Authors: Cichon M. M.D., Farrell, D., Ganjo, S., Sadler, G.
Objective: To survey the symptoms of a large group of breast implant patients displaying illness, and to determine if any clinical or serological features predominate.
Method: A private internal medicine practice.
Results: A referred sample of 415 patients with fatigue of long duration, followed by muscle/joint pain, cognition problems, polyneuropathy, and localized breast pain.
Conclusion: Silicone adjuvant breast disease may be a novel disorder, possibly auto-immune, producing atypical syndromes that do not fit within the classic diagnostic criteria of known conditions. Furthermore, the diversity and distinction of silicone adjuvant breast disease may require the medical community to accept it as a new entity, encompassing a neurological and connective tissue disorder.
Authors:: I. Hauspie¹, I.Campine²*, P. De Becker², K. De Meirleir², M. Kirsch-Volders¹
¹Department of Human Genetics, Free University of Brussels, Brussels, Belgium
²Department of Human Physiology, Free University of Brussels, Brussels, Belgium
* I. Carnpine is supported by funds from the Foundation for Scientific Research, Belgium (F.W.O.).
Objective: Many studies in CFS patients suggest a virally-triggered onset, associated with an abnormal immune function. With recent findings in mind concerning the role of viral proteins taking in cell proliferation control, our aim was to test in vitro cell proliferation in CFS patients and healthy controls, both in normal conditions and after treatment with different mutagens.
Methods: Human lymphocytes from 8 patients and 14 controls were cultured in the presence and absence of different mutagens. Using the cytokinesis blocked micronucleus assay, the proliferation index was assessed and chromosomal abberations were detected. We also examined the effect of ethanol exposure on T-lymphocytes in vitro.
Results: The results show that the proliferation index in CFS patients (in absence of a mutagen) is slightly lower than in controls, but CFS patients show more spontaneous damage during cell division than controls. In the absence of S9, the cell division is reduced in the presence of ethanol in CFS patients. Ethanol also induces damage in dividing T-lymphocytes in CFS patients in the absence of S9. Finally, lymphocytes of CFS patients seem to be more resistant to in vitro treatment with MMS than controls.
Conclusion: These results add information to the existing knowledge of intracellular abnormalities in CFS. Our findings point toward abnormalities in intracellular protein metabolism,
and increased sensitivity to alcohol. We also postulate, from the MMS experience, that lymphocyte cell membrane permeability is altered.
Authors: Lynn Helder. Ph.D., Stacy Wagner, M.S., Robert Keller, M.D., Nancy Klimas, M.D. and Michael Antoni, Ph.D.
Objective: Chronic immune activation, as suggested by abnormal T-cell phenotypes, and psychological distress have often been associated with Chronic Fatigue Syndrome (CFS), although conclusions remain controversial. Our purpose was to further explore the relationship between immune functioning and psychological distress in patients with CFS.
Methods: 25 subjects meeting the Centers for Disease Control criteria for CFS were examined prior to participation in a cognitive therapy intervention. Blood draws and psychological inventories were completed within two weeks prior to the group onset. Analysis of markers included activated T-cells
(CD26+CD2+CD3+), T-helper cells (CD4+CD3+), T-suppressor/cytotoxic cells.(CD8+CD3+), and T4/T8
ratio (CD4/CD8). Subjects were also given the Profile of Mood States (POMS; with Anger, Anxiety,
Depression, Confusion, Fatigue., and Vigor subscales), The Sickness Impact Profile (SIP; measuring
psychosocial impairment), and the Attitudes Towards Self Scale (ATS; with Self-Criticism, Generalization, and High Standards factors).
Results: The POMS depression and anger subscales and the total POMS score were significantly
correlated with the T4/T8 ratio (r = 44, p < .04, r = .50, p < .02; r = .44, p < .05, respectively). In addition, the POMS depression and anger subscales also showed a marginal inverse correlation with T-suppressor/cytotoxic cell percentage (r = .37, p < .09; r = -.40, p < .07, respectively). Similarly, the psychosocial impairment score of the SIP was also correlated with the T4/T8 ratio (r = .33, p < .09) and negatively associated with the percentage of T-suppressor/cytotoxic cells (r = -.36, p < .06). The Generalization factor of the ATS measuring the tendency to generalize negative events, was significantly correlated with activated T-cell numbers (r = .39, p < .04), T4-helper cell numbers (r =.37, p < .06),
and T-helper cell percentages (r = .39, p < .05).
