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Index to Abstracts from AACFS Conference October 1998

Abstracts of Papers Presented at
The Bi-Annual Research Conference of the
American Association for
Chronic Fatigue Syndrome (AACFS)

October 10-11, 1998 -- Cambridge, Massachusetts

Session 2: Clinical
State of the Art in Clinical Studies

Co-chairs: Dedra Buchwald,M.D. and David Klonoff, M.D.
October 10, 1998, 9:45 am-11:15 am

1. The measurement of 5-HIAA urinary concentrations as a predictive marker of efficacy of NADH in Chronic Fatigue Syndrome
L.M. Forsyth MD, A.L. MacDowell-Carneio MD, G.D. Birkrnayer MD, PhD, H.G. Preuss MD and J.A. Bellanti MD.
2. A Phase I trial of autologous ex vivo expanded lymph node derived cells as immunomodulatory therapy in CFS
Nancy Klimas, Mary Ann Fletcher, Kevin Maher, Roberto Patarca, Jean Walling, Mack Smith, Lauren Vitek, and Herb Bresler
3. Rehabilitation from work disability due to Chronic Fatigue Syndrome
David C. Klonoff, M.D.
4. A prospective cohort study of post-infective fatigue: illness characteristics and relationship to immunological and psychological disturbance
Andrew Lloyd, Ian Hickie, Ute Volimer-Conna, Michael Douglas, Catherine Brennan, Sandy Beynon, and Denis Wakefield
5. Effect of growth hormone treatment in patients with Chronic Fatigue Syndrome: a preliminary study
G. Moorkens, H. Wijnants, R. Abs
6. Durability of therapeutic benefit with Ampligen ® treatment of Chronic Fatigue Syndrome (CFS) as measured by the Karnofsky Performance Score (KPS)
David R. Strayer, William A. Carter, Thomas J. McCarron

The measurement of 5-HIAA urinary concentrations as a predictive marker of efficacy of NADH in Chronic Fatigue Syndrome

Authors: L.M. Forsyth, M.D.; A.L. MacDowell-Carneiro, M.D.; G.D. Birkmayer, M.D., Ph.D.; H.O. Preuss, M.D. and J.A. Bellanti M.D. Departments of Pediatrics and Microbiology-Immunology and the Immunology Center, Qeorgetown University Medical Center, Washington, D.C.

Chronic fatigue syndrome (CFS) is a disorder characterized by prolonged, severe fatigue that persists six months or greater in duration and a multitude of symptoms including neurocognitive dysfunction, flu-like symptoms, myalgia, muscle weakness, arthralgia, low-grade fever, sore throat, headache, sleep disturbances and swelling and tenderness of the lymph nodes. The overall goal of the present study was to evaluate the efficacy of reduced nicotinamide adenine dinucleotide (NADH), a natural substance known to trigger energy production through ATP generation and to alleviate symptoms of depression, in a group of 26 patients with CDC-defined CFS using a randomized double-blind, placebo-control crossover design. Medical history, physical examination and laboratory tests were performed at baseline, 4, 8 and 12 weeks. Subjects were randomly assigned to receive either 10 mg of the oral stable form of NADH (ENADA) or placebo at week 0 for a 4-week period, followed by a 4-week wash-out period, followed by a final 4-week period in which subjects were crossed over to an alternate regimen. No significant adverse effects were observed related to the oral form of NADH. The efficacy was measured by an arbitrary scoring system reflecting the symptoms of the patients as well as by laboratory tests, including plasma neurotransmitter concentrations and the urinary concentrations of serotonin metabolites i.e. 5-hydroxy indole acetic acid (5-HIAA). There were 8 patients who showed > 10% improvement while on the drug, in contrast to 2 while on placebo. Assuming that these improvements came from two independent samples of 26 patients, the success rate for the drug is 31% and for the placebo 8% (p < 0.05). The urinary concentrations of 5-HIAA were elevated prior to treatment in 50% of the patients. Following NADH treatment, these elevated 5-HIAA concentrations returned to the normal range, whereas with placebo they remained elevated or increased further above the upper normal range. Further, 18 of 25 (72%) study patients thus far enrolled in a longer open label follow-up study reported significant improvement in clinical symptomatology and energy levels. The results of the present study not only suggest that NADH is a safe, naturally-occurring biologic substance which may be a useful therapeutic adjunct in the management of chronic fatigue syndrome, but also that the measurement of urinary 5-HIAA may serve as an important predictive marker of neurocognitive dysfunction, as well as an objective measure of improvement following therapy.

