Dr. Anthony Komaroff's Lecture to Mass CFIDS
Newton-Wellesley Hospital, Sunday, December 3, 2000

 

Three objects of today's talk:

  • Summarize some recent conferences
  • Most interesting research of last year
  • Fiasco with Centers for Disease Control (CDC) and how it's evolved

Recent conferences/meetings:

National Institutes of Health (NIH) conference "State of Science" about Chronic Fatigue Syndrome (CFS) in Washington. Unusual in how it was structured. Purpose: very small conference earlier in year, small group, not widely publicized and not broad variety of experts, handled in awkward way. Many people brought pressure from patients and congress to have another meeting to have another broader meeting. Bulk of credit Dr. Donna Dean who is now responsible for coordinating CFS at NIH.

CFS has now been brought up to the top level at the NIH (under Dr. Ruth Kirshstein), so it is no longer under The National Institute of Allergy and Infectious Diseases. The conference was organized into groups of different fields (i.e. immunology, endocrinology, neurology, etc.) and they invited one person who works on CFS in that field to give a talk on the state of CFS in that field.

They also invited a group of experts in those fields but who were not CFS experts. The idea was to a) get a discussion going, b) bring in people who have the skill to turn their attention to CFS, and c) bring new ideas about next steps in that field, etc... nearly 300 people came (nearly 200 from NIH and CDC, but few with experience in CFS). Many came not having known much about clinical problem of CFS.

Was it successful? It contained really interesting information and good dialogue and the proof will be in the pudding. He'll wait to see what new ideas and new people come into the study of CFS before he considers the meeting a success. It was an unusual conference in structure, and he hopes it will have a very positive influence in improving the level of work.

The next AACFS conference will be in January in Seattle. Their first meeting was in 1992, and they have an international meeting every 2 years. This year, there were more research studies sent in for presentation than at any conference in the past. That's a mark of the growing interest in the problem and growing amount of research around the world. Very many people presenting research are from outside the US. In the late 80s, very few scientists outside the US were studying CFS, and that's a big change.

The January conference will be structured the same as conferences in recent years -- sessions for scientists (anyone can come), oral presentations of most interesting studies, other studies in "poster sessions" summarize research on large boards. You can read their posters and discuss with people what their research is. Then sessions for practicing clinicians presenting a more practical synthesis of what we know about the problem. Last part is directed at patients, and all speakers will be doing their best to try to avoid talking in jargon, etc. That part will be dominated by discussion between patients and scientists and doctors presenting. Attendance expected to be high. Information is available on the web at www.aacfs.org.

Research:

Over 300 Articles on CFS Published in the Most Prestigious Journals

3500 articles in peer-reviewed scientific literature since mid-1980s, of which 300 are in very most prestigious medical journals. That is important. Sheer number of articles in important measure, but when articles published in top-of-the-line journals, it's also an important marker of how field is growing.

Diagnostic Tests:

Definition of a perfect test:

  • Abnormal in every patient with the disease in question
  • Normal in every healthy person
  • Normal in patients with other diseases that can produce similar symptoms to disease in question
  • Reliably performed by many labs
  • Acceptable cost

Right now there is no diagnostic test which comes close to being a perfect.

In last year, Robert Suhadolnik, Ph.D. test came out in the literature. <complicated diagram> Enzyme pathway in normal people compared when white blood cells believe they are dealing with a viral infection. A chemical is turned on in the RNaseL pathway - which is a natural defense against illness. Dr. Suhadolnik was studying this pathway. He discovered that in many persons with CFIDS (PWCs) this pathway was turned on (the body's white cells think they are dealing with virus). He showed lots more of this RNaseL and 25a produced in PWCs than in healthy (age- and sex-matched) individuals. More studies noticed, not only more, but a lot more of a very novel form ("low molecular weight") of RNaseL in PWCs. He had never seen this low molecular weight in people with other illnesses and healthy people. This could possibly lead to a diagnostic marker.

