CHAPTER 53

The Mononucleosis Syndromes
370 The Polyclonal Lymphoid Diseases PART VII
DEFINITION
• Infectious mononucleosis is defined as any blood lymphocytosis induced in
response to an infectious agent.
• Usually greater than 50 percent of the circulating white cells are lymphocytes,
more than 10 percent of which have the morphology of reactive lymphocytes
(see Fig. 53–1).
• Table 53–1 lists the etiologic agents that produce mononucleosis.
• Pharyngeal form:
— Sore throat preceded by 1 to 2 weeks of lethargy.
— Epstein-Barr virus (EBV) generally is the cause.
• Glandular form without pharyngitis:
— Lymph node enlargement.
— Usually caused by agents other than EBV, e.g., Toxoplasma gondii.
• Typhoidal form:
— Lethargy with fever or diarrhea without pharyngitis, usually as a conse-
quence of cytomegalovirus (CMV).
A B
C D
FIGURE 53–1 A–D. Blood films from patients with EBV-induced mononucleosis. These reactive
lymphocytes exhibit the characteristic changes seen in patients with infectious mononucleosis:
large lymphocytes with abundant cytoplasm. The cytoplasmic margin often spreads around (is in-
dented by) neighboring red cells and the margin may take on a densely basophilic coloration. This
type of reactive T lymphocyte may be seen a variety of diseases and is not specific changes but are
characteristic. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.access-
medicine.com.)
(Source: Williams Hematology, 8th ed, Chap. 84, Fig. 84–1, p. 1202.)
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TABLE 53–2 COMPLICATIONS IN PATIENTS WITH EBV OR CMV MONONUCLEOSIS
EBV CMV
Hemolytic anemia ϩϩ ϩ
Thrombocytopenia ϩ ϩ
Aplastic anemia ϩ Ϫ
Splenic rupture ϩ Ϫ
Jaundice (Ͼ age 25 years) ϩϩ ϩϩ
Guillain-Barré* ϩ ϩϩ
Encephalitis* ϩϩ ϩ/Ϫ
Pneumonitis* ϩ/Ϫ ϩ
Myocarditis* ϩ Ϫ
B-cell lymphoma ϩ Ϫ
Agammaglobulinemia ϩ Ϫ
*Can occur without mononucleosis syndrome. ϩϩ, common; ϩ, infrequent; ϩ/Ϫ, uncom-
mon; Ϫ, not observed.
Source: Williams Hematology, 8th ed, Chap. 84, Table 84–2, p. 1200.
TABLE 53–1 ETIOLOGIC AGENTS ASSOCIATED WITH MONONUCLEOSIS SYNDROME
Epstein-Barr virus Hepatitis A
Cytomegalovirus Adenovirus
Human immunodeficiency virus Toxoplasma gondii
Human herpes virus-6 Bartonella henselae
Metapneumovirus Brucella abortus
Rubella
Source: Williams Hematology, 8th ed, Chap. 84, Table 84–1, p. 1200.
ETIOLOGY AND PATHOGENESIS
• Caused by two members of the herpes virus family: EBV or CMV.
• After the early phase of fever, which lasts for 3 to 7 days, laboratory abnormali-
ties include a blood lymphocyte proportion greater than 50 percent, often with
greater than 10 percent reactive lymphocytes.
• Table 53–2 lists other complications of EBV and CMV mononucleosis.
FEATURES OF MONONUCLEOSIS CAUSED BY EACH ETIOLOGIC AGENT
• Table 53–3 list the signs and symptoms associated with EBV and CMV mono-
nucleosis.
• Target cell for EBV mononucleosis is the B lymphocyte.
• Target cell for CMV mononucleosis is the macrophage.
• The “mononucleosis” for both is the increase in reactive blood T lymphocytes.
• Hepatosplenomegaly common for both EBV and CMV mononucleosis.
• Incubation period for EBV or CMV is 30 to 50 days.
EBV MONONUCLEOSIS
Virology and Pathogenesis
• DNA virus of the gammaherpsevirinae subfamily.
• Infects 90 percent of the world population.
• Peak incidence occurs in the age group from 12 to 25 years and during the sum-
mer months.
