TALK BY DR. NANCY KLIMAS, M.D., ON CFS
May 12, 1994 Lecture at Irvine Center for Special Immunology

FROM THE CFS NEWSWIRE: Dr. Nancy Klimas, M.D. Talk on CFS
X-To: cfs-wire@stjohns.edu
POSTED BY: Camilla Cracchiolo
AUTHOR: Camilla Cracchiolo
COPYRIGHT NOTICE: None


[The following summary was provided by Camilla Cracchiolo, R.N. who attended the May 12 lecture sponsored by the Irvine Center for Special Immunology.]

Immunologist Nancy Klimas, M.D., a researcher at the University of Miami, spoke about Chronic Fatigue Syndrome in San Clemente, CA on May 12. Daniel Prince, my husband Robin, and I attended the lecture. Dr. Klimas is not only one of the leading researchers into CFS in the U.S., she is very well respected for her AIDS research.

Audio and video tapes of the lecture are available from:

The Center for Special Immunology
100 Pacifica, #100
Irvine, CA 92718
Attn: Joyce Swaving

(714) 753-0670

They didn't know the exact cost before we left the conference, but they said they were offering the tapes 'at their cost' and it would probably be in the $15-$20 range.


I'm going to give a full report, but first let me list the new things that she said.

  1. She's seen some nasty cervical cancers in women with CFS, and recommends that women with CFS have pap smears and bimanual pelvic exams every 6 months.
  2. She's seen two people with CFS who went on to develop lymphomas. She's careful to emphasize that the area she works in (Dade County, Florida) has a very high rate of lymphoma and she doesn't know if this is particular to CFS or just a reflection of the high lymphoma rate in general. (She is studying this.) Until the results are in, she strongly recommends that physicians and patients err on the side of conservatism and biopsy any suspicious lymph nodes.
  3. She has reservations about the accuracy of CFS specific tests (NK cell function, cytokine levels) at commercial labs, even the ones like Specialty Labs and Immunosciences She thinks their normal ranges are screwy because they haven't tested enough people to get an accurate normal range. In one lab, she said, they only tested 8 staff people to ge their norms. Thus people who actually have abnormal results are being reported as within the normal range.

    She prefers the labs at the University of Miami and says that physicians don't need to be directly affiliated with the medical center to submit specimens.

  4. Dr. Klimas has seen some people develop osteoporosis from lack of physical activity with CFS. She very strongly emphasizes the need for people with CFS to exercise as much as they can for this reason as well as for exercise's immune strengthening properties.
  5. She states that people with CFS, with the possible exception of the lymphomas and cervical cancers above, are not going on to develop life threatening illness. However, she is seeing a high number of people with CFS who developing autoimmune thyroiditis, Sjogren's syndrome, and carpal tunnel syndrome subsequent to their CFS diagnosis.
  6. Also, she has found a strong correlation between CFS and high triglyceride levels. She believes this is from the effect interleukin-1 has on prostaglandin levels, and has advocated treatment with Omega 6 fatty acids and/or fish oils, levels up to 4000 mg per day.
  7. She is concerned that now that CFS is more widely accepted by physicians, we will start seeing more misdiagnoses of other serious medical problems as CFS. She emphasizes the need for a very complete workup and exclusion of all other possible illnesses before concluding CFS is the culprit.

    Over 90% of the people with CFS type symptoms have definite immune abnormalities. In the other 10% she says she 'looks real hard for some other cause of the symptoms'.


Treatments:

Treatment is symptomatic. Treating sleep disorders is important. She discussed the alpha intrusion in sleep and said that rather than the poor sleep causing the myalgia, she thinks it may be the other way around; pain causing poor sleep. Therefore, she thinks pain control is very important.

Half of all people with CFS develop concurrent depression. Very important to treat this.

Anti-retrovirals are very dangerous and completely inappropriate in CFS.

Ampligen 'had a good placebo controlled trial' and showed significant clinical improvement when studied, but no one can get it because the company is not making it anymore.

