Williams Hematology



Definition and History

Etiology and Pathogenesis

Clinical Features

Laboratory Features

Specific Antibody Tests

Differential Diagnosis
Therapy, Course, and Prognosis

Mononucleosis in Pregnancy

The Compromised Host
Chapter References

Infectious mononucleosis is an acute illness characterized by lymphocytosis in response to infection. Typically, more than 50 percent of the blood white cells are lymphocytes, of which at least 10 percent are atypical. The most common cause of infectious mononucleosis is Epstein-Barr virus (EBV), followed by cytomegalovirus (CMV), Toxoplasma gondii, human immunodeficiency virus type I (HIV-1), and other viruses. Patients with infectious mononucleosis generally present with fever, pharyngitis, lymphadenopathy, and malaise. Depending on the predominant clinical features they may have any one of the three forms: pharyngeal, glandular, or typhoid. About 90 percent of patients with EBV-induced mononucleosis have heterophile antibodies; patients with mononucleosis syndromes caused by other agents that have no heterophile antibodies. Special serologic tests may be needed to determine the specific causative agents. The syndromes generally are self-limited, although complications may occur, especially in immunocompromised patients. Infection occurring during pregnancy may produce congenital anomalies. Treatment of infectious mononucleosis is only symptomatic in most cases. Specific therapy may be indicated in rare cases with serious complications.

Acronyms and abbreviations found in this chapter include: CMV, cytomegalovirus; EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction.

In 1885 Pfeiffer described a disorder that he designated Drüsenfieber (glandular fever).1 The term infectious mononucleosis for what was presumably the same disorder was not introduced until 1920 to describe an acute self-limiting mononuclear leukocytosis seen in patients responding to infection.2 The sera from such patients were subsequently found by Paul and Bunell to contain antibodies that bound the red cells of other species, such as horse or sheep.3 Because of this property, the antibodies were called heterophile antibodies, and patients having such antibodies are referred to as being heterophile-positive. The subsequent development of a differential absorption test greatly improved the specificity of the heterophile antibody titre as a diagnostic measure.4
Clinically, infectious mononucleosis is defined as any blood lymphocytosis induced in response to an infectious disease. Usually, over 50 percent of the circulating white cells of patients with mononucleosis are lymphocytes, over 10 percent of which have the morphology of “atypical” (reactive) lymphocytes,5 T lymphocytes undergoing blastogenesis as part of a cellular immune response to infected host cells.
Table 90-1 lists some of the known causes of the infectious mononucleosis syndrome. Most cases of infectious mononucleosis in the United States and other developed countries are caused by EBV,6,7 a member of the Herpesvirus family. A prolonged period of virus shedding from newly infected cells occurs before establishing latency, and spontaneous reactivation from infected cells may occur frequently during the next 2 years. Immune suppression leads to reactivation of virus from its latent state.8,9 Previous infection with EBV protects against subsequent EBV-induced mononucleosis.10


