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„Approved”
on methodical conference
department of infectious diseases and epidemiology
„____” ____________ 200 р.
Protocol № _____
Chief of Dept., professor __________ V.D. Moskaliuk
METHODOLOGICAL INSTRUCTIONS
to a fifth year student of the Faculty of Medicine
on independent preparation for practical training
Topic: INFECTIOUS MONONUCLEOSIS
Subject:
Major:
Educational degree and qualification degree:
Year of study:
Hours:
Prepared by assistant professor
Infectious Diseases
Medicine
Specialist
5
2
Sydorchuk A.S.
Topic: Infectious Mononucleosis
1. Lesson duration: 2 hours
2. Aims of the lesson:
3.1. Students are to know:
• etiology of infectious mononucleosis, principal properties of Epstein-Barr virus (EBV) ;
• infectious mononucleosis epidemiology;
• pathogenesis of infectious mononucleosis and morphology of organs afflicted by virus;
• symptoms and development of typical and atypical infectious mononucleosis;
• clinical characteristic of jaundice stages;
• infectious mononucleosis complications;
• diagnosis of infectious mononucleosis;
• laboratory methods of examination at infectious mononucleosis;
• differential diagnosis of infectious mononucleosis including distinguishing between similar
diseases;
• treatment of infectious mononucleosis with taking into account of course severity;
• prophylactic and antiepidemic measures at infectious mononucleosis.
3.2. Students are to be able:
• to question a patient in order for obtaining of information on disease history and
epidemiologic anamnesis;
• to perform clinical examination of a patient;
• to formulate and to substantiate the diagnosis of infectious mononucleosis;
• to prepare a plan of additional patient examination;
• to evaluate results of laboratory examination;
• to determinate a form of disease;
• to make differential diagnosis to distinguish between similar diseases (enteral infections
caused by Yersinia pseudotuberculosis, Y. Enterocolitica, acute lacunar tonsillitis, viral
hepatites, Scarlet fever etc.);
• to prescribe adequate pathogen and etiotropic treatment;
• to prepare a plan and organize prophylactic and antiepidemic measures.
3.3. Students are to acquire the following skills:
• to conduct clinical examination of a infectious mononucleosis patient and other acute
respiratory diseases;
• to formulate and substantiate a clinical diagnosis;
• to prepare a plan of paraclinic patient examination;
• to take samples of material (smears from nasopharynx and stomatopharynx) for
immunoenzyme method and other quick analysis methods and serological examination for
revealing of EBV;
• to evaluate results of paraclinic patient examination;
• to organize hospitalization and treatment of a infectious mononucleosis patient (of a person
suspected to have infectious mononucleosis);
• to provide emergency aid at toxic shock;
• to plan and organize prophylactic measures against infectious mononucleosis;
• to plan and organize antiepidemic measures to localize and liquidate a infectious
mononucleosis source.
4. Advice to students.
Infectious mononucleosis was first recognized in 1920, but the etiology was elusive. Discovery
of serologic diagnosis of infectious mononucleosis employing the nonspecific heterophile
antibody was reported in 1932, but it was not until 1968 that Ebstein-Barr virus (EBV) was
identified as the cause of infectious mononucleosis. Infectious mononucleosis is one of the
most common infection seen during adolescence. The classic triad of fever, pharyngitis, and
lymphadenopathy is well known, but the dynamic nature of the clinical presentation, and the
occasional presence of unusual features can mislead many clinicians, resulting in delayed
diagnosis or misdiagnosis. Confusion regarding the association of EBV infection with
infectious mononucleosis is not unusual. Although EBV is the most common cause of
infectious mononucleosis, not all primary EBV infections manifest as infectious
mononucleosis. Furthermore, misconceptions about the serology of infectious mononucleosis
can interfere with or prevent prompt diagnosis. EBV infects primarily children and young
adults. In underdeveloped countries, most children have had asymptomatic EBV infection by 5
years of age. Unlike the asymptomatic primary infection young children, when older children
and young adults acquire primary EBV infection, it is more likely to be symptomatic, with the
most common presentation being infectious mononucleosis. The incidence of EBV-associated
infectious mononucleosis in the USA has been estimated at 45 per 100,000 population and is
highest in adolescent. No seasonal pattern of EBV infection exists. The incubation period for
EBV has not been determined but it is estimated to be 30-50 days. The communicability period
is also indeterminate but may be prolonged; most people have intermittent shedding in throat
washings for at least 3 months after onset of symptoms.
