Abstracts of IACFS/ME conferences 22-25 sept.2011 in Ottawa

ABSTRACTS

IACFS/ME Professional Workshops

Thursday, September 22, 2011

 

Workshop 1

How to Apply for Grants

Dennis F. Mangan, Ph.D.,

Cheryl L. McDonald, M.D.

The National Institutes of Health (NIH), part of the United States Department of Health & Human Services, is the primary U.S. Federal agency for conducting and supporting medical research. To realize its mission of extending healthy life and reducing the burdens of illness and disability, NIH funds grants that support the advancement of fundamental knowledge about the nature and behavior of living systems. As you plan, write and then submit an NIH application for a grant, it is important to know some important submission basics, such as what type of application will be needed (paper or electronic) and which forms are necessary, as well as links to contacts, important deadlines, a general timeline, and guidelines for tracking your application through the process. This Workshop will provide a useful overview of the NIH granting application process. Attendees will receive information on both the grant writing as well as how grants are reviewed to determine scientific and programmatic merit. Award fiscal monitoring, reporting and compliance issues will be discussed. Investigators are encouraged to review the NIH website for the fundamentals of grant writing prior to attending the workshop (http://grants.nih.gov/grants/grants_process.htm).

Workshop 2

Treating Sleep, Pain and Fatigue in ME/ CFS Patients

Charles W. Lapp, M.D. & Lucinda Bateman, M.D.

Two experienced clinicians will discuss current issues in the management of PWCs (Persons with CFS or FM). Using a combination of brief lectures and actual cases, Drs. Bateman and Lapp hope to stimulate engaging discussions about the practical management of sleep, pain, fatigue, orthostatic problems, maladaptive behaviors, and 'whatever.' Attendees are encouraged to bring their questions to the workshop."

Workshop 3

Pediatrics and CFS/ME

Rosamund Vallings, MNZM, MB BS & Teruhisa Miike, M.D, Ph.D.

Workshop will provide an Introduction and brief description of CFS/ME in Paediatrics and will cover an overview of paediatric case definitions and other diagnostic issues: outline of illness severity, principal symptoms, relationship to puberty and immunisations, the importance of setting up a paediatric consultation and getting the parents involved. Attendees will walk through the patient evaluation process focusing on making the diagnosis taking into consideration such factors as history, psychological evaluation, physical examination, laboratory testing and other investigations. Discussion on diagnosis leads to the development of a Management / Treatment Plan with considerations for Lifestyle (including exercise, stress and dietary approaches), Addressing specific symptoms (sleep, pain, orthostatic intolerance etc.), Medication options, Counselling (child and family). Children diagnosed with CFS/ME will have special Educational needs such as Home-schooling, part-time attendance, material for teachers, travel and coping with exams and special social needs such as Social needs, interaction with peers, sports, other activities and the use of Parent and peer support groups to help cope. Discussion will conclude with a discussion on psychological effects on paediatric patients and their families, masked depression, suicide risk, isolation and family dynamics and conclude with a discussion of related conditions such as fibromyalgia, migraine, polycystic ovaries, and irritable bowel.

Workshop 4

Fibromyalgia Theory and Practice

Daniel J. Clauw, M.D.

The workshop will begin with an overview of the latest research findings in fibromyalgia and related chronic pain states, A particular focus will be on research suggesting that there are different underlying mechanisms of pain that will respond to different types of treatment. Attendees will be taught how to perform a clinical assessment that determines the underlying mechanism(s) of pain that an individual is experiencing, and then base treatment on those underlying mechanisms. The advantages of using combined pharmacological and non-pharmacological approaches will be emphasized. This approach moves towards “personalized analgesia” for the chronic pain patient.

Workshop 5

Behavioral Assessment and Treatment of ME/CFS

Fred Friedberg, Ph.D. Leonard Jason, Ph.D.

In this introductory workshop on ME/CFS and FM, participants will learn about practical methods of behavioral assessment and individualized treatment strategies. Our approach consists of self-management focused interventions and non-pharmacologic strategies for clinicians that can offer realistic hope for improvement in these patients. This workshop will benefit clinicians who work with ME/CFS and FM patients.

