An Interview With Dr. John Chia, M.D. Part I by Cort Johnson (8/08)
Like so many researchers and physicians, your interest in this area is
personal – your son has chronic fatigue syndrome (ME/CFS). Can you tell us what
happened to him and what his level of health is now?
He is much better and can go the gym to work out every day. He can run 3
miles easily and swim one mile, 3 times a week. He can stay up 16+ hours every
day. Rarely, he does look tired but it was not like what he had in the past.
When he first got sick, he was not as sick as some of the patients I have seen
over the last 10 years, but his energy level was probably no better than 4-5/10,
and was much worse after minor exertion.
There are many great researcher/ physicians in the academic centers
but few are interested in this illness, partly due to the lack of funding and approach.
There is certainly not a lack of patients.”
Before he became ill with the respiratory infection that was followed by CFS
and GI symptoms, he was able to run 5-10 miles day and playing on the high
school tennis team. His grades dropped due to severe brain fog but he eventually
graduated from UC Irvine with honors in 3/2005. He spent most of his spare time
in the past 7 years working in the laboratory to help me define this illness. He
is applying for medical school at this time and he truly feels that this illness will make him a better physician in dealing with patients who are afflicted with
this illness.
There are many great researcher/physicians in the academic centers but few
are interested in this illness, partly due to the lack of funding and approach.
There is certainly not a lack of patients.
You’re a rare breed of researcher/physician. Do you have a background in
research?
Thank you for your kind comment. There are many great researcher/physicians
in the academic centers but few are interested in this illness, partly due to
the lack of funding and approach. There is certainly not a lack of patients.
I was in academic medicine for a few years (1985-1990), where I had great
teachers who taught me scientific approaches to difficult problems. I worked in
immuno-pathogenesis of infection (the immune response to infections that lead to
disease state), immune responses to HIV. I have always been interested in
undefined medical problems. I continued to publish papers, mostly case reports,
after I left the bench and teaching position at Cedars-Sinai Medical Center in
1990.
I talked to enterovirus experts in the US, including the ones
at CDC, but was told that chronic enterovirus infection does not occur in the
immunocompetent hosts and this is not the cause of CFS.
After my son became ill, I critically looked at the published papers on viral
infections in CFS and eventually decided to work on this area since enterovirus
infection fit(s) the illness the best in most of our patients. I talked to
enterovirus experts in the US, including the ones at CDC, but was told that
chronic enterovirus infection does not occur in the immunocompetent hosts and
this is not the cause of CFS.
Enteroviruses
Enteroviruses have been a kind of shadowy pathogen in chronic fatigue
syndrome (ME/CFS). Some researchers have speculated for years that they play a
central role but study findings have been inconsistent. They’ve never received
the kind of attention that other viruses like HHV-6 and Epstein-Barr Virus (EBV)
have. Now you’ve found evidence of unusually high levels of enteroviral
infection in the stomachs of ME/CFS patients. How did you decide to focus on
this particular type of virus and in this location?
The reason that “finding of enterovirus in the blood of CFS patients is
inconsistent” is that viremia (virus in the blood) ceases after the body mounts
an antibody response that would neutralize any virus that come(s) out of the
dying or damaged cells. The yield for enterovirus RNA in the blood was low even
by the best (researchers) from the UK, but our researchers could not reproduce
the same findings.
The people who studied poliovirus, one of the enteroviruses, realized that
the initial symptoms of the acute infection that led to CFS in many patients
were consistent with enteroviruses. As science advanced, physicians often forgot
the most important part of diagnosing a disease is the history and the relevant
information. Later, but unfortunately, I think most people made the assumption
that virus should be detected in the blood, as in the blood of HIV-infected or
hepatitis B-infected patients, to have a chronic infection.
As science advanced, physicians often forgot the most
important part of diagnosing a disease is the history and the relevant
information. Later.. I think most people made the assumption that virus should
be detected in the blood.
