The only host that the virus infects naturally is the human, although lymphocytes from other species, namely New World primates (i.e., cottontop marmosets, owl monkeys, and tamarins), are infectible.²⁵, ²⁶ EBV has been found in a variety of human tissue types associated with disease (i.e., T lymphocytes, NK cells, HL, leiomyosarcoma, gastric carcinoma, hepatocellular carcinoma, and breast cancer).²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³ The mechanism of EBV infection in these tumors remains to be fully elucidated.

Infection of B lymphocytes begins with attachment of the virus envelope glycoprotein (gp) 350/220 to the complement receptor C3d, also known as CR2 or CD21.³⁴ For entry into B lymphocytes, a complex of three viral proteins (gH-gL-gp42) is required, and human leukocyte antigen (HLA) class II molecules serve as a coreceptor for gp42.³⁵ Epithelium of the oropharynx is a source of viral replication,³⁶ but it has been difficult to determine the mechanism of infection, inasmuch as these cells do not express CD21 or HLA class II molecules. Recent studies have demonstrated that during primary infection, the majority of virions are not internalized after binding to B lymphocytes of the oropharyngeal tissue. And these B lymphocytes can form cellular conjugates with epithelial cells that allow for transfer of EBV virions into the epithelial cells.³⁷ The mechanism for EBV entry into other cell types (e.g., T cells, gastric mucosa, smooth muscle cells, etc.) may also be via direct contact with B cells that have bound virions with subsequent virion internalization. Infection of epithelium leads to the replication of the virus with the release of large quantities of viral particles containing three-part complexes (gH-gL-gp42) that favor infection of HLA class II and CD21-expressing cells (i.e., B lymphocytes located in the oropharyngeal lymphoid tissues of the Waldeyer ring).³⁵ These B lymphocytes may remain latently infected in the oropharynx, but if viral reactivation and replication occur, cellular lysis and death result, and the virus can be shed into the saliva. Virus contained in infectious saliva is produced by B lymphocytes of the oropharynx.³⁸, ³⁹ Salivary virus may then be transmitted to another host.

The mechanisms underlying viral replication are not completely understood as there exist no in vitro models that recapitulate viral replication in humans. Viral replication is initiated through oriLyt.⁴⁰ Two key early immediate genes are first transcribed, BRLF1 and BZLF-1, encoding Z EBV replication activator (ZEBRA) protein.¹³, ¹⁵, ⁴¹ These proteins then up-regulate the expression of early gene products essential for viral replication, including viral DNA polymerase and viral thymidine kinase. Late gene products follow, including viral capsid antigen (VCA), the major envelope glycoprotein (gp350), and the viral protein BCRF-1, which contains 70% homology to interleukin (IL)-10.¹³, ¹⁵, ⁴², ⁴³ Complete viral replication results in the lysis and death of the host cell. Recently, it has been shown that viral proteins associated with type III latency (see below) are associated with viral replication.⁴⁴ What role this plays in B-cell transformation and immortalization remains to be determined.

Alternatively, infected B lymphocytes appear to undergo normal B-cell differentiation and disseminate throughout the body into secondary lymphatic organs (i.e., lymph nodes, spleen, and bone marrow).⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷ Studies have demonstrated that the reservoir for latent EBV infection is a small percentage of postgerminal center, antigen-selected resting memory B lymphocytes.⁴⁷ The number of latently infected B cells is approximately 10-5 to 10-6 of all B cells and remains stable for the majority of the life of the infected individual.⁴⁶, ⁴⁸

Latent infection is characterized by the expression of nine virally encoded proteins. Figures 62.1 and 62.2 illustrate the transcriptions of the nine latent proteins of EBV (EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA leader protein [LP], LMP-1, LMP-2A, and LMP-2B).¹³, ¹⁵, ⁴⁹ Two EBV-encoded RNAs (EBER-1 and EBER-2) are expressed abundantly in all EBV-infected cells and are valuable for making the diagnosis of EBV disease, but do not code for proteins and their function remains to be determined.¹³ In addition, the Bam HI-A rightward transcript (BART) is generally found in infected cells, but its function also remains to be fully delineated.⁵⁰

The state of latent infection is maintained by EBNA-1. The function of EBNA-1 is to bind to a nucleotide sequence called ori-P, part of the DNA origin of EBV replication, thereby allowing the viral genome to be maintained in the nucleus of the latently infected B cell.⁵¹, ⁵² By this mechanism, the EBV DNA is assured of being maintained in B cells that undergo replication.

