Nancy G. Klimas, M.D. is a director of the Department of Immunology of the University of Miami School of Medicine, a member of the CFS Working Group there as well as a board member of the American Association of Chronic Fatigue Syndrome and the co-editor the Journal of Chronic Fatigue Syndrome put out by The Haworth Medical Press. She is also an AIDS researcher and clinician. The following is a summary of a lecture she gave this past spring to an attentive audience of PWCs. CFIDS will be referred to as CFS in this article.

     Dr. Klimas began by explaining the revised case definition (1994, Fukada, Straus, et al) where 4 of the 8 symptom criteria were taken from studies by Anthony Komaroff, M.D.: 

  • memory or concentration impairment (PWCs thoughts are easily disrupted) 
  • sore throat 
  • tender lymphadenopathy (tender lymph glands) 
  • myalgia (pain in the muscle) 
  • arthralgia (pain in joints) 
  • new type of headaches 
  • unrefreshing sleep
  • post-exertional malaise for more than 24 hours
     The last symptom is the answer to disability. Dr. Benjamin Natelson proved the derogatory effects of exercise to PWCs in a study. He administered an IQ test to both PWCs and a sedentary control group. Then the group used a treadmill and took the IQ test again. The control group's IQ improved but the PWC's IQ dropped 20 to 30 points! Twenty-four hours later, the IQ tests were repeated and the PWCs drop persisted. "That's real! That's impressive! That's quantifiable!" said Dr. Klimas. She uses this to fight for her patient's disability. 

     Fibromyalgia Syndrome (FMS) is "often lumped together with CFIDS, but that's not entirely appropriate," she said. It's an overlapping illness, but more than half of the PWCs meet FMS criteria.

FMS CASE DEFINITION (1990 American College of Rheumatology): 

  • widespread pain for more than 3 months
  • pain left and right sided
  • pain above and below waist 
And 11 or more of 18 specified tender points along with general pain. Those FMS patients who have something in addition to CFIDS are told they have "idiopathic FMS" but "idiopathic FMS is CFIDS!" 

     FMS has been "a known entity for 25 years and clinicians are more comfortable with it has been a wee bit more respected...but not much," said Dr. Klimas. "In fact, it is easy to find high tech scientific studies in CFS, but hard to find them in FMS." FMS strikes 1% of the population, takes up 15% of a rheumatologist's case load, and greater than 80% are female. CFIDS is found in at least 3 per 1,000 (Buchwald, et al) or 37 per 100,000 (Lloyd, et al in an Australian study). 

     The pathogenesis that Dr. Klimas believes is responsible for CFS begins with a genetic predisposition. The person then experiences a triggering event which, in turn, leads to immune activation, cellular dysfunction, and viral reactivation. The proof of genetic involvement is the HLA typing done in CFS and FMS: 

  • CFS: HLA DR4, DR3, DQ3 (Keller, et al, 1993) 
  • FMS: None found in study of 60 patients (Honen, et, al, 1992) 
  • Chronic Lyme: HLA DR4 (antibiotic resistant arthritis), HLA PR2 (Steere, et al, 1990) 
     Although the pathogenesis of CFS begins with a genetic predisposition, this does not mean that everyone with a predisposition will get CFS. A trigger begins the body's plunge into the world of CFS. Without this gene plus a virulent trigger, Dr. Klimas believes that a person would not get CFS. This is not unheard of. Reiter's syndrome is an example of an illness that takes a genetic predisposition. 

Do viral infections trigger FMS or CFS? 

  • 11-20% of HIV patients have FMS
  • acute coxsackie virus includes chronic FMS 
  • acute parvovirus includes FMS 18% of 293 FMS patients describe an infectious onset (Goldenberg, 1993) which is a tiny number in comparison to CFS
  • B. burgdorferi is known as a triggering agent (77 to 800 "chronic Lyme patients actually had FMS" (Hsu, et al) while 43 of 77 prior Lyme documented patients had CFS. 
     Under the current definition of CFS, Lyme was the trigger and chronic Lyme is considered CFS. Thus, Lyme is another overlapping illness. Viral infections in CFS are fairly common with 60-80% describing an acute onset. Some begin with acute EBV (Epstein-Barr Virus) while others begin with acute B. burgorferi or acute CMV (cytomegalo virus). All are followed by CFS. The EBV titers in CFS are not that much higher than an average person, but knowledge of HHV-6 is incomplete although it seems interesting. In AIDS, HHV-6 helps HIV to replicate and could be a co-factor in CFS as well. HHV-6 also reacts on the NK (natural killer) cell. "Both of them have the same brain power, but sure as heck not the same fuel," said Dr. Klimas, alluding to the funding of AIDS research vs. CFS research. 

     Dr. Klimas finds both similarities and differences in Gulf War Illness (AKA Gulf War Syndrome). Complaints of fatigue are found in 60% (vs 100% PWCs) with diarrhea the next most common complaint. Rashes are also common at time of onset. She wanted to study GWI, but her grant request was not funded. Dr. Klimas found it most interesting that, although there were a high number of females in the Gulf War, the majority of those with GWI are male. 

     After a quick tour of the immune system, Dr. Klimas illustrated how T-cells get the message if a "bug" enters the body. In AIDS, over 90% of the T-cells are killed off which makes the person get sick and die. A PWC has 100% of their T-cells activated, but a healthy persons immune system is only 60-80% activated. If a healthy person, for an example, cuts their finger, they'll feel pain in that finger. A PWC, on the other hand, has so many of their T-cells activated that the same finger cut will be felt in the brain and the whole body! This is a result of the overactivation found in CFS. 