In science, never consider one study fact until other scientists have replicated the study results. That happened earlier this year, when Dr. LeBleau in France, and Dr. Kenny De Meirleir in Belgium found the same results as Suhadolnik. They measured the ratio of the low molecular weight marker to the normal molecule. They picked a certain ratio and tested how many PWCs had this -- 72% of PWCs had it, 11% of healthy people had it, 0% of people with fibromyalgia had it, and 0% of people with depression had it. These are striking differences.

(Komaroff feels, for a perfect test, you'd want 100% of PWCs and 0% in all others... so it's not quite good enough for diagnostic test. You also need to know that the test could be done in other labs and would be as accurate as when these experts do it. But he is encouraged that this may become a diagnostic test in future.) In any case, there is little doubt that there is objective biological difference between PWCs and these comparison groups -- "patients cannot 'imagine' that!"

Study: De Meirleir, et all Am J Med 2000; 108:99-105

Other Research (highly selective pick of his favorites):

Hypothalamic-Pituitary-Adrenal (HPA) Axis

There is obviously something wrong in with the HPA Axis; there has never been a single paper that hasn't concluded that there is something going wrong in this part of the brain.

There are two centers in the brain: the hypothalamus (which is important for thinking, memory, mood, emotion, vital signs - breathing, pulse rate, etc.). In the hypothalamus are cells that make neuro-endocrine chemicals. These chemicals travel to a lower down gland -- the pituitary gland. In the pituitary gland a whole bunch of other "chemical signals" are made. The hypothalamus sends a signal to the pituitary and then the pituitary releases into the blood another chemical signal that travels through the body looking for hormone-producing glands. The importance of this part of the brain was established in the 1990s.

(Hypothalamus makes:) CRF -> (Pituitary makes:) ACTH -> (Adrenal glands make:) Cortisol

In patients with major depression, hypothalamus makes too much CRF which makes the pituitary make too much ACTH and the adrenal glands make too much cortisol. Some NIH researchers looked at PWCs (expected to find PWCs would have same levels as depression -- since they were looking for evidence of depression). They found the opposite. They saw PWCs' hypothalamus produces too little CRF, the pituitary produces lower amounts of ACTH, and the adrenal glands lower Cortisol. That is an objective biological difference in PWCs. This pointed the finger at the hypothalamus. Since then, there are dozens of studies from around the world about abnormalities of the hypothalamus. In the last year, that evidence grew stronger, and became a more robust part of the evidence of something wrong in the brain (involving neuro-endocrine hormones).

Immunology

TNF-a and IL-10 Production, In response to 2-Adrenergic Agonist: Disturbed Neuroendocrine-immune Interactions

Immune system activates "soldiers" to fight when need to fight outside virus.... and then need to be able to get the immune system to 'step down' and stop fighting. In CFS, it keeps fighting. There is a cytokine (TNF-a). 2-adrenergic agonist should make the system stop fighting, and showed in PWCs it's hard telling cells to stop fighting. Immune system seems to want to continue fighting. Another molecule (IL10) tells parts of immune system to calm down. Supposed to go up when 2. IL10 goes way up in healthy people; in PWCs goes up a little bit. Doesn't go up nearly as much (at a higher level to begin with). A chemical that should be turning on signals that tell immune system to cool it, is having much more trouble telling immune system to cool it in CFS. Those are two examples of this and a number of studies show it.

Study: Kavelaars A, et al. J Clin Endo Metab 2000; 85: 692

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Cancer Patients' vs. Doctor's Views of The Importance of Fatigue (nothing to do with CFS)

Study: Vogelzang NJ, et al. Sem Hematol 1997;34:4

In this study, 61% of the time, cancer patients said fatigue was the most bothersome symptom;

37% of the time doctors identified it as the most. Doctors perceived pain to be the worst more often.

This study -- while not being about CFS -- shows that doctors clearly underestimate the impact of fatigue (compared with pain). There is a tendency in our culture to not think fatigue could possibly be as serious as it really is. This study tells us how people in general (and doctors) under appreciate the significance of fatigue (and CFS) in patients' lives.

