Saturday, January 19, 2008

Startling Revelations

http://www.ncf-net.org/forum/revelations.html

Wistar Institute, Dr. Elaine DeFreitas, and the Cheney-Bell-DeFreitas Work: Startling Revelations from Wistar's World Patent and Serious Reasons for Concern Now Revealed!
By Alan Cocchetto

 As many of you can remember, Dr. Elaine DeFreitas, Dr. Paul Cheney, Dr. 
David Bell, and others published the work done at Wistar, in the Proceedings of the
National Academy of Science in April 1991.  This created quite the excitement 
and stir as information was released by personal interviews that even made the 
cover of the CFIDS Chronicle.  
     It would not be surprising if many of the researchers involved with 
Wistar scientists were unaware of a world patent that was subsequently issued in 
April 1992, one year after the PNAS(Proceedings of the National Academy of Science)
article!  I myself was quite surprised since the contents of this patent have 
major implications due to the depth and scientific quality of the work.  I 
certainly believe too that this has worldwide implications and therefore needs to be carefully
scrutinized by the scientific community.
      I am reporting on the detailed scientific information disclosed in the 
world patent (#WO9205760) issued to Elaine DeFreitas and Brendan Hilliard, inventors
assigned to Wistar Institute.  This patent was applied for in August 1991 
after the PNAS article was published.
     The title of the patent is "Method and Compositions for Diagnosing and 
Treating Chronic Fatigue Immunodysfunction Syndrome.  The abstract reads as follows: 
"The present invention provides compositions and methods for diagnosis, 
treatment and prophylaxis of Chronic Fatigue Immunodysfunction Syndrome (CFIDS) based
on the detection of the presence of a novel CFIDS-associated virus, CAV, in 
the body fluids or tissues of a patient."
      In the first page of the patent disclosure, the following is stated:  
"The invention described herein was made in the course of work under grants or awards from 
The United States National Institutes of Health, the Department of Health and 
Human Services."
      The inventors cover the working case definition of CFIDS and various 
outbreaks associated with the illness.  The inventors then provide information 
associated with the field of retrovirology, disclosing various families and specific viruses 
associated with each of them.
      The summary of the invention is as follows:  "The present invention 
provides a novel, substantially isolated Chronic Fatigue Immunodeficiency
Syndrome-associated virus, hereafter referred to by the name CAV.  
Polynucleotide sequences of CAV and polypeptides of CAV are useful as diagnostic reagents in 
the diagnosis of CFIDS patients.  Polynucleotide sequences of CAV and polypeptide
sequences of CAV are useful in therapeutic or vaccinal compositions for the
treatment or prevention of CFIDS.  Also disclosed by this invention are 
methods and assays for diagnosing and/or treating CFIDS patients.  Antibodies to CAV
antigenic regions and in vitro cells containing CAV polynucleotide sequences 
or polypeptides are also described."
      The inventors go on to report two major CAV DNA nucleotide sequences as
well as electron photomicrographs of T-cells and B-cells infected with the 
CAV.  In the initial descriptive reference to retroviruses in this patent, the 
inventors state:
"CAV may be morphologically characterized as a retrovirus, particularly a 
non-C retrovirus which is capable of infecting humans.  Electron microscopy of viral
particles formed in infected human cell cultures suggests that CAV is a 
non-C-type retrovirus because of its diameter, morphology, formation and location of
intracellular virions.  More specifically, CAV-infected cells could be 
characterized by electron-dense circular virions, some with electron-luscent cores and 
others with electron-dense cores, associated with the rough endoplasmic reticulum and 
inside large abnormally distended mitochondria in the cells.  All particles are the 
same shape and size, 46-50 nm.  No extracellular virus is observed.  No forms 
budding from the cytoplasmic membranes are observed.  Thus, CAV-infected cells could
also be characterized by the presence of intracytoplasmic particles....  The 
apparent location of its virions in the mitochondria distinguishes CAV from HIV."
[Mr.Cocchetto's emphasis here.]
      The inventors then provide additional characteristics of the retrovirus 
such as its ability to infect both T and B-cells and that the primer binding site is for 
the transfer RNA, or tRNA, of lysine indicating that CAV is a non-C type retrovirus.
 The inventors examined low molecular weight sas proteins and found the 
presence of p11-12, p13-14, and p27-28.  Classes of primate and nonprimate animal
retroviruses have such characteristically sized sas proteins.
      The inventors disclose that the virus has the ability to induce the 
presence of viral pap proteins in the nucleus and cytoplasm of cells which it infects.  
This characteristic of viral pap protein localization also indicates a non-C type 
retrovirus. Summaries of correlations of CFIDS retrovirus to known retroviruses are 
included with extensive descriptions and explanations.  Full disclosure of the methods 
appear to be very specific and extensive.  The entire patent is approximately 40 
pages.  If the NIH ignored the depth of this work, since they chose to fund Sidney 
Grossberg, who only had a theory, then the NIH dropped the ball on this one and the 
agency should be held accountable!       The inventors even state "The ability to 
screen blood samples infected by CAV enables producers and distributors of blood
products, e.g. the American Red Cross, to identify and discard donated blood
samples which are intended for use in transfusions or in the isolation of 
plasma, therapeutically useful blood proteins and blood cells.  If unscreened, the 
use of such blood and blood-derived products could contribute to the spread of CFIDS."
The implications here are staggering!
      The inventors mention various cell lines including T-cell 
lymphoblastoid and B-cell lymphoblastoid lines as well as a macrophage monocyte cell line that 
have all been identified to support the growth of CAV.  They then disclose the primer
sequences for CAV and then state that "body fluids of CFIDS patients have 
shown reactivity with antigens of HTLV-I by Western blot....  Moreover, the 
majority of CFIDS patients have serum antibodies to a P27 protein on the HTLV-I Western
blot.  P27 is presumably a product of the tax gene."  "In still another 
aspect, the invention provides a diagnostic method for detecting CAV in a patient sample 
by a conventional reverse transcriptase assay as described in Example 10 below.  
This assay may be performed on body fluids of a suspected CFIDS patient, using a
polyriboadenylate template primer and the divalent cation Mn++.  No other 
known human retrovirus employs this primer or cation in this assay."
     Of course, all inventors identify their test kit - one that is necessary 
for hospitals, doctors, etc. to officially diagnose the patient as having this illness.  
"The methods, probes, primers, and antibodies described herein may be efficiently utilized 
in the assembly of a diagnostic test kit, which may be used by health care providers 
for the diagnosis and/or treatment of CFIDS."
     The inventors also discuss the details of a CFIDS vaccine and the vaccine
composition!  Furthermore, they disclose that "For performance of these
experiments, patient body fluid samples were obtained from clinical practices 
in North Carolina and New York.  The investigators were all blinded by coded
samples in each experiment."
      Under the heading "Morphometric Analysis of CFIDS Retrovirus" the 
inventor disclose: "Electron-dense circular virions, some with electron-luscent cores 
and others with electron-dense cores, were seen associated with the rough 
endoplasmic reticulum and inside large abnormally distended mitochondria inside the 
cells.  All particles were the same shape and size, 46-50 nm. No extracellular virus was
observed.  No forms budding from the cytoplasmic membranes were observed. 
These observations suggest that CAV is a non-C type animal retrovirus for 
three reasons:  First, human C-type viruses like HTLV-I and HTLV-II do not appear to
form intracellular virions.  The only human C-type forming intracellular 
particles is HIV and these are found intracisternally in conjunction with budding forms. 
Circular C-type virions are usually formed as the virus buds from the cell's
cytoplasmic membrane.  Second, neither HTLV-I, II, nor HIV virions have ever
been found inside mitochondria.  Third, the diameter and morphology of these
virions suggest that they may be Primate D-type retroviruses or spuma 
viruses."
      Extensive test results are disclosed at this point and the inventors 
reveal:  "The results of the same PCR analyses of blood samples from adult CFIDS patients 
was compared with persons with whom they live or closely associate, e.g. roommates
and friends (called Exposure Controls).  Nonexposure controls are healthy 
persons selected at random who have not come into contact with CFIDS patients nor
experienced symptoms associated with CFIDS."  The inventors report their data
from CFIDS patients including pediatric CFIDS patients!  To quote the patent, 
"the positive results seen in the Exposure Controls support the possibility that 
this CAV is capable of casual transmission to non-infected persons, as is the case
with  many non-human retroviruses."  [Author's emphasishere.]  Now, if the
NIH ignored this last comment, then something is dramatically wrong with the
agency that is supposed to protect and safeguard the welfare of the citizens 
of the United States!  Again, the implications here are just staggering!  This is 
especially alarming in light of the testing, revealed by the inventors, which continues 
as follows:
      Since the inventors ran four different tests on each patient, exposure 
control, and non-exposure control, then I will report on the high values from each test 
group. For the first group, the patients tested with a positivity of 82%, exposure 
controls at 43%, and non-exposure controls at 0%.  With the first group, there were 11 
patients, 14 exposure controls, and 4 non-exposure controls.
      With the pediatric group, the patients tested with a positivity of 74%, 
exposure controls at 43%, and non-exposure controls at 0%.  With the pediatric group, 
the sample size was 19 patients, 7 exposure controls, and 4 non-exposure controls.
      The inventors then disclose more PCR work, citing "partial viral DNA 
sequence was obtained by the procedure described below from CFIDS patient NY1-12 using
the HTLV-II crap specific primers g2-1 and g-2-2 of Table III...  Figs. 1A 
and 1B illustrate the partial putative CAV viral DNA sequences obtained.  Upon 
analysis on GenBank and EMBL, the putative CAV sequences of Figs. 1A and 1B have not
been found to be significantly similar to the sequences of any known 
retrovirus. Thus, these sequences suggest that CAV may not be identified as any other
known human or animal virus."  [Author's emphasis.]
      At this point, the inventors disclose several other tests completed on 
patient, exposure, and non-exposure controls.  These were primarily specific protein 
and retroviral tests and probes.  Additional testing reveals the following 
results with corresponding comments by the inventors: 
      tRNA primer techniques using sense and antisense methods revealed that 
10 out of 10 CFIDS patient DNA samples showed the same sized products using the
primer for the monkey D-type retrovirus (MPMV).  The inventors suggest that 
these results, from this test, imply that CAV "is either a type of lentivirus, 
primate D-type retrovirus, or Foamy (Spuma) virus, all of which us a tRNA lysine primer."
      Characterization of cracr proteins of CAV reveals that "animal 
retroviruses that have been shown to express cracr proteins of these molecular weights are:  
primate D-type retroviruses; primate C-type; lentiviruses (EIAV but not HIV); mouse 
B-type (MMTV); avian C-type retroviruses, and perhaps Foamy (Spuma) viruses.
     Location of crap proteins in the nucleus reveals that "more than 50% of 
patient samples tested (and none of controls) revealed cells staining for crap 
proteins.  Most importantly, the staining is found in both the cytoplasm and nucleus of the 
positive cells. The only known retroviruses to display nuclear staining for viral 
proteins are the Foamy virus group."
      The last test was for reverse transcriptase (RT) with the inventors 
revealing:  
"CAV appears to prefer a template-primer of polyzA-oligo-(dT) with Mn++. 
Among the retroviruses that show the same RT characteristics as that of CAV
(polyzA-oligo(dT) template-primer and Mn++ preferences) are the Spuma (foamy)
virus and the monkey D-type retroviruses."
      Any way you cut this, the only conclusion that can be reached is that 
this work is very thorough and extensive.  It has been funded by the NIH!  And I 
believe that, much like the work revealed by Grossberg's patent (also funded by the NIH), 
the NIH certainly has more than a singular idea about what is happening to us as
patients, all the while denying the existence of retroviral involvement and 
not providing details to outside scientists for additional examination and perhaps
subsequent replication!  Any retrovirus that can invade the mitochondria 
directly indicates trouble!  Why?  Because the mitochondria are the energy powerhouses 
in the body and a direct infection of them spells major trouble --- alteration of
mitochondrial function and dysfunctional energy production!  This could very 
well account for the patient's lack of stamina and that 'F-word', fatigue!  
     As far as I'm concerned here, there needs to be a criminal investigation 
of the NIH regarding why they refused to fund upon submission of all this data as 
well as the involvement of the NIH in Grossberg's work. They are supposed to fund 
based on productivity and Grossberg had none in comparison.  Maybe then, some heads
will roll and we'll begin to get some real answers!  After all, each and 
every patient certainly deserves this and so much more!

