Chapter 82: Mononucleosis Syndromes

The first clinical description of what was probably infectious mononucleosis was published in 1885 when Pfeiffer¹ described a disorder termed Drüsenfieber (glandular fever). In 1920, Sprunt and Evans² introduced the term infectious mononucleosis for an acute, self-limited syndrome of mononuclear leukocytosis in febrile patients. In 1932, Paul and Bunnell³ showed that the sera from patients with infectious mononucleosis agglutinated red cells from sheep and horses, a reaction that was termed the heterophile antibody test. Paul was investigating heterophile antibodies in human sera that reacted with sheep red blood cells. These antibodies were unrelated by phylogenetic features to the antigen with which they reacted, the so-called Forssman antigen. He found that the highest titer had developed in the serum of an individual recovering from infectious mononucleosis. Davidson showed that serum, after absorption by guinea pig kidney cells, no longer reacted with sheep or horse cells. This absorption of these antibodies made this test very specific for Epstein Barr virus (EBV) infection.⁴ In 1964, Epstein, Ashong, and Barr reported the isolation of a virus from the cells of a patient with African Burkitt lymphoma and hence the derivation of its name, EBV. The etiologic role of EBV in infectious mononucleosis was discovered serendipitously in the laboratory of Gertrude and Werner Henle.⁵ A technician in their laboratory whose serum had been negative for EBV antibodies and was used as a seronegative control was discovered to be EBV antibody-positive after she recovered from infectious mononucleosis. The association later was confirmed in seroepidemiologic studies of college students.^6,7,8,9

Much of the clinical nature and the incubation period of mononucleosis were documented by Hoagland¹⁰ in studies of cadets at West Point. He established that oral transmission was the principal route of viral transmission, which led to mononucleosis being dubbed the “kissing disease.” He also noted that cadets developed the disease approximately 6 weeks after they returned from their vacation.¹¹

Although EBV is the most common cause of infectious mononucleosis, other agents produce a febrile syndrome with a blood lymphocytosis that mimics some aspects of EBV mononucleosis.

The infectious mononucleosis syndrome is most commonly caused by one of two members of the herpes virus family: EBV or cytomegalovirus (CMV). Occasionally the HIV and, less commonly, the parasite Toxoplasma gondii produce a febrile illness with lymphocytosis. Other viral agents produce a febrile syndrome with a blood lymphocytosis, but only infrequently (Table 82–1). For both EBV and CMV mononucleosis, the T-lymphocyte response to the infected target cell, resulting in reactive lymphocytosis, is a hallmark of the disease. The difference is that for EBV, the B lymphocyte is the cell that becomes infected and thus the target of the responding T lymphocyte, whereas it is the macrophage/monocyte lineage that is infected by CMV, which engenders the T-lymphocyte response.^13,14

Some similar and several distinct epidemiologic and clinical differences exist between EBV and CMV infection. Both EBV and CMV infect young children.¹⁵ Those who develop EBV infection at a very young age (1 to 5 years) have an illness similar to other illnesses occurring during their youth. CMV infection presents similarly, but in the young patients there is low-grade fever, mild elevation in liver function, and, quite often, lymphadenopathy. The latter seldom occurs in older people with primary CMV infection.

If an individual escaped EBV infection when he or she was young, it is very common for the individual to develop infection during the teen and young adult years, that is, between the ages of 12 and 25 years.⁸ By contrast, CMV infection is uncommon in that age range but begins to increase in frequency after the age of 25 years.^16,17 Primary CMV infection is also far more common than EBV in those older than 50 years of age.¹⁶ Between the ages of 12 and 25 years, the classic mononucleosis illness develops in the majority of those with primary EBV infection.⁸ In the few older individuals in whom EBV occurs, clinical illness that develops resembles the clinical illness that occurs in those with new CMV infection.¹⁸ Congenital infection with EBV occurs,¹⁹ but it occurs only in babies of mothers who were infected with EBV during pregnancy and it is very uncommon. By contrast, it is estimated that 1 to 2 percent of all livebirths have CMV congenital infection. Furthermore, it occurs associated with primary infection in mothers; it also occurs in babies of mothers who were seropositive preconception.²⁰ CMV infection of the monocyte/macrophage²¹ helps explain its role in disease following solid-organ transplant. Because latent CMV is present in all solid organs of those with previous CMV infection, when immunosuppression is administered latent CMV is reactivated. EBV infection posttransplantation occurs only in those recipients who have not been infected before transplantation and, as with CMV, the EBV is reactivated in the donor organ.²²

VIROLOGY AND PATHOGENESIS

EBV is a DNA virus of the Gammaherpesvirinae subfamily. The virus is estimated to infect 90 percent of the world’s population. In the process of this infection, the EBV intercalates itself primarily into the long-lived memory B cell, not the naïve B cell,²³ and thereafter establishes lifelong residence in its host. Early after infection, the virus is continuously shed into oral secretions. The virus then usually undergoes latency, but it may be reactivated periodically.²⁴

