SOS (State of the Science) Conference
By Jill McLaughlin

State of the Science Conference at the National Institutes of Health: October 23-24, 2000


David Bell, M.D., FAAP, gave his perspective of what it is like providing care for CFS patients. Confidence must be exuded by one's primary care physician (PCP).  In an area where primary care is at its best, good science is artfully applied by the clinician in the prevention of disease, the identification of the illness and its treatment, whether that be for cure, symptom improvement or support.  

"Somewhere," he said, "this process has gone terribly wrong as it applies to CFS."  There are numerous problems in the clinical care area as it relates to CFS.  There is an inherent conflict between the state of the science and the art of medicine. In the era before the maturation of science, supplements and hope were part of the physician's approach, mostly because the results of treatments were dismal.  PCPs trained themselves in compassion and hope in order to make up for the shortcomings of science.

Today, the emphasis is purely to cite a need as a basis of medical care. What is the clinician to do when science does not provide clear cut answers?  Managed care does not present a barrier in ME/CFIDS. Whether a child has ME/CFIDS or leukemia, the physician should recommend superb special care at a good university hospital coupled with good primary care.  There is probably no group of specialized physicians that have taken ME/CFIDS under their wing, so it is now in the field of primary care.

There is an environment of confusion. We don't know the cause. This is acceptable and not a barrier. Primary care physicians are used to treating illnesses where we don't know cause. We treat MS, RA, and cancer but we have the tools to treat these illnesses effectively.  The problem of the primary care physician is whether or not to attempt treatment. Should the patient be dismissed? Does it exist?  A belief has been fostered by an Annals paper that "a psychosomatic illness" such as ME/CFIDS can be encouraged by a sympathetic physician and Plioplys in the Journal Pediatrics suggested that diagnosis not be made for fear of fostering disability!  That presents a real problem and many primary care physicians felt they had the "rug pulled out from under them. There is lingering suspicion that by treating and supporting the patient, you may be worsening the illness which goes against first dictum of medicine: First, do no harm."

If the physician agrees ME/CFIDS is real and legitimate, then there are many questions.   Is it psychological?  Mitochondrial dystrophy?  Is it an injury caused by infection? An anatomical abnormality?  "The list goes on. The answers to these questions will take a lot of time and serious study.  But the lack of comment from both the government and the professional societies such as the American Academy of Pediatrics have encouraged the pervasive confusion that swirls around the principal care practitioner's head."  Too often the PCP will say, "we do not treat tha" and dismiss the patient without care or support. Scientific debate is to be encouraged but the basis of the debate must be to increase understanding and not be to serve as a convenient excuse to discriminate against a person with certain symptoms.

There is a problem with the diagnosis. The CDC took a huge step with a research diagnosis, but we need a clinical diagnosis to get past the concept of this being a wastebasket disease. Clinicians agree that ME/CFIDS has distinct presentation even though the needed support cannot come from negative laboratory testing.  For patients, a diagnosis is critical.

Then there is the problem of disability. Frequently, it is the PCP who must decide if the patient meets the criteria for disability. In the CDC pamphlet it says no lab tests can make the diagnosis, yet to establish disability, one must prove the illness either with abnormal physical findings or laboratory tests.  The physician must prove the disability.  Two different federal agencies are at odds here.

A child is often denied appropriate support because of confusion and lack of understanding. This points to the most crucial problem that ME/CFIDS "is solely the fault of the patient like some ill defined character flaw."

Where do we go from here? We do not have the etiology.  It would be nice to know but we just do not know. But the PCP does not need to know the cause or cure to offer appropriate care.  Just as the patient needs support for the illness, the practitioner needs support as well.  We need a consensus that ME/CFIDS is a legitimate illness regardless of the etiology.  We have to eliminate any talk of this illness being real or not.  We need the support of scientists and science must be provided to give the physician the confidence to treat and to provide ongoing care.