[Ed. Note: Dr. DeFrietas presented much of this work at the Albany Medical Convention in 1991. She also submitted a paper of thework to the PNAS three times but was turned down. Why? Were the same people at the NIH who refused to fund her threatening the publication in some way? The refusal to fund her along with the CFIDS Assoc. pulling her funding lost us more than a decade of work!]
 

* * *
Addendum received from NCF:  An article in our spring 2002 newsletter by Drs. Konstance Knox and Donald Carrigan explained what they were undertaking as well as what had already been followed up by Dr. John Gow from Scotland.   Later issues gave the results of the study.  Only a few articles from each newsletter go online and they are chosen by different people.  I don't believe this or many of the others are on our website.

Tags: , ,

Central Sensitivity Syndrome and Fibromyalgia

Central Sensitivity Syndromes: A New Paradigm and Group Nosology for Fibromyalgia and Overlapping Conditions, and the Related Issue of Disease versus Illness.

Semin Arthritis Rheum. 2008 Jan 11 [Epub ahead of print]
   
Yunus MB.

Professor of Medicine, Section of Rheumatology, The University of Illinois College of Medicine at Peoria, Peoria, Illinois.

PMID: 18191990  


OBJECTIVES: To discuss the current terminologies used for fibromyalgia syndrome (FMS) and related overlapping conditions, to examine if central sensitivity syndromes (CSS) is the appropriate nosology for these disorders, and to explore the issue of disease versus illness.

METHODS: A literature search was performed through PubMed, Web of Science, and ScienceDirect using a number of keywords, eg, functional somatic syndromes, somatoform disorders, medically unexplained symptoms, organic and nonorganic, and diseases and illness. Relevant articles were then reviewed and representative ones cited.

RESULTS: Terminologies currently used for CSS conditions predominantly represent a psychosocial construct and are inappropriate. On the other hand, CSS seems to be the logical nosology based on a biopsychosocial model. Such terms as "medically unexplained symptoms," "somatization," "somatization disorder," and "functional somatic syndromes" in the context of CSS should be abandoned. Given current scientific knowledge, the concept of disease-illness dualism has no rational basis and impedes proper patient-physician communication, resulting in poor patient care. The concept of CSS is likely to promote research, education, and proper patient management.

CONCLUSION: CSS seems to be a useful paradigm and an appropriate terminology for FMS and related conditions. The disease-illness, as well as organic/non-organic dichotomy should be rejected.

Chronic Fatigue Syndrome: Inflammation, Immune Function, and Neuroendocrine Interactions

Current Rheumatology Reports http://www.current-reports.com/archives.cfm

Chronic Fatigue Syndrome: Inflammation, Immune Function, and Neuroendocrine Interactions Nancy G. Klimas, MD, and Anne O'Brien Koneru, MSN

Corresponding author Nancy G. Klimas, MD, University of Miami Miller School of Medicine, 1201 NW 16th Street, VA Medical Center, 200 BMRC, 6th Floor, Miami, FL 33125, USA. E-mail: nancy.klimas@va.gov

Investigations into the underlying cause of chronic fatigue syndrome have advanced the field considerably in the past year. Gene microarray data have led to a better understanding of pathogenesis. Recent research has evaluated genetic signatures, described biologic subgroups, and suggested potential targeted treatments. Acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue. Genomic studies showed that persistent cases express Epstein Barr virus-specific genes and demonstrate abnormalities of mitochondrial function. Studies of immune dysfunction extended observations of natural killer cytotoxic cell dysfunction of the cytotoxic T cell through quantitative evaluation of intracellular perforins and granzymes. Other research has focused on a subgroup of patients with reactivated viral infection. These advances should result in targeted therapies that impact immune function, hypothalamic-pituitary-adrenal axis regulation, and persistent viral reactivation.

Introduction

Chronic fatigue syndrome (CFS) is an illness characterized by unexplained fatigue lasting 6 months or more. The condition is not alleviated with rest and is accompanied by at least four of eight case-defining symptoms including sore throat, tender lymphadenopathy, impaired memory or concentration, myalgia, arthralgia, unrefreshing sleep, postexertional malaise, and headaches [1]. A diagnosis of CFS is made by excluding all other conditions that would cause similar symptoms. The study and clinical management of CFS is complicated by the lack of accepted biomarkers or pathogenomic signs for the illness.

CFS is characterized by a multifactorial pathogenesis. Endocrine, neuroendocrine, psychosocial, and immunologic factors mediate the physiologic response to CFS and the course of the illness. Although a consensus regarding the pathophysiology and etiology of CFS has yet to be developed, a large body of research supports a link between immune dysregulation and CFS.

A number of symptoms of CFS are linked to inflammatory processes (eg, lymphadenopathy, sore throat, myalgia, arthralgia), which has led many researchers to hypothesize that immune dysfunction causes the illness. CFS has been found to be associated with increased immune activation and inflammatory cytokine levels, with subgroups demonstrating viral reactivation and decreased cytotoxicity, alterations in lymphocyte function, activation, and subset distributions [2,3,4*,5**]. In addition, our expanded understanding of the genomics of CFS has reinforced the evidence that the illness is rooted in a biologic pathogenesis that involves cellular dysfunction and interactions between the physiologic stress response and inflammation. Progress in genetic research has provided new avenues for future study of immunomodulating therapies.

Immune Activation

Chronic immune activation has long been thought to be a component of CFS. In patients with CFS, T lymphocytes appear to be chronically activated. CD8 cells in CFS patients typically demonstrate an increase in activation markers (CD38, HLA-DR) and a reduction in CD8 suppressor cells. Levels of CD26, an ectoenzyme known to increase with cell activation, are also elevated in patients with CFS. CD26 is associated with the adenosine deaminase on T cells and plays a critical role in the immune response. Abnormal expression is also commonly seen in autoimmune diseases, HIV-related diseases, and cancer. Compared with controls, CFS patients also show significantly higher levels of CD26+ lymphocytes [4*].

The homeostasis between the cell-mediated or T helper (Th) 1 immune response and the humoral or Th2 immune response is disrupted in CFS. Th1 functions primarily by destroying infected human cells, whereas Th2 functions through antibody production. Increased antibody production contributes to elevations in immune complexes, increased levels of antinuclear antibody production, and the increased prevalence of allergies among CFS patients [4*]. Some researchers have theorized that if infections can lead to an aberrant shift to an unremitting Th2 dominant response, then perhaps vaccines can cause the same reaction, because immunizations are designed to induce a persistent immunity to antigens. Although further investigation is needed, a recent study provides evidence that vaccines do not lead to CFS symptoms [6].

Functional Immune Defects

Essential fatty acids, zinc levels, T cells, and inflammation

In a series of articles by Maes et al. [7-9] cellular levels of various minerals and fatty acids were correlated with immune dysfunction. Maes et al. [7] documented significantly lower serum zinc levels in patients with CFS compared with controls and found evidence that low levels of serum zinc are related to increased signs of inflammation and defects in the early T-cell activation pathways. The results of this study showed a negative correlation between serum zinc, the severity of CFS symptoms, and the subjective experience of infection. Serum zinc was also found to be negatively correlated to increases in the 2 protein fraction. Levels of serum zinc showed a positive correlation with decreases in the expression of a T-cell activation marker (CD69) on CD3 and CD8 T cells. Zinc is a strong antioxidant, and diminished levels in CFS support findings that the illness is accompanied by increased oxidative stress [7].

They also documented a significant positive relationship between lowered serum zinc levels, the omega 3/omega 6 ratio, and lowered mitogen-stimulated CD69 expression on CD3+, CD3+CD4+, and CD3+CD8+ T cells indicating abnormal early T-cell activation. Omega 3/omega 6 and eicosapentaenoic acid/ arachidonic acid ratios were significantly reduced in patients with CFS, with a significant increase in proportionate omega 6 levels. Lowered levels of omega 3 or elevated levels of omega 6 contribute to inflammation and may contribute to CFS symptoms [8].