Following primary infection, varying severity of disease ensues. Infection occurs via virus attachment to the cell surface CD21 glycoprotein, a 140-kDa complement receptor type 2. Infection induces polyclonal proliferation of infected B cells in the nodes in the pharynx. There is increasing evidence that host genetic factors predict the severity and duration of disease following primary EBV infection.^25,26 Specifically, the interferon (IFN)-γ +874T/A or the interleukin (IL)-10 –592C/A polymorphisms are the important genetic factors. Using measures of severity of illness such as fatigue, myalgia, and height of fever, individuals who have the IFN-γ +874TT (high interferon production) allele have a striking increase in the risk of experiencing these severe manifestations compared to those with IFN-γ +874 A and IL-10 –592.²⁴ When a subject’s blood monocytes are tested in vitro, the high-risk group has a higher production of IFN-γ in stimulated cells.²⁷ Other factors in host response, which include the height of the virus load in the blood, the number of CD 8+ cells, and the T-cell granzyme expression in the CD8+ cell also have been described as contributing to disease severity.²⁸ As a corollary to this, variability in the symptoms, signs, physical findings, and laboratory abnormalities occurs in primary infection.^28,29 At the time serology confirms evidence of primary infection, some, but not all individuals with primary infection, have classic symptomatic disease.^28,29 In those who develop the classical syndrome, T lymphocytes recognize viral replicative antigens on the infected B cell as foreign, and an exuberant polyclonal cytotoxic T-cell response ensues. The proliferative rate of CD8+ T cells is estimated to be approximately 50 percent of this population of cells proliferating per day. This translates into a population doubling time of 1.5 days so that 5 × 10⁹ CD8+ T cells per day appear in the blood. The later rate of appearance is two orders of magnitude greater than normal.³⁰ The surface activation marker SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) on T lymphocytes stimulates cell activation in response to a signal from CD244 and CD150 (SLAM) on the T-cell surface.³¹ In the healthy individual, this process subsides over days to weeks. In parallel, the signs and symptoms of the infection subside, although fatigue may persist for a longer period of time.

EPIDEMIOLOGY

There is an apparent seasonal pattern with its peak incidence in the summer. Close person-to-person contact is required for transmission to a susceptible individual.²⁹ Subclinical primary infection²⁸ or frequent asymptomatic reactivation of EBV in the previously infected individual provides an opportunity for transmission at all ages. Although, transmission from breast milk or from the cervix occurs, it is very uncommon.³² Nonetheless, nearly everyone in the developing world is infected by age 5 years and mononucleosis is rarely seen. Similar rates of infection occur in the lower socioeconomic class in the developed world. In the upper socioeconomic strata of the developed world, the majority of persons avoid infection when they are young. However, between the ages of 12 and 25, infection is very common. Characteristically, primary infection occurs in an individual a few months after the individual develops a relationship with someone who has latent infection.^24,28 Transmission occurs from a virus-positive asymptomatic individual who transmits his or her virus to a previously uninfected person. Individuals who are raised in more protected environments may reach their 30s before they are infected. If both individuals in an initial relationship are seronegative, years may pass before they become infected. Individuals who are seropositive usually do not develop clinical disease upon reexposure, although a second infection with a different strain may occur.^33,34,35

CLINICAL MANIFESTATIONS

Clinical manifestations vary by age.^{15,18,36,37,38,39,40,41} When young children acquire illness they develop a typical childhood illness of upper respiratory infection (43 percent), otitis media (29 percent) pharyngitis (21 percent), gastroenteritis (7 percent), or typical mononucleosis (<10 percent). Rashes and/or periorbital swelling occur more frequently in younger children than in the teens. In the age group 12 to 25 years, many, but not all, present with the classical presentation of infectious mononucleosis. However, there are a substantial proportion of newly infected individuals who have minimal or very mild disease.^28,29 Furthermore, evidence of virus in the blood may be present for several days before disease appears.²⁸ For those who present with the classical disease of infectious mononucleosis, the earliest manifestations of disease develop 35 to 42 days after the individual develops infection (Table 82–2). Infection occurs via virus attachment to the cell-surface CD21 glycoprotein, a 140-kDa complement receptor type 2. Infection induces polyclonal proliferation of infected B cells in the nodes in the pharynx. Initial symptoms are lassitude and fever with no evidence of lymphocytosis or pharyngitis. Fever results from infection and proliferation of the B lymphocytes. From the nodes in the pharynx, the infected cells make their way into the circulating lymphocyte pool.^42,43 Although the duration of virus in the blood is much shorter than it is in the secretions, it is the movement into the blood that leads to the manifestation of the disease. Subsequent, massive T-cell response to the neoantigens on the infected B lymphocyte is evident by the lymphocytosis with reactive blood lymphocytes and other disease manifestations. The pharyngitis that develops is a result of the T-cell response to the infected B cells that are found in Waldeyer ring in the tonsils. Sometimes enlargement of the tonsils occurs to the extent that they touch each other in the midline. Blood lymphocytosis occurs in response to the virus in the blood. Periorbital swelling, which occurs in mononucleosis, is an important clue to the diagnosis, even in young adults. Other manifestations include lymphadenopathy, hepatitis and splenic enlargement. (Table 82–2).^8,28 Although the liver is not an organ rich in lymphocytes and hepatocytes are not damaged by the infection, CD4+ and CD8+ lymphocytes are trapped in that organ and their release of cytokines contributes to the inflammation in the liver and the changes in liver function that occur.⁴⁴ However, hyperbilirubinemia is very uncommon. The frequency of each clinical finding of the typical syndrome in newly infected patients is variable (Table 82–3).^28,29 The disease abates with the occurrence of a T-cell–mediated counterresponse to the virus-induced initial polyclonal B-cell proliferation. During this time, dramatic clinical improvement can occur in 24 to 48 hours. Subsequently, EBV remains in the patient’s B cells throughout life, but expresses only Epstein-Barr nuclear antigen-1 (EBNA-1), which does not elicit a T-cell response because of a glycine-alanine repeat that inhibits its processing.⁴⁵

Group A streptococcus is found in the pharynx occasionally (3 to 4 percent of cases) in concert with an EBV primary infection. Although treatment of the streptococcus eradicates the organism, the severe pharyngitis changes little, and the disease follows its usual course. Thus, treatment should be administered only if the test result for β-streptococcus is positive. If a penicillin congener is used, quite often, but not always, a rash develops^46,47 and the patient is labeled “penicillin allergic.” The patient should be reevaluated after the mononucleosis resolves to determine if the patient has a true allergy.

