INFECTIOUS DISEASE DILEMMAS
Educational Objectives
| The goal of this program is to improve the management of Epstein-Barr virus (EBV) infection and acute otitis media (AOM). After hearing and assimilating this program, the clinician will be better able to: |
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1. Describe the host response to EBV infection. |
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2. Recognize the key symptoms (clinical triad) and physical examination findings of infectious mononucleosis (IM). |
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3. Utilize the appropriate laboratory tests to diagnose IM. |
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4. Recognize the importance of analgesia and education in the treatment of AOM. |
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5. Determine when observation is appropriate for AOM. |
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgements
Dr. Eppes was recorded at Pediatric Infections and Pulmonary Diseases: Perspectives 2008, held September 5-7, 2008, in Rehoboth Beach, DE, and sponsored by Nemours. Dr. Homme was recorded at Pediatrics for the Primary Care Physician, held June 27-29, 2008, in Amelia Island, FL, and sponsored by Nemours. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
Epstein-Barr Virus
Stephen C. Eppes, MD, Professor of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, and Chief, Division of Infectious Diseases, Alfred I. duPont Hospital for Children, Wilmington, DE
Epstein-Barr Virus (EBV)
| History: syndrome of glandular fever (drusenfieber) described by German physicians in late 1800s; early 1900s— infectious mononucleosis (IM) thought to be form of leukemia that went into spontaneous and permanent remission; 1920s—investigators characterized IM; Downey and McKinlay gave detailed description of atypical lymphocytes; 1930s—Paul, Bunnell, and Davidson described heterophile antibodies (diagnostic marker); 1950s — Burkitt discovered African type of lymphoma (Burkitt’s lymphoma); 1960s—using electron microscopy, Epstein and Barr discovered herpes-like particles in Burkitt’s lymphoma (not culturable); Henles developed indirect fluorescent antibody (IFA) test; laboratory worker infected with IM, and IFA test used to determine that IM caused by EBV; 1970s—role of EBV in lymphomas and other tumors sought; 1980s—chronic mononucleosis theory; association of EBV with posttransplantation lymphoproliferative disease (PTLD); role of EBV in multiple sclerosis |
| Biology: herpesvirus; infects only humans and other primates; infects pharyngeal epithelial cells and B lymphocytes; causes lytic and latent infection; transforms and immortalizes B lymphocytes; double-stranded DNA genome; has envelope and capsid antigens (basis of diagnostic tests) |
| Host response: robust and complex immune response to virus seen in humans; starts with infection in oropharynx (epithelial cells become infected and die); B lymphocytes—become infected and dispersed through circulation; responsible for production of heterophile antibodies and EBV-specific antibodies that have negative feedback on infection; T lymphocytes—also involved by direct effect or production of lymphokines; have negative feedback on primary infection; develop into atypical lymphocytes; cellular immune response involves cytotoxic T lymphocytes (CD8 cells) and natural killer cells; in primary stages, EBV infection causes anergy and variable degrees of immune deficiency; virus detectable in oropharyngeal secretions for months or years after primary infection and sometimes intermittently shed throughout lifetime of individual |
| Epidemiology: ubiquitous infection; most adult populations seropositive; people from lower socioeconomic strata or developing countries almost always acquire infection during childhood; in United States, ≈50% of children seropositive by 5 yr of age; incidence of IM 45 cases/100 000 annually; rate of IM highest in 15- to 24-yr age range; common cause of hospitalizations at universities and days missed in military; in only 6% of cases does individual infected with IM recall contact with another individual with IM; facilitated by kissing and recently associated with sexual activity; low contagiousness; occasionally acquired through blood transfusion |
| Acute EBV infection: young child likely to have subclinical or mild illness; immune response and disease expression age-dependent; even in adolescents and young adults, inapparent infection more common than clinically apparent one |
Infectious Mononucleosis
| Characteristics: clinical triad of fever, sore throat, and lymphadenopathy; EBV causes all cases of heterophile-positive and most cases of heterophile-negative IM; other etiologies include other viruses (eg, cytomegalovirus [CMV], HIV); incubation period 4 to 6 wk; duration of symptoms 2 to 3 wk; symptoms experienced by most include sore throat, malaise, headache, and anorexia; occasional abdominal and respiratory symptoms (primarily in younger children); physical findings—lymphadenopathy, pharyngitis, and fever in majority; splenomegaly in 50%; hepatomegaly and palatal enanthema in small percentage; jaundice infrequent; rash in younger children; findings according to age—younger children more likely to have splenomegaly, hepatomegaly, respiratory (upper and lower) symptoms, and even changes on chest x-ray; older children more likely to have exudative tonsillitis |