In a later study the Maes group [9] found an immunoglobulin (Ig) M-related immune response in CFS patients directed against disrupted lipid membrane components, by-products of lipid membrane elements, by-products of lipid peroxidation, S-farnesyl-L-cysteine and nitric oxide-modified amino acids. These neoepitopes normally go undetected by the immune system but appear to become immunogenic after undergoing oxidative and nitrosative damages. This study found a significant positive correlation between serum IgM levels directed at fatty acids and the severity of illness [9].

The role of long-chain polyunsaturated fatty acids (PUFA) biosynthesis in the pathophysiology of CFS is an important area of research. A large body of evidence links CFS to a persistent viral infection. Additional evidence suggests that such an infection may play a role in adversely affecting cell membrane structure and the functioning and production of eicosanoids by affecting the biosynthesis of PUFAs. In light of this finding, treatment with long-chain PUFAs may be an area of future promise [10].

Estrogen and immune modulation

Grans et al. [11*] showed reduced levels of estrogen receptor B mRNA in a cohort of patients with CFS. Estrogen is an important steroid hormone that plays a critical physiologic role in various processes including sexual development and the reproductive cycle. CFS prevalence rates are estimated to be two to four times higher in women. A number of autoimmune diseases including rheumatoid arthritis and multiple sclerosis also disproportionately affect females and are thought to have a hormone-related pathogenesis. Estrogen is a potential immunomodulator that functions by binding to the two estrogen receptors, ERalpha and ERbeta. These two receptors have unique and overlapping roles. Grans et al. [11*] found that among a study sample of 30 patients with CFS, lower levels of ERbeta cx mRNA were found in patients with a shorter course of illness. These results should be viewed as preliminary due to the small sample size in this study. However, the role of ER wt protein levels and cellular effects are interesting candidates for future study.

Inflammatory cytokines

Suboptimal functioning of the hypothalamic-pituitary-adrenal (HPA) axis in CFS has been well documented [12,13]. Hypofunctioning of the HPA axis could lead to an exaggerated stress response and a subsequently excessive release of proinflammatory cytokines. Long-term stress increases levels of glucocorticoids and catecholamines, which over time suppress immune function.

A recent study investigated potential immunologic changes in severely fatigued adolescent girls with symptoms similar to patients with CFS and with a symptom constellation of sickness behavior [14]. The immunologic changes under investigation were the levels of mitogen-induced T-cell proliferation and T-cell mitogen- or lipopolysaccharide (LPS)-induced pro- and anti-inflammatory cytokine production. Among the three cohorts studied (severely fatigued adolescent girls, CFS patients, and nonfatigued individuals), the severely fatigued participants reported higher levels of depression, anxiety, fatigue, reduced sleep quality, somatic and CFS-related symptoms. In addition, seasonal variations in cytokine and leukocyte subset distributions were observed among the severely fatigued individuals. No immunologic differences were seen between nonfatigued and fatigued individuals. However, CFS patients exhibited a distinct immune profile compared with severely fatigued and nonfatigued individuals. These patients displayed increased anti-inflammatory cytokines (interleukin [IL]-10, decreased interferon (IFN)-gamma/IL-10 ratio) and reductions in proinflammatory cytokines (IL-6, tumor necrosis factor-alpha).

Viral reactivation

Some of the most robust data exploring the link between immune dysregulation and CFS has been garnered through the investigation of postinfective states. Since the illness was first described, researchers have been interested in the potential role of reactivated viruses, especially after the discovery of human herpes virus (HHV)-6 in the blood sample of a CFS patient [15]. CFS often has an acute postviral onset, and two longitudinal studies observed postinfectious chronic fatigue following Epstein-Barr virus (EBV) infection [5**,16].

In a recent study Hickie et al. [5**] demonstrated that CFS is a fairly common sequel of several types of viral and nonviral infections including EBV, Q fever, and Ross River virus. The investigators conducted a prospective observational study in one rural township in Australia, which confirmed the presence of a postinfective fatigue syndrome linked to these three infections. Among 253 patients, 12% experienced a postinfective fatigue that was present 6 months after acute infection. The best predictor of prolonged fatigue was the severity of the acute infection. Premorbid mood disorders and other potential psychiatric risks were not predictive of risk for prolonged fatigue. This work confirms previous findings that the severity of the acute illness rather than the infective pathogen appeared to be the critical determinant of postinfective fatigue syndrome [16].

Chapenko et al. [17] recently found a significantly higher prevalence of persistent/latent HHV-6 infections and dual HHV-6 and HHV-7 infections among patients with CFS. The study compared levels and characteristics of viral infection using nested polymerase chain reaction, restriction endonuclease analysis, and flow cytometry in 17 patients with CFS, 12 patients with unexplained chronic fatigue, and 20 healthy controls. Researchers found active HHV-6 and dual HHV-6 and HHV-7 infections only in CFS patients, and these infections were present in 40% of those tested. Based on these findings, the researchers concluded that HHV-6 and HHV-7 may be involved in the pathogenesis of CFS and that reactivation of both viruses could cause changes in circulating lymphocytes and a state of chronic immune activation [17].

Petersen et al. [18*] recently published prevalence figures for fatigue post-EBV infection. Their study found an immediate link between EBV infection and fatigue, but also found that the median duration of fatigue was 8 weeks and the majority of the patients recovered within 1 year. Only one of the 10 patients studied had an additional record of fatigue. Based on these findings, the authors concluded that acute fatigue after EBV infection and CFS may share some risk factors but most likely do not share the same etiology [18*].

Enteroviral infections can cause acute respiratory and gastrointestinal infections with tropisms for the heart, muscles, and central nervous system. Enteroviruses have been evaluated in several studies, with early data from Gow et al. [19] initially suggesting muscle infection; however, the same group failed to find levels higher than those in controls in later studies. Maes et al. [20] found elevated serum levels of IgA and IgM against the LPS of gram-negative enterobacteria in a group of CFS patients, indicating increased gut permeability and an anti-LPS immune response. Researchers noted that the intestinal barrier may be weakened by factors that have been shown to trigger CFS such as psychologic stress, strenuous exercise, allergies, surgery, and trauma. These same factors may induce inflammation, immune activation, and oxidative stress. Inflammation may then increase the permeability of the gastrointestinal barrier, and they suggested this may lead to autoimmunity or increased inflammation in patients with an existing fatigue syndrome. Based on these findings, the authors suggested that patients with CFS and other forms of chronic fatigue should be assessed for the presence of increased gut permeability through the measurement of IgA/IgM against the LPS of gram-negative bacteria. The authors also recommend using certain antioxidants to treat patients with increased gut permeability [20]. A recent study evaluated the presence of chronic enterovirus infections in patients with CFS experiencing chronic gastrointestinal complaints [21**]. The study took stomach biopsy specimens from 165 patients with CFS; 82% of CFS patients tested positive for the presence of viral capsid protein 1 within parietal cells compared with only 20% of controls. In addition, enterovirus RNA and noncytopathic viruses were also detected in a subsample of subjects tested. Based on these results, investigators concluded that a significant subset of CFS patients may have a chronic, noncytolytic, potentially disseminated enteroviral infection, which could be diagnosed through stomach biopsy. The investigators noted the tropism with brain and muscle and suggested that the neuroinflammation seen in neuroimaging studies of a subgroup of CFS patients may result from enteroviral infection.

Genomics and Proteomics

Gene expression microarray data has become a highly productive tool in better understanding CFS research. A group of research studies supported by the US Centers for Disease Control and Prevention led to a series of 14 articles published in a dedicated issue of Pharmacogenomics in April 2006. These publications were the result of a multidisciplinary endeavor among an international cadre of 20 molecular biologists, epidemiologists, mathematicians, engineers, and other scientists, who independently analyzed genomic, laboratory, and clinical data collected from 227 study participants. During a 2-day hospital stay, the study participants underwent a comprehensive battery of tests that included measurements of cognitive function, sleep physiology, autonomic nervous system function, and blood analyses of the sequencing and expression of over 20,000 genes. Mitochondrial and ion channel regulatory genes were dysregulated. Microarray data also showed upregulation of proinflammatory cytokine pathways, and subgroup analyses linked different patterns of endocrine, immune, and metabolic dysregulation that identified as many as six subgroups of CFS. Although the investigators could not identify a definitive genetic marker for CFS, they were able to identify 28 single nucleotide polymorphisms to predict with 76% accuracy whether an individual had CFS.

These investigators also found that patients with CFS and control patients demonstrated different levels of gene expression for genes affecting the HPA axis and the sympathetic nervous system. Genes that modulate physiologic response to chemical messengers like hormones released as part of a normal stress response were altered in the CFS group. These data from gene arrays and single nucleotide polymorphisms are consistent with the studies of Jerjes et al. [22**] and others that have shown an enhanced sensitivity of the HPA axis to negative feedback in CFS, as demonstrated using the prednisolone suppression test. Abnormal stress responses in patients with CFS and the link between the deregulation of immune function and abnormalities in HPA axis activity have been investigated in several studies. Anther study, published this year by Rajeevan et al. [23] identified sequence variations in the glucocorticoid receptor gene (NR3C1) in patients with CFS. NR3C1 is a key effector of the HPA axis. The study demonstrated that NR3C1 is a potential mediator of CFS, and further study into variations in this area may broaden our understanding of how CFS manifests [23].

Recent studies using microarray technology have suggested that infectious agents may trigger and perpetuate CFS symptoms. A study by Vernon et al. [24**] found evidence of mitochondrial dysfunction in cases of postinfective fatigue caused by EBV. The investigators compared subjects with acute mononucleosis who developed postinfective fatigue of more than 6 months' duration to HLA-matched subjects who recovered within 3 months. The gene expression profiles of subjects who displayed a postinfective fatigue response lasting more than 6 months differed from those of the controls. Six genes known to be activated during EBV infection were differentially displayed in the postinfective fatigue cases. A number of these differentially expressed genes are known to affect mitochondrial functions, including fatty acid metabolism and the cell cycle [24**].

Immunology Dysregulation and Treatment Modalities

Immune dysregulation has been described by many groups, with evidence of cellular dysfunction and chronic immune activation described in early articles on CFS [25,26]. Studies of the mechanisms of immune dysfunction attempt to discover targets for immune-based therapies. Research into treatments that target humoral immune response and viral loads are important areas of investigation.

