Abstracts of IACFS/ME conferences 22-25 sept.2011 in Ottawa 3

ABSTRACTS

General Session Saturday, September 24, 2011

Session: CASE DEFINITIONS FOR RESEARCH AND PRACTICE

Chair: Kenneth J. Friedman, PhD

The New International Consensus Criteria for ME: Content and Context

Bruce M. Carruthers, M.D., CM. FRCP(C)

Contents- the general thrust of the 2003 Canadian Consensus Criteria was retained and developed further. Several changes were made- e.g. the 6 month waiting period was no longer required, but left to clinical judgment. The symptom pattern of Post-Exertional- Neuroimmune-Exhaustion (PENE) was kept criterial and further articulated. Symptoms and symptom interactive patterns arising from the following subsystems- neurocognitive, pain processing, sleep disturbances, neurosensory and motor, immune, gastrointestinal, genitourinary and endocrine subsystems as well as energy transport impairments (cardiovascular, microvascular, respiratory, thermostatic homeostasis, intolerance of temperature extremes and stress intolerance) are noted if present. Interactive dynamical pattern matches between PENE symptom patterns and those from pathophysiologial subsystems for individuals and groups of patients are noted for causal projectability over time will be mutually confirmative as real kinds. Modifications for paediatric cases were added.

The past historical context is described as well as future implications of this case definition plus any descendents are discussed regarding future research directions, case segregation, and treatments.

In conclusion, it is hoped that this case definition and its descendents will continue to emphasize both the clinical/epidemiological/research realms of observation and challenge all participants to integrate them into a mutual confirmation/disconfirmation process that characterizes both clinical medicine, epidemiology and science in general.

Contrasting Case Definitions

Leonard Jason, Ph.D.

Abigail Brown, Erin Clyne, Lindsey Bartgis, Meredyth Evans, Molly Brown

DePaul University

Objectives:

There has been considerable debate about what case definition to use with the illness commonly known as CFS. For example, some have speculated that the initial definitions of ME ((Dowsett et al., 1994; Goudsmit et al., 2009; Ramsay, 1988)) and later on the Canadian criteria of ME/CFS (Carruthers et al., 2003) select a group of patients that have more severe functional impairments than the Fukuda et al. (1994) criteria. This presentation contrasts individuals diagnosed with the Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) Canadian case definition (Carruthers et al., 2003) with those that did not meet these criteria (Non-ME/CFS) but met the Fukuda et al. (1994) chronic fatigue syndrome (CFS) criteria. The study also compared individuals diagnosed with another case definition involving Myalgic Encephalomyelitis (ME) (based on criteria from Dowset et al., 1994; Goudsmit et al., 2009; Hyde, 2007; Ramsay, 1988) with those that did not meet these criteria (Non-ME), but met the Fukuda et al. criteria.

Methods:

The sample of patients had been diagnosed with CFS by the Fukuda et al. criteria and were later categorized as meeting ME/CFS and/or ME criteria.

Results:

In general, the ME/CFS criteria identified a group of patients with more functional impairments and physical, mental and cognitive problems than the Non-ME/CFS criteria. The ME criteria identified patients with more functional impairments, and more severe physical and cognitive symptoms than the Non-ME condition. Katon and Russo (1992) have argued that a requirement of more symptoms to meet criteria could inadvertently select for individuals with psychiatric problems. Similarly, Kroenke (2003) found similar results examining 15 variables within a fatigued sample. It is certainly possible that the differences on so many measures between the ME/CFS and the Non-ME/CFS groups was due to the larger number of symptoms of higher frequency and severity who met the ME/CFS criteria.

Conclusion:

The current CFS case definition of Fukuda et al. (1994) has been used internationally by researchers for over 15 years. It is possible that some patients meeting these criteria do not have core symptoms such as post-exertional malaise or memory/concentration problems. By specifying 7 symptoms as with the ME/CFS criteria or by specifying 4 symptoms with the ME criteria, it may be possible to identify a more homogenous and impaired group of patients. The current study suggests that these other ME and ME/CFS criteria might be used to identify patients with possibly more homogenous and severe symptomatology and functional impairment. Both ME/CFS and ME criteria appear to select a more severe group of patients than those that only meet the Fukuda et al. criteria.

Leonard A. Jason, Ph.D., Director, Center for Community Research, DePaul University, 990 W. Fullerton Ave., Suite 3100, Chicago,

 

Data Mining

Leonard Jason, Ph.D.