| Complications: hematologic—thrombocytopenia part of infection; autoimmune hemolytic anemia; hemophagocytic lymphohistiocytosis (EBV leading cause); neutropenia (usually mild) part of disease and seen in majority of patients; splenic rupture—dreaded complication; typically occurs in second or third week (possibly earlier); often associated with trauma, but may be spontaneous; no good data to answer question of when safe for teenage athlete with EBV infection to resume sports activities; consensus that safe to return if individual afebrile, well hydrated, clinically asymptomatic, and without palpable spleen; secondary infections—common, since IM temporarily immunocompromising; include Candida and herpesvirus (herpes simplex virus and varicella zoster virus); encephalitis—sometimes most pronounced clinical manifestation; presents with headache, combativeness, seizures, and sometimes focal neurologic findings; often presents early and can be heterophile-negative; other neurologic conditions—metamorphopsia (“Alice in Wonderland” syndrome); spinal cord involvement; Guillain-Barre syndrome; facial palsy; rare complications include pulmonary, cardiac, and renal effects |
| Hospitalization: top 3 reasons include need for diagnostic tests, airway obstruction, and dysphagia with dehydration |
| Mortality: uncommon; infection usually self-limited; X-linked lymphoproliferative syndrome (development of malignancy or profound immune deficiency); splenic rupture usually in older children and young adults; airway obstruction in young children |
| Recovery: rule is 2 to 3 wk for acute signs and symptoms to improve; sometimes 6 mo for malaise; speaker emphasizes return to school as primary goal; “chronic mononucleosis” does not exist; any recurrence probably due to another virus; splenic enlargement, when significant, usually palpable |
| Chronic fatigue: associated with EBV; recent study found genetic basis |
| Laboratory findings: complete blood cell count (CBC) generally shows atypical lymphocytosis; neutropenia and thrombocytopenia usually mild; elevation of transaminases seen in 50% of cases; jaundice occasionally seen |
| Laboratory diagnosis: several components of immune response measurable; heterophile antibodies—observed that serum from individual with IM agglutinates certain mammalian red blood cells (RBCs); Monospot test— commonly used; uses latex beads; easy to perform; highly specific (100%); heterophile response age-dependent and usually occurs in second and third week after infection; age-related sensitivity of Monospot test—usually negative if patient <2 yr of age; ≈40% in early childhood; by teenage years, ≈90% |
| EBV-specific antibody titers: determined by immunofluorescence and enzyme-linked immunosorbent assay (ELISA) techniques; IgG and IgM antibodies to viral capsid antigen measured; also antibodies to early antigens (EA), which come in 2 forms (diffuse [D] and restricted [R], based on IFA staining pattern); D pattern more common in IM; R pattern may persist for years (causes problems diagnostically); antibodies to EB nuclear antigen (EBNA; IgG antibody ) associated with infection in past; antibody titers at given times after infection—first see IgM response to viral capsid antigen; usually subsides after few months, but 15% have R pattern that lasts for years; IgG rises shortly after IgM and stays positive for lifetime of individual; EBNA late-occurring antibody (4-6 mo after infection) and stays positive for lifetime of individual; presence of IgM means acute or recent infection; presence of IgG and EBNA means infection at least 4 to 6 mo previously; how to use laboratory tests—start with Monospot test and CBC (looking for atypical lymphocytes); if Monospot test positive, patient has IM; if negative but CBC suspicious, patient may have acute EBV infection and repeat Monospot test warranted; if Monospot test negative and CBC negative, probably not IM; EBV titers used when first test not diagnostic or in young child who may not have heterophile response |
| Other EBV-associated conditions: in normal hosts—African-type Burkitt’s lymphoma; nasopharyngeal carcinoma; hemophagocytic lymphohistiocytosis (HLH); lymphoma (Hodgkin’s and non-Hodgkin’s); multiple sclerosis; in immunocompromised hosts—X-linked lymphoproliferative syndrome; lymphoma and leukemia; oral hairy leukoplakia (in HIV patients); lymphoid interstitial pneumonitis (in children with HIV) |
| Treatment: antiviral drugs—acyclovir and ganciclovir have antiviral activity in vitro, but not effective in IM; rituximab—anti-CD20 monoclonal antibody; attacks certain kinds of B lymphocytes harboring EBV; used to treat PTLD; supportive care—appropriate for most people; rest, fluids, antipyretics, observation for complications, and counseling; corticosteroids—often given for acute EBV infection; may upset immune response; useful for airway obstruction, severe hematologic complications (idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia), and encephalitis |
Otitis Media: The New Equation
Jason (Jay) H. Homme, MD, Assistant Professor, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN
| Epidemiology: >75% of children, by 3 yr of age, have had 1 episode; accounts for 40% of physician visits; common causative pathogens include Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Moraxella catarrhalis , and certain viruses; number one reason for prescription antibiotics for children in United States; estimated 15 million prescriptions annually; cost $2 to $5 billion annually; one of major contributors to antibiotic resistance |