There are exceptions to the usual situation of most people becoming infected by age 25 years. The first is found in a woman who is protected by her family from intimate male contact. She avoids infection until she is married at which time she may become infected from her husband. The second situation occurs when a long-term relationship is established when a couple is young. If they are both seronegative, infection does not occur. When they reach parenting age or older, they become infected by a child or a grandchild. When that occurs, the presentation is less likely to include lymphadenopathy and pharyngitis (see Table 82–3).^18,40,41 Fever almost always occurs and abdominal pain, hepatomegaly, and abnormal liver function develops in most. Older adults are less likely to develop lymphocytosis, they have fewer reactive lymphocytes, and splenomegaly is less evident. This leads to the clinical impression of infiltrative hepatic disease or cholecystitis. The illness at this age may be very protracted.

LABORATORY FINDINGS

Antibody Responses

By week three of a mononucleosis caused by primary EBV infection, an heterophile antibody response will occur in approximately 85 percent of patients. The test is called the monospot test and may be falsely negative, especially in young children.^36,48

The infection of B cells results in their production of a variety of antibodies against uninvolved infectious agents. The B-cell clones expanded, non-specifically, result in antibodies against Chlamydia, Borrelia burgdorferi, the yellow fever virus, and many other infectious agents. If the patient’s febrile illness is considered a fever of unknown origin, diagnostic conclusions may be misleading. A variety of other antibodies against antigens that are not those of infectious agents also are produced because of polyclonal B-cell activation. These include antiplatelet, anti–red cell (anti-i cold agglutinin), and antinuclear antibodies.

At the time clinical disease is evident, both immunoglobulin (Ig) G and IgM antibodies to Epstein-Barr virus capsid antigen (VCA) usually are detectable. Later, antibody to early antigen (EA) develops. A small proportion of individuals will also have developed antibody to EBNA-1 on presentation. However, usually EBNA-1 antibody does not appear until the recovery phase of the illness. For those patients suspected of having infectious mononucleosis but who do not develop heterophile antibody, detection of IgG and IgM antibody to VCA with the absence of EBNA-1 antibody leads to the diagnosis.⁴⁹ A real-time positive polymerase chain reaction (PCR) is sometimes useful.⁵⁰

Reactive Lymphocytosis

Expansion of cytotoxic T lymphocytes produces lymphocytosis. Reactive lymphocytes are larger than the lymphocytes normally found in the blood (Fig. 82–1). They may have a vacuolated cytoplasm, lobulated and eccentrically placed nucleus, and a cell membrane that often is indented by neighboring erythrocytes. A more darkly staining peripheral cytoplasm, called “skirting,” occurs. Reactive lymphocytes are a hematologic hallmark of infectious mononucleosis, but they are not always found²⁹ and are not pathognomonic. They also are found in CMV infection, roseola (caused by human herpes virus-6), viral hepatitis, toxoplasmosis, rubella, mumps, and drug reactions.

Sheets of lymphocytes are noted on a stained slide preparation of tonsillar exudate. The immunophenotype of lymphocytes in mononucleosis syndromes assessed by multiparametric flow cytometry has confirmed that lymphocytosis results from CD8+ T cells. CD4+ T cells and B cells are not increased. In EBV mononucleosis, the notable populations increased are CD8+CD57– and CD3+γδ+ T cells.⁵¹ If β-streptococcal infection accompanies the EBV infection segmented neutrophils may be present in the tonsillar exudate.

Other Blood Test Abnormalities

Liver function abnormalities are common, especially elevated serum alkaline phosphatase and γ-aminotransferase. There is no or only slight elevation of bilirubin. Studies in Israel have found a higher frequency of hyperbilirubinemia (15 percent), a lower incidence of leukocytosis (46 percent), and elevated liver enzymes (58 percent) than previously reported. The differences may be geographical or genetic.²⁹

COURSE AND PROGNOSIS

Complications of Epstein-Barr Virus Mononucleosis

Hematologic

Virtually all subjects with acute mononucleosis develop a mildly decreased platelet count (see Table 82–2). More-severe hematologic complications occur infrequently, but include severe immune thrombocytopenia with petechiae, immune hemolytic anemia, immune-mediated granulocytopenia, and aplastic anemia.^{52,53,54,55,56,57,58,59,60} Uncommonly, the splenomegaly that accompanies the lymphoid proliferation accentuates an underlying, previously undiagnosed, hereditary spherocytosis.⁶⁰ Splenic rupture is estimated to occur in 1 to 5 per 1000 cases. It is the leading cause of death from EBV mononucleosis.^61,62 Avoidance of athletic activities is prudent until the signs of the disease have disappeared and the spleen has returned to normal size.⁶²

Neurologic

Neurologic complication include Guillain-Barré syndrome, acute encephalitis, acute disseminated encephalomyelitis (Alice-in-Wonderland syndrome), acute cerebellar ataxia, viral meningitis, transverse myelitis, and cranial nerve palsies.^{57,58,63,64,65} There is evidence that antibody to gangliosides plays a role in the pathogenesis of Guillain-Barré syndrome Neurologic complications may occur in the absence of clinical mononucleosis. Diagnosis of EBV-induced neurologic disease requires obtaining specific antibodies to EBV (see “Antibody Responses” above) and a positive PCR for EBV in the cerebrospinal fluid.⁶³ Neurologic disease can be associated with primary infection, reactivated infection or chronic EBV infection.⁶³ Table 82–2 lists other complications.