     The PWC has their NK cells barely functioning. This is why, in Japan, CFS is called Low NK Cell Disease . If it were known by this name in the United States, she said, "We'd be a lot better off." She, personally, prefers the name that researcher Dr. Jay Levy coined for CFS, "Chronic Immune Activation Syndrome (because) it has a kind of ring to it." 

     Turning to the chronology of CFS, Dr. Klimas said that beta 2 (microglobulin found in the serum) is higher in PWCs. Their immune activation is constantly up-regulated. Although it will be higher during a flare or relapse, it is always high. The TNF (tumor necrosis factor) is also much higher in PWCs which correlates very strongly with NK dysfunction. This is a very accurate way to test for CFS. "I could find 90% of my CFS patients using this method of testing," she said. It's pretty impressive data." 

     The immune activation is why PWCs "feel so terrible." If a PWC could shut off their immune system, they'd feel much better. Steroids accomplish this, but "when a PWC goes off the steroid, the immune system responds with a vengeance," she said. The proof of immune dysfunction in CFS includes these important milestones in research: 

  • Chronic Immune activation (Klimas, etal, 1989, Landay and Levy, 1990, Straus etal, 1993) 
  • Lymphocyte dysfunction (Califori, etal, 1993, Straus, etal 1993, Linide, etal, 1992)
  • Cytokine dysregulation (Patarca, etal, 1993, Stause, etal 1993, Linde, etal, 1992)
  • Humoral dysfunction (Komaroff, etal 1988, Read etal. 1995)

  • In contrast, FMS needs much more work in the area of immune dysfunction. The studies for FMS citing immune dysfunction include:

  • IL-2 dysregulation (Harder, etal 1991)
  • reduced NK cell activity (Russel, etal 1988)
  • abnormal lymphocyte (Russel, etal 1988) 

     The cognitive dysfunction found in CFS takes specific testing that can be found by a cognitive psychologist using psychometric testing. The dysfunctions are found in concentration, attention, distractibility, and logical memory. The cognitive problems are different in FMS, Lyme (delayed recall), MS, and depression. This has been documented by Kaplin (1992), Krupp (1994), Riccio (1992), and Millon (1989). Is there a mind-body connection in CFS, as the government keeps suggesting in every one of their CFS publications? Dr. Klimas reminded those in the audience that she is an immunologist that looks at scientifically proven facts. As far as psychosocial interplay that psychiatrists have persisted in studying in great depth in CFS, Dr. Klimas stated, "I don't feel the mind has any idea what the body is doing." There is certainly interplay between the neurotransmitters (incorrect messages sent) and the (resulting) neuroendocrine dysfunction, but it has nothing to do with any psychological problem. 
      The autonomic dysfunction found in CFS is suggestive of a parasympathetic predominance. "Basically, " Dr. Klimas explained, "this means that when a person stands up after being prone for awhile, the heart says, 'I need more blood", and the heart is giving enough blood. But then the parasympathetic system says "O.K., now drop the pressure. (A cardiologist will go beserk if testing this...and finds this important...calls it neurocardiogenic sycope.") This is good to use for objective evidence if someone is going for disability, but Dr. Klimas sees no other reason to test for this abnormality. When treated for this, many PWCs feel better because Florinef keeps the heart full. "Water retention is really the theory," she said and some medications, such as Paxil and Prozac also help with this. 
      "The immune system and the autonomic system are completely tied up to work together," Dr. Klimas continued. When a PWC is tilt-table tested, the pulse falls which is known as bradycardia. This is a phenomena not found in anxiety disorders. Sympathetic withdrawal and parasympathetic stimulation was found in 1995 (Bou-Halaigah, et al from Johns Hopkins) and reduced vago activity was also found the same year (Sisto, 1995), but was documented by Kollai in 1992 and in reconditioned athletes in 1993 (de Gues, et al). Dr Klimas said she studied and published data on PWCs who were hit by Hurricane Andrew. Their parasympathetic stimulation made it possible for them to respond to the emergency and feel fine while they did it but they relapsed dramatically after the event. 
     Addressing sleep studies in FMS/CFS, Dr. Klimas said that there was alpha intrusion during delta sleep. This was reported in both FMS and CFS (Modolfsky), while alpha wave findings in FMS was found by Ware, Gupta, Herrison and Doherty. Subsequently, 15 CFS patients and 4 with FMS were found to have a problem of alpha wave intrusion that did not predict either illness nor that of depression (Menu et al, 1994). [Editor's note: this intrusion means you are not fully asleep when you are supposed to be.] These studies raised concern about seratonin dysfunction and Modolfsky postulates a potential IL-1 (interleukin-1) effect. This is why low-dose anti-depressents can be helpful, such as Doxepin. However, when to take it depends on whether you're a slow or fast metabolizer. Dr. Klimas thinks some are trapped in alpha-wave sleep due to pain. She highly recommended Dr. Pelligrino's book to try and decrease pain (The Fibromyalgia Syndrome by Mark J. Pelligrino. M.D., Anadem Publishing, Inc., 1995 is available by mail. Call 800- 633-0050) 

     Dr. Klimas tries to get her patients off as many medications as possible. Detoxifying PWCs doesn't make the illness go away, she said, but it "can put some beauty in life." 

                -Gail Kansky


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