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Infections in Heterophile-Negative Patients.

To the Editor.--Tsaparas et al[1] published an interesting study describing a cost-effective algorithm for evaluating patients with suspected infectious mononucleosis (IM) and negative heterophile antibody tests. The study has 3 problems. First, the authors assumed that all heterophile antibody-positive patients had IM caused by Epstein-Barr virus (EBV). This incorrect assumption, which unfortunately appears in other published algorithms as well,[2] inflates the cost savings of their algorithm, since approximately 2% to 3% of these patients will not have EBV and will undergo treatment and monitoring for a disease they do not have.[3-5] Second, the heterophile antibody test used in this study had a sensitivity of only 78% for IM. (There were 28 false-negative results detected by EBV IgM enzyme-linked immunosorbent assay. Assuming a false-positive rate of 2.5%, only 102 of the 150 positive results would be true positives. See Bayesian analysis in the Table.) Third, the authors assume a 0% false-negative rate for lymphocyte counts greater than 4 x [10.sup.9]/L or presence of atypical lymphocytes to detect EBV among heterophile antibody-negative patients. While probably true, this assumption was based on results from a very small control group. With only 50 subjects, the 95% confidence interval would include 0% if the actual false-negative rate was between 0% and 1.96%.
Bayesian Analysis of a Diagnostic Test

Test name: Heterophile antibody test
Population: Tsaparas et al study

 Test Negative Test Totals

Disease 102 28 130
No disease 48 1743 1791
 Totals 150 1771 1921

 Sensitivity, % 78
 Specificity, % 97

 Predictive value of positive, % 68
 Predictive value of negative, % 98

 Efficiency of test, % 96
 Disease prevalence, % 6.8

The algorithm developed by Tsaparas et al might save money, although not as much as estimated since the authors assumed that all heterophile antibody-negative patients normally would have received an EBV IgM enzyme-linked immunosorbent assay. (Many physicians would look at the negative heterophile antibody result in conjunction with a complete blood count report and reassess their differential diagnosis.) A better way to achieve substantial cost savings would be to implement a clinical algorithm to differentiate IM and IM-like diseases from other diseases and use it in conjunction with the testing algorithm. Only 170 of 1921 patients (prior probability = 9%) with physician requests for heterophile antibody testing had IM or an IM-like disease. Doubling the prior probability to 18% in British Columbia would result in 5762 fewer heterophile antibody and complete blood count with differential tests, 144 fewer false-positive IM diagnoses, and (using the algorithm generated by Tsaparas et al) 47 fewer sets of viral serology tests.
Shared Laboratory Services,
Chesapeake, VA 23320

[1.] Tsaparas YF, Brigden ME, Mathias R, Thomas E, Raboud J, Doyle PW. Proportion positive for Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, Toxoplasma, and human immunodeficiency virus types 1 and 2 in heterophile-negative patients with an absolute lymphocytosis or an instrument-generated atypical lymphocyte flag. Arch Pathol Lab Med. 2000;124:1324-1330.

[2.] Steeper TA, Horwitz CA, Henle W, Henle G. Selected aspects of acute and chronic infectious mononucleosis and mononucleosis-like illnesses for the practicing allergist. Ann Allergy. 1987;59:243-250.

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

[4.] Horwitz CA, Henle W, Henle G, et al. Persistently false positive rapid tests for infectious mononucleosis: report of five cases with four-six year follow-up data. Am J Clin Pathol. 1979;72:807-811.

[5.] Monogen [package insert COD 3800-0024]. Barcelona, Spain: Biokit SA; September 1999.

In Reply.-- We thank Dr Tetrault for his interest in our study, and we are pleased that it has stimulated further discussion and ideas.[1] Our response to his 3 concerns follows.

It is correct, that for the purposes of the algorithm, we have assumed that all persons with a positive heterophile antibody test had infectious mononucleosis and did not need to be routinely evaluated further virologically. Recent data support this assumption.[2] Regardless, the goal of our study was to develop a cost-effective algorithm for managing heterophile-negative patients, and individuals with a positive heterophile antibody test are a secondary issue.

We appreciate Dr Tetrault's concern that the heterophile antibody test must have sufficient sensitivity and specificity for diagnosing infectious mononucleosis caused by Epstein-Barr virus (EBV). In fact, one could say that in our desire to develop an algorithm to efficiently diagnose the heterophile antibody-negative patients, one of our primary requirements was to diagnose those patients with EBV who are missed by the heterophile antibody test.

Third, with regard to our assumption that all those without atypical lymphocytes and without elevated lymphocyte counts are negative for EBV IgM by enzyme-linked immunosorbent assay, our sample size of 50 patients in the control group does not exclude the possibility of ever finding a patient with these findings who is EBV IgM positive. The algorithm is intended to be used as a general guide for the vast majority of patients. If a patient has a negative heterophile antibody test, no atypical lymphocytes, and a normal lymphocyte count, then further virology testing would not be routinely warranted, as per our algorithm; however, clinical findings could suggest that repeat testing, further virology studies, and possibly other studies may be warranted in a small number of select patients. We believe, however, that our algorithm is appropriate in most instances.
Department of Pathology and
 Laboratory Medicine
Department of Health Care
 and Epidemiology
Department of Otolaryngology
University of British Columbia
Vancouver, British Columbia,

Department of Public Health
University of Toronto
Toronto, Ontario, Canada
Penticton Regional Hospital
Penticton, British Columbia,

[1.] Tsaparas YE Brigden ML, Mathias R, Thomas E, Raboud J, Doyle PW. Proportion positive for Epstein-Barr virus, cytomegalovirus, human herpes virus 6, Toxoplasma, and human immunodeficiency virus types 1 and 2 in heterophile-negative patients with an absolute lymphocytosis or an instrument-generated atypical lymphocyte flag. Arch Pathol Lab Med. 2000;124:1324-1330.

[2.] Bruu A-L, Hjetland R, Holter E, et al. Evaluation of 12 commercial tests for detection of Epstein-Barr virus-specific and heterophile antibodies. Clin Diagn Lab Immunol. 2000;7:451-456.
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Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the Editor
Date:Jul 1, 2001
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