We need to establish guidelines with the emphasis on symptom reduction and the removal of the perception that pain medication and medications used for off label use are not good because the illness may not be real.  We need to establish guidelines for disability to apply to these patients. We need to stop trying to study fatigue. "A full 25% of the population is fatigued."  It is not fatigue.  It is having limits, orthostatic intolerance, aesthenia.  But the PCPs do not understand the patient cannot be upright for more than a few hours at best because they don't have enough blood! We need education on the range of this illness "in order to get past the concept that there are no treatments."  To support the patient, it is essential to remove the stigma accompanying the illness. This can be accomplished by a determined effort to provide information and to encourage aggressive symptomatic care.

A PCP must provide assurance that the patient is taken seriously and will not be dismissed. It has been the general perception that ME/CFIDS patients are "difficult, troublesome, even litigious," but the problem has been generated by medicine rather than by the patients.  "In my experience, patients with CFS have been remarkable individuals facing an uncertain and certainly uncomfortable future and they face this with courage and bravery and dignity.  As such they are entitled to the respect and dignity which most patients with this illness have yet to receive."

Topic Session: Neuroendocrinology (CFS Investigator: Dr. Philip W. Gold, M.D. Subject Experts: Mark Opp, Ph.D., Steve Zalcman, Ph.D.)

Dr. Philip Gold, Chief of Clinical Neuroendorcinology Branch, National Institute of Mental Health (NIMH), NIH, gave a summary of his work at NIH.  (See Forum. "The Gold Standard", 1999, Condy Eckerly)  He presented findings that the hypothalamic-pituitary-adrenal (HPA) axis is down regulated in CFS, which is opposite from what is found in melancholic depression, but pointed out that down regulation is similar to what is seen in an entity known as atypical major depression as well as seasonal affective disorder (SAD).  Future research studies that were suggested by Dr. Gold are for direct comparisons to atypical depression, SAD, and to study the HPA axis at baseline and when challenged to see if there is a distinct fingerprint that separates CFS from these disorders and to determine whether CRH agonists are or will become available as potential treatment modalities.

The subject experts elaborated on the effects of cytokines, IL-1 in particular, on neurochemistry and sleep. Dr. Zalcman presented new evidence that stress can increase central nervous system (CNS) sensitivity to activate various cytokines.  Assays for cytokines becoming more sensitive but may not be sufficient to capture biologically meaningful alterations in CNS cytokine production. Many who have studied cytokines in CFS have been frustrated by need to measure effect of cytokine on symptoms of CFS since they have to be measured in the brain, not blood. and the only way to do that is with a spinal tap.

Topic Session: Cognition (CFS Investigator: John DeLuca, M.D.  Subject Experts: Yaakov Stern, Ph.D., Roderick Mahurin, Ph.D.)

Dr. John DeLuca, Ph.D., Professor and Director of Neuroscience Research, Kessler Institute, New Jersey Medical School, gave an overview of the state of the science of cognition in CFS. He has found two reproducible abnormalities found by many investigators:

1. the difficulty with complex simultaneous information processing tasks. Simplistically known as the inability to walk, talk, and chew gum at the same time.

2. for a single task, simply slowing in the speed of processing. The test used to measure these phenomena have been used by many investigators and is a significant finding in the cognitive psychology literature. These findings are different from major depression, MS and healthy subjects. In studies of cognition where psychiatric status was simultaneously measured and adjusted for, concomitant depression did not appear to explain the cognitive performance deficits on testing. An intriguing new finding is that cognitive deficits are worse in those who do not have coexisting depression or other psychiatric disorders. Since depression can impair cognition it was often thought that cognitive problems could be a secondary reflection of coexisting depression.