Other important studies:

  • Dr. Natelson: Tests of attention worse in PWCs after exercise
  • Dr. Garth Nicolson: Newly discovered bacterium, Mycoplasma Incognitus, may be present more often

Komaroff feels we don't have enough different labs doing the tests for Mycoplasma. Another lab in Washington cannot find what Dr. Nicolson finds. Dr. Komaroff is troubled by this; and he's skeptical that it is not proven if it's true. (It may well be, but he wants to see confirming studies.) So at this point, he does not recommend the long courses of antibiotics.

  • A newly discovered virus, Borna disease virus, may also be present more often

In last year, researchers found that Borna disease, which has known in animals, has now been found that it can be in humans. Other studies found different opinion, so there is some difference of opinion. May be true, but it remains uncertain to date.

  • CFS occurs after a well-documented infection called Q fever

Interesting study from Australia, QFS (post Q Fever CFS): Q fever passed from animals to humans in Australia. Some get Q fever and don't get over it. Here you have a very specific infection (diagnosable), followed by CFS. In most PWCs, it starts with a flu-like illness and now doctor can't find evidence of infection. Here you know what it was, know it was infection. After infection cured, CFS remains. So it's a documented infection that can lead to CFS. This supports the theory that some cases are triggered by infection. Komaroff would be surprised if CFS turns out to be caused by a single triggering agent (like HIV is triggering agent for AIDS). He believes it will be a handful of possible infections that trigger it. Q fever very rare in US, so this is not an explanation of US cases...

  • A special kind of activated CD8+ T cell is present more often in CFS
  • Cortisone replacement therapy does not help

Three studies show cortisone replacement therapy might help a bit at first, but not over long term and can have serious, dangerous side-effects. No good reason to take this.

  • Immune globulin therapy does not help

 

Other Forms of Treatment:

Florinef

Florinef is a hormone that causes the kidneys to retain salt and build up more fluid volume in the blood. This treatment was put forward by researchers at Johns Hopkins (Rowe, et al) who first reported autonomic nervous system abnormalities in CFS (symptoms like neurally mediated hypotension (NMH)). They speculated Florinef might be helpful for PWCs. Bottom line from studies this year: it doesn't help the average PWC, but there is a subset of PWCs that are helped. They don't yet understand why some respond and some don't. He's less enthusiastic about this treatment than before.

NADH

NADH is an energy molecule that you can purchase at health food stores. One brand (ENADA) was studied at Georgetown University. They found around 31% (he thinks) seemed to feel better on this treatment. Only 7% felt better on sugar pill. So there is this one study, that seems to show a benefit. But he cautions you -- a small study (20-30 people studied who got sugar and 20-30 who got the real thing). Can't say it's helpful from such a small study. It's encouraging, but until bigger study is done, we don't yet know if this treatment is beneficial.

Remember that with any compound like this, or other herbal compound, there is no regulatory agency (like the FDA) to make sure the manufacturer makes it properly. With FDA drugs, you may get side-effects, but you can make sure that FDA has regulated it to make sure there is no impurity of manufacturing to hurt you. Be cautious about unregulated treatments because you cannot be sure there aren't impurities. A good example of this is the L-tryptophan scandal from around 10 years ago. L-tryptophan was sold as a sleeping aid, available at health food stores. One Japanese company was making most of the L-tryptophan on the market, and there was an impurity that caused very serious health problems, including deaths.

Study this year about Galantomine -- did not prove to be helpful in CFS.

The CDC mess

Dr. Komaroff was at the CFS coordinating committee (set up by Donna Shalala) to review NIH/CDC CFS work. Dr. Brian Mahey was giving testimony. He answered "yes" when he was asked if the CDC had spent on lab research all money given to CFS lab research. Then half an hour later, Dr. Reeves, who reported to Mahey (and who was responsible for CFS research) was asked the same question -- was all lab money budgeted for CFS research spent on CFS? He turned white and then he was silent and then he said "no." It shocked everyone. He had told the world at a public hearing that his boss lied.