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372 The Polyclonal Lymphoid Diseases PART VII
TABLE 53–3 SIGNS AND SYMPTOMS OF EBV AND CMV: EFFECT OF AGE
(PERCENT OF PATIENTS)
Percent of Subjects
Signs and Symptoms
EBV
(Age 14–35 Years)
EBV
(Age 40–72 Years)
CMV
(Age 30–70 Years)
Fever 95 94 85
Pharyngitis
95 46 15
Lymphadenopathy
98 49 24
Hepatomegaly
23 42 N/A
Splenomegaly
65 33 3
Jaundice 8 27 24
Source: Williams Hematology, 8th ed, Chap. 84, Table 84–3, p. 1200.
• B lymphocytes are the initial target of EBV during primary infection.
• Surface receptor for EBV is CD21 on B cells.
• Initial infection causes polyclonal or oligoclonal B-cell proliferation.
• Neoantigen(s) on EBV-infected B cells induces a cytotoxic T-cell response.
• Most circulating lymphocytes are reactive T cells.
• Cytotoxic T cells destroy most EBV-infected B cells leading to disease resolution.
• Following infection, the virus persists throughout life in a latent form.
Epidemiology
• Transmission requires close mucocutaneous contact.
• In the developing world and in the lowest socioeconomic strata of the developed
world, nearly everyone is subclinically infected by age 5 years and mononucleo-
sis is rarely clinically apparent.
• In the upper socioeconomic strata of the developed world, persons avoid infec-
tion in infancy; instead, they become exposed to the virus between the ages of
12 and 25 years by contact with a latently infected asymptomatic individual.
• Individuals who are raised in more protected environments or in single-child
families may reach an age of 30 years or older before they are infected.
Clinical Manifestations
• Vary by age:
— When young children acquire infection with EBV, they develop a typical
childhood illness of respiratory tract infection (43%), otitis media (29%),
pharyngitis (21%), gastroenteritis (7%), or typical mononucleosis (Ͻ10%).
— Age group 12 to 25 years, the earliest manifestations of disease—fever and
lassitude—develop 30 to 45 days after patients become infected. Initial
symptoms of pharyngitis, tonsillar enlargement, sometimes massive, and
fever result from infection and proliferation of the B lymphocytes that are
found in the pharyngeal of the Waldeyer ring of the lymph nodes.
• Liver function abnormalities, usually cholestatic, are frequently present.
• Maculopapular rash with EBV mononucleosis can be worsened by administra-
tion of ampicillin or amoxicillin.
• Group A streptococcus infection may occur coincidentally, but does not affect
the disease and its usual course.
— Penicillin or erythromycin indicated if group A streptococcus isolated from
throat cultures of symptomatic patients.
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• Complications caused by immune dysregulation or lymphocyte proliferation:
— Immune thrombocytopenic purpura (ITP) or autoimmune hemolytic
anemia.
— Splenic rupture.
— Acute airway obstruction resulting from exaggerated pharyngeal lymphade-
nopathy.
— B-cell lymphoproliferative disorder/lymphoma in immunosuppressed
patients.
• Disease abates with the occurrence of a T-cell-mediated counter-response to the
virus-induced polyclonal B-cell proliferation and clinical improvement occurs
within 24 to 48 hours in most cases.
Laboratory Findings
Table 53–5 lists the laboratory abnormalities for EBV and CMV mononucleosis.
Antibody Responses
• Heterophile antibody is positive only with EBV.
• Autoantibodies:
— Cold agglutinins occur frequently with EBV infection.
• Antibody tests for EBV:
— Antibodies to EBV do not react with CMV or with the heterophile antigen.
— IgM and IgG antivirus capsid antigen (VCA) appear during acute illness
(IgM persists for months, IgG for life).
— Early antigen (EA) specific antibodies appear slightly later than IgG anti-
VCA, and persist for years.
— Antibodies to Epstein-Barr nuclear antigen (EBNA) do not develop until
after the acute illness resolves and persist for life.
— A presumptive diagnosis of EBV infectious mononucleosis may be made if
the patient has antibodies specific for VCA, but not for EBNA.
Reactive Lymphocytes
• Expansion of cytotoxic T lymphocytes produces lymphocytosis. Reactive
lymphocytes are larger than lymphocytes normally found in the blood (see
Fig. 53–1).
• Reactive lymphocytes are a hematologic hallmark of infectious mononucleosis,
but they are not always found and are not pathognomonic.
Other Blood Test Abnormalities
• Liver function abnormalities are common, predominantly elevated serum alka-
line phosphatase and ␥-aminotransferase activity with no or only slight eleva-
tion of bilirubin in most patients.
