You’re an infectious disease specialist and thus the types of patients you see, I presume, have an acute onset of ME/CFS that was associated with an infectious event. Do you have any idea if your findings will relate to gradual onset patients?
I do not pick the patients who came to see me. About 20% or more of the patients have so called gradual onset of CFS without a clear-cut flu-like illness. It is important to look for prior episodes of fatigue following a flu-like illness. Several patients became debilitated without an obvious preceding flu, but already had a prior episode of fatigue that lasted a few weeks to a few months years earlier. Many of them had frequent respiratory infection in the previous year, or “IBS” or functional dyspepsia for years before developing more fatigue.
Many of them had frequent respiratory infection in the previous year, or “IBS” or functional dyspepsia for years before developing more fatigue.
The case I presented at the symposium illustrated this principle. The patient developed a respiratory infection in November but did not have abdominal pain and onset of fatigue until May of the next year. After the colonoscopy performed in August, the patient developed a severe flare of the viral infection, including fevers, myalgia, profound fatigue, abdominal pain, vomiting, and leukopenia, requiring hospitalization. She had 100,000 copies of viral RNA in the 40 micron section of the terminal ileum biopsy obtained one week earlier. It is not an accident that the flare happened after the colonoscopy and biopsy. The infection has been active but at different sites. One would swallow the infected respiratory secretions into the GI tract, but the initial GI symptoms will not manifest since the patient is still fighting the viruses in the respiratory tract.
Later on, which can be months down the line, after the immune response subsided, the viruses in the GI tract will start to grow. These are not necessarily two different infections. One patient had clearly documented viral myocarditis following severe bronchitis in December, but did not develop CFS until June the next year without another infection. We have seen a number of patients who could have respiratory symptoms for one week, to follow by severe GI symptoms; the latter often were attributed to the side-effects of antibiotics. However, the same cycles would occur even without taking the antibiotics. Months later, the patient would develop ME/CFS.
Furthermore, a number of patients would tell me the CFS started in March or April but could not even remember that they had recurrent bronchitis in the previous October through December. The GI symptoms could only be 1-2 days when the patients were traveling, which they thought were self-limited food poisoning. The interval between the initial infection and the onset of ME/CFS can be variable, so the absence of a flu-like illness has to be scrutinized by very thorough questioning.
You related several instances of a patient getting ill with one infection, seeming to recover and then being unable to recover from the next one. They seem to have recovered but apparently they really didn’t. Do you have any ideas concerning what’s happening between that first and second infection?
We have noticed that patients often would have two symptomatic infections before developing ME/CFS; the two episodes could be occurring within one year or years apart. In animal models, one can demonstrate that a prior viral infection can predispose to more severe, subsequent enterovirus infection. I believe, although this is difficult to prove in humans, that pre-existing antibody against a prior strain of virus can bind to, and yet not able to neutralize, the new viruses, and eventually result in uptake by the monocytes. These infected monocytes become the “Trojan horses” that would home into the tissues such as brain, heart and muscles (tropism) and become macrophages. This process could be associated with variable inflammatory symptoms. One could not even start to suspect the “Trojan horses”, if the process is clinically silent !
(Dr. Chia appears to be elucidating the following process; an enteroviral attack results in the production of antibodies against that one strain of enterovirus. Upon a subsequent second attack by a slightly different strain, the immune system misfires and – instead of creating new, different antibodies – , raises the same antibodies, which bind to but are not able to completely neutralize the new virus. Immune cells called monocytes pick up these incompletely neutralized viruses and themselves get infected. As they travel around the body they infect other tissues.)
A closely spaced infection may predispose to a more severe, second infection when the immune response has not shifted back to normal. A shift to the Th2-dominant response occurred when patients received steroids at the onset of the respiratory illness associated with asthma, or when they developed “allergic rashes” after eating shellfish, or severe neck or back pain. Many of the patients who developed recurrent respiratory infections, often with asthma or allergic rhinitis, during childhood are Th2 -polarized in response to the next infection. If the infective pathogens do not persist in the body, then nothing more will happen. If the next infection is capable of persisting in the body, such as EBV, enterovirus, adenovirus, parvovirus and others, then chronic infection will occur.