Pathogenesis:
EBV first infects and replicates in oropharyngeal epithelial cells then infects B-cells, which can
disseminate the virus throughout the lymphoreticular system. EBV infection triggers an
impressive, but self-limited, immune response. Infected B-cells are transformed into
plasmacytoid cells, which secrete a diverse group of immunoglobulins, including heterophile
antibodies, antibodies to specific EBV antigens, and various autoantibodies. Also
immunoglobulins G, A, and M. The spectrum of EBV infection includes asymptomatic
infection, nonspecific febrile illness, infectious mononucleosis with or without various
complications, primary infection with systemic manifestations not meeting the criteria for
infectious mononucleosis, and lymphoproliferative disorders. EVB also has been associated
with neoplastic transformation, some nasopharyngeal carcinomas and most cases of Burkitt’s
lymphoma found in Africa.
CLINICAL MANIFESTATIONS.
Are influenced by age and immune status of the host. Infectious mononucleosis aside from the
classic triad may include splenomegaly, hepatomegaly, eyelid edema, exanthems, and
enanthems. Symptoms may be abrupt or prodromal. There are three classifications: anginose is
the classic triad characterized by abrupt onset of fever, exudative tonsillopharyngitis with
marked pharyngeal edema, and the presence of lymphadenopathy; in the typhoidal syndrome
prolonged high fever is the principal symptom with insignificant pharyngitits and a delay in
appearance of lymphadenopathy; the glandular syndrome is distinguished by mild pharyngitis,
low grade fever, and marked lymphadenopathy disproportionate to the degree of pharyngitis.
Lymphadenopathy is always bilateral with posterior and anterior cervical chain involvement
most common, and axillary and inguinal adenopathy occasionally present. On a large series
(Hoagland et al) only 3% of patients had “bull-neck” appearance caused by extensive cervical
adenopathy. Eight percent had jaundice. Lymphadenopathy and organomegaly were most
pronounced in the second and third weeks of illness. Compared with adolescents and young
adults, children more commonly had splenomegaly or hepatomegaly, URI symptoms, rash,
higher peak leukocyte counts but fewer atypical lymphocytes, and more frequent neutropenia.
Pertinent negative signs include abdominal pain, watery diarrhea, hematuria or dysuria,
arthralgias, rhinorrhea, nasal congestion, paroxysmal cough and chest pain. The diagnosis can
be delayed when unusual manifestations predominate such as abdominal pain, and others. The
clinical diagnosis of infectious mononucleosis is supported by characteristic laboratory
findings: modest peripheral leukocytosis with total white blood count up to 20,000/mm3,
lymphocytes account for more than 50% (or greater than 4,500/mm3) of the leukocytes, and at
least 10% (or greater than 1,000/mm3) are atypical lymphocytes also known as Downy cells.
The increase in absolute lymphocyte count is a result of EBV activation of Я-cells with ensuing
proliferation of T-cells. More than 50% of patients develop a mild thrombocytopenia, with
platelet counts ranging from 100,000 to 140,000/mm3. In the second week of acute illness, a
mild neutropenia can be seen. Ninety percent of patients develop a mild hepatitis in the second
to third week as demonstrated by two-fold increase in LDH, alkaline phosphatase and the
transaminases.
COMPLICATIONS.
The best documented complications of infectious mononucleosis include upper airway
obstruction, immune- mediated phenomena, rash associated with ampicillin administration, and
splenic rupture. Splenic rupture has been estimated to occur in 1 to 2 of every 1,000 cases.