The patient with infectious mononucleosis often has a history of having entered a close interpersonal relationship with the person who transmits the disease; transmission of EBV requires close mucocutaneous contact between the virus-infected transmitter and the susceptible individual.4,11 The transmitter usually has no history of recent illness and may not have a history of having had infectious mononucleosis. Because of the social activity that transpires during the teenage years, most persons become infected with EBV in young adulthood. The few that escape infection remain susceptible and usually become infected in later adulthood.12 Although saliva is believed to be the fluid that most commonly transmits the infection,13 the detection of the virus in fluid from the uterine cervix has raised the question of sexual transmission as well.14
It had been believed that EBV mononucleosis is initiated by entry of EBV into epithelial cells of the oropharynx or B lymphocytes of Waldeyer’s ring.8,15 However, using highly sensitive techniques to detect EBV-DNA and EBV gene products, it has been shown that B lymphocytes are the initial target of EBV during primary infection.16 EBV enters B cells via the cell surface glycoprotein CD21, the 140-kDa complement receptor type 2, and induces polyclonal B-cell proliferation.8,17 A neoantigen expressed on infected B cells elicits a polyclonal T-cell immune response.18 This explains why most of the circulating reactive lymphocytes of patients with infectious mononucleosis are T lymphocytes. Some of these T cells also may be responding nonspecifically.18 In any case, the cellular immune response to EBV generates cytotoxic T cells that destroy infected tonsillar B lymphocytes, leading to severe pharyngitis. These symptoms subside as the counterresponse to the initial polyclonal B-cell proliferation attenuates.17,19 Once an individual is infected with EBV, the virus presents throughout the lifetime. However, in the healthy individual only the EBNA-1 antigen is expressed, and this does not elicit a T-cell response because of a glycine-alanine repeat that inhibits its processing.20
Besides infectious mononucleosis, EBV has been associated with childhood Burkitt’s lymphoma in the malarial belt of Africa,21 nasopharyngeal carcinoma in adults in the Far East,22 oral hairy leukoplakia in patients with HIV-1 infection,23 and with leimyosarcoma or leioma in HIV-1 infected patients and transplant recipients.24,25
Like EBV, cytomegalovirus (CMV) is a member of the Herpesvirus family. This virus replicates slowly in cells, causing them to enlarge. It is the second most common cause of infectious mononucleosis.
As with EBV most persons in the developing world are infected with CMV by the age of 5.26 However, in the United States, childhood infection is less likely to occur. Child-to-child transmission occurs frequently in the child care center, but 60 to 80 percent of 20-year-olds in the United States have never been infected with CMV. For reasons that are not clear, susceptible individuals in their teen years and early twenties are far less likely to become infected with CMV than with EBV. Thus, there is no peak incidence age for CMV mononucleosis.26 Rather, over the ensuing 50 years of adult life, three-quarters of susceptible persons will become infected with this virus. The pathogenesis of CMV infection is less well understood than that of EBV infections. The virus initially may infect neutrophils that subsequently spread the infection to fixed macrophages in the liver, spleen, lung, and possibly other organs.27 Virus-infected cells that express neoantigens in turn may induce a T-cell immune response, resulting in the generation of reactive lymphocytes and blood lymphocytosis. Circulating monocytes may contain CMV DNA or show signs of being infected, as determined by in vitro assays of monocyte function.87 Thus, in contrast to EBV, where the B lymphocyte causes the T-cell response, the “reactive lymphocyte” of the CMV-infected patient is a T cell responding to an infected cell of the monocyte/macrophage lineage.
Primary infection with HIV-1 may present as a heterophile-negative mononucleosis syndrome.28,29 The acute syndrome lasts for a few weeks and is usually self-limited. However, severe opportunistic infections have been reported during this acute phase.28 The pathophysiology of HIV is discussed in Chap. 89. Herpes simplex type II and, less commonly, varicella-zoster virus also may cause a heterophile-negative mononucleosis syndrome. Rubella virus and adenovirus also occasionally may cause such a syndrome. In addition, patients with the clinical picture of acute infectious hepatitis due to hepatitis A or B may have significant lymphocytosis with reactive cells. However, some patients with a heterophile-negative mononucleosis syndrome may not have any evidence for being infected acutely with any of these viruses, suggesting that as yet unidentified agents also may produce this clinical syndrome.
The only nonviral agent that commonly is identified as causing a mononucleosis syndrome is Toxoplasma gondii. Infection with this organism may produce lymphadenopathy associated with fevers. However, more commonly, infected patients are asymptomatic or have isolated lymphadenopathy without fever.30,31 Two routes of spread of T. gondii are ingestion of cysts in raw meat and ingestion of oocysts in cat feces.30,32 There is no documented person-to-person transmission.
The incubation periods for CMV and EBV are similar, ranging from 30 to 50 days. However, there are significant differences in the clinical presentation of patients infected with one or another of these two agents. A listing of the symptoms and signs and their frequency in mononucleosis syndrome caused by one of the three common agents is presented in Table 90-2. Clearly the symptoms from different infectious agents overlap, and, although each agent has a typical picture, as discussed below, an etiologic diagnosis cannot be made reliably from the clinical presentation.