EBNA-2 and LMP-1 appear to be required for B-cell immortalization.¹³ EBNA-2 transactivates the expression of LMP-1 and LMP-2.¹³, ⁵³ EBNA-LP augments the ability of EBNA-2 to up-regulate LMP-1. LMP-1 and LMP-2 are associated with a cellular tyrosine kinase. The function of LMP-1 is similar to that of other members of the tumor necrosis factor (TNF) receptor family and is similar—but not identical—to that of CD40. LMP-1 interacts with TNF-receptor-associated factors and the TNF-receptor-associated death domain in infected cells and activates nuclear factor-kB and c-Jun N-terminal kinase pathways, resulting in B-cell activation and proliferation.⁴⁹, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷ Additionally, LMP-1 expression also induces bcl-2 expression and can prevent apoptosis in B cells.⁵⁷ LMP-2 prevents viral reactivation by blocking tyrosine phosphorylation and promotes B-cell survival.⁵⁸ The EBNA-3 proteins regulate expression of certain cellular genes, including specific cellular receptors such as CD28, CD19, CD21, CD23, and CD30; T-cell co-stimulatory molecules CD80/CD86; adhesion molecules such as intercellular adhesion molecule-1, leukocyte factor antigen-1, and leukocyte factor antigen-3, and a member of the src oncogene family, c-fgr.¹⁵, ⁵⁹

Expression of EBV genes varies along the spectrum of EBV-associated diseases and often differs from in vitro immortalized B cells or normal human resting B cells infected by EBV.⁴⁹, ⁵³ The viral gene expression of viral latency is illustrated in Figure 62.2. Briefly, in type I latency- EBNA-1, EBER-1, and EBER-2 and BART are expressed. Type I latency is observed in BL and a portion of EBV-positive gastric carcinoma. Type II latency is characterized by the expression of EBNA-1, LMP-1, LMP-2A and B, EBER-1, and EBER-2 and is observed in NPC, and other EBV-positive lymphomas, such as T- or NK-cell NHL, and the Reed-Sternberg (RS) cells of HL. EBV-infected cells of LPD observed in immunodeficient patients resemble in vitro immortalized B cells and generally express all nine of the EBV-related latent proteins (type III latency). The site of EBV latency in seropositive healthy individuals, the resting memory B cells does not appear to express EBNA-1 but only LMP-2, EBER-1, and EBER-2 together with BART (type IV latency).⁶⁰

Understanding the immune response to EBV infection is essential to comprehend the pathogenesis of EBV-related disease. EBV is a very potent immune stimulus. The immune system controls lymphoproliferation in the normal host and maintains a host/virus symbiosis. Figure 62.3 illustrates the delicate balance between the host T-cell immune response and control of B-cell proliferation of latently infected B cells. In a healthy individual, although only 10^-5 to 10^-6 B cells are latently infected with EBV, approximately 1% to 5% of all circulating CD8⁺ T cells are capable of reacting against EBV.⁴⁸, ⁶¹, ⁶², ⁶³ Initially, there is B-cell proliferation, producing both EBV-specific and -nonspecific antibodies. The number of these virus-containing B cells rises during the acute phase of the infection but never exceeds 0.03% to 0.1% of the circulating mononuclear cells.⁶⁴, ⁶⁵ A cellular immune response follows, which is composed primarily of an expansion of cytotoxic T lymphocytes (CTLs), with the vast majority being EBV-specific, although some are not EBV-specific.⁶⁶, ⁶⁷ Figure 62.4 illustrates the pathologic consequences of an abnormal CTL response to EBV infection. A deficient CTL response, either quantitative or qualitative, results in an EBV-driven B-cell proliferative process. The lack of an appropriate CTL response can also result in an aggressive, predominantly T-cell and histiocytic reaction that is not EBV-specific. This reaction is characterized by extensive infiltration of lymphoid and parenchymal organs with hemophagocytosis, and tissue destruction is often observed. If unchecked, this reaction can be rapidly fatal.⁶⁸, ⁶⁹