Conclusions: Our findings suggest that immune activation, as defined by elevated activated
T-cells, T-helper cells, and T4/T8 ratios, is associated with measures of psychological distress and attitudes about oneself. The elevations in distress and impairment measures were also associated with a reduction in the percentage of T-suppressor/cytotoxic cells. There may be a subset of CFS patients exhibiting a depleted T-suppressor/cytotoxic cell population that tend to be more symptomatic and more emotionally distressed. Psychological distress may have a stronger relationship with immunologic functioning in those CFS patients who are the most ill, as suggested by increased activated T-cells, T-helper cells, and T4/T8 ratios, and a reduction in T-suppressor/cytotoxic percentages. Since the ATS
was associated with immune activation, attitudes about oneself may mediate the association between
psychological distress and decreased T-suppressor/cytotoxic cells. These findings are based on pilot
data, and therefore, conclusions about whether or not the CFS subjects had significantly elevated T4/T8 ratios or abnormally low T-suppressor/cytotoxic percentages as compared to normal controls can not be made without further study.
AuthorsM.I. Holmes, R. Easingwood, J. Cross, and J. Faed
Objective: This paper describes two blind clinical trials of paired, age, sex and ethnically matched patients with CFS; 24 pairs of patients and controls in the first, and 18 in the second.
In the first, the range of duration of symptoms was 1 to 3.5 (mean 1.5) years and in the second 1 to 5 (mean 1.7) years. Peripheral blood lymphocyte (PBL) cultures were assayed in triplicate for reverse-tran scriptase (RT) activity, and examined by EM for the presence of virus-like structures at days 0 and 12 and CD2, 3, 4, 8, 16, 20, and 31, and B1 phenotypes were counted at day 0 by FACScan.
Methods: A single dose of 1 µg ml-¹Concanavilin A (Con A) was given to all cultures at
day 0. At days 4, 8 and 10 they were given 4.5 ng ml-¹ human recombinant IL-2. Cells were harvested at day 12 for EM studies, and ultracentrifuged supernatants and cells for RT assay using a poly rA:oligo dT template-primer and measuring RT activity by uptake of tritiated thymidine triphosphate.
Results: In Trial 1, RT activity up to 3 times background was observed in 9, and virus-like structures in 7 of 24 patients, and not in controls. Group means showed a significant CD4 cytopenia. In
Trial 2, RT activity at levels of 2 to 4 times background were observed in 5 patients, and virus-like
structures were observed in 4 of these, and not in controls. Group means showed significantly reduced CD4/CD8 ratios and an NK cytopenia. RT activity and EM virus-like structures were seen almost exclusively in the cohort of patients who identified the onset of their condition with a non-specific, acute febrile illness and whose duration of symptoms was 2 years or less.
Conclusion: These studies suggest the in vitro RT activity and the presence of virus-like
structures in PBLs may correlate in CFS with patients who relate the onset of their condition to a
non-specific, acute febrile illness.
Authors: Nancy Klimas, Kevin Maher, Roberto Patarca, Jean Walling, Mack Smith, and Mary Ann Fletcher. 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 and activation status of peripheral blood lymphocytes. There has been no study of the lymph node compartment in this illness.
Methods: Patients who had volunteered to undergo lymph node biopsy while participating in the
pre-clinical phase and phase I studies of a novel immunomodulatory therapy were evaluated. At the time of this abstract 6 lymph nodes have been evaluated. An additional 9 will be studied prior to the October AACFS meeting.
Results: Of the 6 lymph nodes currently available for study, 1 is tonsillar, 2 posterior cervical, and three are axillary. Four demonstrated normal architecture and morphology. Two had a slight
increase in the number of histiocytes. The tonsillar sample was, as expected, predominantly B-cells (56%).
