From September 11 through October 7, 1990, 57 persons (including outpatients, inpatients, and staff) at a community hospital in Puerto Rico had laboratory-confirmed infectious mononucleosis; however, investigation determined that test results may have been misinterpreted. This report describes the investigation of this pseudo-outbreak by the Puerto Rico Department of Health (PRDH) in October 1990.

During September 9-15, three (38%) of eight heterophile agglutination tests (Monophile*) processed in the hospital's laboratory were interpreted as positive; during September 16-22, nine (60%) of the 15 tests processed were interpreted as positive (Figure 1). In comparison, in the first 8 months of 1990, an average of three (19%) of 16 such tests processed each month were positive. Physicians and hospital staff determined the increase indicated an outbreak of infectious mononucleosis.

Additional physicians began testing their patients, and several hospital staff members requested testing for themselves. During September 30-October 6, two local newspapers and a television station reported that the hospital had detected an epidemic of infectious mononucleosis in the surrounding community. Subsequently, outpatients treated in the emergency room requested tests, and persons from other towns came to this hospital for testing. From September 23 through October 7, 45 (45%) of 101 Monophile tests ordered were reported as positive.

On October 8, the PRDH was informed of the outbreak, and an investigation began. All available hospital medical records were reviewed for persons who had tested positive (40 (70%) of 57 persons) and compared with a random sample of half the available medical records for persons who had tested negative (31 (46%) of 67 persons). All patients had listed telephone numbers on their records. They were called on October 8 within an 8-hour period, and a questionnaire was administered to the 28 persons who had tested positive and the 15 persons who had tested negative and who could be reached during that time. Twelve persons with positive tests had blood redrawn and tested at a reference laboratory in Puerto Rico using the same heterophile agglutination test.

Among the 28 persons who had tested positive, illness onset occurred during August 26-October 6. Symptoms included fever (85%), headache (70%), myalgia (70%), and pharyngitis (63%); two (7%) persons were asymptomatic. One patient had lymphadenopathy. Among persons for whom duration of illness was known, 24 were ill 1-15 days (mean: 9 days); one person was ill 27 days. Three persons attended one school, and six persons were employees of the hospital; no other common exposures were reported. The medical records for the 40 persons who tested positive showed that ages ranged from 5 to 55 years; 30% were aged 10-19 years. Twenty-two (55%) were male. Persons resided in five different towns, with 75% residing in the two towns nearest to the hospital. One person had the typical clinical presentation of infectious mononucleosis (i.e., fever, pharyngitis, and lymphadenopathy), and another person had a complete blood count (CBC) consistent with infectious mononucleosis (i.e., greater than 10% atypical cells and greater than 50% lymphocytes). Two (7%) persons were hospitalized for febrile illnesses of unknown origin before being tested for mononucleosis. Persons with negative test results had similar places of residence, dates of illness onset, age range, and symptoms as persons with positive test results.

All persons retested had onset of symptoms less than 2 weeks before the repeat blood was drawn. Only the person whose CBC was compatible with infectious mononucleosis had a positive retest.

Review of the laboratory procedures revealed no technical deficiencies. Tests had been run with controls. Proficiency testing using unknown positive and negative samples had been done correctly throughout the year, and the same reagent lot had been used during July-September. During July, 16% of the tests performed were reported as positive, and during August, 6% of the tests were reported as positive. However, during September, 50% of the tests were reported as positive. No reagents from this lot were available for testing elsewhere. On October 3, another heterophile test (Monosticon) was used. All 18 tests done in the morning were negative. That afternoon, after a new lot of the Monophile test arrived, the laboratory retested the 18 samples; four were positive. Before October 8, 52% of tests done with the new lot of Monophile were reported as positive.

Two technicians with limited experience had begun conducting the test on September 10; they reported positivity rates of 69% and 65%. During this same time, a technician who usually performed the test had a positivity rate of 53%. The inexperienced technicians interpreted some of the tests as weakly positive, an option that does not exist with this test.

During October 7-13, 39 tests were processed by other technicians who usually performed the tests; two (5%) were reported as positive. The following week, 10 tests were processed, none of which were reported as positive (Figure 1).

