can be caused

by multiple different types of infectious agents. For example, bronchitis,

gastroenteritis, hepatitis, urinary infections, and the common cold are each

caused by multiple infectious agents.

 

 

This conference presented evidence that a handful of infectious agents are

plausible triggers of CFS. The evidence was both direct—associations between

an infectious agent and CFS—and indirect—evidence of an immune response in

CFS that suggests the body may be attempting to battle an infectious agent.

 

 

Altogether, both proponents and opponents of the theory that CFS can be

triggered by infectious agents had much food for thought.

 

 

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