Chronic Fatigue

Fatigue is a very prominent feature of acute infectious mononucleosis. Most recover from this fatigue fairly quickly but a few remain fatigued for a very long period of time. The source of this fatigue is not certain but there is evidence that dysfunction of the midbrain plays a role.^68,69 Furthermore, there are genetic factors that are present in those who remain fatigued. Limited information suggests improvement in some with antiviral treatment.⁶⁹

Multiple Sclerosis

There are reports indicating that EBV infection is linked to the development of multiple sclerosis.^70,71 Further studies to clarify which molecular mechanisms link the immune response to a natural infection of humans with EBV to the subsequent development of chronic inflammatory damage to the CNS are required to explain this relationship

Systemic Lupus Erythematosus and Rheumatoid Arthritis

There are epidemiologic links between previous infection with EBV and development of systemic lupus erythematosus (SLE).⁷² Not unexpectedly, virtually everyone with SLE has had previous infection with EBV. Therefore, the link may be fortuitous. Alternatively, a history of infection with EBV might lead to induction of autoimmunity.^73,74 There has also been a suggested relationship between increased viral load in rheumatoid arthritis leading to expansion of CD8+ cells and its consequences.⁷⁵

Chronic Progressive Epstein-Barr Virus Infections, T-Cell or Natural Killer–Cell Lymphoproliferation, Lymphoma, and Hemophagocytic Syndrome

Chronic EBV infection is a rare outcome of primary EBV infection, notable in persons with an immunodeficiency state.^76,77 In chronic EBV infection, fever, marrow hypoplasia, interstitial pneumonia, hepatosplenomegaly, persistent hepatitis often to the point of hepatic failure, lymphadenitis, and uveitis are frequent clinical manifestations. These findings may persist for months or years and eventuate in a high fatality rate.⁷⁵ EBV antibodies may be very elevated (VCA in excess of 1:5120, anti-EA greater than 1:640) but with no detectable EBNA-1 antibody. A persistently elevated blood PCR for EBV is a feature. The more-severe form of this manifestation may evolve into a natural killer (NK)- or T-cell lymphoproliferative disease that ranges from chronic to fulminant.⁷⁸ Alternatively, EBV hemophagocytic syndrome may develop. The latter is a severe multiorgan, inflammatory disease provoked by massive cytokine elaboration. In some case, clonal proliferation induced by EBV develops (Chap. 71).^78,79,80,81

OTHER EPSTEIN-BARR VIRUS–ASSOCIATED DISEASE PROCESSES

Neoplastic Potential of Epstein-Barr Virus

EBV was the first human tumor virus identified⁸² from the cultured cells of a patient with African Burkitt lymphoma. EBV can confer unlimited proliferative potential of infected B lymphocytes in culture.⁸³ EBV has since been associated with tumors other than Burkitt lymphoma, including some patients with Hodgkin lymphoma (Chap. 97). Although proof of causality still eludes investigators, there is an intriguing relationship between EBV and Hodgkin lymphoma.^84,85,86,87 EBV is detectable in the neoplastic B cells (Reed-Sternberg cells) of a significant percent of patients with Hodgkin lymphoma. The etiologic role of EBV in this setting is unknown.^84,85,86,87

There is also a relationship between EBV and lymphoma in immune-deficient individuals including the posttransplantation lymphoproliferative disease (PTLD).⁸⁸ Recipient PTLD is a more serious problem than donor PTLD⁸⁹ and investigators avoid certain immunosuppressive programs if there is a risk of PTLD.⁹⁰ Use of positron emission tomography helps determine who of those at risk for PTLD have evidence for disease.⁹¹ X-chromosome–linked lymphoproliferative disease,⁹² T-cell and NK-cell lymphomas that follow chronic EBV infection,^93,94,95 nasopharyngeal carcinoma in patients in the Far East,⁹⁶ the latter disease generating efforts to develop a vaccine,⁹⁷ leiomyoma and leiomyosarcoma in patients with HIV infection or immunodeficiency posttransplantation,⁹⁸ and a small fraction of cases of gastric carcinoma⁹⁹ are each associated with EBV infection (Table 82–4). In three types of lymphomas, Burkitt, Hodgkin, and PTLD, the cell that mutates to produce the clonal disease is a germinal center B cell with a circular viral genome in the tumor cells that expresses the EBV-encoded latent genes.¹⁰⁰

In the case of PTLD, the most characteristic clinical setting involves an EBV seronegative person receiving an organ from an EBV seropositive donor.⁸⁹ EBV is latent in the B lymphocytes of the transplanted marrow or solid organ. Immunosuppression allows reactivation of the latent virus. Because basiliximab, calcineurin inhibitor, sirolimus, and glucocorticoids seem to increase the frequency of PTLD, that regimen is avoided where the potential for PTLD is present.⁹⁰ Because the recipient is not immune, there is no T-cell response and the B cells may proliferate unchecked, sometimes eventuating in PTLD. In the EBV-seronegative recipient who develops PTLD posttransplantation, this disease usually develops within the first posttransplantation year and often within the first few months. The abnormally proliferating cell almost always is a B cell and the process at an early stage may be monoclonal. In the initial states, the disease may respond to lowering of immunosuppressive medications. Although administration of antiviral prophylaxis seems to lower the frequency of development of the disease, once the disease develops, antiviral agents are ineffective.¹⁰¹ When disease develops, in addition to reduction in immunosuppression, administration of anti-CD20 therapy with rituximab is used. Occasionally, PTLD occurs in a person who is EBV antibody-positive pretransplantation. When this occurs, the onset is usually greater than 1 year posttransplantation.