An appropriate immune response, manifested as fevers, nausea, vomiting along with flu-like symptoms in acute hepatitis B, would usually eradicate the viral infection. But minimal inflammatory symptoms at the onset of this type of infection is often followed by chronic persistence of hepatitis B infection. An appropriate immune response is paramount in controlling and eradicating the initial infection.
(Again this suggests that an inappropriate immune response in ME/CFS patients does not eradicate the virus. This theory contrasts with findings of the Dubbo project which suggest that ME/CFS patients tend to have more severe symptoms during the triggering infection and a heightened cytokine response compared to people with the same infections who did not come down with the disease.)
There is no doubt that an inappropriate immmune response to persisting pathogens is an integral part of this illness, as in tuberculosis or any other disseminated infections.
If I understood this correctly, when you put biopsy tissues into culture the viruses didn’t grow out unless you unless you blocked the immune response. Does this mean that viral infections in chronic fatigue syndrome (ME/CFS) patients persist at least in part because of a problem with the immune response?
This was the only way we could grow viruses from human stomach tissues in monkey kidney cells. The in vitro finding does not necessarily correlate with the in vivo situation, but “this thinking” led to the experimental conditions that allowed us to grow the non-cytopathic virus. There is no doubt that an inappropriate immmune response to persisting pathogens is an integral part of this illness, as in tuberculosis or any other disseminated infections.
Do you accept gut biopsies from patients for testing for enteroviruses? If so, how do they arrange to have them sent to your office? What is the cost? Should they send more than one if possible?
The best area to biopsy is the antrum of the stomach, which is also the best place to look for H. pylori. We will need 5 unstained slides, on charged slides for immunochemical staining. The charge is $250 for the staining. This test is far more sensitive and specific as compared to serum antibody and serum viral RNA testing. The results of the comparison will be presented at the next IACFS meeting. See the attached test request form for more details.
Dig Deeper! For a test requisition form to have Dr. Chia analyze whether pathogens are present in stomach biopsies gathered during an endoscopy.
Is there an effective treatment for these viruses? Are strong anti-virals needed? Will immune supportive therapies help? How about therapies designed to aid the gut such as probiotics?
What is the ultimate drug useful for the chronic viral infection remains unclear. I believe that antivirals directed against RNA replication (interferons) will be useful for this illness. Immune support or modulation may help but these viruses are capable of controlling our immune responses to allow their own persistence. Probiotics may help to change the microbial flora but will not change the viral infection in the lining of the gut.
It’s been reported that some antivirals temporarily worked quite well but that your patients tended to relapse after the therapy has been stopped. This is an atypical response to anti-virals is it not? What’s going on here?
The good news about what we have shown in our patients is that CFS is a treatable disease even if they relapsed after treatment.
It is not an atypical response if one assumes the infection is chronic and persistent. Do any antivirals for HIV actually cure the disease? One would be totally surprised if HIV does not rebound (relapse) when one stops HAART (highly active anti-retroviral therapy) in these patients, and the same often apply to hepatitis B and C. Do antiviral drugs cure herpes virus (HSV1 or 2)? Recurrence of disease is common after treatment for cold sores or genital herpes but this does not make the antiviral an ineffective treatment for the disease. The good news about what we have shown in our patients is that CFS is a treatable disease even if they relapsed after treatment. With better and more tolerable treatment, we should be able to control the symptoms and even put the patient into remission, but a cure may be difficult to achieve.
As someone who’s treated over a thousand chronic fatigue syndrome patients could you outline what you’ve found to be more effective in treating the following symptoms:
My approach is not different from anybody else when treating the symptoms.
- Poor sleep: any medications for sleep but the usual hypnotics do not work well. Most of the patients need more powerful drugs.
- Fatigue: stimulants such as Ritalin or Provigil. The effect is quite variable.
- Pain: Ultram or ultracet. Fetanyl patch seems to work better than the higher potency narcotics.
- Problems with concentration: stimulants as above.