This assumption is obvious incorrect in some cases since reactivation of HSV
or shingles is not usually accompanied by viremia. Furthermore, patients with
HIV and hepatitis B do not usually have CFS symptoms even though they have more
than millions of circulating viruses in the blood.
The first pathogen I worked on was Chlamydia pneumoniae (reported in CID
1999) since persistence in the coronary artery and in the respiratory tract have
already been demonstrated. Ever since I found this intracellular organism as one
of the treatable causes of CFS, I realized that most of the CFS cases are
probably due to persistent infections of intracellular organisms. The largest
groups are the viruses but organisms such as Chlamydia, Coxiella, Brucella can
also do this. I also determined at this time, a proposed pathogen needs to have
a favorable response to a specific antimicrobial drug in order to validate its
role in this illness.
I went on to define the various pathogens in this illness since it is
unlikely that one organism is responsible for all of the cases. It turned out
that the initial symptoms and signs of infection in patients are the most
helpful clues to the diagnosis of the acute infection and then the chronic
persistent infection (diverse etiology of the CFS, CID, 2003). Dr. Stephen
Strauss, the leader of CFS research at the NIH, who was one of my teachers,
showed that EBV and other herpesviruses are not the major causes of this
illness.
I have tried antiviral medications on more than several hundred CFS patients
but only a few responded to therapy. We also saw a number of patients who had
frequent recurrence of shingles in spite of daily antiviral therapy. We realized
that there must a derangement of the immune response, which is not explained by
the T-lymphocyte numbers. Interestingly, most of these patients gave a history
of traveling and GI illness that preceded the onset of shingles. HHV6 and EBV,
if reactivated, are difficult to see, but visible shingles, caused by
Varicella-zoster virus (VZV), is a classic representation of reactivation of
endogenous herpesviruses.
Even the GI doctors in academia do not think about chronic virus
infection in the GI tract.
We also tried to find enterovirus RNA in the blood of CFS patients. We did
more than 2500 blood draws from more than 600+ patients and did more than 200
blood draws with paxgene tubes, which preserved the RNA). The yield for a single
draw in a regular blood tube is probably about 5% but increased to about 30%
when multiple samples were obtained from each patient. The sensitivity of the
paxgene is about 30% for one draw but it still does have not enough sensitivity
as a routine test to capture the virus.
Many of the CFS patients complained of GI symptoms but the evaluation of
these problems are usually done by the GI doctors. Even the GI doctors in
academia do not think about chronic virus infection in the GI tract. In my
recent paper, I talked about how infected respiratory secretions or ingested
contaminated water or food would get (to) the stomach, and not (be) killed by
the acid. Since many patients have upper GI symptoms, this provided the clue to
look for the virus in the stomach.
We’ve seen more and more evidence of gastrointestinal abnormalities in
chronic fatigue syndrome (ME/CFS) including leaky gut problems and increased
rates of the ‘bad’ bacteria. These enteroviruses could clearly be contributing
to the gut problems in ME/CFS but what about the fatigue, cognitive problems,
widespread pain, etc.? Could these be caused by a gut infection?
The brain thinks, the muscles contract on command, the cognitive
dysfunction and myalgia are probably the ongoing response to the viruses in these organs, respectively.
Other investigators clearly demonstrated the presence of viral RNA in the
brain and muscles of CFS patients but these findings were largely ignored. The
cause of the symptoms you mentioned are not the direct effect of the gut
infection but more likely viruses that disseminated to these areas, which are
well-known sites of secondary infection. The brain thinks, the muscles contract
on command, the cognitive dysfunction and myalgia are probably the ongoing
response to the viruses in these organs, respectively.
You found that the stomach biopsies from most chronic fatigue syndrome
(ME/CFS) (95%) patients had evidence of ‘mild inflammation’. As a patient it’s
difficult to see how anything ‘mild’ could translate into something like ME/CFS.
