Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Intravenous IgG was beneficial but had increased adverse effects in the chronic fatigue syndrome

ACP J Club. 1991 Mar-Apr;114:50. doi:10.7326/ACPJC-1991-114-2-050


Source Citation

Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med. 1990; 89:561-8.


Abstract

Objective

To determine the efficacy of intravenous immunoglobulin G (IgG) for the chronic fatigue syndrome.

Design

Randomized, double-blind, placebo-controlled trial lasting 3 months. Response to therapy was evaluated 3 months later.

Setting

2 urban Australian hospitals.

Patients

Patients had the chronic fatigue syndrome, as defined by chronic, disabling fatigue causing functional incapacity in the face of normal blood counts; renal, liver, and thyroid function tests; muscle enzyme assays; rheumatologic tests; and serologic tests for syphilis, hepatitis B, and human immunodeficiency virus. Of the 49 patients enrolled, 49% were women; the mean age was 36 years; and the median duration of the chronic fatigue syndrome was 3.9 years.

Intervention

Intravenous IgG, 2 g/kg body weight (n = 23) or placebo (n = 26) by continuous infusion over 24 hours given monthly for 3 months.

Main outcome measures

Symptom severity, level of disability, and cell-mediated immunity.

Main results

3 months after infusion, a greater proportion of IgG recipients (43%) had improvement in symptoms and disability compared with placebo recipients (11%) (P = 0.03). {This absolute risk improvement of 32% means that 3 patients would need to be treated with IgG (compared with placebo) to prevent symptoms and disability in 1 additional patient, 95% CI 2 to 13; the relative risk improvement was 277%, CI 30% to 1070%.}* However, adverse effects such as phlebitis (55% vs 1%, P < 0.001), transient elevation of serum alanine aminotransferase (SGPT) levels (35% vs 4%, P = 0.02), headaches, and worsened fatigue occurred more commonly in the IgG group than in the placebo group. More frequent adverse effects among those receiving IgG may have partially unblinded the study.

Conclusions

A regimen of intravenous IgG appeared to be more effective than placebo in relieving symptoms in patients with severe, long-standing chronic fatigue syndrome. However, the IgG group had more side effects.

Sources of funding: National Health and Medical Research Council of Australia; New South Wales Institute of Psychiatry; M.E. Society of New South Wales.

Address for article reprint: Dr. J. Dwyer, Division of Medicine, Prince of Wales Hospital, High Street, Randwick, New South Wales 2031, Australia.


Commentary

Intravenous IgG did not benefit patients with the chronic fatique syndrome

In 1985, 2 clinical reports described the features and serologic patterns of a disorder, now termed the chronic fatigue syndrome, which was thought to be associated with persistent or episodic, active Epstein-Barr virus infection (1, 2). Both children and adults were described with illnesses characterized by profound fatigue, myalgia, low-grade fever, pharyngitis, lymphadenopathy, depression, and inability to concentrate; exacerbations of these symptoms occurred frequently and were associated with prolonged periods of disability. However, constitutional symptoms had little relation to objective physical findings. Although many patients had antibody profiles consistent with chronic active Epstein-Barr virus infection, it was recognized that such activation might be superimposed on a disorder of ill-defined cause, and a need for more specific serologic and immunologic markers of active infection was emphasized. The signs and symptoms of the chronic fatigue syndrome closely resemble previously described syndromes including epidemic neuromyasthenia, Royal Free disease, chronic brucellosis, epidemic myalgic encephalomyelitis, Iceland disease, post-viral fatigue syndrome, and post-influenzal neurasthenia.

During the past 6 years, clinical investigations have cast doubt that the Epstein-Barr virus has a direct causal role. Nevertheless, there is evidence of immunologic disregulation in some patients, including persistent suppressor-T-cell activity, reduced Epstein-Barr-virus-specific cytotoxic T-cell function, hypogammaglobulinemia, increased 2-5 oligoadenylate synthetase activity in the absence of elevated circulating interferon, increased numbers of circulating immune complexes, and elevated helper-suppressor lymphocyte ratios. In a small number of such patients, intramuscular immunoglobulin therapy has been reported to be beneficial (3). Moreover, high-dose intravenous immunoglobulin administration has recognized effectiveness in the management of certain immune regulation disorders. Lloyd and colleagues from Australia, and Peterson and colleagues from the United States, both describe attempts to evaluate the use of intravenous immunoglobulin therapy for correction of a putative immunoregulatory defect in patients with the chronic fatigue syndrome. Unfortunately, these two teams reported conflicting results. Results from the two studies may have disagreed for several reasons (4). They were conducted in different countries. The selection criteria were more stringent in the United States, the number of patients studied was fewer, and the dose of IgG was half that in the Australian study. Thus, the U.S. study may have missed a benefit. Still, even though a benefit for immunoglobulin was shown in the Australian study, this was offset by increased adverse effects of IgG compared with placebo.

The conflicting results of these 2 investigations do not permit a definitive answer to the effectiveness of IgG therapy in these patients. The findings do suggest that individuals who experienced clinical improvement also had immunologic improvement. However, until the chronic fatigue syndrome is a less heterogeneous entity from a diagnostic standpoint, or until a discriminating biologic test or specific marker of the disorder is developed, evaluations of therapeutic measures will continue to be difficult to interpret.

James C. Niederman, MD
Yale UniversityNew Haven, Connecticut, USA


References

1. Jones JF, Ray CG, Minnich LL, et al. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985;102:1-7.

2. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985; 102:7-16.

3. DuBois RN. Gamma globulin therapy for chronic mononucleosis syndrome. AIDS Res. 1986;2:191-5.

4. Straus SE. Intravenous immunoglobulin treatment for the chronic fatigue syndrome. Am J Med. 1990; 89:551-3.