The humoral response to EBV is well characterized (Fig. 62.5).⁷⁰, ⁷¹, ⁷², ⁷³ VCA antibodies are the earliest to appear: first immunoglobulin M (IgM) and, later, IgG. IgM antibodies probably arise during the incubation period, peak with symptoms, and then decline rapidly.⁷³ IgA anti-VCA antibodies are seen in some patients and, like IgM anti-VCA antibodies, are gone within several weeks.⁷⁴, ⁷⁵ IgG anti-VCA antibodies reach a peak 2 to 3 weeks after their IgM predecessors and persist for life.⁷⁴, ⁷⁵ The majority of patients also have a transient response to the EBV early antigen (EA), peaking usually within a month of infection.⁷² Antibodies to EBNA may appear several weeks after the onset of the illness in some patients but, in general, take several months to appear, and titers rise slowly over 1 to 2 years and persist for life. The majority of normal individuals have detectable IgG to EBNA by 6 months after EBV infections, although it may take years to develop detectable anti-EBNA titers.⁷⁶ In young children, the anti-VCA and anti-EA responses may be much less intense, and anti-EBNA may take much longer to be seen.⁷⁷

An EBV-nonspecific humoral response also occurs with EBV infection. Paul et al.⁷⁸ first described this phenomenon in 1932 when they reported that the sera of patients with IM contained heterophil antibodies against sheep erythrocytes in concentrations far above normal. The use of heterophil antibodies in the diagnosis of IM is discussed in detail in the section, “Infectious Mononucleosis: Diagnosis.” Many of these EBV-nonspecific antibodies function as autoantibodies and include cold reactive anti-i antibodies, Donath-Landsteiner cold hemolysins, and antibodies against smooth muscle, thyroid, and stomach.⁷⁹, ⁸⁰, ⁸¹, ⁸² In addition, antinuclear antibodies have been found in the sera of some patients,⁸³, ⁸⁴ as well as rheumatoid factors,⁸⁵ including anti-Gm antibodies,⁸⁶ anticardiolipin antibodies, and antiactin and anticytoskeletal antibodies.⁸⁷ The serum of some persons with IM may contain cryoglobulins.⁸⁸ Some of these autoantibodies have been reported to be monoclonal.⁸⁴

Although neutralizing antibodies produced after primary infection may play a role in thwarting the spread to additional B cells, EBV-specific antibodies are most useful for diagnosis,
whereas the cellular response is the most important for control of EBV infections. NK cells and CD4⁺ T cells have been shown to play a role, but CD8⁺ memory cytotoxic T cells (EBV-CTLs) are the primary defense in controlling EBV infections.⁶⁶, ⁶⁷, ⁸⁹, ⁹⁰ The absolute number of NK cells may initially be increased, but a decrease in NK function is usually observed, returning to normal gradually over several weeks.⁹¹ Initially, these EBV-CTLs account for the majority of cells causing the lymphocytosis and the large, pleomorphic, atypical lymphocytes, or “Downey cells,” characteristic of IM.⁶⁶, ⁶⁷, ⁹⁰, ⁹² Of note, it has been shown that the amount of these T cells in the peripheral blood correlates with symptoms seen in IM, not the number of EBV-infected B cells or the viral load.⁹³ Not surprisingly, at first the majority of EBV-CTLs are reactive against lytic viral antigens. During lytic infection three EBV proteins, BNLF2A, BILF1, and BGLF5, function to lower HLA I surface expression, which in effect helps EBV-infected cells evade the immune system.⁹⁴ However, over time the number of EBV-CTLs reactive against latent viral antigens predominates.⁶⁶, ⁶⁷

This symbiosis of EBV and the infected host is maintained by interactions between viral gene expression in latently infected B cells and host EBV-CTL surveillance. The reservoir of viral latency is found among the resting memory B cells.⁴⁶, ⁴⁷ These resting memory B cells do not express high levels of adhesion molecules or T-cell co-stimulatory molecules, making them poor antigen-presenting cells. When these cells divide, EBNA-1 is expressed to ensure passage of viral DNA to progeny cells.⁵² Although CD4⁺ T-cell responses against EBNA-1 have been documented,⁹⁵ EBNA-1-specific cytotoxic T cells are not readily generated.⁹⁶, ⁹⁷ Thus, the reservoir of latent EBV infection is not recognized readily by the immune system.

