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.
(The issue of ‘immunocompetence’ is a central one in chronic fatigue syndrome (ME/CFS). People with impaired immune systems (‘immuno-incompetent’ people) such as untreated HIV/AIDS patients, people with organ transplants, etc. can get severe infections from common viruses the rest of us are able to hold in check. Since chronic fatigue syndrome (ME/CFS) patients don’t display the gross immune abnormalities found in HIV/AIDS patients – and aren’t dying from common pathogens – the assumption was apparently that researchers didn’t need to look deeper for pathogens. But did the more subtle immune abnormalities found still leave patients at peril from hidden infections?)
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.
(Dr. John Chia appears to be stating that the enteroviruses are active inside the cells but are being destroyed as they leave them. Because of this attempts to find them in the blood have been difficult; the few enteroviruses able to successfully get out of the cells and into the blood stream are hard to pick up by our current tests. A similar situation may occur with regard to HHV-6)
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.
(Interferon is a cytokine. As an antiviral treatment it works to boost the immune response thus hopefully clearing out the pathogens present. Interferon is notorious for producing symptoms similar to those seen in chronic fatigue syndrome (ME/CFS). Dr John Chia appears to be suggesting that exercise may increase the viral load thus causing the immune system to respond with cytokines – thus making the patients feel worse, just as they did when he gave them interferon.)
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.