Natural killer cell and cytotoxic T-cell dysfunction: interferon beta use

Natural killer cells are versatile lymphocytes, which - in healthy individuals - can destroy infected cells. Patients with CFS often have reduced natural killer cell cytotoxic activity [27,28,29*]. Maher et al. [4*] found that the natural killer cells of patients with CFS had abnormally low levels ofperforin, which natural killer cells use to penetrate infected cells and inject cytotoxic granzymes. Perforin plays a critical role in immune surveillance and immunomodulation; therefore, a decrease in perforin levels may play a role in the pathogenesis of CFS. This study was the first to examine cytotoxic T cells in CFS. The authors describe a decrease in perforin and granzyme content of the cytotoxic T cells equal to that seen in natural killer cells. The clinical implications are consistent with an immune system that may allow viral reactivation and raises a concern for tumor surveillance as well.

Some researchers have proposed that natural killer cell activity (NKCA) could be used as an immunological sub-group marker in CFS. Siegel et al. [29*] found that relative to CFS patients with normal NKCA, patients with low NKCA levels reported more cognitive dysfunction, more daytime impairment, and less vigor. These patients also scored lower on objective measures of cognitive function relative to patients with normal NKCA levels. Immunomodulatory therapies that target natural killer cell and cytotoxic T-cell function would seem reasonable, using functional and quantitative flow to identify the appropriate subgroup [30*].

One such therapy is postulated by Kerr et al. [30*]. IFN-beta, a licensed treatment for multiple sclerosis, may hold some hope for patients with CFS. To date, no trials have tested the efficacy of IFN-beta on patients with CFS, but the theoretical support for such a trial is compelling. Much like CFS, the pathogenesis of fatigue in multiple sclerosis is thought to be cytokine mediated. IFN-beta is known to regulate humoral immune responses and response to viral infection. IFN-beta increases the activity of natural killer cells and the expression of human leukocyte class 1 antigens while blocking the expression of human leukocyte class 2 antigens. In addition, it can selectively inhibit the expression of several genes implicated in genomic studies of patients with CFS. Based on gene expression data, studies are planned to explore CFS treatment with IFN-beta. A clinical trial of IFN-beta is expected to begin at St. George's University in London.

Chronic Fatigue Syndrome: Inflammation, Immune Function, and Neuroendocrine Part 2

Antiviral treatments

At the 2007 International Association of Chronic Fatigue Syndrome meeting, investigators presented two phase 1 studies of valganciclovir in CFS patients with evidence of HHV-6 or EBV infection. Kogelnik et al. [31*] found evidence of clinical improvement in 20 of 23 subjects with acute onset CFS and high EBV and/or HHV-6 antibody titers. Lerner et al. [32*] presented data from an open-label phase 1 trial supporting EBV reactivation affecting cardiac function in profoundly ill CFS patients. The study, which was a follow-up to his previously published study of 19 CFS patients with cardiac wall motility abnormalities, showed a favorable clinical response from most of the 60 patients to 6 months of oral valganciclovir. Both investigators cautioned that the drug had a significant risk of bone marrow suppression and renal toxicity, and phase 2 placebo control studies are underway.

In an open-label study of folinic acid, authors reported a high incidence of chronic reactivated EBV infection accompanied by B-cell immunodeficiency in patients with CFS. A significant proportion of these patients experienced a marked improvement in symptoms after treatment with folinic acid [33].

A retrospective study measuring the response of patients with CFS to azithromycin found that 58 of the 99 participants reported a decrease in symptom severity [34]. The responders improved to an estimated maximum of 80% of their premorbid level. Those patients who responded to the treatment had lower levels of plasma acetylcarnitine. The investigators theorize that the efficacy of the azithromycin could be attributed to the modulating effect on the chronically primed immune glia-cells in the brain or in the activated immune system of the patients with CFS.

Conclusions

The preponderance of available research confirms that immune dysregulation is a primary characteristic of CFS. New research has further elucidated our understanding of the genomics of the illness and the role of viral infection and reactivation in the pathogenesis. Advances in the field should result in targeted therapies to impact immune function, HPA axis regulation, and persistent viral reactivation in CFS patients. Future research investigating these important areas may lead to promising new discoveries and options for treating CFS.


Footnotes


Acknowledgment

The authors have no potential conflicts, financial or otherwise.


References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as:
*  Of importance
** Of major importance

1.   Fukada K, Straus S, Hickie I: The chronic fatigue syndrome:
      A comprehensive approach to its definition and study. Ann
      Intern Med 1994, 121:953-959.
2.   Landay A, Jessop C, Lennette E, Levy J: Chronic fatigue
      syndrome: Clinical condition associated with immune
      activation. Lancet 1991, 338:707-712.
3.   Plioplys A: Differential diagnosis in medical assessment. In
      Handbook of Chronic Fatigue Syndrome. Edited by Jason
      L, Fennel P, Taylor R. Hoboken: John Wiley and Sons;
      2003:26-41.
4.*  Maher KJ, Klimas NG, Fletcher MA: Chronic fatigue syn-
      drome is associated with diminished intracellular perforin.
      Clin Exp Immunol 2005, 142:505-511.
      First study to see cytotoxic T-cell defects as severe as natural killer
      cell defects using intracellular perforin assay.
5.** Hickie I, Davenport T, Wakefield D, et al.: Post-infec-
      tive and chronic fatigue syndromes precipitated by viral
      pathogens: Prospective cohort study. BMJ 2006, 333:575.
      Identified the severity of the primary infection as the primary
      predictor of the course of illness for patients with CFS.
6.   Appel S, Chapman J, Shoenfeld Y: Infections and vac-
      cination in chronic fatigue syndrome: Myth or reality.
      Autoimmunity 2007, 40:48-53.
7.   Maes M, Mihaylova I, De Ruyter M: Lower serum zinc in
      chronic fatigue syndrome (CFS): Relationships to immune
      dysfunctions and relevance for the oxidative stress status in
      CFS. J Affect Disord 2006, 90:141-147.
8.   Maes M, Mihaylova I, Leunis JC: In chronic fatigue
      syndrome, the decreased levels of omega-3 poly unsaturated
      fatty acids are related to lower serum zinc and defects in T
      cell activation. Neuro Endocrinol Lett 2005, 26:745-751.
9.   Maes M, Mihaylova I, Leunis JC: Chronic fatigue syndrome
      is accompanied by an IgM-related immune response
      directed against neopitopes formed by oxidative or nitrosa-
      tive damage to lipids and proteins. Neuro Endocrinol Lett
      2006, 27:615-621.
10.   Puri BK: Long-chain polyunsaturated fatty acids and the
      pathophysiology of myalgic encephalomyelitis (chronic
      fatigue syndrome). J Clin Pathol 2007, 60:122-124.
11.*  Grans H, Nilsson M, Dahlman-Wright K, Evengard B:
      Reduced levels of oestrogen receptor B (beta) mRNA in
      Swedish patients with chronic fatigue syndrome. J Clin
      Pathol 2007, 60:195-198.
      Described genomic findings related to sex hormone pathway
      abnormalities and CFS.
12.   Cleare AJ, Bearn J, Allain T, et al.: Contrasting neuroendo-
      crine responses in depression and chronic fatigue syndrome.
      J Affect Disord 1995, 34:283-289.
13.   Demitrack MA, Dale JK, Straus SE, et al.: Evidence for
      impaired activation of the hypothalamic-pituitary-adrenal
      axis in patients with chronic fatigue syndrome. J Clin
      Endocrinol Metab 1991, 73:1224-1234.
14.   Ter Wolbeek M, van Doornen LJ, Kavelaars A, et al.: Lon-
      gitudinal analysis of pro- and anti-inflammatory cytokine
      production in severely fatigued adolescents. Brain Behav
      Immun 2007, Epub ahead of print.
15.   Berneman ZN, Ablashi DV, Li G, et al.: Human herpesvirus
      7 is a T-lymphotropic virus and is related to, but signifi-
      cantly different from, human herpesvirus 6 and human
      cytomegalovirus. Proc Natl Acad Sci 1992, 89:10552-10556.
16.   White PD, Thomas JM, Kangro HO, et al.: Predictions
      and associations of fatigue syndrome and mood disorders
      that occur after infectious mononucleosis. Lancet 2001,
      358:1946-1954.
17.   Chapenko S, Krumina A, Kozireva S, et al.: Activation of
      human herpesvirus 6 and 7 in patients with chronic fatigue
      syndrome. J Clin Virol 2006, 37(Suppl 1):S47-51.
18.*  Petersen I, Thomas JM, Hamilton WT, White PD: Risk and
      predictors of fatigue after infectious mononucleosis in a
      large primary care cohort. QJM 2006; 99:49-55.
      Described the results of a study investigating the risk factors and
      predictors of the development of fatigue syndrome following an
      infection with infectious mononucleosis, or EBV. Identified female
      sex and premorbid mood disorder as risk factors for fatigue.
19.   Gow JW, Behan WM, Simpson K, et al.: Studies on entero-
      virus in patients with chronic fatigue syndrome. Clin Infect
      Dis 1994, 18(Suppl 1):S126-129.
20.   Maes M, Mihaylova I, Leunis JC: Increased serum IgA and
      IgM against LPS of enterobacteria higher in chronic fatigue
      syndrome (CFS): Indication for the involvement of gram-
      negative bacteria in the etiology of CFS and for the presence
      of an increased gut-intestinal permeability. J Affect Disord
      2007, 99:237-240.
21.** Chia JK, Chia AY: Chronic fatigue syndrome is associated
      with chronic enterovirus infection of the stomach. J Clin
      Pathol 2007, Epub ahead of print.
      The first study to look at enterovirus in CFS. Researchers found
      enterovirus viral capsid protein 1, RNA, and noncytopathic viruses
      in the stomach biopsy specimens in the majority of CFS patients
      with chronic gastrointestinal complaints.
22.** Jerjes WK, Taylor NF, Wood PJ, Cleare AJ: Enhanced
      feedback sensitivity to prednisolone in chronic fatigue
      syndrome. Psychoneuroendocrinology 2007 32:192-198.
      Described alterations in negative feedback control of HPA axis in
      patients with CFS using dexamethasone suppression test.
23.   Rajeevan MS, Smith AK, Dimulescu I, et al.: Glucocorti-
      coid receptor polymorphisms and haplotypes associated
      with chronic fatigue syndrome. Genes Brain Behav 2007,
      6:167-176.
24.** Vernon SD, Whistler T, Cameron B, et al.: Preliminary
      evidence of mitochondrial dysfunction associated with
      post-infective fatigue after acute infection with Epstein Barr
      Virus. BMC Infect Dis 2006, 6:15.
      Described alterations in gene transcripts among patients with
      postinfective fatigue following acute infection with EBV. Found
      that the patients who developed the postinfective fatigue syndrome
      had gene expression profiles that indicated an altered host response
      during episode of acute mononucleosis when compared with those
      patients who recovered without event.
25.   Klimas NG, Salvato FR, Morgan R, Fletcher MA: Immu-
      nologic abnormalities in chronic fatigue syndrome. J Clin
      Microbiol 1990, 28:1403-1410.
26.   Landay AL, Jessop C, Lennette ET, Levy JA: Chronic
      fatigue syndrome: clinical condition associated with
      immune activation. Lancet 1991, 338:707-712.
27.   Maher K, Klimas N, Fletcher MA: Immunology. In
      Handbook of Chronic Fatigue Syndrome. Edited by Jason
      L, Fennel P, Taylor R. Hoboken: John Wiley and Sons;
      2003:124-151.
28.   Caligiuri M, Murray C, Buchwald D, et al.: Phenotypic and
      functional deficiency in natural killer cells in patients with
      chronic fatigue syndrome. J Immunol 1987, 139:3306-3313.
29.*  Siegel SD, Antoni MH, Fletcher MA, et al.: Impaired
      natural immunity, cognitive dysfunction, and physical
      symptoms in patients with chronic fatigue syndrome:
      Preliminary evidence for a subgroup? J Psychosom Res
      2006, 60:559-566.
      Identified subgroup by immune activation and cell function to
      predict symptom cluster and severity.
30.*  Kerr JR, Hodgetts A, Langford PR, et al.: Current research
      priorities in chronic fatigue syndrome/myalgic encephalitis:
      Disease mechanisms, a diagnostic test and specific treat-
      ments. J Clin Pathol 2007, 60:113-116.
      Reviews potential impact of genomics on diagnosis and treatment
      of CFS.
31.*  Kogelnik AM, Loomis K, Hoegh-Petersen M, et al.: Use
      of valganciclovir in patients with elevated antibody titers
      against Human Herpesvirus-6 (HHV-6) and Epstein-Barr
      Virus (EBV) who were experiencing central nervous system
      dysfunction including long-standing fatigue. J Clin Virol
      2006, 37 Suppl 1:S33-8.
      Phase 1 study of valganciclovir in the subgroup of CFS patients
      with high antibody titers to HHV-6 and/or EBV; phase 2 studies
      are currently underway with this group.
32.*  Lerner AM, Beqaj SH, Deeter RG, et al.: A six-month trial
      of valganciclovir in the Epstein-Barr virus subset of chronic
      fatigue syndrome: improvement in left ventricular function.
      Drugs Today (Barc). 2002, 38:549-561.
      Phase 1 study of valganciclovir suggesting that subgroup responds
      to viral suppression.
33.   Lundell K, Qazi S, Eddy L, Uckun FM: Clinical activity
      of folinic acid in patients with chronic fatigue syndrome.
      Arzneimittelforschung 2006, 56:399-404.
34.   Vermeulen RC, Scholte HR: Azithromycin in chronic
      fatigue syndrome (CFS), an analysis of clinical data. J
      Transl Med 2006, 4:34.