In young males with an X-linked lymphoproliferative syndrome, primary EBV infection leads to unabated B-cell proliferation and evolution into a frank B-cell lymphoma, the so-called Duncan syndrome.⁹² These young males do not develop a T-cell response and hence do not develop mononucleosis. Although control of this effect of EBV infection by treatment with antiviral agents and/or chemotherapy has been attempted, the Duncan syndrome usually is fatal.

Oral hairy leukoplakia, a characteristic white lingual lesion with hairy projections, occurs in patients with HIV infection. It is caused by EBV infection of the lingual epithelium.¹⁰²

FUTURE THERAPEUTIC APPROACHES TO EPSTEIN-BARR VIRUS INFECTION AND NEOPLASIA

Because of the severe consequences of EBV infection, several approaches to preventing or treating these disorders are underway, such as an EBV vaccine,¹⁰³ adoptive transfer of activated cytotoxic T cells,¹⁰⁴ and the development of peptides that inhibit viral replication.¹⁰⁵

HISTORY

The early description of CMV-related disease was that of an uncommon congenital syndrome with abnormal liver function and thrombocytopenia leading to petechiae.¹⁰⁶ Subsequently, it was recognized that previously healthy young children with a primary infection with CMV¹⁰⁷ had prolonged abnormal liver function, hepatosplenomegaly, lymphocytosis, and thrombocytopenia. Later, primary CMV infection was linked to a febrile mononucleosis syndrome.¹⁰⁸

EPIDEMIOLOGY

In the developing world, CMV infects the majority of individuals by the age of 5 or 6 years. Three factors contribute to this. In those societies, mothers are still in their teen years when they deliver their children. These young women have active CMV virus in their cervix that has persisted since they were younger. The cervical virus is aspirated by the child during the birthing process. Transmission to the newborn also occurs through breast milk. In addition, all of these young children play together when they are young and virus is transmitted readily to those who have avoided earlier infection. Infection at the time of birth from the cervical virus or shortly after birth from breast milk or another child does not lead to any known consequences. However, congenital infection occurs in all populations. For less-than-clear reasons, a seropositive mother may deliver a child who has become infected in utero.¹⁰⁹ In the developing world, most often it occurs in the babies whose mothers are seropositive before they become pregnant and the disease in the new born is not clinically obvious at birth.¹⁰⁹ These children, who have asymptomatic congenital infection, may develop unilateral or bilateral hearing deficits later. Congenital CMV infection in the babies of seropositive women and may account for a significant number of people with hearing loss.¹⁰⁹

In the developed world, first children often have parents who have not had CMV infection. If primary infection occurs in the mother at or near the time of impregnation in anticipation of the second child, severe congenital infection may develop.¹¹⁰ It is not clear which of the several possible factors contribute to why that child acquires congenital CMV infection and more study is required to lead to intelligent management decisions.

Presence of CMV in oral secretions and in urine in children living together in families where there is known CMV has been recognized for many years.¹⁰⁷ The source of the virus is not entirely clear. It is not always certain whether these children acquired infection at birth or from breast milk and they continue to have active infection or whether it is resulting from transmission among children. The latter is suspected but not proven.

It is strongly suspected that when a CMV-infected child comes in contact with a CMV-seronegative grandparent, primary infection in that grandparent may occur. This can be associated with CMV disease in the older person, although the development of disease associated with the infection is uncommon.¹⁸ Very little is known about the risk of CMV-infected semen in those undergoing heterosexual intercourse. However, there is a very high frequency of CMV infection in young homosexual males. Almost all active homosexual young men are seropositive to CMV by age 20 years, which contrasts to only 20 percent of heterosexual young men. Presumably that 20 percent of heterosexual men were infected as children.

CLINICAL MANIFESTATIONS

In most cases, the new infection with CMV is clinically silent. However, some newly infected individuals will develop high fever (40^°C often), weight loss, and associated malaise and myalgia.¹¹¹ Abnormal liver function and a palpable spleen similar to that seen with EBV occur. A left shift in the differential white count may occur initially, evidenced by a higher proportion of band neutrophils. The incidence of lymphadenopathy is much higher in the young then in the older person with primary CMV. Infection occurs in the older individual because they have not been infected during their younger years (Tables 82–2 and 82–3 list additional clinical and laboratory findings). Because no classic manifestation, such as severe exudative pharyngitis, develops, CMV is not considered in the differential diagnosis. Instead, it is assumed that the patient has a bacterial infection and antibiotics are administered. How frequently this occurs is uncertain but administration of a β-lactam antibiotic may be associated with development of a rash and the mistaken impression that the recipient is allergic to penicillin. Because the disease occurs in the older population, including those older than age 50 years, the causes of fever of unknown origin often are pursued in an expensive evaluation prior to the diagnosis. A number of the laboratory and physical findings raise many diagnostic possibilities. Development of antinuclear factor and thrombocytopenia (Table 82–5) often erroneously leads to the diagnosis of a collagen vascular disease. The presence of splenomegaly raises the question of lymphoma.