Workshop 6

Exercise Intolerance: Guide to Management and Treatment

Staci R. Stevens, M.A.c. Christopher R. Snell, Ph.D. J. Mark VanNess, Ph.D., Brian D. Moore, Ph.D., ATC

This workshop will provide an overview of exercise intolerance and the management of post-exertional symptoms in CFS/ME. A review of assessment tools for measuring physiological responses during exercise will be included, and case studies examining both successes and common failures of persons with CFS/ME will be presented. Given the problem of exercise intolerance in CFS/ME, the workshop will conclude with a practical model that a clinician can use to safely and successfully implement activity management strategies.

Workshop 7

Fibromyalgia Assessment and Treatment

Roland Staud, M.D.

In 2009, a series of publications emerged from a 5-year OMERACT process that evaluated “domains” in FM and treated the syndrome as a distinct disorder. Representatives of industry, FM experts, clinical trialists, attendees, and patients went through a Delphi consensus process and identified and ranked FM syndrome domain constructs, an endpoint that was later voted on by OMERACT attendees, including those with limited expertise in FM. A “preliminary core dataset for clinical trials in fibromyalgia syndrome,”based on the domain deliberations, was identified. The core set included pain, tenderness, fatigue, patient global severity, multidimensional function, and sleep disturbance. These core sets underwent a detailed statistical analysis using participants in the National Data Bank for Rheumatic Diseases longitudinal study of rheumatic disease outcomes. The main determinants of global severity and quality of life in FM are pain, function, and fatigue. But these variables are also the main determinants in RA and other rheumatic diseases. The content and impact of FM, whether measured by discrete variables or a by a fibromyalgianess scale, seems to be independent of diagnosis. These data argue for a common set of variables rather than disease-specific variables. Current research shows that multidisciplinary pharmacological and non-pharmacological interventions such as antidepressants, exercise and cognitive-behavioural therapy is effective in reducing FM and related symptoms. Physical activity and exercise can improve life quality in FMS patients, increase physical capacity and reduce FM and related symptoms. Furthermore, physical activity appears to increase self-efficacy and self-management. Effective FM treatments include cognitive-behavioral therapy. Current studies do not support the use of passive physical therapies such as massage therapy or manual lymphatic drainage on FMS-symptoms.

Workshop 8

Treating Sleep, Pain and Fatigue in ME/ CFS Patients

Charles W. Lapp, M.D. & Lucinda Bateman, M.D.

Two experienced clinicians will discuss current issues in the management of PWCs (Persons with CFS or FM). Using a combination of brief lectures and actual cases, Drs. Bateman and Lapp hope to stimulate engaging discussions about the practical management of sleep, pain, fatigue, orthostatic problems, maladaptive behaviors, and 'whatever.' Attendees are encouraged to bring their questions to the workshop.

ABSTRACTS

General Session Friday, September 23, 2011

Gammaretroviruses of Mice and Their Links to Prostate Cancer and CFS/ME

Christine Kozak, Ph.D.

Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, 20892-0460, USA

Gammaretroviruses of three distinct host range tropisms have been isolated from the laboratory mouse. These viruses differ in receptor usage, distribution among wild mouse species and strains of laboratory mice, pathogenicity and sensitivity to host restriction factors. Two of these three host range groups, the xenotropic and polytropic mouse leukemia viruses (together termed XP-MLVs) are widely distributed in house mouse species, mice that live in closest contact with humans. XP-MLVs rely on the XPR1 receptor for entry into cells as does the xenotropic murine leukemia virus-related virus (XMRV) initially identified in human patient samples. Despite their initial description as viruses incapable of infecting mouse cells, the xenotropic viruses have the broadest host range of the MLVs. Nearly all nonrodent mammals are susceptible to X-MLVs, as are all wild mouse species and some inbred strains of laboratory mice. Their XPR1 receptor is highly polymorphic, and there are 5 functional variants of Xpr1 in Mus

species and laboratory mouse strains that differ in their ability to support entry of XMRV and various isolates of XP-MLVs. The distribution of XPMLVs and Xpr1 variants in wild mouse populations provides a good example of how diversifying selection can be driven by genetic conflicts. Restrictive receptor variants evolved in Eurasian house mouse populations exposed to XP-MLV infection suggesting that positive selection favors antiviral alleles in virus-infected species. The ecotropic and polytropic MLVs have long been linked to disease induction in mice, and the discovery that all wild mice and some laboratory strains are also susceptible to X-MLV has made it possible to examine the disease inducing potential of these viruses in mice as well as in other model systems. X-MLVs are capable of establishing infection in mice carrying permissive XPR1 alleles, but XMLV does not induce or accelerate disease in mice with permissive receptors inoculated as adults or neonates, and X-MLVs do not readily establish productive infection in monkeys. Host factors that restrict retroviruses effectively limit virus spread and disease induction in mice and other species.