--------
(c) 2007 Current Medicine Group LLC

             

Friday, January 18, 2008

Credibility and Convergence: CFS and the Media

Credibility & Convergence: A Look at CFS
Emerging illnesses don’t just spring forth as public health priorities. There are recognized models for how they gain attention and credibility. This article by Kim McCleary from the fall 2007 CFIDS Chronicle, offers a fascinating look at the factors that contribute to recognition and how CFS has fared so far.
Get the full story>> [in PDF format]

The article is too long to post here in full, so I'll just post a couple excerpts and you can read the original PDF for "the full story".

As we look back over the past 20 years to identify
turning points in the acceptance of CFS, it might
surprise you to know that our struggle and our
progress is also being observed and documented by people
outside the CFS community.

It’s not as if anyone master-planned this course, or, in
getting diagnosed, expected to play a role in bringing a complex
new medical condition to the attention of the public,
medical professionals and scientists. Yet here we are, 23
years after the Incline Village and Lyndonville outbreaks
generated interest in what came to be known as chronic
fatigue syndrome. Let’s try to see our progression as
others might.

In Emerging Illnesses and Society, Randall Packard
and fellow editors describe four factors that determine how
a health condition becomes a recognized illness that warrants
action by health authorities:
■ The epidemiology of the illness;
■ The communications and leadership of the community
of suffering;
■ The culture and constraints of the responsible public
health institutions; and
■ The response of the media.
Let’s apply their model to our history.

Factor one:
epidemiology

Epidemiology is a big word that
basically refers to who gets a particular
condition, how many cases there
are and how it spreads. The epidemiology of CFS has been
a puzzle from the start. ... The
deaths and rapid spread associated with AIDS were dramatic,
compared to the more subtle devastation wrought by
CFS. This contrast impacted visibility and how the study of
CFS was approached by scientists.

Over time, the truly
chronic nature of CFS came into focus as well. The CDC
reported recovery rates as low as 12 percent and compared
the disability associated with CFS to that of multiple sclerosis,
AIDS and COPD.

While the 1994 definition remains the “gold standard”
for research, lack of agreement about how to define CFS—
and what to call it—has created a confusing picture to
those on the outside. This points to areas where more work
is needed—particularly work toward determining the
pathophysiology and establishing a diagnostic test.
Packard and his colleagues echo this thought:
“Part of the uncertainty with illnesses such
as CFS and fibromyalgia has to do with the
difficulty in knowing what constitutes a case
in the absence of a clear diagnostic test.”

Factor two:
community leadership
and communication
Patients organize for action and respect
Support groups formed quickly
in areas where CFS first emerged in
clusters, but it took luck and media
reports to help other patients find each another.

In 1990, researchers recognized the need for a coalition
of science and medical professionals concerned about CFS
and formed the American Association for CFS (AACFS,
now the International Association for CFS/ME). It hosted
its first research and patient conference in 1992 and has
held seven biennial meetings since, providing an important
anchor for the field. Its newsletter and an affiliated Journal
of Chronic Fatigue Syndrome have helped promote information
exchange among researchers and clinicians.
Broader access to the Internet by the late 1990s dramatically
changed the method and frequency of communication
within the CFS community as bulletin boards and
listservs like Co-Cure helped spread information and give
voice to people who couldn’t access local support organizations.

Packard and his colleagues make a similar assessment:
“Groups associated with CFS and fibromyalgia
have been successful in overcoming
the challenges to illness emergence . . .
This activism accounts for much of the
public health attention that these illnesses
have gained.”

Factor three:
the culture and constraints of responsible health institutions
Agency paradigms shift in ways that benefit CFS

Without getting bogged down in the missions of
various health agencies, suffice it to say that the CDC and
National Institutes of Health (NIH) both had major responsibilities
as CFS emerged in the 1980s, and still do today.
These changes are
important to the history of
CFS because as a chronic,
multisystemic illness, it didn’t fit well with either of these
institutions’ traditional approaches.
The CDC has been widely criticized for its initial
response to CFS after Dr. Cheney and his partner Dr. Dan
Peterson asked a team of CDC’s rapid-response officers to
help evaluate the Incline Village patient cluster in 1985.
The CDC team reviewed charts and ended its investigation
after examining just a few patients, quickly dismissing
any possibility of a new public health threat. At the
same time, AIDS fit squarely in CDC’s detect-and-control
paradigm and consumed its available resources, although
AIDS activists would argue that the CDC failed that disease
early on, too.

efforts were largely considered inadequate and lacking a
true sense of CFS beyond the symptom of chronic fatigue.
Public challenges by patient advocates, myself
included, over CDC spending for CFS culminated in 1998
with the CDC’s own principal investigator, Dr. William
Reeves, presenting evidence that officials had lied to
Congress about CFS expenditures. With pressure from the
CFIDS Association and Congress, $13 million in funds was
restored to the CFS program, allowing researchers to rapidly
expand the breadth of research from 1999 to 2006.
Provider education activities and the first national
public awareness campaign were funded after the CDC
documented overwhelming evidence of the magnitude of
CFS and under-recognition by the pubic and medical community.
In the “post-payback” era, the program is contracting
again, but important gene-based studies of the biological
underpinnings and the public commitment of CDC director
Julie Gerberding helped cement the message that CFS is
real and serious.

What about the NIH’s history with CFS? The NIH’s
Stephen Straus was among those who showed EBV not to
be the cause of the mystery illness of the mid-1980s and
later linked CFS to psychological factors when his own
theories didn’t pan out.

Research on the role of the autonomic
nervous system was “hot” after a Johns Hopkins team
linked CFS to neurally mediated hypotension. Expertise
from other disciplines was warranted, so advocates pushed
to transfer responsibility for CFS from the National Institute
of Allergy and Infectious Diseases (NIAID) to the Office of
the NIH Director. A State
of the Science conference
hosted by NIH in 2000
helped identify promising
directions, but funding levels
suffered when NIAID
discontinued support for
the CFS research centers.
An emphasis on neuroimmune mechanisms of CFS
was fostered by Drs. Vivian Pinn and Eleanor Hanna of the
Office of Research on Women’s Health (ORWH)

At the top of the health policy “chain of command,”
the Department of Health and Human Services in 1996 created
one of the only disease-specific advisory committees
formed during the Clinton administration. It was a legacy
left by former Assistant Secretary of Health Philip Lee, a
CFS champion, giving advocates a seat at the table with
officials from five health agencies.
Although the committee’s role has been disparaged by
some in the community, it has helped maintain a dialogue
between the patient community, researchers and those
responsible for implementing public health policy. The
CDC scandal came to light through this committee and an
important Social Security policy ruling—one recognizing
CFS as a disabling condition—was shepherded by the
committee, although much of the work occurred with
CFIDS Association representatives and agency officials in
between the infrequent public meetings.
These developments, geared to forming accountable
partnerships, are in keeping with one of Packard and
colleagues’ keys to success:
“Public health and medical research institutions
can benefit . . . from collaboration.
Medical researchers, public health officials
and communities of suffering need to be
partners.”

