Infectious Mononucleosis Syndromes



Infectious Mononucleosis Syndromes


Carla S. Wilson, MD, PhD





Key Facts


Terminology



  • IM is an acute illness



    • Mainly due to EBV infection


    • ˜ 20% of cases due to CMV or other viral infection


Clinical Issues



  • EBV: Clinical triad of sore throat, fever, and lymphadenopathy


  • CMV: Persistent fever often predominates



    • Pharyngitis and tonsillitis are rare


Microscopic Pathology



  • Hallmark is peripheral blood findings



    • Lymphocytes and monocytes are > 50% of leukocytes


    • > 10% are atypical lymphocytes


    • Marked lymphocyte heterogeneity


  • EBV infection



    • Downey type II and III cells common


    • Autoimmune hemolytic anemia, primarily anti-i antibodies


  • CMV infection



    • Circulating infected endothelial cells in immunosuppressed individuals are diagnostic


  • Bone marrow evaluation usually not required



    • Nonspecific reactive changes: Lymphocytosis, plasmacytosis, granulomatous infiltrates


    • Transient bone marrow suppression


    • CMV-infected cells may appear normal or have “owl’s eye” viral inclusions


Ancillary Tests



  • Immunohistochemistry or in situ hybridization for EBV or CMV are confirmatory






A prominent lymphocytic reaction is present in this peripheral blood smear from a 16-year-old female with infectious mononucleosis and EBV-positive serology.






The blood film from an adolescent male with infectious mononucleosis shows prominent red blood cell clumping. This is caused by cold agglutinin disease associated with EBV infection.


TERMINOLOGY



Abbreviations



  • Infectious mononucleosis (IM)



Definitions



  • IM is an acute illness



    • Caused by primary viral infection



      • 80-90% Epstein-Barr virus (EBV)


      • 7-10% cytomegalovirus (CMV)


      • Other viruses


ETIOLOGY/PATHOGENESIS


Herpesvirus Family



  • Double-stranded DNA viruses



    • Envelope derived from host cell membrane


    • Symptomatic disease associated with lytic virus replication


    • Latent infection after recovery from acute infection


  • EBV



    • Gamma-1 herpes virus


    • Infects B cells



      • Receptors are CD21, MHC class II


      • Majority of infected B cells are rapidly cleared from circulation in immunocompetent individuals


      • Elicits T-cell and early natural killer (NK) cell response


    • Latency established in lymphoid cells or fibroblasts



      • EBV genome circularizes in nucleus of B lymphocytes and is replicated as an episome


      • Memory B cells remain quiescently infected and serve as reservoir for lifelong infection


  • CMV



    • Beta herpes virus


    • Infects epithelial cells, endothelial cells, neuronal cells, smooth muscle cells, fibroblasts, monocytes, macrophages, and T cells



      • Infects cells by endocytosis


      • Does not infect B cells


    • Cell-mediated immunity plays primary role in controlling infection


    • Individuals may develop primary or secondary infection



      • Primary infection occurs in seronegative individuals who were never previously infected


      • Secondary infection is activation of previously latent infection or reinfection by different CMV strain


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Clinically apparent IM



      • More common in populations with delayed primary EBV or CMV exposure


      • EBV-associated IM: 45.2 cases per 100,000 people per year in USA


      • May have primary EBV/CMV coinfection or mixed infection with other organism


    • Clinically silent infection



      • Usually infants or children


      • Frequently negative for heterophile antibody


    • CMV infection in immunosuppressed individuals



      • Most common viral opportunistic infection in AIDS; often multiple CMV strains


      • Reactivation of virus common in stem cell or solid organ transplant patients


      • Infection occurs 1-3 months after transplant if no prophylaxis, 4-8 months if failed prophylaxis treatment


      • CMV viremia seen in 30% of at-risk pediatric lung transplant patients


  • Age



    • Older age suggests CMV rather than EBV infection



      • EBV-associated IM is most prevalent in 15-24 year olds in the United States



      • CMV-associated IM usually affects 20-30 year olds; age range is 18-66 years


    • Age has significant impact on clinical expression



      • In young children, EBV is often asymptomatic or expressed as rashes, neutropenia, or pneumonia