Excluding the tonsillar sample, the lymph nodes showed the following lymphocyte surface phenotype: The CD4 percent ranged from 61% to 83% (mean 70%), the CD8 percent from 8% to 19% (mean 11%) and B-cells (CD 19+) ranging from 13% to 30% (mean 20%). Few natural killer cells were present. CD56+CD3- lymphocytes ranged from 0.9% to 2.2%. The activation marker, CD26 was present on 63% to 77% of the CD2+ lymphocytes. Memory CD4 cells predominated with only 16% (range of 2% to 30%) expressing the naive subset marker, CD45RA. Not surprisingly, the majority of the CD4 cell population also expressed 62L (86%), which is considered to be a lymph node homing adhesion molecule. CD8 cells were predominantly CD38+ (95%) and DR negative.
Discussion: This initial study of the distribution of lymphocyte subsets in the lymph nodes from
patients with CFS offers confirmation of our hypothesis regarding the immunopathogenesis of this syndrome. The data from the first 6 patients presented here indicates a preponderance of activated T-cells that is even higher than that reported in peripheral blood. The CD8 cells express the phenotype CD38+ and DR-, which is associated with cytotoxic T-cells. The ratio of memory to naive CD4 T-cells is skewed upward, as is the case in peripheral blood. These findings are compatible with a chronically activated immune status in this patient group.
Authors: J. LaManca, S. Sisto, J. Ottenweller, A. Peckerman, S. Cook, T. Denny, W. Gause and B.H. Natelson. NJ CFS Research Center, New Jersey Medical School, and VA NJ Health Care System, East Orange, NJ.
Objective: Data have indicated that CFS may involve abnormal immune system functioning.
Exercise can be an useful tool in stimulating an immune response. This study was conducted to
evaluate the immunological response of CFS patients to an exhaustive bout of exercise.
Methods: The two groups, which were matched for age, sex, and socioeconomic background,
consisted of 19 CFS patients meeting the 1988 CDC criteria and 14 non-exercising (i.e. sedentary)
controls respectively. All were females in the luteal phase of the menstrual cycle. Venipuncture was performed pre-, 4 minutes post-, 1 hour post-, and 24 hours post-exercise. The graded exercise test (GXT) consisted of walking on a treadmill with the work load increasing every 3 minutes to voluntary exhaustion. Expired gas was analyzed during the GXT. Peripheral blood cells were labeled with the following monoclonal antibody combinations: CD3/CD8, CD3/CD4, CD3/CDl9, and CD3/CD (16&56). The cytokines: IFN-gamma, IL-2, IL-4, IL-10, IL-12, and TNF-alpha were assayed utilizing a quantitative RT/PCR assay. White blood cells (WBC) and all subset concentrations were adjusted for plasma volume shifts.
Results: During the GXT no significant differences in VO2peak
(28.6 ± 1.7 vs 30.8 ± 1.2 ml:kg-1min
-1), HRpeak(175 ± 4 vs 183 ± 4 bpm) and RER (1.08 ± .02 vs 1.13 ± .02) were seen when comparing CFS to CON. The number of WBC, CD3+CD8+, CD3+CD4+, T-Cells, B-Cells, Natural Killer Cells, and IFN-gamma all were significantly changed across time (all comparisons, p < .0l). No significant group differences were seen for any of the immune variables. Also the changes across time were similar for both groups with the exception of IL-2, where a significant group-by-time interaction was seen (p < .03). Only one of the CFS patients had elevated blood lymphocyte levels 24 hours after the GXT.
Conclusion: The immune response of patients with CFS to a single bout of exhaustive exercise is not significantly different when compared to a group of sedentary healthy controls.
(This work was supported by NIH Center grant AI-32247)
Authors: J.A. Marcusson¹ , G. Lindh², B. Evengård²
¹Department of Dermatology, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
²Division of Infectious Diseases of the Department of Immunology, Microbiology, Pathology and Infectious Diseases, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
Objective: Allergic reactions have been reported to occur more often in patients with CFS, and fatigue is also a common self-reported symptom among patients with allergy. The aim of this study was to study whether allergies to various metals might play a role in the pathogenesis of chronic fatigue syndrome.