Session: VIROLOGY RESEARCH

Session Chair: Jose Montoya, M.D.

Multi-laboratory Evaluations of XMRV Detection Assays

Graham Simmons, Ph.D.,John M. Coffin ², Indira K. Hewlet³,  Shyh-Ching Lo4,A. Mikovits5, William H. Switzer6, Jeffrey M. Linnen7, Francis Ruscetti8, Simone A. Glynn9,and Michael P. Bush1

1Blood Systems Research Institute and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94118, USA
2National Cancer Institute and Department of Molecular Biology & Microbiology and Program in Genetics, Tufts University, Boston, MA 02111, USA.
3Office of Blood Research and Review, FDA, Bethesda, MD 20892, USA
4Division of Cellular and Gene Therapies and Division of Human Tissues, FDA, Bethesda, MD 20892, USA
5Whittemore Peterson Institute and University of Nevada, Reno, NV 89557, USA
6Division of HIV/AIDS Prevention, CDC, Atlanta, GA 30333, USA
7Gen-Probe Incorporated, San Diego, CA, USA
8Laboratory of Experimental Immunology, National Cancer Institute- Frederick, Frederick, MD 21701, USA
9Transfusion Medicine and Cellular Therapeutics Branch, NHLBI, Bethesda, MD 20892, USA

 

Background:

The Blood XMRV Scientific Research Working Group was established to design and coordinate collaborative studies to investigate the prevalence of XMRV in blood donors using standardized XMRV assays.

Materials And Methods:

A multi-phase study has been designed to evaluate XMRV nucleic acid and serological detection assays in terms of sensitivity, specificity and reproducibility; assess assay performance on various specimen types represented in existing blood donor/recipient repositories, and determine the prevalence of XMRV in blood donors. Phase I involved production of whole blood (WB) and plasma analytical performance panels spiked with XMRV infected cells or virus, respectively. These panels were tested in a blinded fashion using XMRV nucleic acid amplification testing (NAT) developed by seven participating laboratories. Phase II represented pilot studies to compare XMRV detection using frozen PBMCs, WB and plasma derived from individuals identified as XMRV viremic in a previous study. Additionally, serology was performed on plasma by two laboratories. Phase III involves further evaluation of the clinical sensitivity and specificity of candidate NAT, serology and culture assays by using a blinded panel of 15 pedigreed positive samples, together with pedigreed negative samples and spiked positive controls.

Results:

In phase I, all laboratories detected at least 136 proviral copies/ml and 5/7 assays demonstrated even more sensitive limits of detection. 5/7 plasma RNA assays performed similarly, with limits of detection of 80 RNA copies/ml or less. The initial unblinded pilot study in phase II resulted in two laboratories detecting MLV-like sequences in the plasma, but not PBMCs or WB, from all four subjects. A third laboratory detected no viral sequences. A second, blinded, pilot study using the same four subjects and two validated negative controls was less conclusive, with three laboratories detecting no viral sequences with any of the samples. A FACS-based serological assay detected antibodies in 3/4 XMRV-positive individuals, but also in 1/2 negative controls. A westernbased assay found no evidence of serology in any sample. Results from Phase III are expected soon.

Conclusions:

The Blood XMRV SRWG has established a collaboration between many of the laboratories conducting research into XMRV and its detection in blood and has initiated steps to compare performance of XMRV assays using analytical and clinical panels comprised of blood samples from XMRV-positive and negative pedigreed subjects.

 
 

Detection Of Anti-XMRV Antibodies In Serum of CFS Patients and Healthy Blood Donors in

Belgium

Kenny De Meirleir, M.D.

Marc Frémont

2, Svetlana Khaliboulina3, Vincent C. Lombardi3, Cassandra Puccinelli3, Kristine Metzger2, Judy A. Mikovits3

1. Department of Human Physiology, Vrije Universiteit Brussel, Brussels, Belgium

2. RED Laboratories, Zellik, Belgium

3. Whittemore Peterson Institute, Reno, Nevada, USA
 

Objectives:

Xenotropic murine leukemia virus–related virus (XMRV) is a new human gammaretrovirus originally identified in prostate cancer patients with a deficiency in the antiviral enzyme RNase L. An association has been made between XMRV and Chronic Fatigue Syndrome (CFS), with a 2009 study reporting the presence of XMRV DNA in the blood of 67% of CFS patients, whereas only 3,7% of healthy controls tested positive. In 2010 another study detected murine leukemia virus (MLV)-like GAG sequences in 86,5% of CFS patients, versus only 6,8% of healthy blood donors. A number of other studies, however, have failed to detect XMRV DNA in the blood of CFS patients.