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A Phase I trial of autologous ex vivo expanded lymph node derived cells as immunomodulatory therapy in CFS

Authors: Nancy Klimas, Mary Ann Fletcher, Kevin Maher, Roberto Patarca, Jean Walling, Mack Smith, Lauren Vitek*, and Herb Bresler**, *Neoprobe Corp, Dublin Ohio; **Ohio State University, Columbus, Ohio; and University of Miami School of Medicine and the Miami Veterans Affairs Medical Center, Miami, Florida.

Objective: Chronic Fatigue Syndrome is an illness which is associated with immune dysfunction, including abnormalities in the function of lymphocytes and expression of pro-inflammatory cytokines. Based on studies demonstrating increasing severity of illness associations with poorer lymphocyte function and greater expression of pro-inflammatory cytokines, it was postulated that immune modulatory therapies may have a role in the treatment of CFS. In this study the investigators apply an immunomodulatory method ex vivo that results in a product containing polyclonally expanded T-cells that are activated and functional. In prior studies of cancer and chronic viral illness, the re-infused cells have little toxicity and pilot data suggests efficacy.

Methods: In this feasibility and safety study, 14 CFS patients have volunteered to undergo lymph node resection and cell re-infusion after the cells have been modified and expanded in the laboratory. The expansion is performed in a closed system using a proprietary methodology (Cira Technologies). At the time of this submission the initial three subjects have undergone the procedure, and the cells have been re-infused. Data, including interim data at the three-month follow up point on all 14 subjects will be presented at the Fourth International AACFS Conference. This abstract will review the make up of the final product in the three pre-clinical, and first three clinical subjects.

Expansion results -- In the 6 expansions, the end product demonstrated a 6-fold to 100-fold expansion of polyclonal populations of lymphocytes. These were predominantly T-cells, with CD4 populations ranging from 40 to 46%, CD8 populations ranging from 52% to 56%. Small numbers of NK and B-cells (1% and 4 to 5% respectively) were present in the final product. More than 90% of the lymphocytes in the final product expressed the activation marker CD26. 84% to 93% of the CD4 cells expressed the phenotype CD4+RO+RA-, demonstrating an expansion of memory phenotype. CD4+CD25+DR+ was also expressed in 45% to 65% of the CD4 cells in the final product. The CD8 cells were more variable in the final product, with 1 of the 3 clinical samples having very low expression of CD38 (3%), yet high expression of DR (64%) and CD25 (59%) - suggesting a preponderance of CD8 cells with low CTL capacity, known to express T-cell anti-viral factor (CAF), as described by Jay Levy and colleagues in an HIV setting. However the other clinical samples, while highly activated and expressing adhesion molecules, also expressed CD38, suggesting an expansion of cytotoxic T-cells.
Feasibility and safety -- There have been no significant adverse health events related to biopsy or cell re-infusion at this time. One subject underwent an unsuccessful biopsy, with no retrievable lymph node.

Conclusion: There have been no adverse events related to the lymph node resection itself. The final product in the pre-clinical and clinical subjects consists of highly activated polyclonal populations of memory CD4 and CD8 cells, expanded 10 to 100 fold from the initial sample. The initial 3 clinical subjects have had minimal-to-no adverse reactions in the initial weeks of therapy. Subjects' health status, phenotyping and cytokine expression of peripheral blood cells will be followed for 6 months. An interim analysis of the 3-month feasibility and safety data will be reported at the October meeting.

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Rehabilitation from work disability due to Chronic Fatigue Syndrome

Author: David C. KIonoff M.D.

Objective: To assess the efficacy of a combined non-pharmacologic and pharmacologic rehabilitation program for work disability due to chronic fatigue syndrome (CF S).