He pointed out that both MR white matter abnormalities and SPECT scan abnormalities appear worse in CFS patients who do not have coexisting depression. Using functional magnetic resonance to look at areas of the brain that are activating, they found that when presented with intellectual tasks CFS patients activate more regions of the brain than controls. Hypothesis is that this could reflect cognitive fatigue described by many patients. Dr. Yaakov Stern, Department of Neurology, Columbia University College of Physicians and Surgeons, Sergievisky Center, New York, presented data from cognition in HIV.  He pointed out difficulty in measuring subtle cognitive problems in any patient group. Dr. Roderick Mahurin, MR Research Laboratory, University of Washington, Seattle, WA, did not have CFS data but demonstrated the power of a variety of new functional imaging techniques to recognize activation patterns and possibly to identify distinct patterns of different disease groups.

Topic Session: Chronic Pain (CFS Experts: Jon Levine, M.D. Subject Experts: Kenneth Casey, M.D., Laurence Bradley, Ph.D}

Dr. Jon Levine, Professor, Department of Oral and Maxillofacial Surgery and Medicine, University of California, San Francisco, showed evidence of a wide variety or disorders that go by different names that are characterized by chronic pain and other chronic symptoms including fatigue. He suggests that all are similar to each other, share certain biological correlates and may be seen as part of a common process and may respond to similar therapies.

Dr. Kenneth Casey, Professor of Neurology and Physiology, University of Michigan School of Medicine, Ann Arbor, MI, gave an overview on neuroanatomy. Dr. Laurence Bradley, Ph.D., Professor of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL, did some comparative studies of CFS and FM, so I am not sure why he was considered a subject expert. His studies suggest that CFS shared symptoms but found qualitative differences which suggest that they may have a different biological basis. The differences or similarities between CFS and FM depends on whether you look at scans during the resting state or during pain stimulation.

Topic Session: Sleep (CFS Expert: Harvey Moldovsky, MD. Subject Experts: Roseanne Armitage Ph.D., James Krueger, Ph.D.)

Dr. Harvey Moldovsky, M.D., University of Toronto Center for Sleep and Chronobiology, The Toronto Hospital, Ontario, Canada, Moldofsky pioneered work on alpha delta sleep abnormalities in both CFS and FM. The first longitudinal population based study of self reported sleep abnormal in CFS conducted with CDC pointed out self reported sleep abnormalities much more common than healthy controls. He found evidence of a 45 min phase shift in circadian rhythm of sleep in both CFS and FM and data that demonstrated a NK cell number correlate - as cortisol level dropped the natural killer (NK) cell numbers dropped as well.

Dr. Roseanne Armitage, Ph.D., Associate Professor of Psychiatry, University of Texas, Dallas, gave an overview of effect of psychoactive drugs, particularly effects of antidepressants on sleep. Dr. James Krueger, Ph.D., Chair, Department of VCAPP, Washington State University, Pullman, WA, used mice studies to highlight the central role of interleukins, tumor necrosis factor (TNF) and pro inflammatory cytokines in inducing non REM sleep. He spoke of TNF blocking drugs used in RA and IBS which theoretically could be beneficial in dealing with CFS.  In RA, patients who receive TNF blockers reports diminished fatigue which is common in RA.  There were interesting studies of acute viral infection in rodents with influenza virus which can increase non REM sleep and destroy circadian rhythm. There was further evidence that the virus enters the brain during acute phase, which would raise the possibility that other virus may reach the CNS (central nervous system.)

Topic session: Immunology (CFS Expert: Nancy Klimas, M.D. Subject Experts: Bruce Rabin, M.D., Ph.D., Jerry Wolinsky, M.D.)

Dr. Nancy Klimas, Professor of Medicine, University of Miami School of Medicine, gave a comprehensive summary of immunology studies on CFS and reported on immunology as a mediator of the disease. For background she noted there has not been much work done on genetic predisposition. Dr. Buchwald has found an increased risk on concordant twins. If there is a genetic predisposition, one wonders about a trigger. In immunological terms triggers of disease are thought of in terms of a hit and run model - something that triggered the immunological process and which perpetuates the disease.  There is very little prospective knowledge of the beginning of the illness, but some insight comes from studies which have documented that 60-80% of patients who report acute onset of a viral like illness. In specific cases, profoundly polyclonally activating viruses (EBV, CMV, Lyme) have been well documented as the onset. There have been 2 prospective studies in the literature - one in London followed EBV (Epstein Barr Virus) and one study by Lloyd in Australia (unpublished but has been presented at conferences) when it followed 3 viruses.