The objectives of this study were to investigate the association between CFS and XMRV in a Belgian population of patients, and to estimate the prevalence of XMRV infections in the general population in Belgium.

Methods:

A flow cytometry-based assay was used to detect the presence of circulating anti-XMRV antibodies in the serum of 84 Belgian CFS patients. A subgroup of these patients (21) have developed CFS after receiving a blood transfusion. Serum obtained from 44 Red Cross healthy blood donors was also tested. Samples were collected in Belgium and sent, blinded, to the Whittemore Peterson Institute in Reno for analysis.

Results:

48 out of 84 patients (57%) presented circulating antibodies against XMRV (10 out of the 21 patients who received a transfusion). In contrast, only 7 out of 44 controls had anti-XMRV antibodies (16%).

Conclusions:

The higher prevalence of serology positives in the patient population, compared to the controls, supports the idea that XMRV is involved in the pathogenesis of CFS. The finding that 16% of healthy blood donors present evidence of infection with XMRV or a related virus raises questions regarding the need to screen blood donors for asymptomatic XMRV infections.

Prof. Kenny De Meirleir, M.D., Ph.D., Department of Human Physiology, Vrije Universiteit Brussel, Pleinlaan 2, B-1051 Brussels

Belgium, Email: de.meirleir@telenet.be
 
 

Detection of MLV-like gag Sequences in Blood and Cell Lines Incubated With Plasma From CFS Patients

and Controls

Maureen Hanson, Ph.D.

L.L. Lee1, L. Lin1, D.E. Bell2, D. Ruppert3, S. Levine4, D.S. Bell5.

1Cornell University, Molecular Biology and Genetics, Ithaca NY, 2State University of New York, Dept. of Medical Anthropology, Buffalo NY, 3Cornell University, School of Operations Research and Information Engineering, Ithaca NY, 4Private Practice, New York City, 5State University of New York, Dept. of Pediatrics, Buffalo NY

Objectives:

To determine whether viruses related to XMRV could be detected in peripheral blood from adult subjects who are either ill with CFS, are recovered from CFS, or have no history of a CFS diagnosis.

Methods:

Subjects were divided into five groups. Ten subjects were severely ill with CFS, ten met Fukuda criteria at one time but now considered themselves recovered, and ten subjects from the same geographic area in Western New York were healthy and had never been diagnosed with CFS. Standard instruments were administered to assess the health status of the subjects in these three groups.

An additional ten ill subjects and ten control subjects lacking any CFS history were recruited from a physician’s practice in New York City and a different region of upstate New York, respectively. Blood was collected in EDTA tubes and nucleic acids made from PBMCs or whole blood. Plasma was incubated with human cells in culture. Nested PCR with USB Hot-Start IT FideliTaq was performed with gag primers. Any PCR products of expected sizes were sequenced. Samples were tested for mouse contamination with primers to IAP and/or mouse mitochondrial DNA. Control experiments in which human nucleic acid samples were spiked with mouse DNA were performed to determine the sensitivity of the assays for mouse contamination.

Results:

The SF-36 scores of the ten individuals who considered themselves recovered were significantly lower than ten members of the healthy control group from the same Western New York area, according to Hotelling’s T2 test. Tukey's multiple comparison of means indicates that there are highly significant differences between the scores of the Western New York "severe" and controls on all 7 instruments. gag sequences were detected in CFS subjects’ blood as well as in some healthy controls. gag sequences were detected that were more similar to the MLV-like sequences reported by Lo et al. (2010) than to the XMRV sequences reported by Lombardi et al. (2009). MLV-like gag sequences could be detected in nucleic acids prepared from whole and fractionated blood that were negative for the presence of mouse DNA when sensitive assays were performed. Possible reasons for false positive and false negative results when performing highly sensitive PCR assays will be presented.

Conclusion:

gag sequences were detected by PCR in whole blood genomic DNAs that were negative for mouse IAP and mitochondrial DNA. gag sequences similar to polytropic MLVs were obtained. The sensitivity of the PCR assays used requires extreme caution in interpreting results.

Maureen R. Hanson, Ph.D., Liberty Hyde Bailey Professor, Dept. of Molecular Biology and Genetics, Cornell University, Biotech.