More than 90% occur in males. Rupture most often occurs between the fourth and twenty-first
day of acute illness. Sometimes it can be the first manifestation. Although not always detected
in physical examination, splenomegaly is always present. Patients present with left upper
quadrant abdominal pain with or without radiation to the left shoulder. Kehr’s sign can be
elicited by applying gentle pressure to the patients abdomen while elevating the foot of the bed.
Abdominal pain should always point towards examination for splenic rupture. Immune
phenomena includes transient production of nonspecific antibodies such as heterophile
antibody, rheumatoid factor, antinuclear antibody, antismooth muscle antibody. Anemia is not
one of the manifestations of uncomplicated infectious mononucleosis, but a mild hemolytic
anemia that is frequently associated with a positive direct Coombs test can occur. A diverse
group of neurologic complications has been temporarily associated with infectious
mononucleosis, including Guillain- Barrй syndrome, cranial nerve palsies, aseptic meningitis
and meningoencephalitis. Metamorphosia a neuropsychiatric manifestation also referred to as
“Alice in Wonderland” syndrome because of its deficits in perception of size, shape and spatial
orientation of objects, has occasionally been associated with EBV infection. It is important to
understand that primary EBV infection is not synonymous with infectious mononucleosis.
Primary EBV can present with neurologic manifestations but without clinical evidence of
infectious mononucleosis.
DIAGNOSIS.
Isolation of EBV in standard cell cultures has not been possible, but indirect culture assays
exist. These test involve inoculation of EBV-infected body fluids (saliva) into cell cultures of
uninfected B-lymphocytes, such as human umbilical cord blood. Isolation of EBV does not
necessarily indicate acute primary infection and may reflect prolonged intermittent shedding
following primary infection of latency. Primary infection with EBV is associated with the
appearance of nonspecific heterophile antibodies. Long before EBV was recognized as the
primary causative agent of infectious mononucleosis, serologic tests were available.
Nonspecific heterophile antibodies were detected by the early tests, whereas antibody to EBVspecific antigens are detected by the newer assays. Heterophile antibodies are so-named
because they can react with antigens from unrelated species, it is one of the many products of
EBV infection. Infectious mononucleosis heterophile antibodies belong to the IgM class. They
are present in 60-70% of patients in the first week of clinical illness and in 80-90% by the
3 months of onset of symptoms in most patients but persisting in some patients for up to 12
months. Fifteen to 20% of patients with EBV-associated IM have negative heterophile antibody
tests. This rate is even higher in children younger than 4 years, approaching 50% in some
studies. Although a variety of diseases can produce heterophile antibody as well, such as
mumps, malaria, rubella, serum sickness and lymphoma, the concentrations of heterophile
antibodies achieved during these disease processes are much lower than those present in
patients with infectious mononucleosis. EBV-specific antibodies are useful for interpretation of
EBV-specific serology. These antigens are classified as early, late, or latent based on the phase
of viral replication in which they are produced. Early antigens are expressed early in the lytic
cycle; they are subclassified based on their distribution in the host cell: the restricted
component (EA/R) is limited to the cytoplasmic region of infected cells, whereas the diffuse
component (EA/D) is diffusely spread over the cytoplasm and membrane an is resistant to
methanol. Late antigens include viral capsid antigen (VCA) and the membrane antigen (MA).
