LAUSR

Dimitri Poddighe Department of Pediatrics, ASST Melegnano e Martesana, Vizzolo Predabissi, Milan and Department of Pediatrics, University of Pavia, Pavia, Italy Tsunoda et al. studied 68 immunocompetent children with acute liver dysfunction unrelated to hepatitis viruses. In particular, they focused on herpesviruses, such as cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpesvirus (HHV)-6. Mild–moderate elevation of liver enzymes in the plasma of patients with infectious mononucleosis is not an uncommon finding, whereas the development of severe hepatitis characterized by jaundice, alteration of coagulation parameters and increase of aspartate aminotransferase and alanine aminotransferase >10–20fold the normal values is an unusual event in this clinical setting, especially in immunocompetent children. In 2014 we described a case of severe EBV hepatitis in a previously healthy 7-year-old girl of Asiatic ethnicity. We achieved a diagnosis of primary EBV infection based on the serology only, given that specific viral capsid antigen (VCA)-immunoglobulin (Ig)M was clearly positive and, despite the presence of high VCA-IgG, EBV nuclear antigen (EBNA)-IgG was absent. The use of polymerase chain reaction (PCR) assay, however, was equally necessary, because it enabled exclusion of co-infection with other herpesviruses and, in particular, with CMV. Indeed, as it was in that case, CMV-IgM serology is often positive during EBV infection, due to antibody cross-reaction, but the co-infection cannot be excluded a priori and, especially in complicated and/or severe clinical settings, it is important to discriminate between viral serology cross-reaction and co-infection, which could affect the clinical course, as regards the duration and/or the severity. Therefore, we completely agree with Tsunoda et al. that the combination of PCR assay and viral serology must be used in order to achieve a precise etiological diagnosis in cases of severe acute liver dysfunction unrelated to hepatitis viruses, both in immunocompromised and immunocompetent children. Moreover, in their study, Tsunoda et al. noted that 10 children with negative EBV VCA-IgM were positive for the viral infection on PCR assay and, among those, two children also had negative EBV VCA-IgG. Interestingly, the latter patients were diagnosed with hemophagocytic lymphohistiocytosis and chronic active EBV infection. Thus, the combined analysis of EBV serology and PCR assay was able to identify children erroneously considered immunocompetent. Finally, thanks to the biochemistry data provided by the authors, we noted also that EBV-related hepatitis seemed to display a trend toward a greater increase of c-glutamyl transpeptidase (c-GTP), compared with both CMV and HHV-6 infections. Recently, we also reviewed acalculous acute cholecystitis (AAC) in previously healthy children, and described that most infectious cases of AAC were identified during EBV infection, in addition to hepatitis A virus hepatitis. Interestingly, in our study severe EBV hepatitis was also associated with AAC. Thus, a greater increase of c-GTP (often indicative of an underlying infectious AAC) might be associated with EBV infection more often, but further research including larger cases series is needed to support such a hypothesis. CMVrelated AAC was almost exclusively described in immunocompromised patients (because of transplantations or HIV infection) and, to our knowledge, only one pediatric case of AAC due to HHV-6 infection was reported very recently. Thus, a major increase in c-GTP in the clinical setting of acute liver dysfunction related to herpesviruses might support the suspicion of EBV infection, instead of CMV and HHV-6.