Bldg., Ithaca, NY 14853 USA. mrh5@cornell.edu
 
 
Chronic Widespread Musculoskeletal Pain, Fatigue, Depression and Disordered Sleep in Chronic Post- SARS Syndrome;
A Case-Controlled Study

Harvey Moldofsky, M.D., Dip.Psych., FRCPC, FAPA

John Patcai
 

Background:

The long term adverse effects of Severe Acute Respiratory Syndrome (SARS), a viral disease, are poorly understood.
 

Methods:

Sleep physiology, somatic and mood symptoms of 22 Toronto subjects, 21 of whom were healthcare workers, (19 females, 3 males, sequences were detected by PCR in whole blood genomic DNAs that were negative for mouse IAP and mitochondrial DNA. gag sequences similar to polytropic MLVs were obtained. The sensitivity of the PCR assays used requires extreme caution in interpreting results. sequences were detected by PCR in whole blood genomic DNAs that were negative for mouse IAP and mitochondrial DNA. gag  sequences similar to polytropic MLVs were obtained. The sensitivity of the PCR assays used requires extreme caution in interpreting results (mean age 46.29 yrs.+/- 11.02) who remained unable to return to their former occupation (mean 19.8 months, range: 13 to 36 months following SARS) were compared to 7 healthy female subjects. Because of their clinical similarities to patients with fibromyalgia syndrome (FMS) these post-SARS subjects were similarly compared to 21 drug free female patients, (mean age 42.4 +/-11.8 yrs.) who fulfilled criteria for fibromyalgia.

 

Results:

Chronic post-SARS is characterized by persistent fatigue, diffuse myalgia, weakness, depression, and nonrestorative sleep with associated REM-related apneas/hypopneas, an elevated sleep EEG cyclical alternating pattern, and alpha EEG sleep anomaly. Post-SARS patients had symptoms of pre and post-sleep fatigue and post sleep sleepiness that were similar to the symptoms of patients with FMS, and similar to symptoms of patients with chronic fatigue syndrome. Both post-SARS and FMS groups had sleep instability as indicated by the high sleep EEG cyclical alternating pattern rate. The post-SARS group had a lower rating of the alpha EEG sleep anomaly as compared to the FMS patients. The post-SARS group also reported less pre-sleep and post-sleep musculoskeletal pain symptoms.

Conclusions:

The clinical and sleep features of chronic post-SARS form a syndrome of chronic fatigue, pain, weakness, depression and sleep disturbance, which overlaps with the clinical and sleep features of FMS and chronic fatigue syndrome.

Publication: Moldofsky and Patcai: Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study.

BMC Neurology 2011 11:37. See: http://www.biomedcentral.com/1471-2377/11/37
 
 

Session: VIROLOGY RESEARCH AND REVIEW

Session Chair: Jose Montoya, M.D.

Role of the Immune Response in CFS

Jose Montoya, M.D.

Abstract Unavailable
 
 

The Case FOR XMRV/Human Gammaretroviruses (HGRVs) in ME/CFS

Judy Mikovits, Ph.D.

In 2009 using a classical virology approach of viral isolation and transmission, electron microscopy, serology and PCR, Lombardi et al demonstrated the first isolation of XMRV from blood from patients with chronic fatigue syndrome (CFS) predominately from the west coast of the United States. In 2010, Lo et al. extended these studies by detecting nucleic acids of MLV-related variants in the peripheral blood mononuclear cells of CFS from the northeastern United States suggesting additional strains capable of infecting humans exist. In a study of 300 CFS patients, 13 developed lymphoproliferative disorders. Of those tested, 11/11 were positive for XMRV and 9/9 positive for clonal TCR gamma rearrangements. Spontaneous development of four immortalized B cells lines occurred during culture of cells from CFS patients. Three developed from B cells isolated from the peripheral blood (two of whom had B cell lymphoma) and one from a bone marrow biopsy. The B cell lines have a mature CD20+, CD23+ phenotype and produce infectious XMRV. Virus production occurred despite extensive hypermutation of the proviruses in these cells by APOBEC3G. Therefore, XMRV infection may accelerate the development of B cell malignancies by either indirect chronic stimulation of the immune system and/or by direct infection of the B-cell lineage. Since viral load in peripheral blood is low, these data suggest that B cells in tissues such as spleen and lymph nodes could be an in vivo reservoir for XMRV. We have also identified an inflammatory cytokine and chemokine signature that distinguishes XMRV infected CFS patients from healthy controls with 94% sensitivity and specificity. Monitoring immune dysfunction affords the opportunity to begin to understand the pathogenesis of XMRVs. In addition to these data, recent advances in developing tests for detection and characterization of variants of XMRV will be also be discussed/