In CFS, most immunological studies have involved lymphocytes, but there have been very few studies on the "other half" of immune system. The "holy grail" of immunology is that the immune system is antigen driven - it takes an antigen to turn the immune system on and conversely it takes the removal of the antigen to turn it off.

There have been 18 studies on CD4/CD8 lymphocytes, which have yielded inconsistent results. There are markers of T cell activation on lymphocyte populations. If you look at the T cell population, there are marked elevations of CD26 in majority of CFS patients. Also the elevation of T cell activation markers in CFS correspond to severity of symptoms.

T cell function has been well studied in CFS. Thirteen published studies have described abnormally low responses to T cell stimulation in vitro. Two separate studies related the severity of T cell function abnormality to the severity of symptoms and to the severity of cognition. A "provocative study" suggests that T cells of CFS patients do not express CD3 receptor. An important function of the CD3 receptor is that it activates cells, which may explain the poor response to antigens.

B cell function in vitro shows reduced responses to viral antigens but enhanced responses to allergens with goes along with cytokine dysfunction.  In vivo, twelve of eighteen studies have show abnormalities in immunoglobulin expression. IgG1 and IgG3 subclasses are the two most responsible in containing viruses. Six studies have shown abnormally low levels of IgG1 and IgG3.

Of twelve studies of NK cell function in CFS, ten have showed low NK cell function. More interesting is NK response to cytokine manipulation in vitro -several studies suggest NK cells in CFS do not respond normally to IL-2 or gamma interferon and that gamma interferon may be impaired. This raises the question of cellular exhaustion in system that is constantly activated - how long can it be "turned on" and be able to be responsive? Dr. Suhadolnik's studies in the literature look at elevation of an anti-viral induction pathway and found abnormal production of a critical enzyme. New literature is looking at the nitric oxide (NO) pathway that impacts NK cell function, which may be a potent immunomodulatory therapy to enhance NK cell function.

Cytokines are the chemical messengers of the immune system. Th1 and Th2 refer to specific cytokine patterns which in the normal immune system are in balance. Th1 is pro-cytotoxic T cell/ pro antiviral side and Th2 is the pro-antibody humoral side. Dr. Klimas described that in healthy individuals, these two systems work like a see-saw - when one side is up the other is down. In CFS, the Th2 is upregulated with pro inflammatory TNF-alpha and IL-2. Th1 enhances NK cell function.  Real action in the immune system takes place in the lymph nodes, not necessarily in peripheral blood. Cytokines deliver messages which promote and regulate cell growth, enhance or turn off cell functions and promote cell death (apoptosis). Two studies have shown increased apoptotic drive in CFS. It appears that when you "lean on the on button" of the immune system it will trigger apoptosis. Cells must rest periodically to persist and can only be in overdrive for finite periods. This is the same concern of the apoptotic drive/cell turnover/cellular exhaustion.

Dr. Gupta did in vitro study and found unstimulated CFS cells, which should be doing nothing, were producing TNF-alpha. Klimas had shown mRNA for TNF alpha up regulated as well as the actual peptide in circulation which she states is "truly remarkable" because cytokines are a lymph node phenomenon and are not supposed to be in peripheral blood but in 29% of patients in their study they measured actual TNF peptide.

More important than cross sectional studies of cytokines is the need to do more studies of cytokine expression over time and what it might be related to. Klimas has done studies of patterns of cytokine expression over time and noted that they change with illness severity with pro-inflammatory Th2 pattern increasing during times of flare. Also a cluster analysis in literature show TNF cluster with IL1 and TH2 type cytokines being expressed.