LABORATORY FINDINGS

The cell that becomes infected initially is not the B lymphocyte but a cell in the monocyte–macrophage lineage and it is that cell or cells to which the T-lymphocyte responds.^112,113 Lymphocytosis that develops is indistinguishable from that of EBV-induced disease. In some patients, neutrophilia with band forms occurs early in the infection. In addition, because the incubation period is 30 to 40 days, IgG and IgM antibodies to CMV have already developed when the disease first becomes manifest. The PCR of a blood sample for CMV usually is positive, and CMV can be isolated from specimens of urine or saliva. Liver function abnormalities (see Tables 82–2 and 82–3) include bilirubin elevation. Jaundice may occur in up to 25 percent of these ill patients.¹⁸ Prolonged illness and severe fatigue is quite common in this subset of ill individuals.

COMPLICATIONS

Hemolytic anemia and thrombocytopenia occur in primary CMV infection and are other findings that may lead the clinician initially to consider a diagnosis of lymphoma. There are a variety of pathogenic factors, which explain these hematologic changes. The most prominent neurologic complication is Guillain-Barré syndrome and, less commonly, transverse myelitis and aseptic meningitis (see Table 82–3). Antibody that develops to CMV-infected cells cross reacts with GM₂ antigen that may explain the development of Guillain-Barré syndrome.^66,67 This antibody can be absorbed with CMV-infected fibroblasts but not by uninfected fibroblasts.

Because it is not the B cell that is the target of infection, but the monocyte–macrophage lineage,^112,113 evolution to unrestrained B-cell replication, lymphoma, and PTLD do not occur.

CYTOMEGALOVIRUS IN TRANSPLANTATION

CMV does not predispose to hematologic malignancy. However, it plays a critical role in all of the transplantation settings, with some very similar findings in lung and allogeneic hematopoietic stem cell transplants. It is rare in autologous hematopoietic stem cell transplantations, but can occur and be a serious infection (Chap. 23 discusses CMV infection in allogeneic hematopoietic stem cell transplantation).

In all solid-organ transplantations, there are three potential types of infection that can occur because of CMV.^114,115,116 The monocyte–macrophage cells in all solid organs, for example, heart, kidney, pancreas, and liver of CMV-seropositive individuals, harbor CMV that can be reactivated. The CMV-seronegative recipient who receives an organ from a CMV-positive donor can develop a primary infection when the CMV reactivates from the donor organ. Because this occurs when the recipient is receiving immunosuppression, this is the most serious clinical problem.^115,116 The classic situation occurs when a parent, who is older and has developed infection in the past, donates a kidney or a segment of their liver containing CMV to their child.¹¹⁶ A second possibility is that the CMV in the seropositive recipient, even when the donor is CMV-seronegative, can be reactivated. Because it is the recipient’s own latent CMV that is reactivated, the clinical manifestations of infection usually are mild or absent.¹¹⁶ The third occurs when both the donor and the recipient are both CMV-seropositive. Clinical disease can sometimes occur, but its severity is difficult to predict. Clinical disease consists of fever, liver function abnormalities, and inflammatory bowel changes. Prior to the availability of antiviral agents, most patients who developed primary CMV infection did well.¹¹⁶ In solid-organ transplantation patients, in the majority of situations, immunosuppressive therapy starts with the transplantation and then is maintained for prolonged periods.

CMV pulmonary problems occur mainly in lung and allogeneic hematopoietic stem cell transplantations. One contributing factor is that an ideal in vitro growth system for CMV is pulmonary macrophages obtained by bronchoalveolar lavage (BAL) from humans.¹¹⁷ That raises the question, does the CMV grow well in the pulmonary macrophage in vivo? Does latency in the macrophage–monocyte cellular system from which it reactivates play an important role in lung and allogeneic hematopoietic stem cell transplant patient populations?^118,119,120 It is in that setting that the infected macrophage is either occurring in a foreign tissue, the lung transplant, or is being seen as foreign by the allogeneic hematopoietic stem cell cellular derivatives.

In patients receiving an allogeneic hematopoietic stem cell transplant, the immunosuppressive regimen is of relatively short duration, unless the patient develops graft-versus-host disease compared to that for solid-organ recipients. If both the recipient and the donor are CMV-seronegative, posttransplantation, CMV infection does not develop.¹²¹ In the allogeneic hematopoietic stem cell transplantation setting, if the recipient is CMV-seronegative and the donor is positive for CMV, infection occurs often, but not in everyone. Although pulmonary involvement is most common, the retina and gastrointestinal tract also can be involved. Because the donor cells are not exposed to immunosuppressive medication, other factors need to come into play for CMV infection to become manifest. The other possible matches with respect to CMV are that the recipient is CMV-seropositive and the donor is negative, or both the recipient and the donor are seropositive. If the recipient is seropositive and has been repeatedly exposed to therapeutic regimens in the process of treatment for the recipient’s underlying disease, reactivation of CMV could occur before the recipient undergoes transplantation. It would be a “self-vaccination” process for some. One needs to consider whether serious infection with CMV is a major problem in allogeneic hematopoietic stem cell transplantations, or whether it is the interaction between the virus, the pulmonary macrophage, and the host.^{117,118,119,120} CMV continues to be a problem, but there are now preliminary studies of a CMV DNA vaccine that are promising.