Course and Prognosis
Complications of EBV Mononucleosis
• Hematologic:
— Occur infrequently, but include severe immune thrombocytopenia with
petechiae, immune hemolytic anemia, immune-mediated agranulocytosis,
and aplastic anemia.
• Neurologic:
— Can occasionally develop encephalitis, acute disseminated encephalomyeli-
tis (Alice in Wonderland (( syndrome), acute cerebellar ataxia, viral meningi- d
tis, Guillain-Barré syndrome, transverse myelitis, and cranial nerve palsies.
— Other complications that may be associated are chronic fatigue, multiple
sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and chronic
progressive EBV infection, T or NK lymphoproliferation, lymphoma, and
hemophagocytic syndrome.
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374 The Polyclonal Lymphoid Diseases PART VII
Other EBV-Associated Disease Processes
Neoplastic Potential of the Virus
• Has been associated Burkitt lymphoma and other tumors (see Table 53–4).
• Detectable in neoplastic B cells (Reed-Sternberg cells) of approximately 35 per-
cent of patients with Hodgkin lymphoma; etiologic role uncertain.
• Because of the severe consequences of EBV infection, several approaches to
preventing or treating these disorders are under way including:
— Development of an EBV vaccine.
— Adoptive transfer of activated cytotoxic T cells.
— Development of peptides that inhibit viral replication.
CMV MONONUCLEOSIS
• Second most common cause of infectious mononucleosis.
Epidemiology
• Teenage mothers carrying CMV in their cervix transmit it to their newborn
child, and transmission also occurs through breast milk.
• Transmission from contact with infected young children also plays a role.
• Sexual transmission.
Clinical Manifestations
• See Table 53–2 and 53–4 for a list of complications and clinical findings.
• The basic clinical disease is fever, often as high as 40 ЊC (104 ЊF), with a palpa-
ble spleen and laboratory abnormalities.
• Commonly occurs in older individuals, often those older than 50 years.
• Reactive lymphocytosis is a result of T cells reacting against CMV-infected
monocytes/macrophages (see Table 53–4).
TABLE 53–4 SPECIAL PROBLEMS WITH EBV OR CMV
Epstein-Barr Virus Cytomegalovirus
Rare congenital infection Congenital infection
Chronic progressive mononucleosis Posttransplant primary infection
Hemophagocytic syndrome Graft-versus-host disease association
X-linked B-cell lymphoma Transfusion-related infection
Posttransplant lymphoproliferative
disease
Aspergillus and/or s Pneumocystis
infection
T or NK lymphoproliferative disease
African Burkitt lymphoma
Approximately 20% of Burkitt
lymphoma in the United States
Approximately 35% of Hodgkin
lymphoma
Nasopharyngeal carcinoma
Approximately 5% of gastric carcinoma
Leiomyoma and leiomyosarcoma in
HIV or immunosuppressed patients
Oral hairy leukoplakia
Source: Williams Hematology, 8th ed, Chap. 84, Table 84–4, p. 1203.
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TABLE 53–6 CLINICAL FINDINGS IN PRIMARY HIV INFECTION
Finding Frequency (%)
Fever 79
Pharyngitis 48
Oral ulcers 29
Lymphadenopathy 44
Splenomegaly 5
Hepatomegaly Ͻ1
Reactive lymphocytes Uncommon
Source: Williams Hematology, 8th ed, Chap. 84, Table 84–6, p. 1205.
Laboratory Findings
• See Table 53–5.
• Polyclonal antibody and heterophile antibody responses do not occur, but spe-
cific anti-CMV antibodies do develop.
• Because the incubation period ranges between 30 and 40 days, IgM and IgG
antibodies to CMV usually are positive at presentation.
• Tests for CMV:
— Primary infection diagnosed by fourfold rise in anti-CMV antibody titer.
— Assay for CMV antigenemia more sensitive than anti-CMV antibody titer.
— Polymerase chain reaction (PCR) for detection of CMV DNA is most sensitive.
Complications
• Hemolytic anemia and thrombocytopenia occur in primary CMV infection and
are other factors that may lead the clinician initially to consider a diagnosis of
lymphoma.
• Various neurologic complications can occur, but Guillain-Barré syndrome is the
most frequent and is usually associated with CMV infection.