Judy A Mikovits, PhD, Research Director, Whittemore Peterson Institute, University of Nevada, Reno MS 0552, 1664 N Virginia St, Reno NV 89557-0552, phone: 775-682-8264, fax 775-996-7159
 
 

The Case AGAINST Human Gamma Retroviruses (HGRV) in CFS/ME

John Coffin, Ph.D.

Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111,USA

Xenotropic MLV-related retrovirus (XMRV) was first reported about 5 in a few cases of prostate cancer, but did not attract much attention until its reported association with a large fraction of chronic fatigue syndrome cases about 2 years ago. The publication of the XMRV-CFS connection created a ripple of excitement and interest in the scientific, medical, and patient communities reminiscent of the reports of the association of another retrovirus—HIV--with AIDS some 25 years previously. However, most of the results of the XMRV paper – isolation of infectious virus from patients, frequent detection of virus in plasma and PBMCs by PCR, detection of antiviral antibodies - remain to be replicated outside of the laboratories that authored the original report despite considerable effort worldwide. Indeed, XMRV is now considered by most virologists to be the consequence of a collection of artifacts originating from endogenous murine leukemia viruses prevalent in laboratory and wild mice.

There are several related, but distinct, issues that need to be considered. First, various mouse (Mus musculus) subspecies carry over a hundred different endogenous proviruses closely (>90%) related to XMRV in their DNA. Second, mice are extremely widespread, as is their DNA, which can be found sporadically on laboratory surfaces, as well as contaminants of common reagents and materials. Sensitive PCR assays can detect “XMRV” related sequences in DNA from tiny fractions of one cell. To detect such contamination, we developed a more sensitive assay based on mouse IAP sequences present in thousands of copies per cell. Third, although only a few of the endogenous MLV proviruses encode infectious virus, it has been known since the 1970s that some of them can give rise to virus that can infect human tumor lines when passaged through nude mice. Indeed, A virus identical to XMRV is produced by the 22RV1 prostate cancer line that was derived in just this way. In initial reports, however, XMRV did not appear to be sufficiently similar to known proviruses to have been derived this way. However, we have recently shown that this is exactly how it did arise, but not from infection of the precursor CWR22 xenograft with a single virus, but rather with a recombinant between the progeny of two previously undescribed proviruses found in the nude mice used for passage. Since the predicted recombinant is ancestral to all XMRV isolates, and cannot have arisen more than once, it must have found its way into many laboratories as the 22Rv1 cell line was distributed worldwide and, by means that remain to be worked out, into clinical samples from CFS patients.
 

 

Session: TREATMENT ADVANCES

Chair: Eleanor Stein, M.D.

Health/Performance and Response Status of XMRV/pMRV Antibody Positive vs. Negative Chronic FatigueSyndrome (CFS)

Subjects in a Phase III Clinical Trial

David R. Strayer, M.D.

Judy A. Mikovits2, Vamsidhar Vurimindi1, William A. Carter1  

1Hemispherx Biopharma, Inc., Philadelphia, PA; 2Whittemore Peterson Institute, Reno, NV

Background:

CFS is a severe disorder consisting of profound fatigue and a variety of other debilitating symptoms that affects up to 4 million Americans. Recently, one of us (JAM) identified DNA from a human gamma retrovirus (XMRV) in 67% of CFS subjects. Evidence also suggested that approximately 50% of the CFS infected subjects mounted a specific antibody response against XMRV (Science 326, 585- 589 (2009)). The objective of this study was to compare demographic parameters, health/performance status and response of XMRV/pMRV antibody positive vs. negative. CFS subjects enrolled in a Phase III clinical trial evaluating the safety and efficacy of a tolllike receptor 3 (TLR3) agonist, rintatolimod (PolyI:PolyC, 12U, Ampligen®).

Materials and Methods:

Two-hundred-eight (208) evaluable subjects, who met the 1988/1994 Case Definitions for CFS, participated in this randomized, placebocontrolled,

double-blinded, multicenter study. Only severely debilitated patients were selected for this study. The primary endpoint was exercise treadmill duration. Subjects received rintatolimod (200-400 mg) or an equivalent volume of placebo twice weekly by IV infusion for 40 weeks. Baseline (or earliest available specimen) serum samples from all 208 subjects were analyzed for antibodies directed against XMRV/pMRV.

