The Molecular Characterization of Fatal Infectious Mononucleosis

Myra J. Wick, PhD, Kristine P. Woronzoff-Dashkoff, MD, Ronald C. McGlennen, MD

Disclosures

Am J Clin Pathol. 2002;117(4) 

In This Article

Abstract and Introduction

We describe a retrospective study of 4 cases of sporadic fatal infectious mononucleosis (IM), 1 case of fatal IM, and 1 case of sporadic severe IM. Patients were 26 months to 17 years old; 3 were male. Five died of complications of IM. All 5 of these patients had the Epstein-Barr virus (EBV) present in examined tissue specimens; EBV was monoclonal in 3 patients and biclonal in 1. EBV clonality studies were not performed in the remaining patient. All 5 patients also had monoclonal gene rearrangements. The sixth patient survived despite a life-threatening clinical course; EBV was oligoclonal, and gene rearrangements were not detected.

EBV clonality and gene rearrangement studies may be useful for predicting which patients with clinically aggressive IM are at highest risk for fatal outcome. Patients in whom IM has a fatal outcome are more likely to have monoclonal or biclonal EBV and immunoglobulin heavy chain or T-cell receptor gene rearrangements. In contrast, patients with nonfatal IM may lack monoclonal EBV and monoclonal rearrangements of the aforementioned genes. The reasons EBV induces a monoclonal proliferation only in some patients remain to be elucidated.

Epstein-Barr virus (EBV) is a ubiquitous DNA virus that infects most of the world's population. It is implicated in a multitude of human diseases from frankly malignant, monoclonal disorders, such as Burkitt lymphoma, to borderline malignant, occasionally polyclonal disorders, such as posttransplant lymphoproliferative disorders. Fortunately, the most common pattern of EBV infection is a clinically silent, childhood infection. When primary infection occurs during adolescence or adulthood, EBV may cause infectious mononucleosis (IM), a typically benign, self-limited disorder. Clinically, IM is characterized by fever, pharyngitis, lymphadenopathy, and, often, splenomegaly; morphologically, it is characterized by exuberant, polyclonal lymphoproliferation. In this disorder, EBV infects B lymphocytes, inducing a cytotoxic T-cell response that eventually curbs viral proliferation and restrains the immune response Figure 1.

Epstein-Barr virus (EBV) infection in healthy and immunodefective people.

In a small number of patients, however, IM pursues a much more aggressive course: early lymphocytosis in peripheral blood is soon followed by lymphocytic invasion of vital organs, hemophagocytosis, massive marrow necrosis, and severe pancytopenia.[1,2,3,4,5] Such patients usually die of opportunistic infections and/or hemorrhage within several weeks.[1,5] The majority of patients with severe or fatal IM (FIM) are immunocompromised, either by an inherited immunodeficiency disorder, such as X-linked lymphoproliferative syndrome, or from administration of immunosuppressive drugs.[6,7,8,9] Thus, they are unable to mount the immunologic response necessary to contain EBV proliferation (Figure 1). A small number of patients with severe or fatal IM, however, apparently are immunocompetent before EBV infection. Cases of sporadic fatal IM (SFIM) occurring in these patients number approximately 1 in 3,000 cases of IM; in these cases, the factors leading to uncontrolled lymphoproliferation are more difficult to define.[3,4]

We studied 5 previously healthy patients and 1 immuno-deficient patient who developed severe or fatal IM. The polymerase chain reaction (PCR) and Southern blot analysis were used to evaluate EBV clonality and immunoglobulin heavy chain (IgH) gene and T-cell receptor (TCR) gene rearrangement status. We also reviewed the morphologic findings in available tissues in each case. Molecular and morphologic findings were correlated with each patient's clinical course, as obtained from medical records.

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