Activated EBV-infected B cells express major histocompatibility complex class I antigens; various adhesion molecules make these proliferating EBV-infected B cells good antigen-presenting cells. Proliferating, latently infected B cells express all latent proteins, including EBNA-2, EBNA-3A, EBNA-3C, LMP-1, and LMP-2 (type III latency). These proliferating EBV-infected B cells are highly susceptible to cellular lysis by EBV-CTL and are eliminated during convalescence, whereas memory EBV-CTL provide lifetime immunosurveillance against EBV-driven B-cell proliferation. The immunodominant epitope of the EBV-CTL response is highly restricted by the HLA type of the individual.⁹⁸ For months after the expansion of EBV-infected B cells is controlled, virus is shed at high titers in the saliva,⁹⁹ indicated ongoing viral replication in infected B cells of the oropharanyx.⁴⁶ Recent studies have demonstrated that EBV-CTL against latent viral antigens home more efficiently to lymphoid tissue of the oropharynx than EBV-CTL against lytic viral antigens.¹⁰⁰ This observation helps explain that the greatest risk of acquiring primary infection is salivary exposure from a recently infected person or a person in early convalescence, although infective virions can be found in the saliva of persons with a long latent infection.

The typical clinical syndrome associated with IM occurs most commonly in young adults, the peak incidence being in persons between 17 and 25 years of age (Fig. 62.6).⁷⁰, ¹⁰¹ Children often acquire immunity to EBV without developing the typical clinical manifestations of IM, for reasons still not understood.¹⁰¹, ¹⁰², ¹⁰³ Because symptoms of EBV correlate with the CTL response,⁹³ this would suggest that young children generally respond with a less exuberant cellular response. The yearly conversion rate to EBV seropositivity among children in the United States is not known. Past studies suggest earlier conversion with lower socioeconomic status, i.e., 51% of Yale University freshmen and 86% of Marine recruits, had antibodies to EBV.¹², ¹⁰⁴ Authors of a British study concluded that 30% to 40% of children had been infected by their fifth year.¹⁰⁵ Generally speaking, the rate of seroconversion is high in developing countries, where standards of hygiene are relatively low compared to higher socioeconomic countries.¹⁰, ⁷⁰ Under these circumstances, primary infection occurs in almost all children before 10 years of age, leaving few young adults susceptible to develop IM, and the observed incidence of IM in such countries is very low.¹⁰, ⁷⁰ IM is sufficiently uncommon in individuals older than 30 years of age and is so rare in those older than 40 years of age that special care is needed when making the diagnosis in persons in their middle or late years. Nevertheless, well-documented cases of this illness in patients older than 40 years of age have been reported.¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸ Complications such as protracted fever, jaundice, pleural effusion, and Guillain-Barré syndrome often dominate the clinical picture in these patients, detracting from the evidence that would allow the clinician to make the correct diagnosis.¹⁰⁷

IM is not as contagious as is commonly believed. It is rare for members of a patient’s family, roommates of the same sex, and other close associates to develop symptoms of IM.¹⁰⁹, ¹¹⁰ “Kissing disease,” the colloquial term for IM, underscores the association of intimate kissing with IM.⁷⁰, ⁹⁹, ¹⁰², ¹¹¹ Although oral shedding occurs throughout the life of a carrier, it peaks shortly after infection but often is readily detectable for 18 months or longer.⁹⁹, ¹¹², ¹¹³ Other modes of acquiring EBV infection include transplantation of organs or hematopoietic cells in which transmission to the transplant recipient is common.¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷ Although it is not thought to occur frequently, there are anecdotal reports of transmission from blood transfusions,¹¹⁸, ¹¹⁹ in utero, or perinatally.¹²⁰, ¹²¹ Although there are anecdotal reports of virus detected in cervical epithelium and semen, sexual transmission has never been demonstrated.¹²²

Many individuals have held that the manifestations of IM are protean and that many disorders may be simulated by this condition. IM is traditionally characterized by the clinical triad of fever, pharyngitis, and generalized adenopathy, with demonstration of an atypical lymphocytosis, defined as an absolute lymphocytosis with more than 50% lymphocytes and 10% or more atypical forms in the differential count, and the presence of heterophil antibodies.¹⁰² Usually, IM occurs only once in the lifetime of a host, although recurrences have been reported, and exacerbations of unresolved infection or transition to a chronic course may also occur. (See the section, “Chronic Active Epstein-Barr Virus Infections.”)

The signs and symptoms of IM are summarized in Table 62.1. The clinical course based on physical signs and symptoms is illustrated in Figures 62.7 and 62.8. In most young adults, the symptoms are fairly abrupt in onset, although close questioning frequently elicits vague complaints of lassitude and ill-being for several days before the onset of more pronounced symptoms. Most of the early symptoms are nonspecific. Myalgias do occur, but they are usually mild and are often confined to the neck and upper back. Excessive fatigue and general malaise may be accompanied by fever, sweating, and chills. Severe rigors rarely occur, and the patterns of fever are generally moderate and nonspecific. The fever is of no characteristic type. It may be transient and slight in degree, but in as many as one third of patients, it reaches a peak of 40°C. A secondary rise in temperature may occur after an initial drop to normal and may accompany the onset of glandular swelling or sore throat.

