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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.