Methods: Each study patient met four criteria:

  1. The patient initially presented with fatigue to a suburban private endocrinology practice between 1/1/95 and 6/30/96;
  2. CFS was diagnosed per the 1994 International CFS Study Group Case Defuntion;
  3. CFS diagnostic criteria were met at or after the initial visit; and
  4. Work disability occurred because of CFS during the study period, which was 12 months from the initial visit.
Recommended treatments included five non-pharmacologic methods:
  1. gradually progressive cardiovascular exercise, emphasizing walking and swimming;
  2. stress reduction techniques, such as biofeedback, hypnosis, or yoga;
  3. a hypoglycemia prevention diet;
  4. a monthly support group led by a Licensed Clinical Social Worker; and
  5. individual psychotherapy.
Recommended treatments utilized one or more pharmacologic agents including:
  1. non-steroidal anti-inflammatory drugs;
  2. symptomatic medications for pain, muscle spasms, headache, or bowel dysfunction;
  3. tricyclic antidepressants (TCAs); and
  4. selective serotonin reuptake inhibitors (SSRIs).
12 months after the initial visit, the investigator interviewed every patient about treatment compliance and work rehabilitation. Compliance was surveyed for six treatments, including:
  1. exercise;
  2. the support group;
  3. individual psychotherapy;
  4. symptomatic medications;
  5. TCAs; and
  6. SSRIs.
Work rehabilitation was defined as returning to full-time work.

Results: 35 patients with CFS were studied. The sex ratio of the study population was female:male 74%:26% (26:9). At presentation, the mean (± SD) patient age was 39 ± 9 years and the mean (± SD) duration of CFS was 47 ± 37 months. The mean (± SD) duration of work disability was 21 ± 28 months. Work rehabilitation was achieved in 26% (9 of 35) of patients. Rehabilitated patients, compared to non-rehabilitated patients, had a shorter duration of work disability (2 ± 1 vs. 28 ± 29 months, p < .0003), were younger (32 ± 13 vs. 42 ± 5 years, p < .06), and had a shorter duration of CFS (31 ± 36 vs. 52 ± 36 months, p < .07). Predictors of rehabilitation following work disability due to CFS included:

  1. disability duration < 4 months (p < .0001),
  2. age at first visit < 30 years (p < .01),
  3. not receiving disability payments (p < .07),
  4. illness duration < 40 months (p < .14), and
  5. male sex (p < .07).
By gender, rehabilitation occurred in 6 of 26 females and 3 of 9 males. No statistically significant prediction of recovery was evident following compliance with any single surveyed treatment.

Conclusions: In CFS, work disability may be reversible. Patients with a work disability duration of < 4 months or a presenting age of < 30 years are the most likely to recover.

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A prospective cohort study of post-infective fatigue: illness characteristics and relationship to immunological and psychological disturbance

Andrew Llovd*, Ian Hickey+, Ute Vollmer-Conna*+, Michael Douglas**, Catherine Brennan**, Sandy Beynon*, and Denis Wakefield*.
*Inflammation Research Unit, School of Pathology, University of New South Wales, Sydney;
+School of Psychiatry, University of New South Wales, Sydney;
**Centre for Population Health, Macquarie Area Health Service, Dubbo, New South Wales, Australia.

Objective: To define the longitudinal relationships between physical and psychological symptoms as well as immunological function following acute infective illnesses.

Methods: A cohort study has been established in which individuals with acute, serologically-documented infection are enrolled and followed prospectively. The subjects have infection with Epstein-Barr virus (EBV), Ross River virus (RRV) - an Australian arbovirus which causes self-limiting arthritis, or Coxiella burnetti - the causative agent of Q-fever. The enrollment assessment includes a structured medical and psychological interview, as well as immunological testing. Follow-up reviews are completed at three and six weeks and then at three monthly intervals if symptoms persist. At each sampling point, standardised self-report questionnaires record physical illness data, as well as psychological and somatic symptom profiles. Immunological assessments are undertaken at each sampling point and include measurement of delayed-type hypersensitivity (DTH) skin responses using the CMI Multitest kit (Meneux, France), and collection of serum, plasma and peripheral blood mononuclear cells which are stored for subsequent cytokine analyses. A control cohort of recovered individuals is matched on a case-control basis to those with persistent symptoms. At three months, cases of post-infective fatigue and control subjects are assessed by a physician and a psychiatrist to exclude alternative medical or psychiatric explanations for the prolonged symptoms.