Acyclovir failed to help in the Straus study. She would like to see a study using acyclovir IV in high doses on the subset of people with CFS who also have high HHV-6 titers. It may also be helpful to patients whose flares are prodromed by herpes cold sores.

Cognitive symptoms are the most bothersome problem to people with CFS; it's the second most common complaint in most studies. In a few CFS studies, it's the most common complaint. She believes that cognitive rehabilitation exercises with a good psychotherapist are of benefit.

SSRIs (Prozac, et al.) were the first drug she studied. She considers it the first line drug. She did a study comparing depressed and non-depressed people with CFS. The non-depressed CFS patients benefitted the most; and you could see improvement in natural killer cell function as well. She believes that SSRIs have an effect on CFS other than anti-depressive. (This study was published sometime last year; I didn't get the reference). Low dosages can be helpful; since you are aiming for it's immune effects you're not necessarily trying to cross blood/brain barrier, therefore you may not have to go as high as full anti-depressant dosages. She starts at 2 mg and works up slowly. The effects may not be noticable until after *four months* of therapy; the usual 3-4 weeks is not enough time to effect immune changes. She gives it a 6 month trial before changing drugs.

Interferon alpha makes you feel lousy. Pilot study in Lancet on 15 patients showed only 1/3 improved, but the improvement in that group was dramatic, from bedridden to back to work. It may be beneficial for a selected subset of people with CFS; this is one of the things she wants to study.

Interleukin-2 makes you feel worse than Interferon alpha; she's not using it.

Interleukin-12 is very exciting; Used to be called 'Natural Killer Cell Stimulating Factor' before it was renamed Interleukin-12. She is trying very hard to get some for a CFS trial; it's only now starting to go into clinical trials for HIV.

Cytokine inhibitors: Her team thinks Tumor Necrosis Factor is one of the key cytokines in CFS; A TNF inhibitor is available called Trental (pentoxifylline). She is starting a placebo controlled trial on this. (For lay people reading this: Trental is a drug commonly used in the treatment of a vascular problem in the lower leg called intermittant claudication.)

Immunoglobulins: The studies on IgG are contradictory. Peterson's study of it here in the US was negative, but Lloyd's study in Australia was positive. The Lloyd study apparently used much higher doses of IgG and suggests that giving high doses of IgG during CFS flares may be beneficial. She's critical of the studies (or at least Peterson's; it was a little hard for me to figure out exactly what she was referring to here) as not selecting out for people with B cell and antibody defects. She calls it 'fatally flawed' and says it needs to be repeated. She recommends that physicians seeing people with CFS try IV IgG on patients who have B cell or antibody production problems *and* who are getting repeated bacterial infections to see if it helps them.

Also she mentioned thalidomide, but I'm sure if it was as a cytokine inhibitor or not.

Allergy shots: She feels they aren't harmful to people with CFS and may be helpful *if* the proper precautions are taken. She recommends starting out at extremely low dilutions, 1:10,000, 1:100,000 or even lower. She also thinks that the dosage should be increased at half the rate allergy shots are for people without CFS.


On to the details:

The lecture was part of an all day program sponsored by the Center for Special Immunology, with special thanks to the CFIDS Association of America. We drove 60 miles to get there and couldn't stay for the entire program, which included their own physicians, and workshops. But we did hear Nancy Klimas and Linda Iger-Miller.

Dr. Klimas is also working on Gulf War Syndrome.

She expects that the CDC definition is going to change to make it more inclusive. The new physical criteria were supposed to be announced at the recent conference on Gulf War Syndrome, but it wasn't. She thinks we people with CFS need to fight for a good definition for disability; the case definition was never intended to be used for clinical diagnosis.

As to clinical purposes, she sees no need to exclude people from a diagnosis of CFS who have other medical conditions, if the medical conditions are of long standing, stable, and would not reasonably produce CFS type symptoms. Example: hypothyroidism that started many years ago that has been properly treated. Or a person who had a one episode of reactive depression many years ago.