Results:

Seventy (33.7%) of the 208 CFS subjects were positive for antibodies directed against XMRV/pMRV, while 138 (66.3%) were negative. There was no significant difference in the number of CFS subjects positive or negative for antibody with regard to age, gender, duration of CFS, cognitive dimension (SCL90-R), exercise treadmill duration, or SF-36 vitality score (p>0.3). However, the subjects negative for antibody had a lower Activity of Daily Living score (66.9 vs. 71.2, p=0.010, ANOVA) and a lower overall activity level based upon a lower activity monitor score (183K vs. 210K, p=0.033, ANOVA). The percent of subjects with a >25% increase in exercise treadmill tolerance (ETT) at Week 40 compared to Baseline was significantly greater for subjects receiving rintatolimod (39%) vs. placebo (23%), p=0.016 (2 tailed Fisher’s Exact Test). Although, there was a trend for greater improvement in exercise duration with rintatolimod treatment for both the XMRV/pMRV antibody cohorts receiving rintatolimod, the antibody positive subgroup had a greater relative percent of subjects showing a >25% increase in ETT with rintatolimod compared to placebo than the antibody negative cohort. An analysis of concomitant medications utilized by CFS subjects to help treat symptoms of CFS showed that, when compared to placebo, the rintatolimod treated cohort positive for antibodies had a greater percentage of subjects with a decrease in CFS-related medication use at the end of the study (24%), p=0.039 vs. the antibody negative subjects (13%), p>0.10.
 

Conclusions:

These results indicate that approximately 1/3 of the CFS subjects have a detectable immune response directed against XMRV/pMRV and that this antibody positive group may respond more favorably to rintatolimod, an antiviral and immune modulator, than the antibody negative cohort. Additional studies to further evaluate XMRV/pMRV in this CFS population are underway.

 

Rifampin Augments the Effects of Oxymatrine/Equilibrant (oxm/equi) In Patients with Myalgic

Encephalomyelitis/CFS

John K. Chia, M.D.

Andrew Chia. EV Med Research

Rifampin augments the effects of oxymatrine/Equilibrant (oxm/equi) in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). John Chia, Andrew Chia. EV Med Research

Objectives:

Chronic enterovirus infection has been implicated in the immunopathogenesis of ME/CFS. Previously, we demonstrated the benefit of oxm/equi, an herbal immune booster, in 50% of ME/CFS patients. Concomitant administration of rifampin in one patient resulted in flu-like symptoms and ulceration of infected pharyngeal tissues, which was followed by symptomatic improvement and decrease of chronically elevated Coxsackievirus B3, 4 antibodies. We evaluated the adjunctive effect of rifampin in patients who were taking oxm/equi.

Method:

46 patients who fulfilled the CDC criteria for ME/aureus) infections served as controls. Laboratory studies including CBC, chemistry panel, CPK were obtained before and during treatment if patiCFS were treated with rifampin 300 mg po bid for 7 days while taking oxm/equi (32 responders and 14 non-responders, duration 1.32±0.86 years). 45 patients treated with oxm/equi without rifampin, and 45 outpatients treated with doxycycline and rifampin for MRSA (methicillin-resistant Staphylococcus ent had flu-like symptoms. Cytokine gene expression of peripheral blood was performed before and during rifampin treatment for 10 ME/CFS treatments.

Results:

31/46 (67%) patients developed significant flu-like symptoms lasting few days during or after the one-week rifampin treatment.
23/33 (70%) of responders and 0/13 non-responders had additional improvement of fatigue and other symptoms ( p <0.01, X2 test).
21/33 (64%) responders who had taken oxm/equi 1-2 years were able to discontinue the herbs within weeks or months of flu-like symptoms and remained in remission. 0/45 ME/CFS patients on oxm/equi alone and 0/45 MRSA-infected patients on doxycycline and rifampin developed flu-like symptoms. Laboratory studies showed no significant changes, and gene expression study of 12 cytokines demonstrated increase of TNF- 21/33 (64%) responders who had taken oxm/equi 1-2 years were able to discontinue the herbs within weeks or months of flu-like symptoms and remained in remission. 0/45 ME/CFS patients on oxm/equi alone and 0/45 MRSA-infected patients on doxycycline and rifampin developed flu-like symptoms. Laboratory studies showed no significant changes, and gene expression study of 12 cytokines demonstrated increase of TNF-α and IL-1α,β mRNA while on rifampin and oxm/equi.

