Myalgic encephalomyelitis: International Consensus Criteria.

The label 'chronic fatigue syndrome' (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term 'myalgic encephalomyelitis' (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization's International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

Chronic fatigue syndrome is associated with diminished intracellular perforin.

Chronic fatigue syndrome (CFS) is an illness characterized by unexplained and prolonged fatigue that is often accompanied by abnormalities of immune, endocrine and cognitive functions. Diminished natural killer cell cytotoxicity (NKCC) is a frequently reported finding. However, the molecular basis of this defect of in vitro cytotoxicy has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells and is a key factor in the lytic processes mediated by these cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in CFS subjects and healthy controls. A significant reduction in the NK cell associated perforin levels in samples from CFS patients, compared to healthy controls, was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of CFS subjects, providing the first evidence, to our knowledge, to suggest a T cell associated cytotoxic deficit in CFS. Because perforin is important in immune surveillance and homeostasis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of CFS and its analysis may prove useful as a biomarker in the study of CFS.

Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors.

The literature is reviewed and data are presented that relate to a model we have developed to account for the perpetuation of the perplexing disorder currently termed chronic fatigue syndrome (CFS). In patients with CFS there is chronic lymphocyte overactivation with cytokine abnormalities that include perturbations in plasma levels of proinflammatory cytokines and decrease in the ratio of Type 1 to Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation. The initiation of the syndrome is frequently sudden and often follows an acute viral illness. Our model for the subsequent chronicity of this disorder holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and the immunologic dysfunction contribute to (a) CFS-related physical symptoms (e.g., perception of fatigue and cognitive difficulties, fever, muscle and joint pain) and increases in illness burden and (b) impaired immune surveillance associated with cytotoxic lymphocytes with resulting activation of latent herpes viruses.

Autonomic and cardiovascular function in HIV spectrum disease: early indications of cardiac pathophysiology.

Autonomic dysfunction in persons with acquired immune deficiency syndrome (AIDS) has been reported previously but its incidence in early stage HIV infection and its relation to cardiovascular function have not been fully examined. The present study evaluated cardiovascular and autonomic function in 55 HIV-seronegative, and 52 HIV-asymptomatic and 31 HIV-symptomatic seropositive men. Measures of hemodynamic and autonomic function were obtained at rest and during a standardized battery of autonomic tests. Results were compared across groups while controlling for age, body mass, and physical activity. Analyses indicated that measures of autonomic function did not differ among groups. However, at rest, both HIV seropositive groups exhibited diminished stroke volume and elevated diastolic blood pressure, albeit within normotensive levels. In addition, the ability to sustain a blood pressure response during prolonged challenge and the relationship between stroke volume and baroreceptor/vagal responsiveness were disrupted in the HIV-symptomatic group. Therefore, in the pre-AIDS stages of infection, autonomic functioning appeared intact; yet alterations in baroreceptor/vagal function associated with depressed myocardial function may be an early warning signal reflecting cardiovascular pathological processes potentially exacerbated by HIV spectrum disease.

Enhancing adherence to combination antiretroviral therapy in non-adherent HIV-positive men.

This paper describes a preliminary study aimed at testing the efficacy of a brief medication counselling and behavioural intervention in improving adherence to combination antiretroviral medication therapy and prophylactic treatment among non-adherent men living with HIV. Twenty-one non-adherent HIV-positive men obtaining primary care clinical services at a Veterans Affairs Medical Center were recruited by health care providers. Intervention participants were primarily African-Americans with histories of intravenous drug use. During a period of five months, participants were provided with monthly medication counselling and a weekly medication pill organizer. Participants were compared with 21 non-adherent matched controls receiving standard pharmacy care including review of medications. Intervention and control subjects were compared on several variables: medication refill timeliness, appointment attendance, hospitalizations and opportunistic infections. Medical information was obtained from hospital and pharmacy records at baseline and post-intervention. Pre- to post-intervention rates of adherence to medication refills and clinic appointments increased significantly among intervention participants. Relative to matched controls, intervention participants also significantly increased drop-in visits and showed fewer hospitalizations. Intervention participants also showed significant decreases in the number of opportunistic infections. Results suggest that exposure to medication counselling and behavioural interventions increase adherence, with associated reductions in negative clinical outcomes.