| Diagnosis: not easy; wide variation among practitioners; issues—difficult patients; uncertainty about diagnostic criteria; pressure from caregivers; patients—otherwise healthy children, ≥2 mo of age, with no AOM in past 30 days and no recent antibiotic use (within previous 2-3 mo); components—recent or abrupt onset of illness, presence of middle ear effusion (MEE), and signs and symptoms of middle ear inflammation; MEE—eardrum bulging or appears full; limited or absent mobility (using insufflator); air-fluid level or air bubbles; otorrhea; middle ear inflammation—bulging or full tympanic membrane and distinct erythema or distinct ear discomfort (otalgia; prevents normal activity or disrupts sleep); pitfalls in diagnosis—cerumen blocking eardrum; noncompliant patient; 3-dimensional vs 2-dimensional view; neglecting to assess mobility; American Academy of Pediatrics tutorial www.aap.org/otitismedia |
| Treatment: involves analgesia, education, antibiotics, and observation; analgesia—speaker considers mandatory; appropriate doses of acetaminophen or ibuprofen most effective; analgesic ear drops (antipyrine and benzocaine [A/B otic drops; formerly Auralgan]); speaker gives prescription for analgesic ear drops in advance (shown to reduce visits to emergency department and acute visits to clinic); education—mandatory; teach families signs and symptoms suggestive of ear infection; home care measures; when to see doctor; preventive measures (eg, breast- feeding, avoiding passive exposure to smoke); antibiotics—optional; for most of patient population, amoxicillin appropriate choice; necessary to know practice setting to determine whether standard dosing or high dosing needed; other reasonable choices, as stated in Centers for Disease Control and Prevention (CDC) guidelines, include amoxicillin–potassium clavulanate (Augmentin; 80-90 mg/kg commonly used), cephalosporin, ceftriaxone (not first option), and others; amoxicillin first-line treatment; duration of antibiotic treatment—traditionally 10 days; other factors to consider include age (younger child more likely to require longer course), severity of illness (bilateral disease more likely to have longer duration of symptoms and potentially longer course of treatment), and presence of risk factors for resistance (eg, recent antibiotic use, daycare setting); observation—commonly practiced in Europe; due to high resolution rate for uncomplicated AOM (75%-80%); appropriate in children with nonsevere disease, absence of complicating factors, and reliable follow-up; has led to wait-and-see prescription (WASP) or safety-net antibiotic prescription (SNAP); spontaneous resolution leads to improvement in symptoms within 24 to 72 hr; no reports of higher rate of complications in those countries where antibiotics infrequently used |
| Summary of guideline recommendations: accurate diagnosis of AOM; pain relief; option for observation and treatment if necessary; antibiotics for those most likely to benefit; amoxicillin appropriate for most children |
| Speaker’s method: make attempt at accurate diagnosis (eg, using insufflator regularly); stratify patients according to age, recent antibiotic use, and history of complications; if child ≥2 yr of age with uncomplicated infection, observation recommended (study found that children <2 yr of age more likely to have persistent symptoms requiring treatment); educate family about home care measures (eg, weight-appropriate dosing, analgesic ear drops) and who and how to call if questions arise; amoxicillin first choice (generally in high doses), unless patient has had recent antibiotics or has allergy or is intolerant; if patient <15 mo of age, 10-day course (shorter courses [5-7 days] for those 15 mo to 2 yr of age); observation and WASP for those >2 yr of age; new equation states AOM does not necessarily mean antibiotics |
Suggested Reading
Chao JH et al: Comparison of two approaches to observation therapy for acute otitis media in the emergency department. Pediatrics 121:e1352, 2008; Fafi-Kremer S et al: Long-term shedding of infectious epstein-barr virus after infectious mononucleosis. J Infect Dis 191:985, 2005; Higgins CD et al: A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J Infect Dis 195:474, 2007; Hurt C et al: Diagnostic evaluation of mononucleosis-like illnesses. Am J Med 120:911, 2007; Little P: Delayed prescribing--a sensible approach to the management of acute otitis media. JAMA 296:1290, 2006; Meropol SB: Valuing reduced antibiotic use for pediatric acute otitis media. Pediatrics 121:669, 2008; Mischler M et al: Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease: a mimicker of sepsis in the pediatric intensive care unit. Pediatrics 119:e1212, 2007; Pohl D et al: High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 67:2063, 2006; Ramakrishnan K et al: Diagnosis and treatment of otitis media. Am Fam Physician 76:1650, 2007; Siegel RM et al: A safety-net antibiotic prescription for otitis media: the effects of a PBRN study on patients and practitioners. Clin Pediatr (Phila) 45:518, 2006; Spiro DM et al: Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial. JAMA 296:1235, 2006; Thompson SK et al: Infectious mononucleosis and corticosteroids: management practices and outcomes. Arch Otolaryngol Head Neck Surg 131:900, 2005; Varrasso DA: Otitis media: the need for a new paradigm in medical education. Pediatrics 118:1731, 2006; Williams H et al: Analysis of immune activation and clinical events in acute infectious mononucleosis. J Infect Dis 190:63, 2004; Yamamoto LG et al: Does crying turn tympanic membranes red? Clin Pediatr (Phila) 44:693, 2005.
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