Factor four:
media response
Controversy gives way
to credibility
When the cluster of illness
occurred in Incline Village, a media
frenzy followed Cheney’s and
Peterson’s reports to the authorities.
Nightline and 20/20 covered the resort town outbreak.
Fears of contagion caused panic and stigmatized sufferers.
But the “mysterious” nature of the illness also helped
attract more moderate journalists to it. Newsweek’s
Geoffrey Cowley wrote the November 12, 1990, cover
story about CFS, and science writer Joseph Palca penned
“In Search of an Elusive Disease” for Science magazine
in 1992.
Firsthand accounts like Hillary Johnson’s “Journey
Into Fear” published in Rolling Stone helpedbroaden the
view beyond the early years’ “yuppie flu” stereotype that
painted sufferers as type-A burnouts. The Golden Girls
creator Susan Harris, also a CFS patient, told her story
through character Dorothy in a two-part series that opened
the 1989 season and still resonates in reruns seen today.
So what happened? With this initial influx of affirming
media, why didn’t public opinion swell in support of CFS
patients? Perhaps the contest within the medical community
and public health institutions over theories of causation,
coupled with premature reports of research breakthroughs,
contributed to frustration, then apathy, on the part of journalists.
Without the “medical certification” required for
widespread support, serious media attention languished.
Still, as Packard and colleagues documented, in the 1990s
there were roughly 1,400 newspaper articles that mentioned
or discussed CFS, “helping keep CFS on the public health
agenda.”
Fast-forward to the CDC-funded public awareness
campaign launched with the CFIDS Association in 2006. It
has ushered in a new era of CFS media coverage. On April
20, 2006, CDC director Julie Gerberding briefed the press
on a series of CFS studies, generating significant coverage
by a large number of general and scientific news outlets.
On November 3, 2006, she appeared as the lead speaker on
a panel of CFS experts at the National Press Club, garnering
repetition around the world, literally, of the message,
“CDC: CFS Real, Brutal” (UPI, November 3, 2006).

Although today’s information-saturated environment
demands constant reinforcement of the basic messages
about CFS, since the press conference, thousands of articles,
broadcast reports and interviews with experts have
eclipsed lingering doubts about the illness. Recent reports
of viruses linked to CFS subsets now secure serious media
attention and hard-earned credibility, contributing to scientific
interest, rather than controversy.

Looking back; looking ahead
Whether you view our history from inside the community
or as an outsider, it’s clear we still have much work
ahead to make CFS a truly mainstream medical concern.
Does Packard’s book offer a way forward to even greater
visibility and higher public health priority? Regrettably, no.
In fact, the editors write the following:
“The process of emergence becomes more
complicated as one moves [toward greater
acceptance]. … There is no single pathway to
getting placed on the health agenda.”
Nonetheless, viewed through the emerging illness
model, the destination is clear. Concentrating on the four
factors, we need to increase research to find a diagnostic
test, work together on national issues, collaborate with and
influence public health institutions and keep the media
momentum going. With the ground we’ve covered and all
that’s at stake, there is simply no going back.

* * *

Unfortunately, there are doctors and journalists who latched onto the "all in their heads" notion and will not let go of it.

One is the co-worker of someone who later developed CFS.  Her thought was that he would see her problems and change his stance because he knew she was not an emotional basket case.  Wrong.  In the 2006 CDC press conference, someone used the word "stress" (referring to either emotional or physical stressors that would tax the immune system), and that journalist wrote his article to stress stress, with almost no mention at all of the genetic and other abnormalities cited in that press conference.  Worse yet, his article was picked up by smaller newspapers across the country who had not had someone at the press conference.  So, while half the country was celebrating that CDC had finally acknowledged it wasn't "all in our heads", the other half was being told that that's exactly what it was.

One of our local TV stations has started a new segment where twice a week on the evening news, the doctor who is their medical correspondent addresses patient questions.  I know he's been sent questions about CFS referring to some of the new studies showing biological abnormalities.  He hasn't answered any of them; he's another of those who made up his mind long ago that it's psychiatric and has rejected any information that shows otherwise.

So, we still have a long way to go in educating the media that what they were told 20 years ago by Straus & Co. was not accurate and that they need to open their minds to the new information.

Dr. John on Dr. Vallings, and Dr. Vallings on Dr. John

This is the first of two very similar replies from me to two similar
articles published in two different newspapers in New Zealand. Both are,
principally, about the New Year honour of the New Zealand Order of Merit
awarded to Dr Ros Vallings, which I think will be generally thought
well-deserved and I know that she is thought of highly, at home and abroad
but each article contains other elements that need a response.

The link for this article is below Dr Valling's reply to my letter below.

For anyone who can manage it, the e-mail address for this one is
lisahh@times.co.nz

I am still struggling, after weeks, against a vicious flu virus. I have
never been so ill in all my life, rarely up, washed, dressed and still with
the most dreadful symptoms that only a pact with the devil, or someone
putting me out of my misery with an elephant gun seem the remaining options.
We could not have managed without our amazing volunteers at ME Free For All
and I have had to utterly depend on a few personal friends for essentials
such as shopping, spoon-feeding chicken soup, peeling grapes, bathing in
asses milk ....

Back to full capacity when I can.
Cheers
John

*Letter to the Editor (also author of this piece)*.

Dear Lisah,

The honour of New Zealand Order of Merit (MNZM) awarded to Dr Ros Vallings (
*Friend to chronically fatigued patients, Howick and Pakuranga Times, New
Zealand, 10 January 2008 *)  is thoroughly well-deserved and I add my
congratulations to those which come from the M.E. Community, around the
world, who admire her personally and for her enormous contribution.

It is one myth, born of flawed logic, that M.E. (*Myalgic Encephalomyelitis*)
is a more common illness than most people imagine and it is a second myth
that it is becoming even more common. It needs no more than common
observation to see that the first is not true. Think for a moment, of all
the people you know - friends, family, neighbours and the wider general
population - how many have M.E.? None, perhaps? One? Two, maybe? Now, of the
same population, how many do not have M.E.? Lots? Oodles? Squillions? We
don't have to be very accurate with numbers, at this stage, to see that it
is not a common illness. Yet these two myths are gaining currency, globally,
by repetition of false logic and a little prestidigitation
. We may trace the
process of both in order to understand the unreliable origins of this
conjuring trick.

There is ample evidence, both *post mortem* and in living patients, for
Myalgic Encephalomyelitis (*Myalgic*, relating to the muscles; *encephalo-*,
the brain and spinal cord and *-itis* meaning inflammation). It holds good
more than fifty years after first being used by the late Dr Melvin Ramsay
and needs no other diagnostic labels foist upon it. But this is what has
happened, without justification, in the last twenty years or so and this is
why it may appear that it is becoming increasingly more common when it is
not in reality.

The illusion is created by focusing on only one symptom of fatigue, which is
especially frustrating for M.E. sufferers who protest - on deaf ears, it
seems - that, whatever is their overwhelming and omnipresent feeling of
lassitude, it is not, repeat not, a million times not, fatigue because it
doesn't present like the tiredness we normally understand and expect from
physical or mental exertion; nor is it repaired by any amount of sleep, as
fatigue is usually. Arrogantly ignoring this experience of the patient and
also the fact that the other symptoms of M.E. (including muscle pain,
swollen lymph glands, cognitive dysfunction, dizziness etc.) are not always
present in, or typical of, other illnesses, having chronic fatigue as a
principal symptom
, the *Chronic Fatigue Syndrome *magicians indiscriminately
bundle them all together under the same umbrella of CFS.

Now, although adding all these clinically and symptomatically different
illnesses together obviously increases the total number of patients under
the newly-invented term CFS (just as adding apples + oranges + bananas etc.
= more total *fruit*, the generic name for all, in the basket), we should,
nevertheless, maintain the correct number for each discrete illness (just as
the numbers of x apples, y oranges, z bananas etc. are still known
separately, even when they are considered collectively as fruit) but, for
the next part of the trick, ladies and gentlemen, the CFS magic circle now
declare that M.E. and CFS are synonymous and interchangeable and give
it/them the hybrid name CFS/ME. Theyhave created a monster.

The next sleight is to make M.E. disappear altogether by referring only to
CFS (and no longer CFS/ME), which now has the increased number of sufferers
from whatever source of chronic fatigue, whether due to any illness, or
after surgery, vaccination, chemical poisoning, or any other cause as yet
unknown. If the ugly head of M.E  does ever re-appear, the audience is
reminded that, since it the same as CFS (haven't they just proved it?) and
since CFS is common and has increased in number (you saw it with your own
eyes, didn't you?) and since CFS = M.E. (We've already agreed that, haven't
we?) then - Hey Pesto! -  so must M.E. be more common and on the increase.

Of course, it's a trick. It's a cruel trick for people who have M.E. *(Myalgic
Encephalomyelitis *) because it forces all patients into one kind of
treatment regime, which is of no lasting benefit for M.E. sufferers and may
do some of them irrecoverable harm, leaving them in a wheelchair or bed
bound and, by denying that it exists as a discrete neurological illness,
denies M.E. the research that it desperately needs to discover the physical
cause and suggest treatment towards cure.

On behalf of all chronically ill M.E. sufferers and researchers (of which
this Research Psychologist, diagnosed for two decades with M.E., is both), I
appeal for this sorcery to stop and for properly funded scientific research
worldwide.

Yours truly
drjohngreensmith@mefreeforall.org
Dr John H Greensmith
ME Free For All. org

From: Dr Rosamund Vallings

The Editor

Howick and Pakuranga Times

In response to the letter from Dr Greensmith in Bristol, UK, I do agree in
many ways with what he is saying. The term ME (myalgic encephalomyelitis)
was coined many years ago as a then apt description of this debilitating
illness.  However as research advanced it was deemed inaccurate terminology
and as a result many in the medical community became skeptical about the
credibility of the illness.  "-itis" means inflammation and no inflammatory
change had been shown.  As a result of many international meetings of world
experts in CFS/ME and much discussion, the illness was renamed Chronic
Fatigue Syndrome.  This term, although in many ways inadequate, was accurate
and medically acceptable until such time as the research showed us exactly
what was going on pathologically. i.e. the illness is chronic with
associated abnormal fatigue and a number of very specific symptoms thus
making it a syndrome.

