The vagaries of IgM: a case report of EBV infection with concomitantly false-positive IgM for CMV, VZV, and HSV

Serum IgM (immunoglobulin M) testing is commonly used to diagnose acute viral infections. However, most clinicians are unaware of the vagaries of IgM testing, including antigenic cross-reactivity between multiple viruses and risk misdiagnosis. We report a case of infectious mononucleosis with concomitantly positive IgM for EBV, CMV, VZV, and HSV. A 26-year-old man presented with acute infectious mononucleosis picture. His blood work showed a total bilirubin level of 7.7 mg/dl, ALT 1077 U/L, AST 806 U/L, ALP 325 U/L, and INR 1.0. Monospot was positive; peripheral blood smear showed atypical lymphocytes; however, because EBV infectious mononucleosis does not typically cause elevation of liver enzymes over 1000, other etiologies were explored. Tests for hepatitis A, B, C, HIV, ANA, and ASMA returned negative. IgM for EBV-VCA, CMV, HSV, and VZV all returned positive, and the diagnosis of EBV IM was called into question. Subsequent tests of CMV and HSV PCR for viral load were negative (VZV was not clinically suspected), and later on, EBV-EBNA returned negative and EBV-VCA IgM and IgG returned positive, confirming the diagnosis of acute EBV infection. We believe that IgM seropositivity can result from cross-reactivity among several viruses (especially herpes viruses), and although often relied on, a positive IgM should not serve as the sole determinant for diagnosis of acute viral infections.


Background
Serum IgM testing is commonly used to diagnose many acute viral infections. However, despite many reports of false-positive results, most clinicians are unaware of the vagaries of IgM and they risk misdiagnosis. Here, we report a case of infectious mononucleosis with concomitantly positive IgM for EBV, CMV, VZV, and HSV

Case presentation
A previously healthy 26-year-old man presented with several days' history of fever, fatigue, nausea, and vomiting. He reported no illicit drug or alcohol use, no STD exposure, and no use of over-the-counter medications. He was noticed to have scleral icterus, palatal petechiae, and posterior cervical lymphadenopathy. Blood work revealed a lymphocyte predominant WBC of 16,000 cells/ uL, total bilirubin of 7.7 mg/dl, ALT 1077 U/L, AST 806 U/L, ALP 325 U/L, and INR 1.0. UDS; acetaminophen and alcohol levels were all negative. His Monospot test was positive, and the peripheral smear showed atypical lymphocytes, but because EBV infectious mononucleosis (IM) does not typically cause elevation of the liver enzymes over 1000, other etiologies were explored. Tests for hepatitis A, B, C, HIV, ANA, and ASMA came back negative; however, IgM for EBV-VCA, CMV, HSV, and VZV all returned positive and the diagnosis of EBV IM was called into question. Subsequently, tests for viral load were obtained; CMV and HSV PCR were both negative, and VZV was not suspected based on the clinical scenario, so it was not performed, and later on, EBV-EBNA returned negative and EBV-VCA IgM and IgG returned positive, confirming the diagnosis of acute EBV IM. See Table 1.

Discussion
Considering recent visit to his fiancée, compatible signs on physical exam (cervical LAD and palatal petechiae) and in addition to the presence of atypical lymphocytes in the blood smear and positive Monospot test suspicion for infectious mononucleosis was high; however, given the severity of the symptoms and significantly higher than expected elevation of the liver enzymes, we felt obligated to rule out other etiologies. Viral hepatitis panel including Hep A, B, and C were negative. Acetaminophen level, urine drug screen, and HIV test were all negative as well. Autoimmune workup including ANA and ASMA was also negative.
To our surprise, IgM for CMV, VZV, and HSV in addition to EBV-VCA all came back positive.
Subsequently and in order to confirm/rule out those infections, we obtained viral load for CMV and HSV (both of which came back negative). VZV molecular testing was not performed given very low suspicion for the disease. EBNA antibody was negative; EBV-VCA IgM and IgG were both positive confirming acute EBV virus infection [1].
The first association of parvovirus with false-positive IgM for measles was described in 1994 in Alaska [2]. Also, false-positive IgM for EBV capsid antigen was reported in approximately in 3% of patients with acute HIV and in 30% of acute hepatitis infection [3]. Different explanations have been suggested for this phenomenon such as concomitant infection with different viruses or reactivation of latent infection as EBV is known to cause transient immune suppression (this option was excluded in our case by negative viral load); it may also be the result of polyclonal stimulation of different B cells during acute EBV infection [4][5][6] or antigenic cross-reactivity especially among the herpes viruses [7].
Consequences for this phenomenon also vary; Landry ML et al. [8] describe several cases where a positive IgM titers and the clinical presentation did not "match." The diagnosis was then incorrectly based on the IgM titers leading to unnecessary testing and hospitalization, call back of high number of health care workers, inappropriate management of contacts, and even failure to provide antiviral therapy to meningitis cases.

Conclusion
We believe that IgM seropositivity can be a misleading diagnostic tool. False-positive IgM titers are common and have been reported in many cases; we believe that clinicians are still unaware and often over-rely on IgM titers to secure the diagnosis. IgM should not be used as the sole determinant of diagnosis and further confirmatory testing such as molecular tests or paired sera is required to confirm the diagnosis.