Conclusion:

Flu-like symptoms were commonly observed in patients who took oxm/equi concomitantly with rifampin, as compared to controls. Subsequent symptomatic improvement was observed in > 60% of oxm/equi responders. Short course of rifampin may be beneficial in ME/CFS patients who are responding to oxm/equi. The possible mechanism of enhanced immune response will be discussed and further investigated.

 

Brief Self-Management of UCF/CFS in Primary Care: A Randomized Trial

Fred Friedberg, Ph.D.

Janna Coronel, MA

Objective:

The objective of this study was to test a brief self-management protocol in a primary care setting, in people with medically unexplained chronic fatigue (UCF) and chronic fatigue syndrome (CFS). An effective self-management plan has the potential (1) to improve the generally poor outcomes for UCF and CFS patients in primary care, (2) to greatly expand the availability of behavioral health care for UCF and CFS, and (3) to reduce medical and behavioral utilization for UCF and CFS. The proposed study is an extension of an efficacious two-session self-management clinical trial for CFS in secondary care (Powell et al., 2001).

The hypothesis was tested that a brief self-management- focused cognitive-behavioral intervention will yield improvements in fatigue, physical and role functioning, and psychological distress in comparison to the two control conditions: standard medical care alone or standard medical care plus an attention control symptom monitoring condition.

Methods:

We tested the efficacy of a two - session self-management-focused cognitive-behavioral intervention in a target sample of 108 persons with UCF or CFS. Participants were randomly assigned to one of three study conditions: (1) standard medical care alone; (2) standard medical care plus a nurse-delivered attention control condition of symptom monitoring; or (3) standard medical care plus a nurse-delivered self-management cognitive-behavioral treatment delivered by a nurse.

Results:

At the three month follow-up, sample sizes were as follows: fatigue self-management (FSM) = 21; Symptom Monitoring (SM) = 26; and Usual care (UC) = 21. Forty percent met Fukuda criteria for CFS. Controlling for age, sex and illness duration at the threemonth follow-up assessment, a significant reduction was found on the fatigue severity scale (p<.05). No significant changes were found on diary fatigue ratings, the SF-36PF, Beck Anxiety Inventory or the Beck Depression Inventory. Actigraphy significantly declined across all conditions (p<.05).

Patient global impression of change (PGIC) ratings were as follows for the three conditions (FSM/SM/UC): Improved (13/ 6/4); Unchanged (5/9/11); Worse (2/5/2). Despite little change on our standard measures, brief interviews with study participants revealed that both worsened and unchanged patients across conditions attributed their PGIC ratings to external negative events or lack of healthy activities, whereas improved patients reported increased awareness of their behaviors and affirmative steps to pursue healthy activities.

Conclusion:

A brief, standardized illness management service for UCF/CFS showed modest improvement in fatigue severity and PGIC ratings. PGIC ratings of improved, unchanged, and worsened overall appeared to reflect different attitudes toward the illness and/or differential exposures to negative major life events. These findings indicate a role for self-management activities in generating improved outcomes.

Fred Friedberg, PhD, Research Associate Professor, Department of Psychiatry, Putnam Hall/South Campus, Stony Brook University,

Stony Brook, NY 11794-8790. fred.friedberg@stonybrook.edu

 

Session: FIBROMYALGIA: ARE TENDER POINTS NECESSARY? A DEBATE

Chair: Lucinda Bateman, M.D.

Tender Points are Important

Roland Staud, M.D.

Population studies have demonstrated moderately strong associations (odds ratios range 1.3-3.1) between the presence of pain in a body segment and the presence of tender points within that segment. Further, there is evidence of increasing number of tender points with increasing number of painful segments. The reporting of non-specific pain, aching, or stiffness, is also associated with high tender point counts. Importantly, there is no unique cut off at which local pains and tender points occur concurrently in a widespread form. This is consistent with the observation that fibromyalgia (FM) represents one end of a spectrum of musculoskeletal pain and tender points, and that both traits are continuous in the general population. Tender points have been successfully used for the definition of study populations like fibromyalgia. For clinical purposes, however, tender points seem to provide little mechanistic information about individuals’ pain and associated symptoms.

Tender Points are Unnecessary

Daniel J. Clauw, M.D

Abstract Unavailable

 
 

 

 

 

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