Serum neopterin and somatization in women with chemical intolerance, depressives, and normals.

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several controversial polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf 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. This study compared middle-aged women with CI (who had high levels of affective distress; n = 14), depressives without CI (n = 10), and normals (n = 11). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the CI alone 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.

Individual differences in neural sensitization and the role of context in illness from low-level environmental chemical exposures.

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena.

Immunological correlates of disease severity in pediatric slow progressors with human immunodeficiency virus type 1 infection.

Pediatric slow progressors are a group of HIV-1-infected individuals who are homogeneous for route and length of infection and standard of care and are therefore amenable to cross-sectional population studies on the immunological correlates of disease progression. We report here that both clinical and immunological categorizations of pediatric slow progressors based on the 1994 CDC criteria for symptom and immunosupression severity levels yield similar immunological findings: declining proportions of CD4 T cells are associated with increasing proportions of CD8 and CD4-CD8- T cells and with declining IL-2, -5, and -10 production levels by peripheral blood cells in response to the T cell-dependent mitogen, phytohemagglutinin, but not to the T and B cell-dependent mitogen from pokeweed. The latter cross-sectional results point to potential prognostic and nosologic markers and therapeutic targets among HIV-infected pediatric slow progressors. Longitudinal studies will help to assess further the relevance of these findings.

Predictors of survival in human immunodeficiency virus type 1-seropositive intravenous drug users.

In an ongoing prospective study of street-recruited intravenous drug users (IDUs) in Miami, Fla., 116 human immunodeficiency virus type 1 (HIV-1)-infected IDUs were monitored for up to 7 years. This provided an opportunity to evaluate baseline immunological parameters as potential predictors of survival among HIV-1-infected IDUs. As expected, HIV-1-infected IDUs who had an advanced stage of the disease (Centers for Disease Control and Prevention classification III or IV); p24 antigenemia; human T-cell leukemia virus type 1/2 seropositivity; low CD4 counts (< or = 200); low hemoglobin (< or = 14), high serum immunoglobulin A (IgA) (> 500 mg/dl), or high serum IgG (> or = 3,500 mg/dl) levels; or low proliferative responses to pokeweed mitogen (< or = 1,500 cpm) and to phytohemagglutinin (< or = 80,000 cpm) at baseline had worse survival rates. Results from multivariate Cox's models of survival showed that the baseline serum IgG level, serum IgA level, and CD4 count independently predict survival in HIV-1-infected IDUs. Cross-validation procedures verified the above-mentioned findings. These findings support the routine consideration of serum immunoglobulin levels in addition to CD4 count, especially in early evaluation of disease stage, as these evaluations may modify application of prophylaxis and treatment for HIV-1-infected IDUs. We recommend consideration of use of serum IgG and IgA as immunological markers for long-range prediction of survival in HIV-1-infected IDUs. These determinations are less onerous and more appropriate for use in field studies and financially less favored settings.

Lung cancer in patients with human immunodeficiency virus infection.

This retrospective study determined the clinical course of lung cancer in patients with human immunodeficiency virus (HIV) infection. A total of 23 patients with HIV infection archived as lung cancer were studied: 16 were identified from about 1,000 lung cancer patients entered in the tumor registry and medical records of Jackson Memorial Hospital, 7 were identified from about 1,000 HIV-positive patients entered in the Special Immunology registry of Veterans Administration Medical Center, 4 patients did not have pathologic confirmation of lung cancer, and 19 patients, all men, met the criteria for analysis (histopathologic diagnosis of lung cancer and HIV+ by serology). The median age was 47 (range: 36-66). Risk factors for HIV were homosexuality (6 patients), blood transfusion (3), promiscuity (5), intravenous drug abuse (4), and none (3). Six patients had a history of coexistent pulmonary tuberculosis and 5 had Pneumocystis carinii pneumonia. Median survival from diagnosis of lung cancer was 3 months. Advanced stages of both HIV infection and lung cancer may account for the poor survival. All patients were men and noted to be younger than other patients with lung cancer.