Anorexia is a common early symptom. Its intensity and duration are often linked to the severity of sore throat and dysphagia. The anorexia often persists for several weeks. Nausea is equally common and may be one of the earliest symptoms of IM, but
vomiting is rare. Sore throat and dysphagia are among the most important manifestations of IM and may be the only symptoms in some patients. These symptoms usually develop gradually and subside in 1 to 2 weeks. For most patients, the symptoms of pharyngitis are mild, but occasionally, even taking sips of water may be painful.

Lymph node enlargement is invariably present at some time.¹²³, ¹²⁴, ¹²⁵ Adenopathy usually appears during the first week of illness and slowly resolves thereafter. Anterior and posterior cervical node enlargement is almost always present, and palpable axillary and inguinal nodes are common. Radiographically detectable hilar adenopathy is rare (<1%).¹²⁶ Although splenomegaly is expected, the spleen is palpable in only one half to three fourths of all patients, and massive splenomegaly is rare.¹²⁷ Hepatomegaly is detected in 15% to 25% of patients and is usually accompanied by percussion tenderness over the liver and discomfort on palpation. The course of hepatomegaly closely follows that of adenopathy and splenomegaly.¹²⁷ Pharyngeal inflammation usually appears in the first week and then subsides rapidly. In approximately 25% of patients, pharyngitis first occurs after the initial week of illness, and there are no pathognomonic features. It varies in intensity, but rarely, massive tonsillar and pharyngeal edema may cause virtually complete pharyngeal obstruction.¹²⁵ Severe cough is relatively rare, although mild cough is common.

Headaches occur early, as well as photophobia, and ocular muscle pain can occur. Ocular manifestations occur in approximately one third of patients and include eyelid edema, conjunctivitis, dry eyes, keratitis, uveitis, choroiditis, retinitis, papillitis, and ophthalmoplegia.¹²⁸ Rashes are also common with primary EBV infection and may be the only symptom in young children.¹²⁹, ¹³⁰ Several observers have noted that patients experiencing IM are peculiarly prone to rashes when treated with ampicillin, which appear to be the result of vasculitis caused by circulating ampicillin-antibody complexes.¹³¹, ¹³², ¹³³

Hematologic abnormalities in IM are observed in virtually all patients. The hematologic changes persist for a minimum of 2 weeks and usually persist for 1 to 2 months. One of the classic features of IM is the atypical lymphocytosis. The pleomorphism of the mononuclear cells found in the blood is usually striking. In addition to normal lymphocytes and monocytes, large mononuclear cells, or atypical lymphocytes, are observed in the blood (Fig. 62.9). Although nonspecific⁴ because they may be found in the blood of patients with a variety of conditions, including other viral infections,¹³⁴ they are a prominent feature of IM. The abnormal cells vary greatly in size and shape. They possess a nucleus that may be oval, kidney-shaped, or slightly lobulated and cytoplasm that most often is nongranular and vacuolated or foamy. The nuclear chromatin forms a coarse network of strands and masses and is not clearly differentiated from the parachromatin. The identity of these cells has been shown to be CD8⁺ T lymphocytes, as discussed previously (see the section, “Immune Response to Epstein-Barr Virus Infection’). The rapid proliferation of these activated T cells is responsible for the large numbers of atypical cells seen in the peripheral blood, whereas the proliferating B cells are primarily responsible for the generalized lymphadenopathy, hepatosplenomegaly, tonsillar and adenoidal changes, and the cellular infiltration seen in many parenchymal organs; this is discussed in detail in the section, “Infectious Mononucleosis: Histologic Findings.”

Most patients with IM have slightly or moderately increased total white blood cell counts in the range of 10.0 to 20.0 × 10⁹ cells/L, with approximately 15% of patients reaching levels in excess of 20.0 × 10⁹/L.¹¹¹, ¹³⁵, ¹³⁶ The absolute lymphocyte count most often exceeds 5.0 × 10⁹ cells/L; with atypical lymphocytes usually >20%.¹¹¹ Lymphocytosis begins toward the end of the first week of illness and reaches a peak corresponding to symptoms, as does the total leukocyte count (Fig. 62.10). Leukopenia has also been observed and can be manifested as lymphopenia or granulocytopenia.¹³⁶ Most patients with IM have normal hemoglobin levels, and severe thrombocytopenia is rare, although mild depressions of platelet counts may be found in perhaps one half of patients.¹³⁷ Severe neutropenia and thrombocytopenia may be very ominous signs, as they are frequently seen in the hemophagocytic reactions (VAHS or EBV-HLH).