Pharyngitis is a prominent part of the presentation of individuals with primary EBV infection. Usually pharyngitis occurs after a week or so of malaise, but it may sometimes be delayed for 2 or 3 weeks. A significant tonsillar exudate is generally present. The pharyngitis that occasionally occurs with CMV is mild, and exudates are absent. Since mononucleosis caused by EBV has such characteristic exudative tonsillitis and almost always presents with lymphadenopathy, the diagnosis is made easily and quickly.12 The so-called typhoidal form of infectious mononucleosis has a strong component of gastrointestinal symptoms and is much more characteristic of CMV infection, although it may also be caused by EBV.33 Often unusual diseases are considered and a work-up is well underway before the diagnosis of CMV mononucleosis is appreciated.26
Individuals acutely infected with either CMV or EBV may have a fine maculopapular rash as part of their presentation. For both, the frequency of the rash is increased dramatically by administration of ampicillin or amoxicillin. For both infections, palpable hepatomegaly and/or splenomegaly are common. Other manifestations, such as pulmonary or cardiac findings, are uncommon (see Table 90-3). In EBV infection, aplastic anemia or agranulocytosis34,35 has been noted, as has renal failure.36 A variety of neurologic syndromes may occur, including encephalopathy/encephalitis, aseptic meningitis, transverse myelitis, psychoses, or cranial nerve palsies.12,37,26,38,39 The neurologic syndrome most frequently associated with CMV-induced mononucleosis is the Guillain-Barré syndrome. In a case-control study involving 154 Guillain-Barré syndrome patients, CMV was associated with 13 percent of cases.39 The central nervous system (CNS) syndrome may develop instead of, prior to, or after the development of the mononucleosis syndrome.


Infectious mononucleosis in middle-aged and aged patients usually is due to CMV and not EBV. However, when EBV is the cause, it generally is more severe than in the young.40
Infectious mononucleosis caused by agents other than EBV or CMV may have different features. Patients with hepatitis A or B may present with mononucleosis associated with abdominal pain and low-grade fever. These symptoms generally remit prior to the appearance of jaundice. Toxoplasmosis also will produce prominent lymphadenopathy, especially posterior auricular, but it does not produce pharyngitis. Hepatosplenomegaly is less prominent in toxoplasmosis than in either EBV or CMV mononucleosis. A faint rash occasionally occurs. Fever is usually low-grade or absent. Encephalitis or meningitis can occur.30,31 The other agents that produce mononucleosis syndrome may sometimes produce lymphadenopathy. Rubella usually produces a rash; adenovirus usually causes pharyngitis.
Patients with mononucleosis induced by primary infection with HIV generally present with fever, malaise, sore throat, weight loss, and myalgia. The common physical abnormalities are pharyngits, rash, lymphadenopathy, oral or genital ulceration.41 Neurologic manifestations such as aseptic meningitis, encephalitis, and polyneuropathy are also frequently reported.28
The principal diagnostic feature is the presence of the blood lymphocytosis exceeding 50 percent of the blood white count, with at least 10 percent of blood lymphocytes being reactive. The blood of most cases of infectious mononucleosis are flagged as abnormal by modern hematology analyzers.42 The one feature that distinguishes EBV from all other infectious causes of mononucleosis is the development of the heterophile antibody. Ninety percent of patients develop detectable antibody after 7 to 21 days of illness. The heterophile antibody is not cross-reactive with EBV itself. Rather, the target antigen is found on the surface of beef, horse, or sheep red blood cells but not guinea pig kidney.43 The horse erythrocyte has the greatest degree of sensitivity for detecting these antibodies.
A variety of other antibodies are produced, presumably resulting from the polyclonal B-cell activation induced by infection with EBV. Antibodies directed against a variety of self-antigens may be detected. These include platelet glycoproteins, nuclear antigens, and the i antigen of human cord; red blood cells commonly are detected in patients with primary EBV infection. The anti-i autoantibodies usually are cold agglutinins that do not react well with red blood cells at 37°C. However, occasionally patients with acute primary EBV infection may develop severe thrombocytopenia or hemolytic anemia secondary to induced autoantibodies.44,45 and 46 Liver function abnormalities, which are predominantly cholestatic but also hepatocellular in nature, are found regularly, whereas jaundice is decidedly uncommon.37 With the exception of the heterophile antibody, these laboratory abnormalities also may occur in primary infection with CMV (see Table 90-4). Infectious mononucleosis secondary to acute infection with hepatitis A or B, on the other hand, is associated predominantly with elevation of hepatocellular enzyme levels in the serum and with cholestasis, often culminating in the development of frank jaundice. The typical laboratory findings in HIV-1-induced mononucleosis include thrombocytopenia, leukopenia, and lymphopenia, followed by CD8 T lymphocytosis and depletion of CD4 cells.28


