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A Diagnostic Blind Spot: Acute Infectious Mononucleosis or Acute Retroviral Syndrome

      To the Editor:
      Acute retroviral syndrome and acute infectious mononucleosis have similar clinical presentations and require definite diagnosis to be made by serological studies. However, sensitivity and specificity of these tests are not perfect. We report a case of a middle-aged woman with acute infectious mononucleosis who was initially misdiagnosed with acute human immunodeficiency virus (HIV) infection.

      Case Presentation

      A 60-year-old woman without significant past medical history presented to our institution with a 2-week history of fever and myalgias. She reported recent unprotected sexual encounters with a new male partner. Physical examination was remarkable for icteric sclera, multiple sub-centimeter cervical lymphadenopathy, and marked splenomegaly. Initial laboratory investigation was remarkable for leukopenia, thrombocytopenia, elevated lactate dehydrogenase, and abnormal liver enzymes suggestive of a cholestatic pattern. Computed tomography scan of abdomen and pelvis demonstrated splenomegaly without intra-/extrahepatic duct dilatation or other pathology. Initial investigations, including monospot test (Sure-Vue Mono, Fisher HealthCare, Pittsburgh, Pa), blood culture for bacteria, mycobacterium and fungus, viral hepatitis profile, polymerase chain reaction and antibody test for cytomegalovirus, anaplasmosis and ehrlichiosis, serum cryptococcal antigen, urine histoplasma antigen, and review of peripheral blood smears, were negative. The result of the third generation of HIV enzyme-linked immunosorbent assay (ADVIA Centaur, Siemens, Erlangen, Germany) was positive, and she was given a preliminarily diagnosis of acute retroviral syndrome. However, her subsequent HIV Western blot (GS HIV-1 Western blot, Bio-Rad Laboratories, Hercules, Calif) and viral load (COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, Roche Molecular Systems Inc., Pleasanton, Calif) were negative. A repeat monospot test performed 9 days after the first was positive, as were the Epstein-Barr virus viral capsid antigen immunoglobulin M and the serum polymerase chain reaction for Epstein-Barr virus DNA. She was finally diagnosed with acute infectious mononucleosis with false-positive enzyme-linked immunosorbent assay for HIV antibody test.

      Discussion

      Infectious mononucleosis caused by Epstein-Barr virus and mononucleosis-like illnesses caused by other viruses, particularly cytomegalovirus and HIV, are often clinically indistinguishable, requiring definite diagnosis to be made by serology.
      The heterophile antibody test or monospot test is a widely used screening test for acute infectious mononucleosis caused by Epstein-Barr virus, but has a sensitivity of only 75% during the first week of illness, which may increase to 85% in later stages of the illness.
      • Hurt C.
      • Tammaro D.
      Diagnostic evaluation of mononucleosis-like illnesses.
      • Luzuriaga K.
      • Sullivan J.L.
      Infectious mononucleosis.
      Although the enzyme-linked immunosorbent assay test for HIV is generally considered a very sensitive and specific screening test (100% sensitivity and 99.9% specificity for ADVIA Centaur),

      Siemens Healthcare Diagnostics. HIV 1/O/2 Enhanced (EHIV) Assay for the Detection of Antibodies to Human Immunodeficiency Virus Type 1, Including Group O (HIV-1 + “O”) and/or Type 2 (HIV-2) [ADVIA Centaur and ADVIA Centaur XP assay manual]. Tarrytown, NY: Siemens Healthcare Diagnostics. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/ucm091286.pdf. Accessed Feb 24, 2013.

      a positive result is routinely confirmed by a Western blot analysis. Our patient had a perfect combination of a falsely negative monospot test and a falsely positive enzyme-linked immunosorbent assay test for HIV, leading to the incorrect preliminary diagnosis of acute retroviral syndrome. The probability of this happening would be 1-2 in 10,000. We hypothesize that her Epstein-Barr virus infection was the cause of the falsely positive enzyme-linked immunosorbent assay for HIV test. Even though the association between Epstein-Barr virus infection and false positivity has been documented,
      • Mortimer P.P.
      • Parry J.V.
      • Mortimer J.Y.
      Which anti-HTLV III/LAV assays for screening and confirmatory testing?.
      the data from the package insert disclose that ADVIA Centaur did not have cross-activity in positive Epstein-Barr virus immunoglobulin M and immunoglobulin G patients.

      Siemens Healthcare Diagnostics. HIV 1/O/2 Enhanced (EHIV) Assay for the Detection of Antibodies to Human Immunodeficiency Virus Type 1, Including Group O (HIV-1 + “O”) and/or Type 2 (HIV-2) [ADVIA Centaur and ADVIA Centaur XP assay manual]. Tarrytown, NY: Siemens Healthcare Diagnostics. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/ucm091286.pdf. Accessed Feb 24, 2013.

      Our case illustrates how a diagnostic blind spot can be created by the intersection of a false-positive result of one diagnostic test in combination with a false negative of another. Clinicians need to understand the limitations of the diagnostic testing, especially when multiple tests are used in combination. We hypothesize that if a fourth-generation HIV test that incorporates the detection of P24 antigen had been used, the incorrect initial diagnosis may have been avoided.

      References

        • Hurt C.
        • Tammaro D.
        Diagnostic evaluation of mononucleosis-like illnesses.
        Am J Med. 2007; 120: 911.e1-911.e8
        • Luzuriaga K.
        • Sullivan J.L.
        Infectious mononucleosis.
        N Engl J Med. 2010; 362: 1993-2000
      1. Siemens Healthcare Diagnostics. HIV 1/O/2 Enhanced (EHIV) Assay for the Detection of Antibodies to Human Immunodeficiency Virus Type 1, Including Group O (HIV-1 + “O”) and/or Type 2 (HIV-2) [ADVIA Centaur and ADVIA Centaur XP assay manual]. Tarrytown, NY: Siemens Healthcare Diagnostics. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/ucm091286.pdf. Accessed Feb 24, 2013.

        • Mortimer P.P.
        • Parry J.V.
        • Mortimer J.Y.
        Which anti-HTLV III/LAV assays for screening and confirmatory testing?.
        Lancet. 1985; 2: 873-877