Hurricane Andrew study showed after the hurricane everyone with chronic diseases became worse and study of HIV showed increased viral expression and that the stress of the hurricane caused increased viral replication. CFS patients showed dramatic increases in severity of illness but also IL-1 expression tracking along with the severity of illness. Important studies to track the illness over time are ongoing. At least one study in Europe is looking at type 2 shift that seems to occur later in illness rather than at onset.

The literature has its flaws because of too many cross sectional studies. The literature suggests an antigen driven system that is stuck "on." The question has been raised whether it is polyclonal or oligoclonal activation. It is possible to tell if polyclonal or oligoclonal activation by the diversity of the immune response. It does not appear to be polyclonal, but rather oligoclonal or antigen specific. It appears to be antigen specific but we do not know the antigen (the cause). We must reinforce the importance of subgrouping. 

In conclusion we know that immune system abnormalities are playing a role in CFS and contribute to the symptom complex and the dysregulation of other soluble mediators in the neuroendocrine system and that the pattern of immune activation and cytokine exposure suggests persistent antigen exposure. Immune based therapies are reasonable to consider. There are TNF inhibitors and other ways to manipulate the immune system towards a Th1 shift, and some studies (but not many) are ongoing.

Dr. Bruce Rabin, Professor of Clinical Immunopathology at the University of Pittsburgh, was contacted because he studies the effect of stress on the immune system. It is known that stress increases susceptibility to viral infections. He seemed unable to integrate his work directly into a presentation since he has never seen a CFS patient, was previously unfamiliar with the illness and seemed overwhelmed by the inconsistencies, though he recognized that they were the result of many variables. He says this points out that with all the years of study, there is still the tremendous need for basic science and well controlled studies and much more intense research.

He obviously saw CFS as more than a neuroendocrine/behavioral model and proposed the analogy to chronic active hepatitis, which involves immune dysregulation. He also suggested that C-reactive protein, which is associated with inflammation and can indicate those at high risk for heart disease should be tested in CFS patients.

Dr. Jerry Wolinsky, Professor of Neurology at the University of Texas in Houston, a multiple sclerosis investigator, brought his expertise in the field of MS and how it may apply to the study of CFS. In MS, there is known pathology of the target organ - special stains can show the characteristic demyelinization and inflammation. There are other markers such as oligoclonal antibodies which were expected to lead to the discovery of the infectious agent but seems to be a nonspecific antibody response due to immune dysfunction. An important new marker is the MRI, but lesions come and go (as in ME/CFIDS) so images are different over time. It is known that the disease process begins before the first clinical attack so in order to treat it, it is important to know that the disease changes over time. He said, "I shouldn't come here to tell you how to do your work," but went on to outline:

1. It is important to constrain diagnostic criteria for research purposes.  You must add markers to be sure you are dealing with a uniform group of patients. Reject these markers when they become inappropriate ("even if you have built a career around them!")

2. Concentrate on early diagnosis. You're more likely to show abnormalities of causal relevance early than late and also more likely to find things that respond to therapeutic interventions. Long established patients may give false leads. Any insights you get into late cohorts must be quickly reestablished in earlier cohorts to be significant. Equally important it is know in MS that treatment failures in the long established patients may falsely discourage you to attempt treatments which will work early on.

3. Avoid treatment contaminated patients - e.g., treating with neuroleptics could alter cytokine profile.

During the Q and A period, Dr. Wolinsky was asked if he knew of any studies on the occurrence of familial occurrence of CFS and MS. He said he did not know of any studies, but said that in his MS clinic he has patients referred to him who have CFS, because, quote, "I cannot force them to have MS no matter how hard I try with the markers I have." He noted that many features are very similar which raises the point that the brain can respond to any particular insult in just so many ways and therefore you "have to be careful not to use only symptoms to make a diagnosis but have to figure out what our markers are to be sure where the symptoms are coming from."

Topic Session: Fatigue, Functional Status, and Disability (CFS Investigator: Dedra Buchwald, Subject Experts: Warren Tyron, Ph.D, Gloria Furst, OTRL/L, M.P.H., Lauren Krupp, M.D., Steve Passik, Ph.D.)