Immunofluorescence techniques to measure specific antiviral antibodies can help establish the diagnosis of primary EBV infection. Even the 10 percent of patients with acute EBV infection who fail to develop a heterophile antibody develop the same antibody response to EBV antigens as do EBV-infected individuals who are heterophile-positive.47,48,49,50 and 51 EBV antibodies do not react with CMV or with the heterophile antigen.
Almost all infected patients who are acutely ill already have developed IgG and IgM antibody to the virus capsid antigen when first evaluated. The IgM antibody to virus capsid antigen is a sign of acute infection, persisting for only a few months. The IgG antivirus capsid antigen, on the other hand, persists for life. The heterophile antibody titer rises shortly after the appearance of the antivirus capsid antigen antibodies, peaks 1 to 3 weeks after symptoms develop, and remains high for 1 to 3 months thereafter. Early antigen-specific antibody (i.e., IgG antibody to nuclear antigens that are synthesized by infected B cells before viral-directed DNA synthesis commences) appears slightly later in the illness than IgG anti-Virus capsid antigen and then may persist for years.47,48,49,50 and 51 Specific antibody to Epstein-Barr nuclear antigen (EBNA) does not develop until after the acute phase of illness and then persists for life. Complement-fixing antibody and neutralizing antibody also develop. Most laboratories that conduct these studies measure virus capsid antigen and EBNA antibodies. The more difficult tests, for IgM antibody or for antibody to early antigen, are reserved for special cases. A presumptive diagnosis of EBV-induced infectious mononucleosis can be reached if the patient is found to have antivirus capsid antigen antibodies but not anti-EBNA antibodies. Culture techniques can help establish that the patient is infected with EBV and is shedding virus.
Culture techniques can detect CMV, but newer methods such as CMV antigenemia assay and polymerase chain reaction (PCR) for detection of CMV DNA are more sensitive than CMV culture in the diagnosis of CMV infection.52
Assaying for antibodies to CMV also may help establish the diagnosis of CMV-induced mononucleosis. Antibodies to CMV antigens are not as well defined as those to EBV. IgM and IgG antibody to antigens in CMV-infected fibroblasts can be demonstrated by immunofluorescence or enzyme-linked immunosorbent assay (ELISA).53,54,55 and 56 Immunofluorescence techniques, however, may detect IgM antibody to CMV-infected cells in the serum of patients with EBV mononucleosis.57 An IgM cytolytic antibody to CMV-infected cells, however, is not detected in patients with EBV mononucleosis and may help distinguish patients with primary CMV infection.58 To determine whether an individual has an acute infection with CMV, it is often necessary to measure changes in the anti-CMV antibody titer. A fourfold rise in complement-fixing anti-CMV antibody titer is considered diagnostic. In most cases, the antibody increase with acute infection is at least 16-fold.
The sera of patients who have a mononucleosis-like illness secondary to primary infection with HIV usually lack specific antibodies to HIV. However, viral p24 antigen or high-titer viral RNA can be detected in the blood of such patients.41 Between 1 and 2 months after their initial presentation, such patients may develop anti-HIV-1 antibodies.28
Patients with acute primary toxoplasmosis infection generally have high titers of anti-toxoplasmosis antibodies.59 Patients with primary infection have particularly high titers of IgM anti-toxoplasmosis antibodies. In contrast, patients with AIDS and CNS toxoplasmosis generally have low titers of anti-toxoplasmosis antibody that almost invariably are of the IgG isotype. Both IgG and IgM anti-toxoplasmosis antibodies may be detected using specific tests, such as the Sabin-Feldman dye test, immunofluorescence assays, or ELISA. These tests are available commercially.