She sees the steps involved in developing CFS as follows:



            Genetic Predisposition

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                Etiologic Event

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              Immunologic Response

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               Perpetuating Factor

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                Health Outcome

1. Genetic Predisposition: she talks about a small study she did on tissue typing on 110 people with CFS compared to 1600 normal controls that she did. (She notes that 110 people is considered a small sample size for genetic studies). She found:

People with CFS were 4.05 times more likely to have genetic marker DR 4 than the controls.

People with CFS were 6.36 times more likely to have genetic marker DR 5 than controls.

People with CFS were 1.83 times more likely to have genetic marker DQ 3 than controls.

2. Etiologic Agent: This is 'the black box' of CFS research. No longitudinal trials of people with CFS going on. She talked about how Epstein-Barr virus was finally identified based on the blood of one woman who was a lab tech and had stored her serum as normal controls for years before she became ill. When this woman came down with mono, they were able to study her blood from before the illness. We don't have that with CFS. The alternative is a long term longitudinal study, that follows people for years and sees who gets CFS.

Possible etiologic agents: Her model of studies assumes that the cause of CFS is either something 'profoundly immune activating or profoundly immune suppressing'.

Possibly activating agents include:

infection
allergy
autoimmunity

Possibly immune suppressing agents include:

immune toxins
certain infections
acute and chronic stressors

  1. Stress is well documented to cause immune depression, but it must be profound stress. Discussed a study she worked on with gay men who were tested for HIV but not told results until end of study. None had any signs of AIDS. They were divided into 3 groups, comparing aerobic exercise with relaxation and no intervention.

    All started out about 80% of normal immune function, whether HIV - or +.

    Exercise group showed the most profound effects, with all participants returning to 100% of normal in 6 weeks, regardless of HIV status. Lymphocyte counts rose at least by 100.

    Relaxation group also returned to 100% of normal but it took about 12 weeks.

    The control group dropped down to 50% of normal regardless of HIV status just from the stress of not knowing their test results. They were told their HIV results after this. The HIV neg men gradually rose back to the 80% baseline; the HIV + men dropped even further and stayed down.

    In other words, chronic stressors can have profoundly suppressant effects on the immune system. However, CFS is *not* a stress disease; almost all people with CFS have contact with some infectious agent at onset as well.

  2. Autoimmunity: she suggests there may be some kind of autoimmune process going on that we don't know how to test for yet.

    Whatever it is, we know it's not inflammatory enough to make a sed rate rise significantly, but all rheumatologic illnesses need to be thoroughly ruled out. 20% of her patients have autoimmune thyroiditis (Hashimoto's Thyroiditis). She suggests that there may be some autoantibody being produced that we don't know about yet. Very important to rule out MS and Reiter's syndrome. Mentioned Fibromyalgia studies and serotonin antibodies.

    Endocrinologic factors may play a part in this. (She mentions Demitrack's work on the hypothalmic-pituitary-adrenal axis).

  3. Foreign antigen (allergic response).

    Most people report onset with a flu-like illness. Three possibilities for a virus:

  1. 'novel' virus; something new, like Goldstein's Agent X. In other words, we got the virus, we're still infected, never got over it.
  2. 'hit and run' virus (which I think should be proposed as a name for this thing!) in other words, a virus that comes in, stays for a couple of months, does its damage and vanishes.
  3. Maybe what we've been terming a 'latent' infection, like EBV, CMV, HHV-6 wasn't latent at all; maybe it was the first time we got infected with the agent and that's why we felt flu-like symptoms.

    Here in US we look a lot at herpes family viruses, like EBV, CMV, herpes simplex I & II and HHV-6. In Europe, more attention is being given to coxsackie virus and enterovirus. She said "It would be very interesting indeed if coxsackie virus turned out to be the culprit'.

    Other possibilities are bacteria and parasites.

