John M. Dwyer

Longitudinal study of outcome of chronic fatigue syndrome

Abstract Objective : To examine the predictors of long term outcome for patients with the chronic fatigue syndrome. Design : Cohort study. Subjects : 139 subjects previously enrolled in two treatment trials; 103 (74%) were reassessed a mean of 3.2 years after start of the trials. Setting : University hospital referral centre. Main outcome measures : Age at onset, duration of illness, psychological and immunological status at initial assessment. Ongoing symptom severity, levels of disability, and immunological function at follow up. Results - 65 subjects had improved but only six reported no current symptoms. An alternative medical diagnosis had been made in two and psychiatric illness diagnosed in 20. The assignment of a primary psychiatric diagnosis at follow up and the strength of the belief that a physical disease process explained all symptoms at entry to the trials both predicted poor outcome. Age at onset of illness, duration of illness, neuroticism, premorbid psychiatric diagnoses, and cell mediated immune function did not predict outcome. Conclusion : Though most patients with the chronic fatigue syndrome improve, a substantial proportion remain functionally impaired. Psychological factors such as illness attitudes and coping style seem more important predictors of long term outcome than immunological or demographic variables.

Depression of Cell-Mediated Immunity during Acute Infectious Mononucleosis

Abstract To elucidate mechanisms responsible for depression of cell-mediated immunity associated with viral infections, we studied 41 patients with infectious mononucleosis. Intradermal tests, lymphocyte stimulation in vitro and enumeration of peripheral blood T and B cells were performed. There was significant anergy and diminished lymphocyte responsiveness in vitro to mitogens and antigens during the first weeks of illness. This depression of cell-mediated immunity was accompanied by increased numbers of peripheral blood T and B cells. The numbers of atypical lymphocytes in the peripheral blood of several patients were too great to be classified as entirely T or B cells in type, and probably represent both types of lymphocytes. On the basis of these data, we hypothesize that T-cell response to viral infections results in antigenic competition, which is the major mechanism responsible for depression of cell-mediated immunity during infectious mononucleosis. (N Engl J Med 291:1149–1153, 1974)

Immunologic and psychologic therapy for patients with chronic fatigue syndrome: A double-blind, placebo-controlled trial

PURPOSE To evaluate the potential benefit of immunologic therapy with dialyzable leukocyte extract and psychologic treatment in the form of cognitive-behavioral therapy (CBT) in patients with chronic fatigue syndrome (CFS). PATIENTS AND METHODS Immunologic and psychologic treatments were administered to 90 adult patients who fulfilled diagnostic criteria for CFS in a double-blind, randomized, and placebo-controlled study. A four-cell trial design allowed the assessment of benefit from immunologic and psychologic treatment individually or in combination. Outcome was evaluated by measurement of global well-being (visual analogue scales), physical capacity (standardized diaries of daily activities), functional status (Karnofsky performance scale), and psychologic morbidity (Profile of Mood States questionnaire), and cell-mediated immunity was evaluated by peripheral blood T-cell subset analysis and delayed-type hypersensitivity skin testing. RESULTS Neither dialyzable leukocyte extract nor CBT (alone or in combination) provided greater benefit than the nonspecific treatment regimens. CONCLUSIONS In this study, patients with CFS did not demonstrate a specific response to immunologic and/or psychologic therapy. The improvement recorded in the group as a whole may reflect both nonspecific treatment effects and a propensity to remission in the natural history of this disorder.

A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF INTRAVENOUS IMMUNOGLOBULIN THERAPY IN PATIENTS WITH CHRONIC FATIGUE SYNDROME

PURPOSE The chronic fatigue syndrome (CFS) is characterized by profound fatigue, neuropsychiatric dysfunction, and frequent abnormalities in cell-mediated immunity. No effective therapy is known. PATIENTS AND METHODS Forty-nine patients (40 with abnormal cell-mediated immunity) participated in a randomized, double-blind, placebo-controlled trial to determine the effectiveness of high-dose intravenously administered immunoglobulin G. The patients received three intravenous infusions of a placebo solution or immunoglobulin at a dose of 2 g/kg/month. Assessment of the severity of symptoms and associated disability, both before and after treatment, was completed at detailed interviews by a physician and psychiatrist, who were unaware of the treatment status. In addition, any change in physical symptoms and functional capacity was recorded using visual analogue scales, while changes in psychologic morbidity were assessed using patient-rated indices of depression. Cell-mediated immunity was evaluated by T-cell subset analysis, delayed-type hypersensitivity skin testing, and lymphocyte transformation with phytohemagglutinin. RESULTS At the interview conducted by the physician 3 months after the final infusion, 10 of 23 (43%) immunoglobulin recipients and three of the 26 (12%) placebo recipients were assessed as having responded with a substantial reduction in their symptoms and recommencement of work, leisure, and social activities. The patients designated as having responded had improvement in physical, psychologic, and immunologic measures (p less than 0.01 for each). CONCLUSION Immunomodulatory treatment with immunoglobulin is effective in a significant number of patients with CFS, a finding that supports the concept that an immunologic disturbance may be important in the pathogenesis of this disorder.

Evidence for defective immunoregulation in the syndrome of familial candidiasis endocrinopathy.

