Clinical Features. Infectious mononucleosis classically manifests with fever, sore throat, and lymphadenitis, but atypical presentations are not unusual. Sometimes there is little or no fever and only fatigue and lymphadenopathy exist, raising the specter of lymphoma; fever of unknown origin, unassociated with lymphadenopathy or other localized findings; hepatitis that is difficult to differentiate from one of the hepatotropic viral syndromes (Chapter 16); or a febrile rash resembling rubella. Ultimately, the diagnosis depends on the following, in increasing order of specificity: (1) the presence of atypical lymphocytes in the peripheral blood; (2) a positive heterophil reaction (Monospot test); and (3) a rising titer of antibodies specific for EBV antigens. In most patients, mononucleosis resolves within 4 to 6 weeks, but sometimes the fatigue lasts longer. Occasionally, one or more complications supervene. Perhaps the most common of these is hepatic dysfunction, associated with jaundice, elevated liver enzyme levels, disturbed appetite, and, rarely, even liver failure. Other complications involve the nervous system, kidneys, bone marrow, lungs, eyes, heart, and spleen (including fatal splenic rupture).
Fig. 12.12 Atypicallymphocytesininfectiousmononucleosis.
EBV is a potent transforming virus that plays a role in the pathogenesis of a number of human malignancies, including several types of B cell lymphoma (Chapter 6). A serious complication in those lacking T cell immunity is unimpeded EBV-driven B cell proliferation. This process can be initiated by an acute infection or by the reactivation of a latent B cell infection and generally begins as a polyclonal proliferation that transforms to overt monoclonal B cell lymphoma over time. Reconstitution of immunity (e.g., by cessation of immunosuppressive drugs) is sometimes sufficient to cause complete regression of the B cell proliferation, which is uniformly fatal if left untreated.
The importance of the cellular immune response in controlling EBV infection also is driven home by X-linked lymphoproliferative syndrome (XLP), a rare inherited immunodeficiency characterized by an ineffective response to EBV. Most affected boys have mutations in the SH2D1A gene, which encodes a signaling protein that participates in the activation of T and NK cells. In more than 50% of cases, EBV causes an acute overwhelming infection, often complicated by hemophagocytic lymphohistiocytosis (HLH, described later), whereas other patients succumb to EBV-driven lymphoma or secondary infections related to hypogammaglobulinemia, the basis of which is not understood.
Infections and nonmicrobial inflammatory stimuli often activate immune cells residing in lymph nodes, which act as defensive barriers. Any immune response against foreign antigens can lead to lymph node enlargement (lymphadenopathy). Infections causing lymphadenitis are varied and numerous, and may be acute or chronic. In most instances the histologic appearance of the lymph node reaction is nonspecific. A somewhat distinctive form of lymphadenitis that occurs with cat-scratch disease is described separately later.
This form of lymphadenitis may be isolated to a group of nodes draining a local infection, or be generalized, as in systemic infectious and inflammatory conditions.