This session took most of Tuesday afternoon and went the way of most "fatigue" studies. Once you open up the "chronic fatigue" pandora's box, it begins to turn into a linear model of degrees of fatigue, with CFS being on the far end of "fatigueness." The whole fatigue argument of David Bell, M.D. seemed to have had no impression on these people. One of the "experts" was studying fatigue in cancer patients after their disease was in remission and with no further physiological explanation. This session was uninspiring and I found myself walking out on several times. On one occasion I found a patient in tears in the ladies room from what she perceived to be a complete lack of understanding and misrepresentations of the illness that many misconceptions have generated.

One person asked if there was evidence that CFS patients had higher than average levels of child abuse or physical abuse in their history, and Dr. Dedra Buchwald said she has seen evidence to support this. Fortunately Dr. David Bell found a microphone and said he has found no such association and quickly shut down that discussion.

Lay audience session:

This last session was disappointing. It was listed in the agenda as lay audience session, and I assumed there would be a lay audience summary and a discussion/Q & A. It ended up as a submission of anonymous questions from the audience handed in on cards which were screened/edited/censored by Dr . Komaroff. Many of the experts had left by then and this was mostly rehashing what had already been said. An actual panel discussion between the experts and an informal doctor to doctor session would have been more productive.


This meeting was very professional and well organized. There were folders with brochures, agenda, bibliographies, etc. and it was professionally videotaped and audio taped. It was well attended - there were over 250 registered participants and some walk-ins. There were some reporters in attendance.

During the introduction and opening remarks Dr. Komaroff repeatedly referred to CFS as a "problem," instead of a disease or, at the least, an illness. At one of the breaks, I was standing with a group of people I did not know except for John Sterling, the CFSCC Co-chair. Some were discussing Lerner's work and its merits and I said he should have been invited to present. Sterling interjected glibly, with no sense of concern or disapproval, but everyone knows that Lerner's work is referred to as "cardiology of the paranormal." Not once during the entire conference did I see anyone from the CAA or CFSCC submit a question card.

Was it a "success?" I think it is hard to say. In fact "we", in the patient community, do not have any way of really knowing. Only the CAA/CFSCC have access to any real information. The real answer depends on how this information will be utilized.

Will the information and ideas translate into any direct action on the part of the federal health agencies? Will it have any influence on intramural or extra mural research? Will it generate RFP's and will this information be included? Will it be able to effect the review boards for extra mural grants?

Was the purpose of the meeting to inform the "subject experts" in the hope of attracting them to CFS research (which if this was the case, it would have been more productive for them to be invited to listen to presentations by CFS experts)? Or was having twice the number of presentations by "subject experts" to "CFS experts" to give CFS experts "new ideas?"

Some of the information and ideas, particularly Dr. Wolinsky's, were excellent and could eventually lead to good research. But this is pure academic research, which under the best circumstances, is a slow process. What came out loud and clear was a recognition of the lack of basic science that should have been done years ago. More than 10 years into the science, there needs to be a more active push to move the science forward.

There should be no more need for further studies of psychosocial correlates or comparisons with depression, and there was virtually no emphasis on searching for a cause(s). It would not be possible to elucidate the nature or pathophysiology of any disease by continuing to study individual symptoms separately.

Also, the majority of what was presented by CFS experts was not new; in fact, much was at least 5 to 10 years old but has not been advanced or been applied in any meaningful way.  The patent who spoke sincerely requested that scientists give doctors the "tools" to help patients.  Certainly Dr. Bell tried his utmost to show what is really needed for the physician and the patient.   Maybe this will happen -- someday.  What was missing in most of the presenters was any sense of urgency.  The "sickest" patients are being ignored.   You do not try to "rehabilitate" someone who is very ill.  No one ever died from fatigue -- or from a 45-minute shift in circadian rhythm.

The National CFIDS Foundation * 103 Aletha Rd, Needham Ma 02492 * (781) 449-3535 Fax (781) 449-8606