Beth Skendrovic, Jacob Furst, Molly Brown, Meredyth Evans, Abby Brown

DePaul University

Objectives:

Data mining may be a useful tool in aiding in the diagnosis of ME/CFS. There are many challenges in diagnosing ME/CFS. Some symptoms associated with it are common of other illnesses, and there are competing definitions that investigators may use. More work with data mining in ME/CFS research could aid in further identification of cardinal symptoms, leading to better diagnostic ability. This would also combine an objective, computer driven decision with a physician’s medically influenced decision to come up with a better and more reliable way to diagnose and treat ME/CFS. This article contrasts two case definitions for Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). We compared the empiric CFS case definition (Reeves et al., 2005) and the Canadian ME/CFS Clinical case definition (Carruthers et al., 2003) with a sample of individuals with CFS as defined by the Fukuda et al. (1994) criteria versus those without CFS from a community-based sample.

Methods:

Data mining with decision trees was used to identify the best items to identify patients with CFS. Data mining is a statistical technique that was used to help determine which of the survey questions were most effective for accurately classifying cases as defined by the two case definitions versus others contained by the study.

Results:

The empiric criteria identified 79% of patients with CFS and the Canadian criteria identified 87% of patients with CFS. Items identified by the Canadian criteria had more construct validity. ME/CFS is often thought to include post-exertional malaise and neurocognitive disorders, and both did emerge as predictive factors for the Canadian criteria, but not when using the Reeves et al. (2005) empiric case criteria. In addition, sleeping disorders and pain symptoms, other key symptoms of ME/CFS, did emerge for the Canadian criteria as well as in the immune areas (i.e., sore throat and multiple chemical sensitivities), and this supports evidence for the Canadian criteria. In contrast, the empiric criteria tended to identify more general areas, including less activity, social and role functioning problems, and some pain issues. However, critical symptoms such as post-exertional malaise, neurocognitive symptoms and sleep disorders were not identified as discriminating symptoms with the Reeves et al. (2005) criteria.

Conclusion:

The study’s overall findings were that the Reeves et al. (2005) criteria were not as capable of identifying cases from non-cases as the Canadian criteria (Carruthers et al., 2003). The Reeves criteria have been criticized as being more general and broader than the Fukuda et al. (1994) criteria, and the results of this study suggest that these criteria are only able to discriminate 79% of cases from others, whereas the Canadian criteria were able to 87% of cases. In addition, when examining the items selected in both analyses, it is apparent that the Canadian criteria appear to select cardinal and central features of the illness.

Leonard A. Jason, Ph.D., Director, Center for Community Research, DePaul University, 990 W. Fullerton Ave., Suite 3100, Chicago,

Il. 60614. Ljason@depaul.edu

Pathways to Pathogenesis: Standardized Measures of CFS/ME Illness Domains

Elizabeth R.Unger, M.D., Ph.D.

Case definitions are used in at least two different circumstances. First, a case definition, when simply and easily applied, may be used as a substitute for a specific diagnostic test to measure disease in a population. This would be done when use of the diagnostic test is impractical for delivering information in a timely and cost-effective manner. An example of this situation is use of “flu-like illness” determined by telephone interview as a surrogate to monitor seasonal or pandemic influenza. A second circumstance occurs when there is no diagnostic test, and case identification requires the use of specific descriptive measures. This is the current situation with CFS/ME, a complex and heterogeneous disorder likely to involve multiple pathways to pathogenesis. Case definitions are essential for public health agencies to determine burden of illness, for clinicians to appropriately diagnose and manage patients, and for researchers to identify risk factors and the underlying biologic basis for illnesses. Limitations in the ability of case definitions to identify homogenous patient populations could be addressed by standardizing how the definitions are applied, or by narrowing the definitions through increased criteria needed to meet the definition, or both. An alternative approach is to improve measures of illness domains (questionnaires and biologic) to allow patients identified by any case definition to be phenotypically sub-grouped in a way that allows the underlying biology to be discovered.

Presenting author: Elizabeth R. Unger PhD, MD, Chronic Viral Diseases Branch, Division of High-Consequence Pathogens and Pathology, NCEZID, Centers for Disease Control and Prevention, 1600 Clifton Road, MS G41, Atlanta, GA 20222, USA. eunger@cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency.

 

Session: IDENTIFYING ABNORMALITIES IN CFS/ME: THE IMPORTANCE OF EXERCISE CHALLENGE

Chair Staci R. Stevens,M.A.

Exercise Testing to Quantify Effects of Fatigue on Functional Capacity in Patients With CFS

Betsy A. Keller, B.A.