PRIMARY HIV INFECTION
• Mononucleosis can occur soon after primary infection (see Chap. 52).
• See Table 53–6 for the clinical findings.
• Mononucleosis symptoms are self-limited but may last for several weeks.
TABLE 53–5 LABORATORY ABNORMALITIES IN MONONUCLEOSIS SYNDROME
Frequency
EBV CMV
Heterophile antibody ϩϩϩ Ϫ
Lymphocytosis
ϩϩϩ ϩϩ
Reactive lymphocytes
ϩϩϩ ϩϩ
Abnormal liver function
ϩϩ ϩϩ
Antinuclear factor
ϩ ϩ
Cold agglutinins
ϩ ϩ
Cryoglobulins
ϩ ϩ
Decreased platelets
ϩϩ ϩ
ϩϩϩ, Characteristic; ϩϩ, common; ϩ, occurs.
Source: Williams Hematology, 8th ed, Chap. 84, Table 84–5, p. 1204.
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376 The Polyclonal Lymphoid Diseases PART VII
• Leukopenia, thrombocytopenia, a relative increase in band neutrophils, and a
small proportion of reactive lymphocytes usually can be identified on the blood.
• Lymphocytosis is uncommon.
OTHER AGENTS LINKED TO MONONUCLEOSIS SYNDROME
• Herpes virus-6
• Varicella zoster.
• Hepatitis A or B.
• Rubella.
• Adenovirus.
• T. gondii:
— Only nonviral agent commonly identified as causing a mononucleosis
syndrome.
— Infection secondary to ingestion of cysts in raw meat or of oocysts in cat feces.
— There is no documented person-to-person transmission.
— Is usually asymptomatic or isolated lymphadenopathy without fever.
— Patients do not commonly have pharyngitis.
DIFFERENTIAL DIAGNOSIS
• Acute pharyngitis can be caused by infection with ␤-hemolytic streptococcus,
adenovirus, Arcanobacterium haemolyticum.
• Fever, lymphocytosis, and splenomegaly may raise consideration of lymphoma.
• CMV infection can be associated with presence of antinuclear antibodies simi-
lar to those of patients with new-onset systemic lupus erythematosus.
• Mononucleosis syndrome of toxoplasmosis can be distinguished from
that caused by other infections by presence of high-titer antitoxoplasma
antibodies.
• Patients with mononucleosis syndrome secondary to hepatitis virus infection
generally have abnormal liver function tests.
THERAPY AND COURSE
• Disease is usually self-limited.
• Acetaminophen and/or gargling with saline for fever and pharyngitis.
• Prednisone 40 to 60 mg/day for 7 to 10 days, then taper dose over 1 week for
severe or life-threatening complications, such as:
— Imminent upper airway obstruction.
— Immune thrombocytopenia purpura.
— Immune hemolytic anemia.
— Central nervous system involvement.
• Acyclovir generally is ineffective in the treatment of infectious mononucleosis.
• Ganciclovir may be beneficial for immunocompromised patients or in patients
with severe, complicated primary EBV mononucleosis.
• Ganciclovir (5 mg/kg day for 14 days) is effective against CMV, but recommended
only for patients with severe disease and/or who are immunocompromised.
• Antiretroviral therapy for primary HIV-1 infection can clear viremia and restore
CD4 lymphocytes (see Chap. 52).
Mononucleosis in Pregnancy
• Abortion may be considered for any pregnant woman who develops infectious
mononucleosis as a result of primary infection with EBV, CMV, or toxoplasmo-
sis, especially during the first trimester.
• EBV mononucleosis during gestation can produce severe congenital anomalies,
including microcephaly, hepatosplenomegaly, cataracts, mental retardation, or
death.
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• About half of the infants born to mothers who develop primary CMV infection
during pregnancy will have congenital infection. Of these, about one-quarter
will be symptomatic and/or have congenital anomalies.
• Primary toxoplasmosis infection in first trimester also can result in congenital
abnormalities.
• Mothers with antitoxoplasmosis antibodies before pregnancy do not transmit
the organism to the developing infant.
• HIV-1 can be transmitted to the infant during primary infection and should be
treated with zidovudine alone or in combination with elective caesarean section
to reduce the rate of maternal-infant HIV-1 transmission (see Chap. 52).
For a more detailed discussion, see Robert F. Betts: Mononucleosis
Syndromes. Chap. 84, p. 1199 in Williams Hematology, 8th ed.
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