Adoptive CD8+ T-cell immunotherapy of AIDS patients with Kaposi's sarcoma.

This article reviews published and original findings from two clinical trials of adoptive CD8+ T-cell immunotherapy of patients with acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma (KS). In the first trial, AIDS patients with either KS or oral hairy leukoplakia (OHL) received five rounds of reinfusions of 10(8)-10(10) ex vivo expanded and activated autologous CD8+ T cells. Recombinant interleukin-2 (rIL-2) was coadministered only with the fifth and final infusion. Improvement, and in some cases, resolution of OHL, KS, and candidiasis was observed with no side effects. The observation that clinical improvement of KS was more pronounced when reinfusion of CD8+ T cells was followed by rIL-2 infusion led to a second clinical trial designed to examine the effect of repeated infusions of autologous CD8+ T cells with concomitant rIL-2 administration in the treatment of AIDS-related KS. Improvement of KS status was observed in four out of the eight patients studied (three partial and one complete response). The CD8+ T-cell immunotherapy protocol also provided the opportunity to comparatively study CD8+ T-cell-associated genetic programs. Baseline expression patterns of soluble and surface immune markers by CD8+ T cells from AIDS patients and uninfected controls were predominantly of the type 1 type and differed mainly at a quantitative or kinetic level. Deficiencies in immune mediator expression by CD8+ T cells from AIDS patients tended to dissipate with progression through the protocol. Findings are discussed in the context of current knowledge and therapeutic implications of CD8+ T-cell function in AIDS and neoplasia.

Megestrol acetate in patients with AIDS-related cachexia.

OBJECTIVES: To compare the effects of oral suspensions of megestrol acetate, 800 mg/d, and placebo on body weight in patients with acquired immunodeficiency syndrome (AIDS)-related weight loss. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient community and university patient care setting. PATIENTS: Consecutive patients with AIDS who had substantial weight loss and anorexia were enrolled. Of 271 patients, 270 and 195 were evaluable for safety and efficacy, respectively. INTERVENTIONS: Patients were randomly assigned to receive placebo or megestrol acetate (100 mg, 400 mg, or 800 mg) daily for 12 weeks. MAIN OUTCOME MEASURES: The primary efficacy criterion was weight gain. Patients were evaluated at 4-week intervals for changes in weight and body composition, caloric intake, sense of well-being, toxic effects, and appetite. RESULTS: For evaluable patients receiving 800 mg of megestrol acetate per day, 64.2% gained 2.27 kg (5 pounds) or more compared with 21.4% of patients receiving placebo (P < 0.001). An intent-to-treat analysis showed significant differences (P = 0.002) between those receiving placebo and those receiving 800 mg of megestrol acetate for the number of patients who gained 2.27 kg (5 pounds) or more (8 of 32 [25%] compared with 38 of 61 [62.3%], respectively). Compared with patients receiving placebo at the time of maximum weight change, evaluable patients receiving megestrol acetate, 800 mg/d, reported improvement in overall well-being and had an increase in mean weight gain (-0.725 compared with 3.54 kg [-1.6 compared with +7.8 pounds]; P < 0.001), lean body mass (-0.772 compared with +1.14 kg [-1.7 compared with +2.5 pounds]; P < 0.001), appetite grade (P < 0.001), and caloric intake (-107 compared with +645.6 calories/d; P = 0.001). CONCLUSIONS: In patients with AIDS-related weight loss, megestrol acetate can stimulate appetite, food intake, and statistically significant weight gain that is associated with a patient-reported improvement in an overall sense of well-being.