Is this mild inflammation enough to cause chronic fatigue syndrome (ME/CFS) or
is something else going on?
Good question but another common assumption. The inflammatory response may
not be directly responsible for the dysfunction and only means something is
there to attract a few inflammatory cells. We have not yet seen the true power
of the viruses in our experimental approaches.
If I’m reading this correctly you’ve suggested in a past paper that
enteroviral activity in chronic fatigue syndrome (ME/CFS) is a function of
metabolic activity; i.e. the more patients exercise the more active
enteroviruses are. Is there a way to measure this? Could you do something as
simple as have patients exercise and then test for evidence of enteroviral
activity?
We have not yet seen the true power of the viruses in our
experimental approaches.
This is a difficult test to do since the increase in viral replication is in
the muscle cells but the infection is not cytopathic (does not kill the cells
they live in), so one cannot easily measure the viral load in the blood after
exercise. We have done these types of experiments but the results are not any
more positive than the pre-exercise blood results. This just means that we
cannot easily measure the virus's effect in the blood, which has made the search
for these viruses difficult for the past 27 years. This does not mean we cannot
measure the activity in muscles but this is not the area we work on.
What about the post-exertional fatigue in ME/CFS? In my case I can often get
through an initial exercise period ok but it’s the aftereffects in the hours and
even days later that really get to me. Can you account for post-exertional
malaise using enteroviruses?
I think the muscle fatigue, soreness and weakness are easier to explain based
on the local effect of viruses in the muscle cells. What causes the
post-exertional malaise is still a difficult phenomenon for me to explain. This
may be due to increase in cytokine production in response to increase in tissue
viral load, but it is also difficult to measure. The patients who felt so
fatigued to start with, actually felt worse during interferon treatment. After
the treatment finished, the patient felt much better as the tissue viral load
decreased. This may be a partial answer to your question.
The study on cytokine profiles should be in the tissue compartment
rather than the blood... no one has done this, just like no one has looked into
the stomach for the viruses!
You’ve suggested that the production of double-stranded enteroviral RNA produces
an inflammatory reaction in CFS and this causes the symptoms of the disease. An
inflammatory reaction seems to be a necessary component of most ‘pathogenic
paradigms’ in ME/CFS. But while we do see increased oxidative stress, the
results of the cytokine studies have been mixed. Shouldn’t we be seeing really
high levels of pro-inflammatory cytokines, particularly in exercise studies?
The studies on cytokines are all measured in the blood, an easy compartment
to do studies, but the actions of these viruses are in the deeper tissues. The
study on cytokine profiles should be in the tissue compartment rather than the
blood. The results may still turn out to be the same but no one has done this,
just like no one has looked into the stomach for the viruses!
The effects of these viruses on our cells/tissues are more complex than most
of us think. Inflammatory responses to viruses are not the same as the responses
to bacteria. Furthermore, the dysfunction seen in the tissues may not be related
to inflammatory responses but to other properties of these viruses, as
demonstrated in a transgenic mouse model of viral myocarditis.
Enteroviruses can be found all over the body; the gut, the muscles, the
heart, the brain. Some studies have found evidence of enteroviral infection in
the muscles of chronic fatigue syndrome (ME/CFS) patients but others have not.
If you find enteroviruses in the stomach are they likely to be elsewhere? Do you
plan to look elsewhere?
We do not plan to look elsewhere since there is a dilution effect with
hematogenous dissemination (viruses spread from the initial site of replication
through the blood to the secondary sites). If the virus is in the secondary
sites of infection, it must have the capability to persistent in the primary
sites of infection (i.e. the stomach). The other sites, like the blood, are too
difficult to find the viral RNA consistently to be useful for long-term
investigations. The nice data from other investigators are consistent with the
pathogenesis of this infection, and provide a reasonable explanation for this
disease when taken together.
To
an Introduction to Dr. Chia's Interview
Part II of the Interview