Results: Seventy-five subjects have been enrolled in the first 12 months of the study, including 22 with EBV, 25 with RRV, and 28 with Q-fever infections. During the acute phase of these illnesses, profound fatigue and malaise were the most common symptoms, surpassmg even fevers and chills in prevalence. Classical symptoms of depression or anxiety disorder were uncommon. However, the majority of subjects met cut-offs for classification as cases of both fatigue syndrome (Schedule of fatigue and Anergia, SOFA; Hickie et al, 1996) and psychological distress (General Health Questionnaire, GHQ). At enrollment, approximately 50% of subjects in each cohort were unable to mount a delayed-type hypersensitivity (DTH) skin response (i.e cutaneous anergy) using the CMI Multitest kit (Meneux, France). By six weeks, the typical features of acute infection such as fever, had resolved in almost all subjects, whereas self-reported fatigue, malaise, as well as myalgia and arthralgia remained prevalent. Similarly, a high prevalence of cutaneous anergy remained evident. Approximately 25% of subjects in each cohort were still classified as SOFA cases at six weeks and a similar proportion met the cut-off for GHQ caseness. A significant correlation was detected between the pattern of persistence (or resolution) of fatigue and DTH skin responsiveness.

Conclusions:These acute infective illnesses are commonly accompanied by a range of prolonged somatic and psychological symptoms, particularly fatigue, rather than depression or anxiety. Following the resolution of the classical features of acute infection such as fever, symptoms suggestive of Chronic Fatigue Syndrome commonly persist. Resolution of prolonged fatigue is associated with improvement in cell-mediated immunity. This ongoing, prospective cohort of subjects with well-characterised post-infective fatigue states will provide a powerful model in which to investigate specific immunological and psychological hypotheses of the pathogenesis of prolonged fatigue and chronic fatigue syndrome.

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Effect of growth hormone treatment in patients with Chronic Fatigue Syndrome: a preliminary study

Authors: G. Moorkens*, H. Wijnants*, R. Abs**
*Department of Internal Medicine0 and Endocrinology
**University Hospital Antwerp, Belgium

Objective: Patients with CFS and adults with growth hormone deficiency show striking clinical similarities. The nocturnal secretion of GH has been shown to be approximately half of that in age- and sex-matched controls. In the present study the therapeutic efficacy of GH therapy was evaluated in patients with CFS who had nocturnal GH peak levels below 10 µg/l during stage-controlled sleep.

Methods: Twenty patients (7 men, 13 women; age range 30-60 years) with CFS were randomized to receive placebo or GH therapy, 6.7 µg/kg/day (0.02IU/kg/day), for 12 weeks. Following this double-blind treatment period, GH therapy at the above dose was given for an open period of 9 months. Three patients dropped out.

Results: Mean serum levels of Insulin-Like Growth Factor-I(IGF-I) increased during 12 months of GH treatment, from 173 ± 46 µg/l to 296 89 µg/l (p < 0.001); IGF-I SDS values also increased from -0.45 ± 1.14 to +1.43 ± 1.09 (p < 0.001). No significant changes were seen in weight, muscle strength or skinfold thickness after 12 months of treatment, compared with baseline. Serum levels of thyrotrophin, free tri-iodothyronine, free thyroxine, prolactin, cortisol, follicle-stimulating hormone, luteinizing hormone, testosterone and sex-hormone-binding globulin were not significantly different from baseline after 12 months of treatment. Serum lipoprotein(a) levels increased from 26.3 ± 28.7 mg/dl at baseline to 37.0 ± 51.9 mg/dl after 12 months of treatment (p=0.003). The levels of six amino acids (tyrosine, valine, tryptophane, phenylalanine, isoleucine and leucine) increased significantly during GH treatment (p < 0.005). Bioimpedance analysis showed significant increases in fat-free mass (from 49.3 ± 8.7 kg to 51 ± 9.7 kg; p=0.006) and total body water (from 35.4 ± 6.2 litres to 37.0 ± 7.0 litres; p=0.003) following 12 months of treatment, but no significant changes in fat mass or BMI were observed. No significant changes were seen in quality-of-life parameters (NHP and QoL-AGHDA). However, four patients resumed work after a prolonged period of sick leave.