EBV-infected host cells in latency phase express a nuclear antigen (EBNA). Antibodies to
these specific antigens can be detected by different methods including indirect
immunofluorescence assays, enzyme immunoassays, and immunoblot techniques. IgM
antibody to VCA appears at the onset of symptoms and then disappears within 1-3 months. IgG
antibody to VCA begins to rise at or shortly after onset of symptoms, peaks at 2 to 3 months,
then gradually decreases until it reaches a steady state concentration for life. Anti-EA/R
antibody is seen in children younger than 4 years with primary EBV infection or those with
subclinical infection. In patients with extended illness the antibody to EA/D is replaced by
antibody EA/R. Antibodies to EBNA appear during convalescence and persist for life. The
absence of detectable antibodies to EBNA together with the presence of IgM anti-VCA is
consistent with acute, primary infection. Because of the potential for false-positive IgM antiVCA measurements with elevated rheumatoid factor, it is prudent to obtain IgG anti-VCA
simultaneously. With past infection, there is no detectable IgM anti-VCA or IgG anti-EA,
whereas IgG anti-VCA and anti-EBNA concentrations are present. Remember: heterophile
antibody tests are a rapid, inexpensive method for diagnosis of recent EBV infection, but these
tests are limited by their nonspecificity but more importantly by their insensitivity, particularly
in young children.
DIFFERENTIAL DIAGNOSIS.
Causes of heterophile-negative infectious mononucleosis-like syndrome are varied, such as:
adenovirus, CMV, group A Я-hemolytic streptococci, hepatitis A virus, HHV-6, HIV, rubella,
Toxoplasma gondii, and also noninfectious causes like medications (phenytoin, sulfa) and
malignancies (lymphoma, leukemia). Of these, CMV is the most common cause of heterophilenegative infectious mononucleosis. An important cause to consider in the sexually active of
intravenous drug-using young adult is primary HIV infection. Many patients who have recently
acquired HIV infection have no symptoms, but some have a febrile illness indistinguishable for
EBV-associated infectious mononucleosis.
TREATMENT.
Treatment is primarily supportive, but in certain settings corticosteroid or antiviral therapy may
be considered. Limited activity to what is tolerated, administering antipyretics or analgesics for
relief of fever, sore throat and headaches; antibiotic use should be limited to documented
bacterial infections; strenous exercise and contact sports should be avoided for the duration of
splenomegaly, usually one month after onset of symptoms. To further reduce the risk of
spontaneous splenic rupture, consideration should be given to dietary changes to avoid
constipation and use of a mild laxative of constipation occurs. Acyclovir is a deoxyguanosine
analogue antiviral agent with activity limited to herpesvirus. When activated by viral thymidine
kinase, acyclovir competitively inhibits viral DNA polymerase, thereby blocking viral DNA
synthesis. Acyclovir is most active against HSV-1 and HSV-2 followed by VZV. Although
acyclovir does inhibit lytic EBV infection in vitro, it has no effect on latent or persistent
infection. Several studies show that oropharyngeal shedding of EBV was dramatically reduced
during acyclovir therapy, but EBV replication resumed when antiviral therapy was
discontinued. Duration of symptoms did not differ between acyclovir and placebo groups. The
anti-inflammatory
effects
of
corticosteroids
may
shorten
the
duration
of
fever,
lymphadenopathy, and constitutional symptoms, but controversy exists regarding the the use of
steroids for treatment of uncomplicated infectious mononucleosis because the potential risk for
steroid inhibition of the cellular immune response. Studies show no significant difference in
duration of symptomatology. Consequently, drug therapy for EVB-associated infectious
mononucleosis is very limited. Acyclovir is not recommended for acute EBV-associated
infectious mononucleosis and neither are steroids, except for reducing the edema in patients
with impending airway obstruction.
5. Test questions.
1. What is infectious mononucleosis?
2. What causes mono?
3. Who gets infectious mononucleosis?
4. How is infectious mononucleosis spread?
5. What are the symptoms of infectious mononucleosis?
6. How soon do symptoms appear?
7. When and for how long is a person able to spread infectious mononucleosis?
8. How is mono diagnosed?
9. What is the treatment for infectious mononucleosis?
10. What can a person do to minimize the spread of infectious mononucleosis?
11. Does patient need an antibiotic?
6. Literature:
1. Harrison A. Internal Diseases. Part of Infectious Diseases.
2. Nikitin E., Andreychyn M., Servetskyy K., Kachor V., Holovchenko A., Usychenko
E. Infectious Diseases. – Ternopil: Ukrmedknyga, 2004. – P. 179-198.