Method: Fifty patients fulfilling the chronic fatigue syndrome (CFS) criteria according to CDC, and 73 sex and age-matched healthy controls without history of metal allergy or symptoms of fatigue, were percutaneously patch-tested with eight different metal salts. The following metal salts were used as test reagents: potassium dichromate, metallic mercury, cobalt chloride, nickel sulphate, gold sodium thiosulphate, palladium dichloride, tin and silver nitrate. Test reagents and test chambers were obtained from Chemotechnique Diagnostics AB, Malmö, Sweden. The test chambers were removed after 2 days and the skin reaction was graded after another 2 days as 0, 1+, 2+ and 3+ respectively. Only 2+ and 3+ reactions were accepted as true positive.
Result: Some type of contact allergy to tested metal salts was noted in 46% of the patients with CFS and in 36% of the healthy coritrols. Nickel sulphate allergy was significantly more common among the CFS patients, and this was even more noteworthy among the females. We found nickel allergy in 52% of the female CFS patients compared to 19% of the female control group (p < 0.05). No significant difference was found in skin reaction to the other metal salts tested in this study.
Nickel allergy was significantly more common among CFS patients than among healthy controls.
The overall metal allergy was, however, not significantly increased among CFS patients.
These findings suggest a possibility that nickel, and/or metals crossreacting with nickel, might play a specific role in the pathogenesis of CFS causing chronic stimulation of the immune system. However, nickel allergy may be just a marker symptom leading us to further knowledge about the mechanisms involved in the CFS.
Authors:Roberto Patarca, Nancy G. Klimas, Iris R. Bell, and Elizabeth Hardin
Department of Medicine, University of Miami School of Medicine, Miami, Florida, and
Department of Psychiatry, University of Arizona Health Sciences Center, Tucson, Arizona.
The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several polysymptomatic conditions that overlap symptomatically with depression and
somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf
War syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with L-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. We compared middle-aged women with CI (who had high levels of distress) (n=14), depressives without CI (n=10), and normals (n=l1). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the Clalone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of "unexplained" multiple somatic symptoms in subtypes of apparent somatizing disorders.
Authors: J. Visser¹ W. Graffelman² B. Blauw¹, I. Haspels¹, E.R. de Kloet*, and Lex Nagelkerken¹.
¹Division of Immunological and Infectious Diseases, TNO Prevention and Health Leiden
²Division of General Practice, University of Leiden and
*Division of Medical Pharmacolbgy, LACDR, Leiden, The Netherlands.
Recently, we have shown that CD4+ T cells from patients with the chronic fatigue syndrome
(CFS) produce less IFN-gamma and display an increased sensitivity to glucocorticoids (GC) with regard to proliferation and IL-4 production (J Infect Dis 1998;177:451-4). Further studies with healthy donors studying IL-10 and IL-12 (two very important regulating cytokines for IFN-gamma) revealed that IL-12 was very sensitive to GC suppression, while IL-10 was relatively resistant (Blood, vol. 91, No. 11 (June 1), 1998: pp 4255-4264). In view of the importance of these cytokines in the regulation of IFN-gamma, we studied the regulation of IL-10 and IL-12 by endogenous and exogenous GC in whole blood cultures of CFS patients. Thirty patients, as well as age- and sex-matched controls, were used in this study. CFS patients showed an increased production of lps induced IL-l0 (p < 0.05), and a reduced production of IL-12 (p=0.06). No differences in sensitivity to dexamethasone (DEX) was detected with regard to TNF-alpha and IL-12 (p40) production, but the patients showed an increased sensitivity
with regard to IL-10. Although IL-10 is relatively resistant, we observed that relatively more patients were
sensitive for DEX, and approximately 6-fold less DEX was required to suppress the IL-10 production by 50%. This might imply an improper functioning of GC-receptors (GR), since IL-10 production showed an inverse correlation with serum levels of cortisol in the controls, but not in the patients. Further studies regarding the number and affinity of GR in lymphocytes from CFS patients in relation to cytokine secretion are being performed to get more insight in the altered regulation of cytokines by GC in CFS