EBV mononucleosis presents as a systemic syndrome with severe pharyngitis. The differential diagnosis should include infections by other organisms that may cause pharyngitis, such as b-hemolytic streptococcus, adenovirus, and Arcanobacter hemolyticum. Most other viral causes of pharyngitis evolve fairly quickly into typical upper respiratory symptoms. Group A streptococci frequently are isolated from pharyngeal cultures obtained from patients with typical EBV-induced mononucleosis. Although recovery of this organism from the throat cultures of symptomatic patients usually mandates antibiotic therapy, such treatment seldom produces any clinical improvement.
Patients with primary CMV infection present with fever and splenomegaly without other specific findings. Often such patients are suspected to have an underlying lymphoma. Alternatively, the presence of antinuclear antibodies associated with primary CMV infection may suggest that such patients have new-onset systemic lupus erythematosus.
The mononucleosis syndrome of toxoplasmosis has several features that help distinguish it from EBV or CMV mononucleosis (see clinical features). In addition, liver function tests are generally normal. Lymphocytosis occurs in a small percentage of these individuals.31 Toxoplasma antibody tests can establish the diagnosis.59 Toxoplasma infection in the CNS of HIV-positive patients generally does not produce a mononucleosis syndrome.
Hepatitis A or B virus also can cause a mononucleosis-like syndrome associated with circulating reactive lymphocytosis and abnormal liver function tests. However, the sera of patients with mononucleosis caused by these viruses generally have marked elevations in serum levels of hepatocellular enzymes. Furthermore, when liver function tests on the sera become abnormal for patients with hepatitis, the fever abates. Symptomatic primary HIV-1 infection has been described in all of the major risk groups. Such a diagnosis should be considered in any patient with an infectious mononucleosis syndrome who is at risk of HIV-1 infection. One of the major manifestations of HIV-1 mononucleosis is aseptic meningitis. Other causes of this process must be considered.
A central feature of this syndrome is severe fatigue lasting more than 6 months and reducing activity by 50 percent or more.60 Initial reports implicated EBV as causing this poorly understood syndrome. However, careful epidemiologic and serologic studies largely have excluded EBV as a major cause for this syndrome.61 Although antibody titers to EBV antigens may be elevated in some subjects, so are antibody titers to other infectious agents.62 Since blood mononucleosis is not a component of this syndrome, whereas fatigue is, the descriptor chronic mononucleosis is a misnomer and should no longer be used. Instead this syndrome has been designated the chronic fatigue syndrome.
Both heterophile-positive and heterophile-negative syndromes are self-limited. Thus, only symptomatic therapy is indicated in most cases. If the spleen is enlarged, patients should temporarily limit their activity because of the small but definite risk of splenic rupture. Although aspirin has been recommended to reduce the fever and pharyngeal inflammation, reports of aspirin producing Reye syndrome in children with EBV63 make acetaminophen and/or gargling with saline preferable alternatives. Penicillin or erythromycin is indicated if group A streptococcus is isolated from throat cultures of symptomatic patients.
Limited studies suggest that there is very little benefit from glucocorticoid therapy beyond the first 48 to 96 h.64 There have been reports of encephalitis or myocarditis associated with corticosteroid use in patients with mononucleosis.65 Most clinicians are reluctant to administer glucocorticoids unless there are severe or life-threatening complications, such as imminent upper airway obstruction, thrombocytopenic purpura, hemolytic anemia, or central nervous system involvement (see Table 90-3).66 When used, prednisone is given orally at a dose of 40 to 60 mg per day for 4 days. The dosage is slowly reduced over 5 to 7 days and discontinued. Acyclovir alone or in combination with corticosteroid provides no clinical benefit for uncomplicated infectious mononucleosis.67,68 In an immunocompromised patient with severe, complicated primary EBV infection and infectious mononucleosis, treatment with ganciclovir may produce a favorable outcome.69 EBV-induced lymphoproliferative disorders are generally not responsive to acyclovir.70 Various attempts employing interferon-a, interferon-b, interleukin-2, adoptive transfer of EBV-specific T cells, or reducing immunosupressants have been reported to have some beneficial effects in treating these disorders.71,72 Ganciclovir and foscarnet are effective against cytomegalovirus infection, but their toxicity precludes their use in this self-limited disease except in the immunocompromised host.73
