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


Therapeutics

Intravenous IgG did not benefit patients with the chronic fatique syndrome

ACP J Club. 1991 Mar-April;114:51. doi:10.7326/ACPJC-1991-114-2-051


Source Citation

Peterson PK, Shepard J, Macres M, et al. A controlled trial of intravenous IgG in chronic fatigue syndrome. Am J Med. 1990;89:554-60.


Abstract

Objective

To evaluate the efficacy of intravenous immunoglobulin G (IgG) in the chronic fatigue syndrome.

Design

Randomized, double-blind, placebo-controlled trial with follow-up at 5 months.

Setting

A medical center in the United States.

Patients

Patients were recruited from a local chronic fatigue syndrome research program. The patients had to meet standardized criteria that ruled out medical or psychiatric cause for their chronic fatigue. Of the 30 patients enrolled, 73% were women, 43% were unable to work, the mean age was 40.8 years, and the mean duration of illness was 3.8 years. 28 patients (93%) completed the trial.

Intervention

Intravenous IgG, 1 g/kg body weight (n = 15), or 1% albumin solution (n = 15) was infused over several hours every month for 6 treatments.

Main outcome measures

Self-assessment of symptoms and functioning, and quantitative IgG levels.

Main results

2 patients (1 in each group) dropped out because of adverse reactions and were not analyzed. No difference existed in symptoms between or within treatment groups. The study had a power of 76% to detect a difference between the 2 treatment groups assuming that IgG would lead to asymptomatic benefit in 67% of patients and 25% would improve with placebo. Both groups declined in physical functioning from baseline (P < 0.05 for placebo group). The placebo group had a slight relative improvement in social functioning compared with the IgG group (P < 0.05). There was an improvement in health perceptions within the IV IgG group by the end of the study (P < 0.05). IgG1 levels returned to normal in the IgG group but not in the placebo group. No difference was found in the distribution of major adverse reactions (3 in each group).

Conclusion

Intravenous IgG was not beneficial in patients with the chronic fatigue syndrome.

Source of funding: Baxter Healthcare Corporation.

Address for article reprint: Dr. P.K. Peterson, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA.


Commentary

Intravenous IgG was beneficial but had increased adverse effects in the chronic fatigue 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 dysregulation 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 few patients, intramuscular immunoglobulin therapy was 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 chronic fatigue syndrome. Unfortunately, these 2 teams reported conflicting results. Results from the 2 studies may have disagreed for several reasons (4). They were done 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, although 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 persons 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.