Micale, FG

Ithaca College

Objective:

The purpose of this study was to assess the effects of post-exertional malaise (PEM) on functional capacity and anaerobic threshold in subjects diagnosed with chronic fatigue syndrome (CFS).

Methods:

Subjects were 10 females and 2 males (41.3+1.11 yrs) diagnosed with CFS by a physician experienced in the diagnosis of CFS. To induce PEM, each subject completed a maximum exercise test on a cycle ergometer. A second maximum exercise test was performed 24 hrs later to assess the effects of exercise-induced PEM on functional capacity. Maximum oxygen consumption (VO 2max), maximum heart rate (HRmax), anaerobic threshold (AT), maximum workload (Wmax), workload at AT (ATwork), and respiratory exchange ratio (RER) were measured. RER is an objective indicator of substrate utilization and subject effort during exercise.

Results:

Significant decreases from test 1 to test 2 were 13.5% for VO2max (21.5 to 18.6 ml.kg-1.min-1; p<0.01), 8 bpm for HRmax (p<0.01),

18.8% for AT (12.0 to 9.7 ml .kg-1.min-1; p<0.05), 9.4% for Wmax (121 to 109 W, p<0.05), and 17.3% for ATwork (58.3 to 48.2 W; p<0.05). However, there was no change in maximum RER indicating that subject effort was maximum and also comparable during both tests.

Conclusion:

Results indicate that PEM decreased maximum functional capacity by more than 13% to below 5 METS; a level at or below that which is required by many job-related activities and IADLs. To compare, VO2max in healthy individuals is highly reproducible over days and even months (r>.95) 1, with a SEM of < 6%1,2. Thus, for subjects in this study, an expected variation between tests would be 1.29 ml.kg-1.min-1 in contrast to the observed decrease of 2.9 ml.kg-1.min-1. Furthermore, PEM decreased AT to below 3 METS (e.g., light-moderate speed walking), which is a level of many activities considered to be sedentary in nature. Thus, completion of sedentary ADLs and IADLs for those with CFS requires production of energy via anaerobic processes that will further contribute to PEM and exacerbate symptoms of CFS. Since many daily activities fall into the 3-5 MET range, individuals with CFS will exacerbate symptoms associated with PEM simply by completing normal daily activities.

1Taylor, HL, Buskirk, E & Henschel, A. (1955). Maximal oxygen intake as an objective measure of cardiorespiratory performance. J Appl Physiol, 8, 73-80.
2 Katch, VL, Sady, SS & Freedson, P. (1982). Biological variability in maximum aerobic power. Med Sci Sports & Ex, 14(1), 21-25.

Betsy A. Keller, PhD, Professor, Exercise & Sport Sciences, Ithaca College, 318 Center for Health Sciences, Ithaca, NY 14850

keller@ithaca.edu

Frank G. Micale, M.S., Clinical Associate Professor, Exercise & Sport Sciences, Ithaca College, 317 Center for Health Sciences,

Ithaca, NY 14850 fmicale@ithaca.edu

 

The Importance of Exercise Challenge

Christopher Snell, Ph.D.

The absence of reliable diagnostic laboratory tests or biomarkers presents significant problems for persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), treating physicians, and the ME/CFS research community alike. Typically ME/CFS diagnoses rely on self-report measures. An alternative to this approach is to employ direct, objective multi-system, measures of physical function that may also provide insights to the underlying pathophysiology of ME/CFS. One such methodology is cardiopulmonary exercise testing (CPET). The principles underlying CPET are simple. Physical exertion requires that the cardiovascular system supply oxygen (O2) to active muscles and the pulmonary system remove carbon dioxide (CO2) from the blood. Taxing these systems has the capacity to reveal abnormalities that may not be apparent at rest and thus elucidate the mechanisms underlying exercise intolerance in ME/CFS. Some key measures available from CPET include: maximal aerobic capacity (Peak VO2 or VO2 max ); ventilatory or anaerobic threshold (VT); and peak respiratory exchange ratio (RER). CPET permits accurate comparison of subjects across serial exercise tests and should be of prime consideration for any clinical intervention trial with functional endpoints. CPET data also allow for the more reliable interpretation of results when an exercise challenge is used to elicit ME/CFS symptoms. As a quantifiable measure of both physiological stress and effort, CPET enables direct comparison between patients and controls on these measures. CPET also has the capacity to objectively document PEM in ME/CFS patients. A significant change in exercise capacity over consecutive tests, it could be argued, is clear evidence of PEM.
 

Session: THE LATEST RESEARCH IN IMMUNOLOGY

Chair: Nancy Klimas, M.D.