Reported by: L Diaz, S Miranda, MPH, JC Nunez, MD, EI Ponce, MPH, MV Ramos, MPH, H Pedroga, JV Rullan, MD, Commonwealth Epidemiologist, Div of Epidemiology, Puerto Rico Dept of Health. Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases; Div of Field Epidemiology, Epidemiology Program Office, CDC.

Editorial Note

Editorial Note:

The incubation period for infectious mononucleosis is 4-6 weeks, and person-to-person oropharyngeal transmission commonly occurs through saliva. More than 90% of mononucleosis syndromes are caused by Epstein-Barr virus (EBV), and an estimated 90%-95% of persons greater than 21 years of age have antibody to EBV (1,2). In the United States, the disease occurs most often among older children and young adults; however, in certain socioeconomically depressed areas EBV infection most often occurs without symptoms among younger children.

The findings in this investigation are not consistent with an outbreak of infectious mononucleosis because 1) reported cases were not consistent with the incubation period and mode of spread of infectious mononucleosis and the probable high level of immunity to EBV already present in the community, 2) the distribution of cases is not concentrated in one geographic area, 3) the epidemiologic characteristics of persons with negative tests were similar to those with positive tests, 4) no person had both the clinical and hematologic findings consistent with infectious mononucleosis, and 5) repeat blood testing in a reference laboratory confirmed only one positive test of 12 tested.

Previous pseudo-outbreaks of infectious mononucleosis have been linked to laboratory error (3,4). False-positives can occur when blood from persons who have leukemia, rheumatoid arthritis, and viral infections other than infectious mononucleosis is tested or when samples of hemolyzed or contaminated blood are tested. However, the sensitivity of horse-cell agglutination tests such as Monophile to detect infectious mononucleosis is reportedly 96%, and the specificity, 93% (5). Heterophile tests do not directly measure EBV antibody and usually become positive 7-10 days after onset of symptoms and remain positive for less than or equal to 8 weeks (5). They are considered reliable routine diagnostic tests (6).

The two technicians who had recently begun to conduct the test may have misinterpreted results. However, one of the technicians who usually conducted the test also had a higher rate of positivity than reported by this laboratory for the 8 months before this pseudo-outbreak. This technician's test interpretations may have been influenced by the large increase in the number of tests processed and by the number of reportedly positive test results. Because different lots were used, it is unlikely this high rate of positivity was caused by bad reagents.

Diagnostic testing in a population with a low prevalence of the disease results in the test having a lower positive predictive value. In this investigation, the health-care professionals who made the diagnoses assumed that positive tests alone meant persons had infectious mononucleosis, beginning a cycle whereby, as more tests were reported as positive, more tests were requested. Past pseudo-outbreaks have had similar cycles (3,4).

All laboratory personnel should be appropriately trained and monitored. If a personnel change in a laboratory is followed by a change in the pattern of test results, these variations should be investigated by the laboratory supervisor. Physicians should use appropriate clinical criteria when ordering and interpreting diagnostic tests.

References

1. Henle G, Henle W, Clifford P, et al. Antibodies to Epstein-Barr virus in Burkitt's lymphoma and control groups. J Natl Cancer Inst 1969;43:1147-57.

2. Pereira MS, Blake JM, Macrae AD. EB virus antibody at different ages. Br Med J 1969;4:526.

3. Armstrong CW, Hackler RL, Miller GB. Two pseudo-outbreaks of infectious mononucleosis. Pediatr Infect Dis J 1986;5:325-7.

4. Herbert JT, Feorino P, Caldwell GG. False positive epidemic infectious mononucleosis. Am Fam Physician 1977;15:119-21.

5. Evans AS, Niederman JC, Cenabre LC, et al. A prospective evaluation of heterophile and Epstein-Barr virus specific IgM antibody tests in clinical and subclinical infectious mononucleosis; specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975;132:546-54.

6. Feorino PM, Dye LA, Humphrey DD. Comparison of diagnostic tests for infectious mono nucleosis. J Am Coll Health Assoc 1971;19:190-3.

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