Patients have however never liked the term for the very reasons Dr
Greensmith has pointed out.  So often, people who are chronically tired (and fatigue is a feature in many illnesses, both physical and mental) are inadvertently given the label Chronic Fatigue for want of anything else specific coming to light, and this has then been confused with Chronic Fatigue Syndrome.  This has of course meant the debate about the reality of the illness CFS has resurfaced again and again, through lack of understanding of the confusing terminology.  Thankfully a huge body of exciting international research at prestigious institutions has clarified our understanding of the illness.

At a recent medical meeting of the International Association for CFS,
nomenclature was again discussed in light of current genetic, neurological
and immunological research.  It was unanimously decided that the name should
be changed to CFS/ME – "ME" now representing the medically acceptable term
"Myalgic Encephalopathy".  This means that there is abnormal brain pathology
but not inflammation as the original term indicated
.

This may all seem somewhat pedantic, but our patients deserve correct
acknowledgement and understanding.  If we endlessly change the name, the
illness lacks credibility and we as health professionals can easily become
confused, which may end up with our patients being inadequately treated for
this very serious illness.

Rosamund Vallings.

http://www.times.co.nz/cms/news/2008/01/art100018948.php

Friend to chronically fatigued patients
By Lisah Henry

Thursday, 10 January 2008

For once it is the doctor and not her patients feeling overwhelmed.

"It has been a little overwhelming," the Clevedon resident told the Times
between patients at her Ridge Rd practice.

She is New Zealand's leading specialist on chronic fatigue syndrome; an
interest peaked back in the early 1960s while working in her native-England.

"I was working in a hospital in London and we saw it quite a bit among the
staff at another nearby hospital – who became chronically ill.

"It became known as Royal Free disease, in reference to the hospital where

these people were working."

In 1966 came to New Zealand and set up her general practice in Bucklands
Beach  before setting up in Howick several years later.

In 1973 she was a co-researcher into the condition also known as Myalgic
Encephalopathy (ME) at the Department of Rheumatology at the University of
Auckland.

"During and after the research I kept in touch with some of the participants
as their doctor.

"I also established an education and support group where people could go to
learn more about their condition and how to manage it."

CFS, ME or Tapanui Flu – are all common names for the condition and Dr
Vallings says it is a lot more common that people think.

"It's thankfully a lot more recognised today too, among the general public,
but more importantly among the medical community."

Dr Vallings can take a fair share of the credit for that greater
recognition, as she travels extensively attending conferences, giving
lectures, participating in research, and producing comprehensive information
for patients and doctors.

"I recently had an article published in NZ Doctor and write and maintain the
management guidelines for doctors."

She has published and presented papers at many international conferences and
was elected to the editorial board of the US Journal of Chronic Fatigue
Syndrome in 2001.

Dr Vallings says CFS is a real medical condition that can strike at the most
healthiest of people.

"You often find very busy people or very sporty people who have had a virus
of some sort and then not had time to recover properly can be susceptible
the condition.

"We're not talking about being a little tired.  This condition, as the name
suggests, is chronic and can be life altering to those with it and ongoing
for years."

As the only GP few specialising in the area, she is in constant demand with
patients from throughout New Zealand and even some overseas.

She has been medical advisor to the Associated New Zealand Myalgic
Encephalopathy Society (ANZMES) since 1980 and was president for seven
years.

In hearing of the honour, Whatakane ME sufferer Steve Napier said: "Dr
Valling's very sound and practical advice allow me to continue working
through my illness.  Without her help I would have had to close my business
down."

CFS and Serotonin

CFS Gene Study Targets Serotonin Function

One of the most recent studies on serotonin in CFS was published last month in the journal Psychoneuroendocrinology. In this study, investigators looked for genetic differences in people with CFS, focusing on several genes important to the function of the serotonergic system. They found that differences in one receptor for serotonin were associated with CFS. Laboratory experiments showed that these variations might cause different levels of this receptor to be available. This is significant because if there aren't enough receptors for serotonin, an imbalance in the body could result. It’s the first study to show an association of CFS with this specific gene.

Serotonin has been around since the dawn of life. It appears to be evolutionarily conserved among many living organisms, from worms to humans. When something remains relatively unchanged for this long and in this many different organisms, it clearly plays a fundamentally critical role in maintaining life. Serotonin and the serotonergic system are essential for maintaining energy balance and homeostasis—elements people with CFS long to improve and increase.

The serotonergic system is a complex network of nerves, chemicals, transporters and receptors. It might be helpful to think of the serotonergic system like roads (nerves), people (serotonin), cars (transporters) and parking spaces at destinations (receptors). In humans, most of the nerves that respond to serotonin are in the brain and, in fact, highly concentrated in a part of the brain that has been implicated in CFS: the hypothalamus. Receptors on these nerves allow serotonin to temporarily “park,” and this sends a signal to the nerve that then initiates a response.

A well-characterized serotonin response is energy balance, where serotonin helps us regulate our relationship with the environment (such as finding and eating food), which in turn affects what happens inside our body (digesting food for energy storage and use). Though most of the nerves that respond to serotonin are in the brain, 95 percent of the body’s serotonin is found in the gut, and there are even bits of serotonin in our tongue. So, when we initiate a behavior such as eating, serotonin spurs a series of events that is essential for maintaining the body’s overall balance and homeostasis.

As reported in Psychoneuroendocrinology, the study examined 77 differences in genes related to serotonin function, uncovering three markers in the receptor subtype called HTRA2a that appear to be associated with CFS. Further analysis supported the implication that this receptor subtype may play a role in the pathogenesis of the illness.

Smith AK, Dimulescu I, Falkenberg VR, Narasimhan S, Heim C, Vernon SD, Rajeevan MS. Genetic evaluation of the serotonergic system in chronic fatigue syndrome. Psychoneuroendocrinology 2007; Dec 11 [Epub ahead of print]

* * *

Dr. Murphree (www.DrRodger.com ) tipped me off to the serotonin connection several years ago.  He has a theory that your sleep pattern indicates what biochemicals you need to work on, and I was one of those who raised my hand for the sleep pattern that indicates low serotonin.  He recommends 5HTP + Vitamin C + B complex + 750 mg magnesium to build up your serotonin levels.  And, sure enough, when I found the right dosage of 5HTP for me (the maximum dosage he recommends), I started to sleep without sleeping pills for the first time in years.

Through his website, you can order his CFS/Fibro formula vitamins or his Jump Start package.  I'll recommend them.  I took his pills and for the first time in years, I got through the winter without sinus problems -- there had been years that I spent the whole winter horizontal because the sinus problems were so bad that I got dizzy sitting up for just a few minutes.  Even though I didn't leap off the couch and start running marathons, they did keep me from getting sicker at a time of year when I generally did get sicker. 

I do have a new bottle of them here to see what happens now that I'm sleeping decently.  At this point, they might give me enough of a boost to increase my stamina.

Dr. Klimas explains CFS

http://www.immunesupport.com/library/showarticle.cfm/id/8116

University of Miami ME/CFS Researcher Nancy Klimas, MD, Explains Complexity of Chronic Fatigue Syndrome in Terms That Anybody Can Understand


ImmuneSupport.com

01-11-2008

 
The following article highlights the work of Dr. Nancy Klimas, MD, an international leader in ME/CFS research, and features her succinct explanation of the basic mechanisms involved in ME/CFS. It is reproduced with kind permission from the Spring 2007 issue of University of Miami Medicine, the magazine of the Leonard M. Miller Schol of Medicine at the University of Miami (FL), where Dr. Klimas is Professor of Medicine, Psychology, Microbiology, and Immunology, and Director of the Allergy and Immunology Clinic.

______________

Sick and Tired

By Jeanne Antol Krull

After 20 years of research, the cause of Chronic Fatigue Syndrome is still elusive – but physicians and scientists at the Miller School of Medicine are at the forefront of efforts to understand and develop effective treatments for the debilitating disease.

In 1984 a woman suffering from severe fatigue, body aches, and difficulty concentrating walked into the office of clinical immunologist Nancy Klimas, MD, with a medical file several inches thick - the result of visits to more than a dozen doctors. One piece of treatment advice she was given: “Change your hair color and get a manicure. You’ll feel better.”

But the patient knew better, telling Klimas simply, “I think there’s something wrong with my immune system.”

Those words would dramatically change the course of Klimas’s academic medical career and land her and her collaborators at the Miller School of Medicine at the forefront of understanding and trying to find a treatment for a baffling and debilitating disease that would come to be known as chronic fatigue syndrome.

If there was something wrong with your immune system, Klimas was the one to see in South Florida, and at the time her practice was mainly HIV patients. Klimas sent the patient’s blood sample to colleague Mary Ann Fletcher, Ph.D., professor of medicine, microbiology/immunology, and psychology, and asked her to “look at this any way you know how.” Fletcher’s lab was already doing groundbreaking work on the role of the body’s natural killer cells, which kill tumor cells or any pathogens in the blood.

“Mary Ann reports back, ‘There is something very odd about her blood work. She has less natural killer cell function than we see in end-stage AIDS patients, and her immune activation markers are very high,’” Klimas recalls. “I called the patient and told her, ‘I can’t tell you what’s wrong, but your labs are very abnormal.’ She burst into tears, she was so happy to hear something was wrong with her.”

It would be four more years before the Centers for Disease Control and Prevention (CDC) would formally define chronic fatigue syndrome, and the original definition would change over time as scientific knowledge evolved. Before then the disease was known as chronic Epstein-Barr virus syndrome, but that name was eliminated as other viruses and etiologies came into play.

The disease is characterized by profound fatigue that is not improved by bed rest and may be worsened by physical or even mental activity. No matter what the name or how debilitating the symptoms, those who suffered from it—mainly women—were called everything from hypochondriacs to just plain crackpots.

After a 17-year nursing career, Bonnie Mayer, then 45 years old, was fulfilling a lifelong dream of getting a degree in fine arts at Florida International University. She went to bed on April 6, 1994, feeling well and happy and woke up the next day very ill. “The room was spinning wildly, I was extremely dizzy, sick to my stomach, I couldn’t walk, and I was very weak,” Mayer remembers. She was diagnosed with a virus, which had affected the inner ear or balance mechanism, but the worst was yet to come.