Two approaches have been taken to manage CMV infection for solid-organ recipients. The first is to provide anti-CMV antiviral agents when the donor, the recipient, or both are CMV-seropositive. Antiviral prophylaxis is initiated at transplantation and continued for up to 120 days thereafter. The second is to provide CMV antiviral prophylaxis only for those situations where the donor is seropositive and the recipient is seronegative. For other situations, weekly monitoring for CMV by PCR is done. If that result is positive, the subject is treated for approximately 1 month. In those who undergo specific monitoring, fewer people receive anti-CMV antiviral drugs and for those who do, the duration is shorter. It also makes the best sense as those recipients who were seropositive pre–solid-organ transplantation have a very low frequency of disease.¹¹⁶

For solid-organ transplantations, clinical illness caused by CMV and rejection of the transplanted organ are difficult to differentiate. Fever develops in the recipient when they begin to mount an immune response. Because the cells in the transplanted organ are now “more foreign” than they were prior to virus reactivation, an immune response occurs directed at the infected monocyte. Although both hepatic and gastrointestinal changes occur, mononucleosis usually does not. There is the potential for rejection of the donated organ. Reactivation of one’s own latent CMV in a solid-organ recipient does not lead to a problem.¹¹⁶ On occasion, reactivation of CMV in the donor organ in a previously seropositive recipient can lead to illness.

Other infectious problems develop in solid-organ recipients. It is proposed that reactivation of the CMV in the macrophage system inhibits the protective function of that system. In the lung where inhalation of potentially infectious agents occurs continuously, new infection can develop because of impairment of the protective action of the macrophages or the neutrophils.^122,123 In addition, a number of organisms can, in the case of renal transplantation, be transplanted with the kidney. Besides the viruses discussed above, these can include bacteria, yeast, and parasites, such as Strongyloides sp.

When fever develops there is a tendency for the transplantation physician to increase immunosuppression under the assumption that rejection is occurring. If the fever is a result of development of primary infection with CMV, the immunosuppressive therapy leads to permanent interference with development of posttransplantation immunity to the CMV. That, in turn, leads to life-long continued problems with CMV infection.

One of the other confusing features for the transplantation physician has stemmed from the common practice to provide ganciclovir prophylaxis to prevent CMV infection posttransplantation to everyone (see above). Those who are seronegative, receive an organ from a seropositive donor, and receive ganciclovir that suppresses reactivation from that organ. When the ganciclovir is discontinued, CMV sometimes reactivates from that organ and primary infection can develop several months later. When this happens, patients present with fever and diarrhea and often have a negative blood CMV by PCR. CMV-induced bowel disease develops because the colonic mucosal cells, as noted previously, are targets for primary infection and virus replication. However, because the blood PCR for CMV is negative, the diagnosis eludes the transplant clinician until colonoscopy and biopsy are carried out.

There are other clinical settings where CMV may play a role. There are hints that HIV patients with pneumocystis pneumonia who also have CMV secretions do less well than those who simply have pneumocystis pneumonia.¹²⁴ In the intensive care unit, CMV reactivation may occur in the very ill nonimmunosuppressed patient. It is uncertain what role the virus plays in this setting.

An acute syndrome develops very frequently at the time of development of primary infection with HIV.^{124,125,126,127} The frequency with which the HIV mononucleosis syndrome develops is uncertain, but for this discussion the difference in features is more important. The acute retroviral syndrome must be recognized for both the patient’s health and the public health. Fever is sudden in onset, followed by sore throat, lymphadenopathy, tonsillar hypertrophy, painful oral ulcerations, conjunctivitis, and rash. Nausea, vomiting, and diarrhea also occur. Leucopenia, thrombocytopenia, a relative increase in band neutrophils, and a small proportion of reactive lymphocytes usually can be identified on the blood film. Although absolute lymphocytosis is uncommon, the syndrome is referred to as HIV mononucleosis. Uncommonly, patients may also develop a heterophile antibody.¹²⁶ Among a group of 563 heterophile antibody-positive patient samples retrospectively tested for HIV-1 RNA and p24 antigen, approximately 1 percent had evidence of primary HIV-1 infection.¹²⁶ In another study, none of 132 cases was positive.¹²⁷ Because in this situation, anti-HIV antibody response has not yet developed, HIV load in the blood should be measured by PCR to make a diagnosis of HIV infection. Usually, viral load is very high (greater than 50,000 viral particles per milliliter of blood). Early treatment may reduce the incidence of HIV-1 complications (Chap. 81). Acute HIV-1 infection may be particularly contagious.¹²⁸ Discussion of the findings with the patient may prevent transmission to a sexual partner.^124,128

Human herpes virus-6 occasionally has been associated with a mononucleosis-type syndrome as has metapneumonia virus (see Table 82–1).^129,130 Hepatitis A and rubella virus infection have produced the typical blood lymphocytic changes. Pharyngitis is not a prominent feature in patients infected with T. gondii. Lymphocytosis is mild, and liver functions are normal even when the liver is enlarged. Usually, toxoplasmosis presents as posterior cervical lymphadenopathy. In the United States, exposure to oocysts from cat feces is the primary route of infection. In other countries, ingestion of partially cooked meat, especially from sheep, is a route of infection. The IgM immunofluorescent antibody test for T. gondii is useful in diagnosing the disease.

Cat scratch disease, Corynebacterium diphtheriae pharyngitis, infection with brucellosis, or lymphoma can be mistaken for mononucleosis. Other, as yet unidentified, agents probably produce the classic syndrome as laboratory studies for all of the known infectious agents, including EBV and CMV, are negative in a small percentage of typical mononucleosis cases.