Nonhematologic abnormalities are also commonly observed in patients with IM. Many patients show mild to moderate abnormal liver function tests.¹³⁶ The reported incidence varies from 40% to 100%, depending on the severity of the disease, the time of testing, and the diligence with which the changes were sought. Reported enzyme changes include elevations of lactate dehydrogenase, alkaline phosphatase, glutamic pyruvate transaminase, phosphohexose isomerase, and aldolase, in roughly that order of frequency. Perhaps one third of patients have mild to moderate elevations of serum bilirubin values; levels above 8 mg/dl (135 µmol/L) are exceedingly rare but have been reported.¹³⁶, ¹³⁸ Occasionally, proteinuria or hematuria is present, but renal function is usually unimpaired. When the patient is jaundiced, bile and increased concentrations of urobilinogen may be found. When
lumbar puncture has been performed to evaluate patients with severe headaches, the cerebrospinal fluid (CSF) pressure may be elevated, and pleocytosis and increased levels of protein are often noted. The sugar content is normal. In a few patients, heterophil antibodies have even been demonstrated in the CSF.¹³⁹

The main pathologic feature of IM is a notable proliferative response within the reticuloendothelial system, especially by the lymph nodes and the spleen. It can be difficult to distinguish between malignant lymphoma and nonmalignant disease associated with EBV infection, especially in the immunodeficient patient population.⁶⁹ In summary, the histologic diagnosis of IM is one of suspicion rather than certainty.⁶⁹, ¹⁴⁰

The lymph node architecture is generally intact¹⁴¹, ¹⁴² but may be distorted.¹⁴⁰, ¹⁴¹, ¹⁴², ¹⁴³ Other morphologic features mimicking lymphoma include extensive immunoblastic proliferation in sheets and nodules and significant cellular atypia.¹⁴¹ Clonality studies are often necessary to differentiate IM from malignant disease. The germinal centers are usually identifiable, but follicular prominence is diminished, probably because of the irregular and vaguely defined borders that result from the lymphocytic and reticuloendothelial hyperplasia of paracortical structures and, to a lesser extent, the medullary cords. This intense proliferative activity within the paracortical areas is in keeping with the characterization of atypical lymphocytes as T cells.¹⁴³ In addition, focal proliferations of macrophages are noted, as is, most characteristically, the presence of “typical” IM cells throughout the pulp, on the edges of germinal centers, and in the sinuses.¹⁴² RS-like cells¹⁴⁰, ¹⁴¹, ¹⁴³ are often observed in association with areas of necrosis.⁶⁹ Because the presence of EBV has been demonstrated in approximately 50% of HL specimens,¹⁴⁴, ¹⁴⁵, ¹⁴⁶ the identification of
the virus or EBV-determined antigens is not particularly helpful in the differential diagnosis of these two disorders.

The spleen is striking for infiltration of its fibromuscular structures by mononuclear cells.¹⁴⁷ Both the capsule and trabeculae are often thin and invaded by proliferating lymphocytes. This may explain the occurrence of splenic rupture in this disease. In vitro hybridization studies can be used to track the distribution pattern of cells carrying the viral genome.¹⁴⁰, ¹⁴⁸ Most labeled cells are found in the hyperplastic T-cell zones, the paracortical or interfollicular areas¹⁴⁰, ¹⁴⁸; smaller numbers are found within the epithelioid venules, the lymph node sinuses, and, occasionally, the germinal centers and the mantle zone.¹⁴⁸ In the spleen, labeled cells are found mainly within pulp cords.¹⁴⁸ Most of the labeled cells are small lymphocytes, but occasional labeled blasts, dendritic cells, and macrophages can be identified.¹⁴⁸

The bone marrow may be cellular with generalized hyperplasia of erythroid, myeloid, and megakaryocytic elements.¹⁴⁹ With special techniques, sarcoidlike granulomas may also be demonstrated.¹⁴⁹, ¹⁵⁰, ¹⁵¹ In most instances, however, routine marrow aspiration reveals no abnormalities of note.