Serological cross reactivity to CMV and EBV causes problems in the diagnosis of acute hepatitis E virus infection

Abstract

Hepatitis E virus (HEV) infection is an important public health concern as a major cause of enterically-transmitted hepatitis worldwide. The detectable window of viraemia is narrow, and HEV IgM and IgG rise simultaneously in acute infection. Furthermore, previous investigators have shown HEV IgM false positive reactions occur against EBV, CMV and potentially hepatitis A. A retrospective analysis of HEV serology testing was performed at a London tertiary referral hospital over a 3-year period. A thousand four hundred and twenty three serum samples were tested for HEV serology, with 33 samples HEV IgM positive and 28 HEV IgM equivocal. One hundred and eleven samples were HEV IgG positive but IgM negative suggesting past infection. No patients with HEV IgM positivity had false positive reactions against hepatitis A. A high degree of EBV and CMV cross reactivity was noted, with 33.3% and 24.2% of HEV IgM positive samples also testing positive for EBV and CMV IgM, respectively. HEV RNA was detected in four HEV IgM positive samples, indicating true positivity, although three demonstrated cross reactivity against EBV. Only 13.3% of samples with positive HEV IgM were HEV PCR positive, highlighting a low positive predictive value of serology testing. Overall a high level of HEV, EBV and CMV IgM cross reactivity was demonstrated, indicating that serology is unreliable in the diagnosis of acute viral hepatitis. It is concluded that that the diagnosis of viral hepatitis should be based on clinical features, raised transaminases, serology, and confirmatory PCR testing.

Immunoglobulin M for Acute Infection: True or False?

“…In the first situation, multiple tests are performed for the same clinical syndrome and multiple positive results are generated, e.g., mononucleosis and CMV, EBV, and HIV infections (16)(17)(18)(19); acute hepatitis and HAV, HEV, CMV, and EBV infections (16,23,33); rash illness and measles virus, parvovirus, rubella virus, and HHV-6 infections (26,28,34,35); arbovirus CNS disease and WNV, St. Louis encephalitis (SLE) virus, and Jamestown Canyon virus infections (32,36); and arbovirus rash illness and Zika, dengue, and chikungunya virus infections (37,38). In the second situation, another etiology is confirmed by another method.…”

“…In other cases, the test results may be inconclusive and may be reported as representative of a recent flavivirus infection (http://www.cdc.gov /zika/hc-providers/diagnostic.html). Herpesviruses are commonly associated with increases in heterologous IgM levels, crossreactivity, or subclinical reactivations leading to multiple positive IgM test results (16,17). Lyme disease IgM immunoblotting is prone to false positives because of inappropriate ordering, weak criteria for positivity, and inaccurate reading (10).…”

“…Comments. Positive IgM antibodies to both CMV and EBV, as well as false-positive monospot test results, commonly occur in mononucleosis (16)(17)(18)(19), which obscures the true etiology. To confirm primary EBV infection, testing all three antibodies is key.…”

Serologic evidence for hepatitis E virus infection among patients with undifferentiated acute febrile illness in Kibera, Kenya

“…The investigators hypothesized that alternative infectious agents may cause cross-reactivity of HEV EIAs, resulting in false positives. Other research has demonstrated EIA cross reactivity between EBV and CMV [13–14], hepatitis A [15], and HIV [16–17], suggesting a ‘molecular mimicry’ phenomenon. Our findings of a significant association between HIV and HEV IgM positivity, lack of HEV RNA, and lower rates of HEV EIA positivity among healthy control residents may be suggestive of such a process.…”

A rare case of primary EBV infection causing acute acalculous cholecystitis

“…The patient's initial Monospot test was negative which reflects the high false negative rate reported during the first week of symptoms [23]. Subsequent EBV and CMV IgM antibodies were both positive, likely due to high levels of cross-reactivity [24]. EBV PCR finally confirmed the diagnosis of primary EBV infection.…”