Delayed-type hypersensitivity skin tests are an independent predictor of human immunodeficiency virus disease progression. Department of Veterans Affairs Cooperative Study Group.

Delayed-type hypersensitivity (DTH) testing was evaluated as a predictor of human immunodeficiency virus (HIV) disease progression in 336 symptomatic patients with baseline CD4 cell counts of 200-500/mm3 who were participating in a randomized trial of early versus late therapy with zidovudine. Patients with a response of > 2 mm to any of seven antigens were categorized as reactive; those without were anergic. Anergic patients were significantly more likely than reactive patients to have HIV disease progression as evidenced by decrease in CD4 cell count (52% vs. 27%), development of AIDS (33% vs. 17%), or death (18% vs. 9%) (P < or = .02), irrespective of time of zidovudine initiation. By multivariate analysis, DTH results were an independent predictor of HIV progression separate from CD4 cell count, p24 antigen positivity, or level of beta 2-microglobulin. DTH skin tests are an independent predictor of HIV disease progression and may be of value in the evaluation of a patient's immune status.

Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression.

Among a group of 70 individuals who met the criteria established by the Centers for Disease Control and Prevention (Atlanta) for chronic fatigue syndrome (CFS), 12%-28% had serum levels exceeding 95% of control values for tumor necrosis factor (TNF) alpha, TNF-beta, interleukin (IL) 1 alpha, IL-2, soluble IL-2 receptor (sIL-2R), or neopterin; overall, 60% of patients had elevated levels of one or more of the nine soluble immune mediators tested. Nevertheless, only the distributions for circulating levels of TNF-alpha and TNF-beta differed significantly in the two populations. In patients with CFS--but not in controls--serum levels of TNF-alpha, IL-1 alpha, IL-4, and sIL-2R correlated significantly with one another and (in the 10 cases analyzed) with relative amounts (as compared to beta-globin or beta-actin) of the only mRNAs detectable by reverse transcriptase-coupled polymerase chain reaction in peripheral-blood mononuclear cells: TNF-beta, unspliced and spliced; IL-1 beta, lymphocyte fraction; and IL-6 (in order of appearance). These findings point to polycellular activation and may be relevant to the etiology and nosology of CFS.

Absence of HIV transmission from an infected dentist to his patients. An epidemiologic and DNA sequence analysis.

OBJECTIVE: To determine if a general dentist with human immunodeficiency virus (HIV) infection transmitted HIV to any of his patients. DESIGN: A cohort study in which all patients treated by a dentist who developed the acquired immunodeficiency syndrome (AIDS) were identified and attempts were made to contact all patients for HIV antibody testing. SETTING: A general dentistry clinic operated by the Department of Veterans Affairs in southeastern Florida. PARTICIPANTS: All patients treated by a dentist during the 5 3/4 years before he developed AIDS were identified in a computerized registry of dental care. MAIN OUTCOME MEASURES: Attempts were made to contact all living patients for counseling and HIV antibody testing. Living patients with newly identified HIV infection were interviewed, and DNA sequence analysis was performed to compare genetic relatedness of their HIV to that of the dentist. Death certificates were obtained for decreased patients, and the medical records of those with diagnoses suggestive of HIV disease or drug abuse and those dying under the age of 50 years were reviewed in detail. RESULTS: There were 1192 patients who had undergone 9267 procedures, of whom 124 were deceased. A review of the death certificates of the deceased patients identified five who had died with HIV infection, all of whom were either homosexuals or users of illicit intravenous drugs. We were able to locate 962 (92%) of the remaining 1048 patients, and 900 agreed to be tested. Infection with HIV was documented in five of the 900 patients, including four who had clear evidence of risk factors for acquiring HIV infection. One patient who had only a single evaluation by the dentist denied high-risk behavior. Comparative DNA sequence analysis demonstrated that the viruses from the dentist and these five patients were not closely related. CONCLUSION: This study indicates that the risk for transmission of HIV from a general dentist to his patients is minimal in a setting in which universal precautions are strictly observed. Programs to ensure compliance with universal precautions would appear preferable to programs for widespread testing of dentists.