  4. Maybe a terrible allergic reaction sets this off and we continue to be exposed to allergens.
  5. Toxins: best example may be Gulf War Syndrome.

3. Immunologic Response:

Here's what's happening:

  1. Chronic immune activation, via cytokines and receptors
  2. Cellular dysfunction, of which by far most profound is natural killer cell dysfunction. Japanese call this illness "Natural Killer Cell Disease'. HHV-6 directly infects natural killer cells, and one possible line of therapy might turn out to be anti-HHV-6 therapies.

She has found that the severity of the illness correlates to the levels of cytokines and cell function.

She thinks researchers may finally have identified which cytokines can distinguish various groups of patients and how severe their symptoms are. These are: Interleukin-1 and Tumor Necrosis Factor. Interleukin-4 and Interleukin-6 are allergy related. and Il-6 stimulates autoimmunity as well.

Theraputic interventions have to be directed either towards calming down cytokines or activating cellular function.

She has great reservations about using cortisone to treat this.

Psychoneuroimmunological interventions may be beneficial.

She did a study after Hurricane Andrew hit Florida between people woth CFS who lived in affected counties and people who didn't. People in the affected counties had more relapses, more severe symptoms and relapsed for much longer periods of time. Many are still not recovered.


For those of you who like to look up the studies yourself, attached below is a partial bibliography of Dr. Klimas' work.

CFS related work:

  1. Antoni MH; Brickman A; Lutgendorf S; Klimas N; and others
    Psychosocial correlates of illness burden in chronic fatigue syndrome.
    Department of Psychology, University of Miami, Coral Gables, Florida 33124.
    Clin Infect Dis 1994 Jan;18 Suppl 1:S73-8
  2. Keller RH; Lane JL; Klimas N; Reiter WM; and others
    Association between HLA class II antigens and the chronic fatigue immune dysfunction syndrome.
    Center for Special Immunology, Community Blood Centers of South Florida, Fort Lauderdale 33316.
    Clin Infect Dis 1994 Jan;18 Suppl 1:S154-6
  3. Patarca R; Klimas NG; Lugtendorf S; Antoni M; Fletcher MA
    Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression.
    E. M. Papper Laboratory of Clinical Immunology, University of Miami School of Medicine, Florida.
    Clin Infect Dis 1994 Jan;18 Suppl 1:S147-53
  4. Goodnick PJ; Sandoval R; Brickman A; Klimas NG
    Bupropion treatment of fluoxetine-resistant chronic fatigue syndrome.
    Department of Psychiatry, University of Miami, Florida 33136.
    Biol Psychiatry 1992 Nov 1;32(9):834-8
  5. Klimas NG; Salvato FR; Morgan R; Fletcher MA
    Immunologic abnormalities in chronic fatigue syndrome.
    Miami Veterans Administration Medical Center, Florida.
    J Clin Microbiol 1990 Jun;28(6):1403-10
  6. Pflugfelder SC; Tseng SC; Pepose JS; Fletcher MA; and others
    Epstein-Barr virus infection and immunologic dysfunction in patients with aqueous tear deficiency.
    Department of Ophthalmology, University of Miami School of Medicine, FL.
    Ophthalmology 1990 Mar;97(3):313-23

Non-CFS work referred to in the report above:

  1. LaPerriere A; Fletcher MA; Antoni MH; Klimas NG; and others
    Aerobic exercise training in an AIDS risk group.
    Center for the Biopsychosocial Studies of AIDS, University of Miami.
    Int J Sports Med 1991 Jun;12 Suppl 1:S53-7
  2. LaPerriere AR; Antoni MH; Schneiderman N; Ironson G; and others
    Exercise intervention attenuates emotional distress and natural killer cell decrements following notification of positive serologic status for HIV-1.
    Center for the Biopsychosocial Studies of AIDS, University of Miami, Florida.
    Biofeedback Self Regul 1990 Sep;15(3):229-42

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