Patients with the acute infectious mononucleosis syndrome due to T. gondii usually do not require therapy.30,31,74 If the patient is pregnant, immunocompromised, or has an infection involving vital organs, then pyrimethamine and sulfadiazine should be used.74 Therapy is initiated with 100 to 200 mg pyrimethamine orally in two divided doses, followed by 1 mg/kg per day in a single dose. In addition, sulfadiazine is given at 75 to 100 mg/kg per day in four divided doses. Treatment is continued for 2 to 4 weeks. Folinic acid (calcium leucovorin) 10 to 20 mg/day may prevent hematologic toxicity.
For patients with acute primary HIV-1 infection, very high titers of HIV are detectable during the acute phase of the illness, i.e., during the mononucleosis-like syndrome. After the resolution of symptoms, the plasma viral RNA level declines rapidly and reaches an inflection point 120 days after infection, then gradually increases. Viral levels 120 to 365 days after acquisition are associated with faster disease progressions.75 Antiretroviral treatment of primary HIV-1 infection has resulted in clearance of viremia and restoration of CD4 lymphocytes.41,76 However, the long-term clinical benefit remains to be determined.
Most women of childbearing age are immune to infection with EBV. Hence, congenital infection is rare. This is fortunate, as EBV mononucleosis during gestation may produce severe congenital anomalies, including microcephaly, hepatosplenomegaly, cataracts, mental retardation, and/or death.37,77 On the other hand, most infants born with congenital CMV are asymptomatic at birth, and 90 percent will develop normally. Such infants generally are born of mothers who were infected many months prior to the onset of pregnancy.78 However, if a mother develops primary CMV infection, approximately 50 percent of infants will have congenital infection.79,80 Of these, about one-quarter may be symptomatic. Abortion may be considered for any pregnant woman who develops either CMV or EBV mononucleosis syndrome during pregnancy, especially during the first trimester.
Congenital infection with toxoplasmosis also may produce developmental abnormalities. The mother who already has anti-toxoplasmosis antibody before pregnancy does not transmit the organism to her developing infant. However, if the mother develops a primary infection during her first trimester, there is a risk that the infant may develop congenital abnormalities. Several treatment regimens have been employed to prevent and treat congenital toxoplasmosis. Pyrimethamine, in combination with sulfonamides and/or spiramycin, may eradicate parasites in the placenta and also in the fetus.32,81 However, multicenter trials testing the safety and efficacy of these regimens are lacking.
HIV-1 can be transmitted from mothers to babies before birth, during labor and delivery, or even after birth (through breast feeding). The maternal plasma HIV-1 RNA level has been demonstrated to be the strongest predictor of the perinatal transmission of HIV-1.82 With its extremely high level of plasma HI-1 RNA, primary HIV-1 infection during pregnancy may pose a significantly high risk of perinatal HIV-1 transmission. Recent studies have shown that perinatal treatment with zidovudine alone or in combination with elective caesarean section substantially reduces the rate of maternal-infant HIV-1 transmission.83,84
In the compromised host, CMV can cause primary infection if transmitted by blood transfusion or by allografts85 (Table 90-5). In transplant patients, CMV causes both direct injury involving multiple organs and indirect effects such as allograft rejection and bacterial superinfection.73 Prevention of CMV infection is of great importance in this population. The use of prophylactic antibiotics has been shown to be safe and effective in reducing CMV disease after organ transplantation.86



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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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