“A week later I was still sick, I had extreme fatigue, I couldn’t think, I couldn’t even get out of bed.” Over the next six months she would consult six different doctors before she received a chronic fatigue diagnosis.

“There are a lot of people who have this illness and don’t know it, and I was one of them,” Mayer says.

Patients like Mayer found some vindication late last year when the full weight of the federal government was brought to bear against the disease. At a news conference in Washington, the CDC kicked off the first-ever national public awareness campaign on the disease.

Invited to be one of only a handful of speakers was Klimas, who spent a six-month sabbatical doing research on chronic fatigue for the CDC. “I had been waiting for that day for a very long time,” says Klimas. “After treating more than 2,000 chronic fatigue syndrome patients over more than 20 years, I’ve seen patients who were angry and frustrated at trying to convince their physicians and loved ones that this is a real illness. They experience a level of disability equal to that of patients with late-stage AIDS and patients undergoing chemotherapy—and now finally they have a powerful voice on their side.”

The CDC estimates that 4 million Americans have chronic fatigue syndrome, and almost 80 percent of all cases are undiagnosed. Among those numbers are veterans with Gulf War illness who suffer symptoms identical to chronic fatigue.

The problem with making a diagnosis is that there is no laboratory test, and treatment is aimed only at symptom relief and improved function.

More than half the patients have sudden or acute onset, usually following a viral infection. “A recent prospective study found the one single predictor of who is going to stay sick after a viral infection is the severity of the initial viral infection,” says Klimas. “The other patients have a slow onset, they suffer for a year or two before they realize they just aren’t getting any better, and by that time they have many other complicating factors such as depression.”

When it comes to treating patients, Klimas says you don’t have to be a chronic fatigue expert — it comes down to basic clinical principles. Patients tend to have three main problems in addition to fatigue: sleep disruption, autonomic dysfunction (delayed drops in blood pressure after standing), and pain.

“As you take care of each of the pieces, one by one, your patient starts coming together and getting better and better,” says Klimas. “In particular, the patient takes a big step forward the day you get their sleep better. Sleep is a huge part of helping patients feel better right from the beginning.”

Even though discovery of a cause is still elusive after more than two decades of searching, scientists have zeroed in on several key areas: infectious agents such as viruses, problems with hormone regulation in the body’s endocrine system, disturbances in the autonomic regulation of blood pressure and pulse, and immunologic dysfunction.

A multidisciplinary group led by Klimas at the Miller School of Medicine was among the first to recognize and report immune system abnormalities in chronic fatigue patients. As director of AIDS research at the Miami Veterans Affairs Medical Center, Klimas was already working with an existing team of UM and VA researchers on HIV, and she tapped into their expertise for this new battle.

“We were this big, diverse, multidisciplinary team in HIV, and I said, ‘Why can’t we do the same thing in chronic fatigue?’ Instead of looking at it myopically through one discipline, we’re the group that says, ‘These systems are all integrated to create what we call chronic fatigue syndrome,’” says Klimas.

"In looking at what generally happens to someone with this disease, it's easy to see how everything can go haywire. Think about when you get a virus: You feel pretty rotten, your immune system kicks in, everything quiets back down, and eventually you feel better. In chronic fatigue something revs up the immune system, but it never quiets back down.

For example, explains Klimas, “Whatever has stirred up your immune system in the first place can end up disturbing your sleep. When you don’t sleep properly, never going into stage three and stage four sleep, your body doesn’t release the nighttime hormones such as cortisol. A stress hormone, cortisol is a big part of why we quiet our immune system. It peaks in the morning when we wake up and resets the immune system for the day.”

When that doesn’t happen, the immune system that was activated yesterday gets even more activated today and the next day, and it starts releasing far too many cytokines, which are molecules that can make you ache all over and disrupt stage four sleep. These molecules can also cause adverse effects in the brain, leading to cognitive and memory problems.

“What you end up with is this vicious cycle of fairly subtle dysregulation between the body’s hormone system, the autonomic nervous system, and the immune system,” Klimas says. “Everything is just a little off kilter - and instead of helping each other, these systems together are amplifying the problem.”

Fletcher, the scientist who tested the very first patient’s blood, is the director of the E. M. Papper Clinical Immunology Laboratory at the Miller School and has done groundbreaking work since the early 1980s on the immune system and, in particular, on the role of natural killer cells in chronic fatigue.

“Initially it was quite difficult to get funding,” remembers Fletcher. “This was seen as a hysterical condition that middle-aged women might come down with.”

Fletcher recently received a new National Institutes of Health (NIH) grant to study the role of specific peptides—neuropeptide Y (NPY) and dipeptidyl-peptidase (CD26)—in the development of chronic fatigue. These molecules are important in the regulation of many physiological and disease processes in the immune, nervous, and endocrine systems. The study will examine the relationship between blood concentrations of NPY and CD26 and the severity of chronic fatigue symptoms. And that’s not all.

Fletcher and Klimas are now recruiting 150 patients for a five-year longitudinal NIH study that will assess patients at baseline, again on a day when they feel good, and on a day when they feel bad, even if they have to go to their homes to collect the blood.

“We’re going to be looking at a large menu of immunologic markers at each of these intervals and compare them to 90 healthy subjects,” says Fletcher. “We’re hoping to see which of the markers will be instructive and will they correspond to the symptoms. This should give us a much more complete picture of the disease, and hopefully we can set a menu both to facilitate the diagnosis of chronic fatigue syndrome and to measure the efficacy of new treatments.”

Problems with the autonomic nervous system, which controls cardiovascular, digestive, and respiratory functions (as well as the immune system), are common in patients with chronic fatigue. Many have difficulty with fainting spells and lightheadedness, especially shortly after standing. Researchers have found many of these same patients have low or below-normal red blood cell volumes.

Klimas and Barry Hurwitz, Ph.D., professor of psychology and medicine and part of the UM Behavioral Medicine Research Program at the VA Medical Center, headed a four-year NIH study that looked at whether the anemia drug Procrit could help these patients by increasing their red blood cell volume.

“Our preliminary findings show while the drug corrected their anemia, it did not decrease their fatigue,” says Hurwitz. “However, we did find there was a slight improvement in their ability to stay standing for a longer period of time without a drop in blood pressure. Every little piece we can add to the puzzle will help us discover the root cause or causes of this illness.”

An increase in stress plays a very significant role in managing chronic fatigue symptoms. “On a good day I am easily fatigued—I can get out of breath scrambling an egg,” says Bonnie Mayer. “But if I have a particularly long, stressful day, it is much harder to function for the next couple of days.

“For me life is an adaptation, and thanks to a great deal of family support, my life is certainly better now than it was at the beginning of this journey.”

For more than 20 years faculty in the Behavioral Medicine Research Program have been studying stress management among patients who have diseases that affect the immune system. Much of their early work focused on HIV patients, but there was reason to believe that stress also played a big role among chronic fatigue patients.

A UM study conducted after Hurricane Andrew in 1992 found that chronic fatigue patients who lived in Miami-Dade County and went through the stress of the storm had a serious exacerbation of their symptoms, while patients in Broward County did not.

“We also found patients who were more optimistic and had more social support as they moved through the hurricane did better,” says Michael Antoni, Ph.D., professor of psychology and psychiatry and behavioral sciences. “We took these findings and designed a study to evaluate the effect of a ten-week cognitive behavioral stress management intervention group during which chronic fatigue patients were taught techniques to deal with stress. We found a very positive outcome on better stress and symptom management.”

Since many chronic fatigue patients often don’t feel well enough to attend regular therapy sessions, the NIH recently funded an extension of the study to see if the same effect can be achieved through a telephone-based cognitive behavioral stress management intervention . A similar program has already been found to be beneficial among dementia caregivers.

The next frontier is clearly studying genetic factors in chronic fatigue. Findings released earlier this year showed patients have a genetic make-up that affects the body’s ability to adapt to change. Taking that research a step further, Klimas has received VA funding to conduct a gene microarray analysis of chronic fatigue and Gulf War illness patients both before and after exercise.

“The knowledge is coming at us very quickly now. It is going to translate into effective therapies, and I am so excited to be a part of it,” says Klimas. “On a personal level, it is really important to ask yourself if you made a difference that affected a lot of people beyond your own patient base, and the answer is yes, I think I did. But there’s still a lot more to do.”

* * *

Female patients I know have been given contradictory advice ranging from "quit your job" to "get a job"; if you're single you need to get married, if you're married you need to get divorced, if you're divorced you need to get remarried.  Doctors going for the quick-fix rather than making the effort to figure out what's wrong with the patient.

In 1987, my boss and I had similar symptoms; mine were a lot worse.  His doctor put him on planes all over the state for different tests, with an eye toward getting him back to work -- no one ever told him what I was told, "just tell your spouse you want to quit your job". (In the long run, he was diagnosed with something completely different than I was.)  Although both of us had believed that women got equal treatment in the post-feminist era, our first-hand experience proved that the medical profession was still extremely misogynistic. 

I was sick while I was working, I was sick after I lost my job.  I had symptoms before, during and after my marriage.  What does that tell you about any theory that employment or marital status is the root of the problem?

In fact, my first CFS specialist in 1988 had told me exactly what Dr. Klimas says today: step one is to address the sleep problem.  When I finally found a doctor willing to give me sleeping pills instead of insisting on trying every anti-depressant available first, a lot of the other major problems became minor problems.  I could tell it was working -- after a few months of good sleep, my immune system regenerated enough to fight off the virus: I had a 101 fever for six months.  When the fever finally broke, I felt much better.

But if you say "it all started with a virus" and "my immune system beat back the virus", there will always be some naysayer who refuses to accept that CFS is biological or that a virus could affect you for years afterward, and tries to write off the virus as "coincidental".

I got sick at 28, so I was initially spared the BS about "normal aging" and "menopause", though I did hear those theories this time around.  And how does menopause explain the symptoms in patients named Mike, Peter and Steve?  Or in 5-year-olds?  All inconvenient truths that the naysayers try to sweep under the carpet.

As far as the theory that CFS is caused by deconditioning, I offer you not only my own experience of getting sick and relapsing while exercising daily, but another article from Immune Support, Even the Fittest of People Can Get Chronic Fatigue Syndrome .