Dr. Komaroff believes this is a good example of the patient community rooting out the problem and knowing what question to ask and finally getting it aired. Good news now -- all funds that should've been spent have been added back over next 3 years. It may well have delayed progress in areas, but it won't change the investment spent by CDC/NIH. It showed what a community of activated and dedicated patients can do when something goes wrong.  See editor's notes below

Summary

In the last year -- it was another good year, but also another frustrating year because there are still no definitive answers to the questions we want answered. There is more progress; there are more people getting involved worldwide. 

Questions & Answers:

1. With all the studies showing organic causes, why is the CBT (Cognitive Behavioral Therapy) and exercise cure still being advocated by some?

Graded exercise and very mild aerobics that go up cautiously, can help with symptoms. It's not a cure, but helpful. CBT -- in skilled hands -- can be helpful. CBT is misunderstood by many. It's helpful in helping patients of any chronic illness.

2. What does he think of guaifenesin?

He thinks that, if you believe it helps you or your patients, then you should do a blinded study where you give patients either sugar pill or real thing and you see what happens. If people getting real thing get better more often than sugar pill, than you have evidence. He's never seen that kind of evidence for guaifenesin, but there is anecdotal evidence - some doctors and patients find it useful.

3. What are the risks of being treated by hydocortisone?

Cortisone is natural substance in body, but if you give it in the form of a pill, the body may stop making it. If the body stops making natural cortisol, then you have serious problems (like no ability to make more when your body needs to fight off an infection).

4. What's available to help families cope with a family member with CFS?

Some of the therapeutic groups that have been formed, including one at the Mind Body Center at Beth Israel Deaconess Medical Center, make a point of including family members. However, he's not aware of any programs that are totally focused on the family.

5. Does the fatigue of CFS cause the autonomic nervous system problem of orthostatic hypotension (OH) or does the OH cause the fatigue?

Most likely the OH is a reflection of whatever is going on in the brain, whatever causes the fatigue. Whatever that is, it causes both OH and the fatigue. Really bad OH can cause fatigue when standing, but that doesn't explain the fatigue at rest when you are sitting or laying down.

6. Any recommended treatments of cognitive symptoms?

No. There are treatments used, but not ones subjected to scientific studies. One example, tricyclic drugs are used for cognitive problems, but it probably works by improving the quality of sleep.

7. What is the connection between Gulf War Syndrome (GWS) and CFS?

Several studies in Texas, by Dr. Bob Haley, about GWS. He's shown there is a small group of soldiers from The Gulf War, who probably do have problems in the brain. He's studied group of about 30. He's studied the same people with different ways of looking at the brain. But that's 25-30 people, and there were 100s of thousands who were in the Gulf War, and there are about 80,000 people with GWS. Using the same 25-30 people doesn't really prove that most of the people with GWS have the same problem.

[Ed.note:  A recent medical journal publication on Gulf War Illness and blood coagulation problems, funded by the NCF, found similar problems as well.   The study author is Hannon et al..]

8. Do we see irregular heartbeats by PWCs?

That has never been studied. To study it, you'd need to put on heart monitors for long periods of time (and compare the results to people who are healthy and depressed and other illnesses). Some PWCs do have heartbeat irregularities. He believes these are not the dangerous kinds of rhythm irregularities. He's not sure it's related to CFS.

9. Are there side-effects to taking NADH?

Not that he's aware of. That doesn't mean there might not be some identified in the future. He urges caution, as always.

10. Can he comment on vaccines possibly being a CFS trigger for kids and teens?

Is it a plausible idea that someone reacts to a vaccine by developing something like CFS? yes, but if it happens, it must be very unlikely, since there are so many people who get vaccines and don't get it. If there is something about you that makes your immune system overreact to things. It could be that if you get a vaccine, which is meant to affect your immune system, it's possible your system could overreact to the vaccine. There is not a shred of evidence that it happens.

11. Any common principals or pathways for the various agents that have been implicated as triggering CFS?

Good question. He doesn't believe it will be one single germ, etc.  It's reasonable to say there is something wrong with the LIMBIC system of the brain. There are many possible triggers - viral, head injury,etc.  Whatever the multiple triggers may be, he thinks they will all converge on the hypothalamus and the LIMBIC system (the hypothalamus is part of the LIMBIC system) and the most effective treatments will have their action there.