- Depression/anxiety: SSRIs and anxiolytics.
- Orthostatic intolerance: Midodrine
Dig Deeper! Midrodrine and Chronic Fatigue Syndrome (ME/CFS) Treatment
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Dig Deeper! Pharmaceutical Drugs For Sleep in Chronic Fatigue Syndrome (ME/CFS)
We’d like to get more funding to study Chinese herbs, since “Western medicine” is not going to come through for many years, especially when people are studying different viruses after 28 years of investigation
Several of your patients have mentioned that you’re trying oxymatrine. Is it an important part of your protocol? Are there any other over the counter immune enhancers you recommend or are exploring?
We have tried a number of Chinese herbs alone or in combination. The response is variable. Oxymatrine could boost the immune response, and we will present data at the next IACFS meeting. We’d like to get more funding to study Chinese herbs, since “Western medicine” is not going to come through for many years, especially when people are studying different viruses after 28 years of investigations. Some of the OTC (over the counter) immune enhancers have not been too helpful when tested in a carefully controlled study conducted by the National Institute of Complementary and Alternative Medicine. Thymosins from other species are not effective in the human since these proteins are species-specific.
(After a talk with Dr. Chia’s son, Andrew, a patient of Dr. Chia’s reported that Andrew received substantial benefit from Chinese herbs. The interferon course helped greatly but he was still plagued with a sore throat and could not exercise consistently. The Chinese herbs put him over the top and he is healthy today. She reported that about 50% of ME/CFS patients receive substantial help from Chinese herbs)
Dig Deeper! Oxymatrine and ME/CFS
Your attempts to identify the specific viruses (varicella-zoster, parainfluenza viruses, adenovirus and respiratory syncytial virus) present probably failed, as you noted, because of some technical problems. Is it necessary to identify the specific enteroviral agent present in order to come up with the right therapy? Where do you go now in your attempts to identify the pathogens?
The failure to identify these agents by staining did not mean the testing failed but rather meant these viruses were not found in stomach by our testing. We have used multiple antiviral antibodies to see if other agents are in the stomach. The absence of other viral agents made the enterovirus even more important in our paper.
The NIH turned its back on pathogen research in chronic fatigue syndrome (ME/CFS) a couple of years ago. You, Dr. Montoya and Dr. Lerner, however, have recently come out with studies suggesting pathogens can play an important role for at least some chronic fatigue syndrome (ME/CFS) patients. You attended the Grantsmanship Workshop held by the Office of Research for Women’s Health (ORWH) last September that was designed to provide CFS researchers opportunities outside of the NIH’s CFS research program. How did that go for you? Did you find any funding opportunities?
I appreciated the opportunity to go to the Grantsmanship Workshop and met the delightful directors/leaders of ORWH who are genuinely interested in helping with this elusive illness. There are funding opportunities for CFS but there is not yet a clearly designated source of funding where one can easily get money. The funding will probably take 24 months from the start of the grant writing process, approval process and then final allocation of money. I hope that some of the great investigators can get funding quickly for their projects.
EV Med Research is a privately-funded R&D laboratory whose mission is to define the most common pathogens responsible for CFS and to develop effective treatment strategies for this illness.
Do you have funding for more studies? What’s the next step for you?
I have funding for our studies at this time. EV Med Research is a privately-funded R&D laboratory whose mission is to define the most common pathogens responsible for CFS and to develop effective treatment strategies for this illness. We will try to define the mechanism of viral persistence and immune response in the stomach tissues, a place we can consistently find the viral protein. We have reproducibly grown the enteroviruses from some of the stomach biopsies with special techniques. We’d eventually like to look at chemicals that can stop viral replication. We’d like to define the “viral form” that persists in the tissue.
Dr. Chia’s Research Foundation, the Enviromed Foundation, accepts donations. The Enviromed Foundation is focusing on developing diagnostic tests and treatment for chronic fatigue syndrome (ME/CFS).
A Test Requisition Form to have Dr. Chia analyze whether pathogens are present in stomach biopsies gathered during an endoscopy ($250)