We studied three children with candidiasis endocrinopathy syndrome, together with their parents and five siblings, to explore the possibility that defective immunoregulation allows autoimmune phenomena to be involved in the pathogenesis of this syndrome. Inheritance of the syndrome appeared to be autosomal recessive. Immunologic abnormalities in this family included hypergammaglobulinemia, selective IgA deficiency, anergy, autoimmune endocrinopathies and active chronic hepatitis. Defective suppressor T-cell function was noted in the two surviving children with clinically apparent disease and in a clinically normal sibling. Analysis of the immunologic abnormalities in the family suggests that defective immunoregulation rather than disordered effector mechanisms may explain the large number of immunologic defects noted. These defects, in turn, may result in the clinical manifestation of the syndrome.

Cell‐mediated immunity in patients with chronic fatigue syndrome, healthy control subjects and patients with major depression

The chronic fatigue syndrome (CFS) is characterized by severe persistent fatigue and neuropsychiatric symptoms. It has been proposed that the abnormalities in cell‐mediated immunity which have been documented in patients with CFS may be attributable to a clinical depression, prevalent in patients with this disorder. Cell‐mediated immune status was evaluated in patients with carefully defined CFS and compared with that of matched subjects with major depression (non‐melancholic, non‐psychotic) as well as healthy control subjects. Patients with CFS demonstrated impaired lymphocyte responses to phytohaemagglutinin (PHA) stimulation, and reduced or absent delayed‐type hypersensitivity (DTH) skin responses when compared either with subjects with major depression or with healthy control subjects (P < 0·05 for each analysis). Although depression is common in patients with CFS, the disturbances of cell‐mediated immunity in this disorder differ in prevalence and magnitude from those associated with major depression. These observations strengthen the likelihood of a direct relationship between abnormal cell‐mediated immunity and the etiology of CFS.

Intravenous Immunoglobulin is Ineffective in the Treatment of Patients with Chronic Fatigue Syndrome

PURPOSE To determine whether the reported therapeutic benefit of intravenous immunoglobulin in patients with chronic fatigue syndrome (CFS) is dose dependent. PATIENTS AND METHODS Ninety-nine adult patients, who fulfilled diagnostic criteria for CFS, participated in this double-blind, randomized, and placebo-controlled trial. Patients received intravenous infusions with either a placebo solution (1% albumin) or one of three doses of immunoglobulin (0.5, 1, or 2 g/kg) on a monthly basis for 3 months, followed by a treatment-free follow-up period of 3 months. Outcome was assessed by changes in a series of self-reported measures (quality-of-life visual analog scales, standardized diaries of daily activities, the profile of mood states questionnaire) and the Karnofsky performance scale. Cell-mediated immunity was evaluated by T-cell subset analysis and delayed-type hypersensitivity (DTH) skin testing. RESULTS No dose of intravenous immunoglobulin was associated with a specific therapeutic benefit. Adverse reactions, typically constitutional symptoms, were reported by 70% to 80% of patients, with no relationship to immunoglobulin treatment. CONCLUSIONS Intravenous immunoglobulin cannot be recommended as a therapy for the treatment of CFS. A better understanding of the pathophysiology of this disorder is needed before effective treatment can be developed.

Successful Reversal of ECHOvirus Encephalitis in X-Linked Hypogammaglobulinemia by Intraventricular Administration of Immunoglobulin

BECAUSE of the central role of immunoglobulins in protection from bacterial infections, hypogammaglobulinemic states frequently result in serious infections with these organisms.1 However, patients...

Depressed delayed cutaneous hypersensitivity in alcoholic hepatitis

Delayed cutaneous hypersensitivity was studied in 10 patients with severe alcoholic hepatitis, 9 patients with either inactive alcoholic cirrhosis or alcoholic fatty liver, and 10 age-matched controls. The mean response of the alcoholic hepatitis group was significantly less compared to controls for SK-SD (P<0.001), mumps (P<0.001), trichophyton (P<0.025), andCandida albicans (P<0.025). Upon clinical recovery, the response of the 6 surviving patients with alcoholic hepatitis was similar to controls for 4 of the 5 antigens tested, and the improvements in response to SK-SD andCandida albicans were significant (P<0.02 and P<0.05). The mean percentage and absolute numbers of thymus-derived lymphocytes were significantly less in the alcoholic hepatitis group compared with controls. Both the alcoholic hepatitis patients and patients with less advanced alcoholic liver disease had a diminished response to concanavalin A and phytohemagglutinin. This study demonstrates a reversible depression of delayed cutaneous hypersensitivity in alcoholic hepatitis. Several mechanisms may help account for this finding. We recommend that skin tests in patients with alcoholic hepatitis be interpreted with this phenomenon in mind.

Identification of lymphocytes in percutaneous liver biopsy cores. Different T:B cell ratio in HB sAg-positive and -negative hepatitis

The lymphocytes infiltrating the liver were isolated and characterized as T or B cells in three groups of patients: 20 patients with hepatitis B surface antigen (HB sAg)-positive acute and chronic hepatitis, 8 patients with HBsAg-negative chronic hepatitis with prior evidence for hepatitis B virus (HBV) infection, and 5 patients with HBsAg-negative chronic hepatitis without prior evidence for HBV infection. The predominant cell infiltrating the liver was shown to be a T cell in all categories; however, the ratio of T:B cells was significantly lower (1.96) in the patients without evidence for HBV infection than in the patients who were HBsAg-positive at (7.86), or before (8.85) the time of study. The significantly (P less than 0.001) higher number of B cells in the patients with chronic hepatitis of unknown etiology suggests that a different immunopathogenetic mechanism is operative in this group. A peripheral T lymphocytopenia was observed in patients with both antecedent and existent HBs-antigenemia, but not in the patients without evidence for HBV infection.