Natural Killer Cell Number and Function in a ProspectiveCohort of Adolescents with

Chronic Fatigue Syndrome and Controls Following Mononucleosis

Benjamin Katz, M.D.

Maurice O’Gorman2, Deli Wang3, Cynthia Mears1, Yukiko Shiraishi4, Renee Taylor4

1Pediatrics, Northwestern University Feinberg School of Medicine

2 Pathology, Northwestern University Feinberg School of Medicine

3 Biostatistics Research Core, Children’s Memorial Research Center

4 Occupational Health, University of Illinois at Chicago

 

Introduction:

Chronic fatigue syndrome (CFS) is a complex condition involving severe fatigue and disabling musculoskeletal and cognitive symptoms. Whether immunologic dysfunction accompanies CFS is controversial. Arguably the most consistent immunologic disturbance associated with CFS is reduced function of natural killer (NK) cells.

Objectives:

We examined NK function in our cohort of adolescents following infectious mononucleosis (IM) and recovered controls matched for age, sex and Tanner stage.

Methods:

Nine adolescents with CFS and 9 matched, recovered controls had blood drawn for NK cell quantitation and functional analysis that was performed blinded at 6, 12 and 24 months following IM. At each time point, NK cell quantification was ascertained by flow cytometry as %CD56+ cells, and NK cell function was determined using K562 cells and 3 different dilutions of patient lymphocytes.

NK cell numbers were scored as high, normal or low. NK cell function was scored as normal, low or borderline by pre-determined parameters by an investigator blinded as to the patient’s diagnosis. Statistical analysis was conducted using generalized linear mixed model with repeated measurements and linear mixed model with SAS 9.2.

Results:

There were 27 evaluable time points for the CFS patients and 25 for the controls. There was no difference in NK numbers between cases and recovered controls. NK function was significantly higher in case patients with CFS 6 months following IM than in recovered controls (p=0.02).

Conclusion:

We could not confirm decreased NK cell function in adolescents with CFS following IM.

Acknowledgement: Funded by R01HD4330101AI from the National Institute of Child Health and Human Development

Presenting author: Ben Z. Katz, MD, Professor of Pediatrics, Northwestern University Feinberg School of Medicine

Attending Physician, Division of Infectious Diseases, Children’s Memorial Hospital 2300 Children’s Plaza, Chicago, IL 60614,

 

Disparities In Innate and Adaptive Immune Cell Activities in Chronic Fatigue Syndrome

Ekua W. Brenu, PhD candidate

M. Van Driel

1,2, K.J. Ashton2, S.B. Ramos2, J. Keane2, D.R. Staines1,3 , S. Marshall-Gradisnik1,2

1. Faculty of Health Science and Medicine, Population Health and Neuroimmunology Unit, Bond University, Robina, Queensland, Australia.

2. Faculty of Health Science and Medicine, Bond University, Robina, Queensland, Australia.

3. Queensland Health, Gold Coast Public Health Unit, Southport, Robina, Gold Coast, Queensland, Australia

Objective:

Cell specific immune investigations have demonstrated a possible link between Chronic Fatigue Syndrome (CFS) and failure to maintain immunological homeostasis. The most common immune cells with known dysfunction in CFS are cytotoxic cells, Natural killer cells and CD8+T cells. This study examined cytotoxic function and markers in CFS patients at 6 months intervals to determine the stability of these observations over time.

Methods:

90 CFS patients (mean age 46.5yrs ±11.7) and 50 healthy controls (mean age 41.9yrs ± 9.6) participated in the study. Flow cytometeric protocols were used in the assessment of cytotoxic activity and cell phenotypes and RT-qPCR analysis in screening for levels of cytoxic molecules that depict the various cytotoxic pathways. These molecules include, granzymes, perforin, interferon (IFN)-γ and tumour necreosis (TNF-α).

Results:

Preliminary results indicate that compared to the healthy controls, CFS patients demonstrate significant decreases in cytotoxic activity at baseline, at 6 and at 12 months. Additionally, NK CD56 bright cells remained decreased in the CFS participants. Cytotoxic, molecules were also differentially expressed in these cells in comparison to the healthy group.

Conclusion:

This study demonstrates and confirms reduced immune function in patients with CFS. These findings substantiate the use of NK cell cytotoxic function as a potential biomarker for CFS.