12. About the report in the Wall Street Journal (WSJ) that viruses, certain herpes viruses, may cause heart problems in CFS.

For about 10 years, Dr. Martin Lerner (who is a PWC), has believed that the fatigue in CFS may be caused by subtle abnormalities in the heart. However none of the research he's presented to date has proved that there's anything wrong in the heart. It's plausible, but it's another example of the "strangeness" of how the WSJ handles CFS -- a study on its front page from a non-peer reviewed article about how surgery on the neck will cure CFS... at the same time they run op ed pieces that say CFS is all in the head!... Their front page and op ed editors are obviously not talking to each other, and their front page editors are just not thinking!

13. Is the immune system reacting to some agent or is there a genetic predisposition?

Both. He thinks it's plausible that it is both. There are a lot of studies that show PWCs tend to have more allergies than the general public. Allergies are when your immune overreacts to a common agent -- fighting when it's not appropriate. It's possible that your body is constantly overreacting to a perceived virus, etc....

14. CFS appearing in several members of family -- is there a connection or coincidence?

He doesn't know answer to that question. Don't know what you should do about it. There is very little evidence that you can transmit CFS to others. Vast majority of PWCs do not have other family members with CFS. Wishes he had a better answer, but he does not.

15. Question about clamydia pneumonia (CP)-- is that a plausible idea?

Absolutely. His team (with the person who originally found CP) was the first to look ten years ago and they didn't find it. But other scientists have found it. Won't know until other scientists prove it. It's possible but not proven. Many people have CP and don't have any illness, so it's especially hard to prove it's involved (about 50% of adults are exposed to this).

16. Is there any evidence that the numbers of new incidence of CFS has decreased?

No. You'd have to have had very careful studies of new cases throughout the years, to see if there are differences. There have been studies in the 1990s, all around the same time, but nothing done over the course of time to show rising incidence. He hasn't seen anything to point to that. He thinks it's been around it for a long time.

17. Have prions been studied in CFS?

Prions are a kind of germ that until 3-4 years ago, most serious scientists said didn't exist and could not exist. There was a scientist in San Francisco, in the late 1970-1980s who said that certain diseases of man and animal (e.g. mad cow and JCD) had no RNA in them. For 15-20 years, he labored under ridicule. Then in the early 1990s, he was taken seriously. Over 2 years, it went from ridicule to getting the Nobel Prize in medicine. That is the closest parallel to CFS -- nothing in CFS leads to it being like a prion, except that doctors should learn from the lesson of prions and humility in science.

18. Has the CDC changed it's dismissive attitude toward CFS?

Yes, the CDC has a new director, Dr. Jeffrey Koplan. Komaroff believes he fully understands what happened and that they know they need to study CFS. He believes that it was mostly one person in a fairly powerful position who was able to exercise his negative attitudes. Not that there weren't other people who went along, but it's not a widespread conspiracy, in his opinion.

19. Who is doing research into cognitive problems in CFS?

Lots of researchers. In the US, in NJ, Dr. John DeLuca at the NIH-funded CFS center. Dr. Fred Friedberg, and in the UK several groups. Contact Dr. John DeLuca and/or search the web for his research.

On a final note (and in response to an offhanded comment from the audience about Gore inventing the internet...) Dr. Komaroff explained the story of Gore putting together and pushing through legislation to open the internet to the public (because, before that, it had been private for the government and government contractors only). That was the genus of the unfortunate quote about Gore "inventing" the internet (when, in fact, he took the lead in "reinventing" it for public use). But Dr. Komaroff was not making a politically biased statement for one candidate or the other.


Editor's Note:  The NCF learned that Kristen Thorson actually brought up the question of itemized spending first to the CDC.   She later resigned in disgust from the CFSCC when she saw no real progress, which was confirmed by the latest GAO report saying the CFSCC has not coordinated anything since inception.  Back to notes

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