Article CFIDS An Immunologists Perspective - N. Klimas

Discussion in 'Fibromyalgia Main Forum' started by TerriM, Feb 17, 2003.

  1. TerriM

    TerriM New Member

    Hi everyone . . . I've been searching for clinical info. on the immune system TH1/TH2 issues and came across this article by Nancy Klimas (the researcher in Miami that is doing several studies on CFIDS at this time) . . . it is from a List Serv at St. John's University . . .

    Subj: File: "CFIDS923 KLIMAS"
    Date: 2/17/2003 10:16:38 AM Central Standard Time
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    Diagnosing CFIDS: An Immunologist's Perspective by Nancy Klimas, MD

    Our group in Miami has been actively working to better understand
    CFIDS since 1985. This work has focused on the immunologic
    abnormalities seen in the majority of patients, both in a descriptive
    (How often? How severe? How specific or diffuse in the CFIDS
    population?) and mechanistic fashion (What causes this problem?
    Which cytokines help to make the problem persist? What drives the
    high level of cell activation? How do the various cells interact?
    What role does re-activation virus play in the vicious cycle?). Some
    of this work has helped to develop a sense of diagnostic certainty in
    the evaluation of CFIDS patients, as well as to identify subgroups
    that are immunologically different from the majority of CFIDS
    patients evaluated.

    The Clinical Diagnosis
    First, of course, we attempt a clinical diagnosis, using the CDC
    criteria to help to eliminate other illnesses that also present with
    fatigue. The CDC criteria are particularly useful to investigators
    to define study populations in a uniform way and reduce the risk of
    comparing "apples to oranges" in the final analysis. For individual
    patients, the CDC criteria are less useful, as they rigidly eliminate
    people with any other preexisting health problems. A strict
    application of the CDC criteria is appropriate for a scientist
    worrying about purity of data sets, but it is frustrating indeed for
    CFIDS patients with preexisting and stable illnesses who are being
    denied disability status based on the CDC criteria. Whether a
    patient meets the CDC criteria can be established by gathering
    history and through physical examination. The time spent obtaining a
    careful history of present illness cannot be overrated and often
    exceeds the classic one-hour appointment.
    Having established a clinical diagnosis based on the CDC criteria
    (or based on the criteria with the exception of a preexisting stable
    medical illness), we would go on to a laboratory workup. Part one of
    that evaluation would be designed to eliminate other possible
    illnesses. This is done in a cost-effective fashion with a CBC with
    differential and platelet count, Chem 23, thyroid function screen,
    ANA and rheumatoid factor, and a sedimentation rate (ESR).

    Evaluation of the Immune System
    We have found the immune evaluation to be quite important, as it
    not only helps classify the patient, but often helps to direct the
    care of the patient. At minimum, such an evaluation must touch on
    three points:

    1: Level of T Cell Activation
    While there are many markers of T cell activation, including
    soluble markers (B2 microglobulin, soluble CD8 receptor, soluble IL2
    receptor), the most sensitive in CFIDS is CD3+CD26+ phenotype by flow
    cytometry, the T cell expressing transferrin receptor. In "normals,"
    about 18 percent of circulating T cells express this activation
    marker, while CFIDS patients show double to triple these levels of
    activation. Other phenotypic markers help to fill out the picture.
    CD8+DR, or activated cytotoxic T cells, are elevated in the majority
    of patients with recent exacerbations, but seem to normalize during
    healthier times. Other phenotype subsets tell the clinician whether
    there are adequate numbers of certain cell types, or disproportionate
    numbers of functional subsets.

    2: Diminished Cell Function
    CFIDS patients have diminished T and B cell function in response
    to cell activators (mitogens) in culture. The most sensitive is
    diminished response to Poke-weed mitogen (PWM), which reflects poor T
    and B cell interaction. Even more remarkable is the very poor
    ability of NK cells to kill virally infected target cells in culture,
    a test which is most accurately reported as percent cytotoxicity and
    is calculated on a "per effector cell" basis. This means the test
    should tell you the number of killed target cells in a given period
    of time for every natural killer cell in the assay. People with
    CFIDS often have very diminished NK cell function, and this function
    seems to improve during relatively "good" times, and worsen during
    relatively "bad" times. While we routinely look at both mitogen
    response and NK cytotoxicity, I believe assessing NK cytotoxicity is
    more important. We also routinely assess B cell function by looking
    at immunoglobulin production. Basically, this is accomplished by
    looking at total immunoglobulins (IgG, IgA, IgM), at IgG Subclasses
    (IgG, IgG2, IgG3, IgG4) and, if these suggest an immunoglobulin
    production defect, response to vaccine challenge (with killed, never
    live vaccines). A clinical history heavy on recurrent bacterial
    infections of a serious nature more strongly suggests a B cell defect
    of immunoglobulin production.

    3: Evidence of Viral Reactivation
    Serology for common reactivation viruses such as EBV, CMV, and
    HHV-6 adds further evidence that the immune dysfunction now
    quantified is of a serious enough nature to cause secondary viral
    reactivation. Serology is difficult to interpret, however, and is
    confounded by the presence of polyclonal T and B cell activation,
    which causes "false positive" low-titer positive serology for
    autoantibodies, VDRLs, etc. When a system is polyclonally activated,
    it can also falsely "bump" the baseline titers of protective
    antibodies to old viral infections, and not necessarily reflect
    actual chronic viremia. The buzz words "viral load" would be ideally
    suited to CFIDS, as what would be most useful would be accurate
    knowledge of the amount of active virus infection at any given time
    -- a focus of the research effort by Dr. Jones' group in Denver and
    others. While the research goes on, the best information we have is
    that provided by viral serology testing -- EBV, CMV, and HHV-6
    titers, one or more of which show a classic "reactivation" pattern in
    CFIDS patients.
    While the clinical history tends to drive the workup in a
    particular direction, this "immune approach" reflects the thinking of
    the Miami group. Some individuals end up with other evaluations,
    occasionally autoimmune in focus; more frequently, fairly standard
    allergy evaluations are ordered. Neurology and cognitive assessments
    are routine as well.
    Assessing cytokine production and levels will begin to play a role
    as cytokine-specific therapeutic interventions are developed for the
    treatment of CFIDS.

    Gaining A Better Understanding
    The Miami group's enthusiasm and excitement are based on the sense
    that our understanding of the underlying immune defects are finally
    sharply focused. This clear understanding of the immune disorder is
    driving new therapeutic approaches. The group is feverishly working
    to develop protocols specifically designed to reduce T cell
    activation without harming cell function. Combination approaches to
    "calm" the system while enhancing cell function will follow.


    Terri


  2. Sweetmia

    Sweetmia New Member

    Great post Terri--I particularily liked the final statement that the scientists are feverishly looking for an answer to our problems--gives me hope for a better day.

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