Effects of retroviral infections on immune function in African-American intravenous drug users.

OBJECTIVES: To determine the effect of retrovirus infection and co-infection, and intravenous substance use, on immune function in African-Americans. DESIGN: A cohort of South Florida street-recruited African-American intravenous drug users formed the study population. The cohort consisted of 90 HIV-negative & human T-lymphotropic virus (HTLV)-negative, one HIV-negative & HTLV-I-positive, 11 HIV-negative & HTLV-II-positive, 79 HIV-positive & HTLV-negative, one HIV-positive & HTLV-I-positive and 21 HIV-positive & HTLV-II-positive individuals. The results reported are for the cross-sectional, baseline assessment of immune parameters. METHODS: Lymphocyte phenotypic distributions and functional markers, including proliferative response to mitogens and natural killer cell cytotoxicity, were determined. Serum immunoglobulin (Ig) levels were determined as a measure of B-cell activity. RESULTS: HTLV-II infection was associated with increases in CD8 lymphocyte count and serum Ig, but with no other significant immunologic changes. The distribution of CD4 and CD8 percentages, CD4:CD8 ratio, phytohemagglutinin (PHA) and pokeweed mitogen (PWM) reactivity, IgA and IgG for the four retrovirus serostatus groups suggested the possibility of interactive effects in the co-infected group, as demonstrated by a trend toward lower medians for CD4 and for PHA and PWM response and higher medians for IgG, IgA and CD8. Retrovirus-seronegative intravenous drug users had significantly impaired immune status compared with non-drug-using control individuals. CONCLUSIONS: Immunologic dysfunction attributable to HTLV-II infection was minor compared with HIV infection in this population. Study subjects who were co-infected with HIV and HTLV demonstrated more impairment of immune function than individuals with single retrovirus infections.

Bupropion treatment of fluoxetine-resistant chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) includes many symptoms of major depression. For this reason, many antidepressants have been used to treat the symptoms of this disorder. Among the more recently released antidepressants are fluoxetine and bupropion. In this open study, nine CFS patients who either could not tolerate or did not respond to fluoxetine showed significant response when administered 300 mg/day of bupropion for an 8-week period in both rating of HDRS (t = 4.80, p < 0.01) and BDI (t = 2.48, p < 0.05). Furthermore, bupropion improvement in Hamilton Depression Rating Scale correlated significantly with change in plasma homovanillic acid (HVA) (r = 0.96, p < 0.01). Plasma total methylhydroxyphenolglycol (MHPG) also increased significantly during bupropion treatment (t = 2.37, p = 0.05). Measures of T1 microsomal antibodies also decreased over treatment time; increases in natural killer cell numbers correlated inversely with change in plasma levels of free MHPG (r = -0.88, p < 0.05). Bupropion responders were more likely to have trough blood levels above 30 ng/ml (chi 2 = 3.6, p = 0.05).

Active coping style is associated with natural killer cell cytotoxicity in asymptomatic HIV-1 seropositive homosexual men.

The aim of this study was to examine the hypothesis that a psychosocial model was associated with natural killer cell cytotoxicity (NKCC) in HIV-1 infection. A sample of 62 HIV-1 seropositive homosexual men at CDC stages II and III were given a psychosocial battery assessing life stressors, social support, and coping style. A regression model quantifying these variables along with control variables for alcohol use, substance use and nutritional status was estimated. Active coping style was directly and positively associated with NKCC, and trends toward a negative relationship of life stressors and a buffering effect of social support on lives stressors were also observed. The results suggest that (1) control variables should be included with psychosocial models and that (2) psychosocial factors, especially active coping, may have a deterrent effect on loss of NK cell function. Active coping style may merit a specific focus in future research of life stressors and the immune system.