At a very young age, EBV and CMV mimic each other. They present as one of the many febrile illnesses in young children.¹⁵ The difference here is that the children with CMV present with abnormal liver function tests.¹⁰⁷ The importance of documenting primary CMV is that with this information, one can develop a strategy to prevent transmission to a pregnant woman when she might not be immune. By so doing, a severe congenital CMV infection may be avoided.¹¹⁰ The latter possibility is much more likely in the developed world, because only 20 to 30 percent of women have been infected with CMV before they reach reproductive age. In the older teenage child, both EBV and CMV may cause the mononucleosis syndrome but EBV is far more common. If exudative pharyngitis or lymphadenopathy is present then it is most likely to be EBV. If the patient has intraoral ulcers tests for HIV should be done.

In the sexually active teen, both EBV and HIV testing should be done but CMV remains a possibility.¹⁰⁸ Simultaneous infection with EBV and HIV has occurred, although this, too, is very uncommon. Presence of heterophile antibody strongly supports EBV, although these have been reported in HIV.¹²⁷ In adults in their 30s or 40s, mononucleosis more likely results from infection with CMV than EBV because almost all individuals have been infected with EBV by age 25 years. Furthermore, absence of exudative pharyngitis points to CMV, but HIV also should be considered in this age group. Patients infected with either CMV or HIV can present with blood neutrophilia with an increased proportion of band neutrophils. Rash or aseptic meningitis is more common in patients infected with HIV than CMV. In the middle-aged patient, primary CMV infection is by far the most important possibility, although the unusual individual who has escaped infection with EBV earlier in life may present with EBV with clinical manifestations similar to patients with primary CMV infection at that age.^18,40,41

For the majority of patients with primary CMV or EBV infection, treatment is supportive. Salicylates or other analgesics are appropriate for control of fever, headache, and sore throat. Contact sports should be avoided until the spleen has returned to normal size because splenic rupture can occur in the first few weeks after diagnosis. The vast majority of subjects improve and have resolution of most symptoms. Almost half of patients recovering from EBV mononucleosis still feel fatigued at 60 days and a small percent at 6 months. Severe fatigue can persist after CMV mononucleosis as well.

Antiviral therapy may be considered in special settings for treatment of EBV mononucleosis. The nucleoside analogue acyclovir blocks EBV replication by inhibition of viral DNA polymerase and can prevent viral shedding from the oropharynx.^131,132 However, acyclovir has little if any effect on the course of mononucleosis, presumably because the disease at that point results from the immunopathologic process and not viral proliferation. Antiviral therapy may be useful in chronic aggressive EBV infection and in EBV infection posttransplantation.

Glucocorticoids have been used for management of specific complications. Their specific benefit is difficult to determine because glucocorticoids often are started late in the clinical course, when immunologic reaction to infection is leading to improvement. One carefully controlled trial showed little benefit from glucocorticoids in EBV mononucleosis, and the treated group did less well at 30 days than the placebo group.¹³³ Nevertheless, treatment with glucocorticoid is reasonable when the tonsils are touching in the midline when airway obstruction is imminent. Prednisone 40 to 60 mg/day is given for 7 to 10 days, then rapidly tapered once a clinical response is achieved. Urgent tonsillectomy and adenoidectomy may be required.^134,135 The same prednisone regimen is used for severe immune hemolytic anemia, severe symptomatic immune thrombocytopenia, neurologic complications, pancreatitis, and myocarditis.

The same dose of glucocorticoid has been used for the hematologic or neurologic complications of CMV mononucleosis. Results of ganciclovir 5 mg/kg/day given intravenously for 14 days for severe CMV mononucleosis occasionally have been dramatic. However, ganciclovir is seldom used because of the potential long-term risk to spermatogenesis (aspermia) or potentially on female fertility. Thus, when the disease appears to be self-limited, many physicians do not treat it. Therapy that already was started is stopped after a few weeks. Antiretroviral therapy has been suggested for severe HIV primary disease.

Acyclovir use for other manifestations of EBV infection not resulting from host response but from a high titer of EBV replication, such as oral hairy leukoplakia of AIDS, rapidly resolves lingual lesions.¹³⁶ However, treatment with acyclovir does not appear to be effective for the carrier state.¹³⁷

CYTOMEGALOVIRUS AND EPSTEIN-BARR VIRUS INFECTION

For CMV, immunity does not necessarily protect against congenital infection.¹⁰⁹ CMV viruria at birth occurs in babies of mothers known to be seropositive before they became pregnant. Some viruric children whose mother is seropositive at conception go on to develop unilateral or bilateral hearing loss. The reason for the susceptibility to this type of infection in the apparently immune mother is not clear. If primary CMV infection occurs during gestation the baby can have very severe disease. Microcephaly, mental retardation, cataracts, hepatosplenomegaly, and fetal loss or postnatal death have can occur.¹¹⁰ When EBV mononucleosis occurs during pregnancy, severe abnormalities similar to those as described for CMV have occurred (see Table 82–4).^138,139 Ganciclovir for congenital CMV infection in a very young child is being studied for those who are viruric at birth. Antiviral therapy with famciclovir or valacyclovir has been used for EBV primary infection during pregnancy, but the number of patients treated is too small to draw conclusions.

HIV INFECTION

Primary infection with HIV during pregnancy may not be recognized because HIV antibody is absent early in infection and the antibody screening process is performed at the first prenatal visit. If suspicion of HIV infection is raised during pregnancy and the antibody test for HIV is negative, then viral load should be measured. If positive, antiretroviral therapy for the mother to prevent HIV transmission to the fetus or newborn is indicated.¹⁴⁰

TOXOPLASMA INFECTION

T. gondii producing primary infection during pregnancy can lead to congenital abnormalities. Although no controlled trials are available, treatment of the mother with pyrimethamine plus sulfonamides or spiramycin may eradicate parasites from the infant and the placenta.^141,142