      • Primary CMV in pregnant women may lead to congenital infection of neonate


  • Ethnicity



    • EBV-associated IM is 30x more frequent in whites than blacks


Presentation



  • EBV and CMV are spread through intimate contact



    • Often by asymptomatic shedders of virus to susceptible individuals



      • Spread through kissing, sharing of food, other intimate contact


    • Transmitted by blood transfusions and open heart surgery



      • Risk increases with increased volume of blood transfused


      • CMV also transmitted with leukocyte transfusions


      • Risk reduced when blood is screened for antibodies or with use of leukocyte-filtered/-reduced products


  • Symptoms of IM



    • EBV



      • Triad of sore throat, fever, lymphadenopathy


      • Symmetrical, slightly tender lymphadenopathy, especially posterior cervical region in adolescents


      • Hepatosplenomegaly, jaundice, rash


      • Malaise, headache, myalgias, chills, nausea


      • Studies suggest incubation period of 30-50 days


    • CMV



      • Systemic symptoms (typhoidal)


      • Persistent fever may predominate (average duration ~ 19 days)


      • Pharyngitis and tonsillitis are rare


      • Often mild asymptomatic hepatitis


      • Lymphadenopathy or splenomegaly is uncommon but may occur


      • Interstitial pneumonia is a rare complication, especially in stem cell recipients


Laboratory Tests



  • CBC and peripheral blood smear



    • Peripheral blood smear findings often precede heterophile antibody positivity in EBV infection


    • Morphologic findings help in making diagnosis



      • Confirmation of EBV infection is required in heterophile negative cases


      • Diagnosis of CMV infection requires laboratory confirmation


  • Heterophile antibody (monospot) test



    • Positive



      • Majority of EBV-associated IM


      • 90% of adolescents, 80% of children > 4 years of age


      • EBV-specific serology unnecessary to make diagnosis


      • Occasional patients with lymphoma or hepatitis are positive


    • Negative



      • 50% of young children with symptomatic EBV infection


  • EBV-specific antibody test by indirect immunofluorescence



    • Acute EBV infection



      • Elevated IgM antibody to anti-viral capsid antigens (VCAs) detected in 80% of children > 4 years


      • Anti-early antigens (anti-EAs)


      • Antibody to EBV nuclear antigen (EBNA) 3-4 weeks after onset


    • EBV viral load



      • EBV DNA quantitated with real-time PCR


      • Not usually necessary for diagnosis of IM


      • Helpful for evaluation of other EBV-associated diseases


  • CMV testing



    • CMV pp65 antigenemia assay



      • Detects CMV-infected leukocytes in blood


      • Results generally available within 24 hours



    • Molecular tests for active infection



      • Quantitative PCR for viral load


      • Hybridization capture assay using RNA probes for CMV DNA


    • Shell viral cultures using monoclonal probes to early antigens


  • Liver function tests



    • Abnormal in almost all cases


    • Maximum elevation in 2nd week of illness


  • Immunologic findings possible with EBV or CMV



    • Cryoproteins or cold agglutinins



      • Slightly increased in 90-95% of patients with EBV infection


    • Rheumatoid factor


    • Antinuclear antibodies


    • Anti-complement antibodies


Natural History



  • Most patients with IM recover without complications



    • EBV IM spontaneously resolves in 2-3 weeks


  • Complications of EBV



    • Autoimmune hemolytic anemia (< 3% of patients)



      • IgM-type cold agglutinin


      • Anti-i specificity in 20-70% of cases


    • Splenic rupture


    • Death



      • Rare; secondary to neurologic complications, splenic rupture, upper airway obstruction


  • CMV infection in immunocompetent individuals



    • Infection is usually self-limiting with low mortality


  • CMV infection in immunosuppressed individuals



    • Development of CMV pneumonia after transplantation or chemotherapy; may be life-threatening


  • Complications of secondary CMV infection



    • Interstitial pneumonitis, hepatitis, Guillain-Barré syndrome, encephalitis, retinitis


    • Gastrointestinal infections, pericarditis, myocarditis, myeloradiculopathy



Treatment



  • Supportive therapy is sufficient in most cases


  • Corticosteroids for EBV-associated complications



    • Tonsillar enlargement with compromised airway


    • Autoimmune hemolytic anemia


    • Aplastic anemia


  • Antiviral therapy for CMV in immunocompromised patients



    • Ganciclovir, foscarnet, cidofovir


MICROSCOPIC PATHOLOGY


EBV-Associated Peripheral Blood Findings

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Infectious Mononucleosis Syndromes

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