Conclusion: To our knowledge , this study is the first to use GH therapy in patients with CFS. The administration of GH induced important changes in body composition. Although all 17 patients reported feeling better no significant improvements were recorded in the NHP and QoL-AGHDA questionnaires. Further studies are necessary to confirm these findings and to investigate the changes in body composition and metabolism of amino acids.

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Durability of therapeutic benefit with Ampligen ® treatment of Chronic Fatigue Syndrome (CFS) as measured by the Karnofsky Performance Score (KPS)

Authors: David R. Strayer, William A. Carter, Thomas J. McCarron. Hahnemann/Allegheny University and Hemispher, Biopharma Inc.; Philadelphia, PA

NOTE: The paper that was actually presented at the meetings had more up-to-date information in it. As soon as I get a copy of the paper, or an abstract, I will upload it here or provide it on another website with a hyperlink. If anyone has a copy of the paper that was presented, or has a good set of notes, I would appreciate it if you could share a copy with me. Thanks -- Mary Schweitzer, at schweit2@ix.netcom.com.

Objective: To review Karnofsky Performance Score (KPS) results derived from studies using Ampligen ® for treatment of Chronic Fatigue Syndrome (CF S) during a maximum period of three years.

Methods: Chronic Fatigue Syndrome is a symptom complex characterized by both cognitive as well as physical impairments. Although the causes of CFS remain under investigation, the presenting symptoms have been codified by the CDC to assist in defining a CFS diagnosis. The primary and most salient feature of CFS is persistent and pervasive fatigue and a decrease in physical performance. Accordingly, we have studied a Quality of Life (QoL) instrument, the Karnofsky Performance Score, a self-reported and physician-completed instrument evaluating functionality, as the primary endpoint in trials assessing the clinical benefit of Ampligen ®. We studied changes in KPS during 24 weeks of therapy in a placebo-controlled study involving 92 patients and during the extension phase of that trial. In the open-label extension phase, a minimum period of one year, 22 subjects were enrolled and KPS data were analyzed. Ampligen ® dosage levels (400 mgs twice weekly) and data collection intervals (every 4 weeks for the KPS) were maintained in the extension phase as they had been in the 24-week randomized trial.

Results:The extension phase which followed the 24-week double-blind, placebo-controlled study enrolled 22 patients. One cohort of 15 patients was selected based on the degree of responsiveness (KPS improvement of > 20 points) displayed in the initial trial; another group of 7 subjects independently chose to enter the extension. The 22 member extension population contained patients who had originally been on Ampligen ® (13) or placebo (9). We were primarily concerned with

  1. the stability and perpetuation of the benefit gained in the first 24 weeks,
  2. the differences between the self-chosen group and the cohort selected because of initial responsiveness, and
  3. any distinctions between the Ampligen ® and placebo subsets.
Two patients (9%) had lower KPS scores at the extension phase endpoint then they had at 24 weeks. Six patients (27%) retained the improvement they evinced at 24 weeks, but displayed no additional improvement. Fourteen patients (64%) had a mean improvement of 16.4 KPS points over the improvement shown at 24 weeks. There was a significant difference in KPS change between the self-chosen (+6.7) and selected (+16.5) groups at 24 weeks (p=.02, Wilcoxon signed-rank test). No further statistical significances emerged when evaluating KPS improvements during the extension phase for either the self-chosen or selected groups or the initial Ampligen ® vs. placebo groups (all Wilcoxon p values > 0.17). The average baseline KPS for the entire group (n=22) prior to any Ampligen ® therapy was 50, "Requires considerable assistance for daily care". The average KPS after the extension-treatment was 80, "Normal activity with effort; some signs or symptoms of disease". Time-in-study had a progressively palliative effect. Spearman ranked-order correlations (R= -.91, p=0.000l) showed that there was a strong inverse relationship between the baseline KPS and the percent of KPS change over baseline at the extension endpoint.

Conclusions: In summary, a review of long-term results using Ampligen ® in CFS demonstrates the therapeutic advantages of the treatment as revealed in the magnitude of KPS improvement. The 22 patients in the extension phase had an average KPS change of 29.9 and a baseline standard deviation of 11.6. This KPS change represents a large physical improvement, which is highly significant (one-sided paired t-test, p < 0.0001). In conclusion, physical performance improved dramatically with the supplemental Ampligen ® treatment provided in the extension phase and the Ampligen ® treatment was generally well-tolerated.

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