Ekua Weba Brenu HBSc, Grad Dip BMed, Faculty of Health Science and Medicine, Bond University, Gold Coast, Queensland 4229,

Australia, Email: ebrenu@student.bond.edu.au
 

Longitudinal Assessment of Adaptive Immune Regulation in Chronic Fatigue Syndrome

Ekua W. Brenu, PhD candidate,

K.J. Ashton2, M. Van Driel1,2, S. Hardcastle1,2, D.R. Staines1,2,S. Marshall-Gradisnik1,2

4. Faculty of Health Science and Medicine, Population Health and Neuroimmunology Unit, Bond University, Robina, Queensland, Australia.

5. Faculty of Health Science and Medicine, Bond University, Robina, Queensland, Australia.

6. Queensland Health, Gold Coast Population Health Unit, Southport, Gold Coast, Queensland, Australia.

Objective:

Chronic Fatigue Syndrome (CFS) is known to persist for more than 6 months with a very slow recovery rate. It is not known whether immunological abnormalities in CFS remain stable over time or change during the course of the disease. Additionally cytokine measurements have not been consistent across studies which may be associated with the fluctuating pattern of the disease. This longitudinal study assesses proteins and receptors secreted and expressed by CD4+T lymphocytes in CFS patients over time, at baseline, 6 and 12 months.

Method:

50 CFS meeting the CDC case definition and 30 non-CFS control participants were recruited from two states in Australia. Peripheral blood mononuclear cells were preferentially isolated from whole blood samples collected from participants. The samples were then assessed for the expression of Th1, Th2, Th17 cytokines, IL-1α, IL-1β and TGF-β using cytometric bead array and flex set kit.

Result:

At baseline there was an increase in IL-10, TNF- α and IFN-γ in the CFS group compared to the healthy control group. However, after 6 months IL-2 was significantly increased and IL-10 and IL-17A were significantly decreased in the CFS group while after 12 months only IL-2 was observed to be significantly increased in the CFS group.

Conclusion:

These results suggest that the cytokine profile in CFS changes during disease progression. This may be associated with disease severity and/or concurrent environmental stressors. Hence there is a need to match experimental findings with data on clinical disease progression.

Ekua Weba Brenu HBSc, Grad Dip BMed, Faculty of Health Science and Medicine, Bond University, Gold Coast, Queensland 4229, Australia, Email: ebrenu@student.bond.edu.au

 

Promoter DNA Methylation and Expression of Perforin in CFS and Controls

Virginia R. Falkenberg, Ph.D.

Toni Whistler, Janna Murray, Elizabeth R Unger, Mangalathu S.

Rajeevan. Chronic Viral Diseases Branch, Centers for Disease Control and Prevention, Atlanta,GA 30333

Objectives:

Perforin plays a key role in immune surveillance and several studies report decreased perforin protein and mRNA in peripheral blood of patients with chronic fatigue syndrome (CFS). Factors that modulate gene-environmental interaction and thus the pathophysiology of disease include gene silencing by DNA methylation. The objectives of this study were to determine the pattern of perforin gene methylation in conjunction with perforin gene expression and whether these features were altered in CFS.

Methods:

Subjects (34 CFS and 47 non-fatigued, NF) selected from a population based study underwent the Trier Social Stress Test (TSST), a standardized psychosocial test that induces stress, and is known to influence cortisol secretion. Blood samples were collected prior to (10:30am, T1), and after the TSST (3:05 pm, T2). DNA extracted from peripheral blood mononuclear cells (PBMC) was used to examine site-specific CpG methylation levels in the methylation sensitive region (MSR) of the promoter (sites -876, -776, -744, -720, -691, -670 and -650). This was quantified by bisulfite treatment of DNA followed by pyrosequencing. RNA from PBMCs collected at the same time points was used to quantify perforin mRNA expression by LightCycler real-time RT-PCR. Total RNA from peripheral blood collected at the same time points was used in the Affymetrix Human Exon Array 1.0 platform.

Results:

Methylation of the MSR ranged from 38%-79% and no differences in CpG site-specific methylation of perforin was detected between CFS and NF at T1 or T2. In PBMC, there was no difference in the perforin expression between CFS and NF at T1 but expression was significantly higher in CFS than NF (1.4 fold, p=0.02) at T2. NF subjects had reduced perforin expression (0.8 fold, p=0.008) and methylation levels were increased by 4% (range 2.6-4.3, p= 0.01-0.05) at four CpG sites (-876, -744, -691, and -670) at T2 compared to T1. However in CFS subjects, methylation levels were increased by 6% (range 4.7-6.8, p=0.02-0.03) at T2 compared to T1 at two positions (-776 and -744) without a corresponding change in expression. Expression results by real-time RT-PCR and exon arrays were concordant.

 
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