Chronic Fatigue Possibly Related to Epstein-Barr Virus -- Nevada

From November 1984 through August 1985, approximately 90 patients evaluated for persistent fatigue were diagnosed as having chronic Epstein-Barr virus (CEBV) disease by a two-physician community internal medicine practice near Lake Tahoe, Nevada. The diagnoses were made by detecting antibody to the diffuse (EA-D) or the restricted (EA-R) components of early antigen of EBV, as suggested by two recent studies (1,2).

Because of controversy about whether CEBV disease exists, two serologic studies were conducted to evaluate whether a syndrome of chronic fatigue could be statistically associated with a specific pattern of antibody titers against EBV. Fifteen "case" patients, felt to be the most likely to have CEBV, were identified by interviewing 134 of the 139 patients tested for EBV serology in the internal medicine practice between January 1, and August 20, 1985. By definition, these patients had persistent or relapsing unexplained fatigue for at least 2 months, which forced them to stop usual daily activities for at least 2 weeks. Other less universal symptoms included intermittent low-grade fever, sore throat, myalgias, arthralgias, and headaches. All 15 patients were white; 13 were female. The median age was 40 years (range 13-52 years).

In the first serologic study, the 15 patients were compared with 118 of the 119 patients who had serologic testing for EBV (the serologic test results on one patient were not available). All 118 of these patients were white; 79 (66.9%) were female. The median age was 36 years (range 10-71 years). The case patients were more likely to have reciprocal EA-D titers of 160 or higher (45.5%, compared with 11.6%; p = 0.014) and EBV viral capsid antigen IgG (VCA-IgG) 160 or greater (80.0%, compared with 51.7%; p = 0.033) in the first serum tested. No evidence of acute EBV infection, manifested by positive IgM titers to VCA, was detected in either the cases or the others tested.

Detailed information on physical findings was obtained for all 15 case patients and from 11 of 18 other patients whose duration and severity of illness met the clinical case criteria but who, on review of their medical records, had other possible etiologies. Palpable splenomegaly was noted at some time during the illnesses of 13 of the 15 case patients and two of the 11 other patients (p = 0.0002).

In the second serologic study, blood specimens for EBV serologic testing were collected in October 1985 from the 15 case patients and from 30 age-, sex-, and race-matched controls. The controls consisted of patients and office workers who had no complaints of fatigue and had not previously undergone EBV serologic testing. The sera were tested simultaneously by the commercial reference laboratory used by the two physicians, by the EBV laboratory at CDC, and by a laboratory at Georgetown University in Washington, D.C. Case patients tended to have higher titers of VCA-IgG and of anti-EA than controls, but the specific test results and the tests in which the differences were significant varied considerably among the laboratories.

IgG antibody titers to herpes simplex virus (HSV) types 1 and 2 and cytomegalovirus (CMV) were also measured. Case patients had significantly higher CMV titers than controls, both by indirect hemagglutination (reciprocal geometric mean titer (GMT) 292, compared with 31, p = 0.046) and by enzyme immunoassay (GMT 276, compared with 74; p = 0.04). Case patients also tended to have higher titers to HSV-1 (GMT 154, compared with 82) and to HSV-2 (GMT 140, compared with 34).

To help evaluate the reproducibility of the EBV serologic test results within a single laboratory, 19 sera, obtained earlier from 12 of the case patients and subsequently frozen, were retested in the same laboratory. Fourfold or greater variations between the initial and repeated titers were detected in 17.6% of the samples tested for anti-EA-D, 26.3% tested for VCA-IgG and 33.3% tested for anti-EA-R. All sera with fourfold or greater changes in anti-EA-D or VCA-IgG had a decrease in titer with the repeat testing, and all those with changes in anti-EA-R had increased titers. Reported by D Peterson, MD, P Cheney, MD, Incline Village, M Ford, MPH, B Hunt, Washoe County District Health Dept, G Reynolds, Acting State Epidemiologist, Nevada Div of Health; Viral Exanthems and Herpesvirus Br, Epidemiology Office, Div of Viral Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: In January 1985, two publications reported the association of a chronic, mononucleosis-like illness with evidence of persistent active Epstein-Barr virus activity among young, previously healthy adults (1,2). These patients had no other discernible cause for their illnesses, and many demonstrated an apparently unusual pattern of anti-EBV antibodies when compared with controls. However, several questions have been raised about these studies, including whether CEBV actually exists (3-5).

In the Nevada investigation, the 15 case patients were more likely to have abnormal EBV serologic markers than other patients, and, in addition to increased fatigue, were more likely to have palpable splenomegaly. These findings suggest that, as a group, these patients have an abnormality, or abnormalities, associated in some way with high antibody titers to EBV and CMV.

The study highlights several problems associated with the diagnosis of CEBV. First, the clinical syndrome is comprised of a wide range of nonspecific symptoms, and is inadequate for diagnosing CEBV without a confirmatory laboratory test.

Second, "elevated" anti-EBV serologic titers do not prove that a chronic illness in an individual is due to EBV. There is a great deal of overlap in the antibody titers of case patients and the general population, indicating that "normal" titers can vary substantially. In a recently published study, several asymptomatic persons followed for up to 8 years after recovery from acute infectious mononucleosis maintained anti-EA titers well into the range considered to indicate CEBV (6).

Third, the reproducibility of the serologic tests for EBV is poor, both within and between laboratories. The currently available indirect immunofluorescence technique for EBV serologic tests necessitates a subjective measurement of the fluorescence produced and is subject to variability between cell lots and between individual technicians. Comparability of titers can only be confirmed by testing specimens in parallel.

Currently available data neither prove nor disprove the hypothesis that EBV activity is responsible for chronic illness, but it is clear that the diagnosis of CEBV using current clinical and laboratory criteria in an individual patient is unreliable. Further examinations of immune function in these patients, as well as studies for other possible etiologies, are needed to define this syndrome and provide a framework for epidemiologic and therapeutic studies.

In the meantime, CEBV should be a diagnosis of exclusion. Physicians evaluating patients thought to have CEBV should continue to search for the more definable, and possibly treatable, conditions that may be responsible for their symptoms, such as endocrine and autoimmune diseases; malignancies; chronic heart, liver, kidney, and pulmonary disease; anxiety and depression; and chronic infectious diseases, such as CMV and tuberculosis.

The patients reported here are only a portion of the cases reported to CDC with chronic, often severe, debilitating disease diagnosed as CEBV. Further etiologic studies are indicated, including known viruses such as EBV, CMV, and adenoviruses, in addition to viruses which have not yet been identified. Once the syndrome is better defined, epidemiologic and therapeutic studies can be initiated.

References

1. Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO. 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. Armstrong CW, Wetterhall SF. Epstein-Barr virus and unexplained illness (Letter). Ann Intern Med 1985;102:722.

4. Jones SR. Epstein-Barr virus and unexplained illness (Letter). Ann Intern Med 1985;102:723.

5. Merlin TL. Chronic mononucleosis: pitfalls in the laboratory diagnosis. Hum Pathol 1986;17:2-8.

6. Horwitz CA, Henle W, Henle G, Rudnick H, Latts E. Long-term serological follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis. J Infect Dis 1985;151:1150-3.

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