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Italian children seem to be spared from the mysterious severe acute hepatitis outbreak: A report by SIGENP Acute Hepatitis Group

      Keywords

      To the Editor:
      In the period April 5th-May 26th, 650 probable cases of severe acute hepatitis of unknown origin from 33 countries were reported to the World Health Organization (WHO).
      World Health Organization
      Disease outbreak news; acute hepatitis of unknown aetiology in children - multi-country.
      So far, due to the absence of a defined aetiology, only either probable or epi-linked cases can be considered. According to the WHO, a probable case is defined as an individual aged 16 or younger presenting since 1 October 2021 with an acute hepatitis (non hep A-E) characterized by serum aminotransferases >500 IU/L (AST or ALT).
      World Health Organization
      Disease outbreak news; acute hepatitis of unknown aetiology in children - multi-country.
      Although several pathogens have been isolated in the reported cases, none of them have been clearly demonstrated to be causal. In the absence of defined diagnostic criteria, it is very difficult to understand how the few cases of severe acute hepatitis reported in countries other than the UK have been assimilated to the latter. Despite the presumed infectious origin of the outbreak, there were no family clusters except for 2 children who were close contacts with 2 other cases.
      • Marsh K.
      • Tayler R.
      • Pollock L.
      • Roy K.
      • Lakha F.
      • Ho A.
      • et al.
      Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022.
      Furthermore, in the reports available so far, an extensive evaluation of the non-infectious causes of acute hepatitis was not always carried out.
      • Mücke M.M.
      • Zeuzem S.
      The recent outbreak of acute severe hepatitis in children of unknown origin - what is known so far.
      ,
      • de Kleine R.H.
      • Lexmond W.S.
      • Buescher G.
      • Sturm E.
      • Kelly D.
      • Lohse A.W.
      • et al.
      Severe acute hepatitis and acute liver failure of unknown origin in children: a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022.
      On the other hand, a trend towards the overestimation of cases following the emotional wave of the COVID-19 pandemic cannot be excluded.
      A survey study was conducted by the liver group of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) for a case estimation in Italy in the period January-May 2022 using a permanent mailing list that includes all the main paediatric liver units distributed throughout the country. The online survey aimed to explore the demographic and clinical features of the observed cases, the identified aetiologies, the diagnostic work-up, the outcome of the patients, and comparison with the previous 3 years.
      On May 20, 27 Italian paediatric centres, including 4 paediatric liver transplant centres, reported on 44 patients. Six patients were excluded: 5 because of AST and ALT values <500 IU/L and 1 because they fell outside the study period. In 4/38 cases, a putative aetiology was later found: 2 autoimmune hepatitis (AIH), 1 coeliac disease in which the rise in transaminases was explained by an influenza infection (with AST and ALT decreasing before the start of the gluten free diet), and 1 myositis with liver involvement due to Mycoplasma infection. Among the 34 patients fulfilling inclusion criteria (median age 51.5 months, range 1-171), 18 (52.9%) aged <5 years, 24 (70.6%) were observed between March and May 2022. Only 2 cases had a recent travel history. The geographic distribution of the cases was: Northern Italy 17 (50%), Centre 8 (23.5%), Southern and Islands 9 (26.5%). The most frequent symptoms were: fever (52.9%), vomiting (47.1%), abdominal pain (38.2%), diarrhoea (26.5%), jaundice (20.6%), other (38.2%). Acute liver failure (international normalized ratio >2) was diagnosed in 3 patients.
      • Di Giorgio A.
      • Bartolini E.
      • Calvo P.L.
      • Cananzi M.
      • Cirillo F.
      • Della Corte C.
      • et al.
      Diagnostic approach to acute liver failure in children: a position paper by the SIGENP liver disease working group.
      HAV and HEV results were not available at the survey time in 17.6% and 58.8%, respectively. Notably, HEV infection is rarely observed in Italian children.

      EpiCentro - Istituto Superiore di Sanità website. Epidemiology - SEIEVA data (Publication date: 15 January 2021). Available at: https://www.epicentro.iss.it/en/hepatitis/data-seieva#e.

      HBV and HCV infections were ruled out in 31 (91.2%) and 25 (73.5%) patients, respectively. HBV and HCV screening was probably not performed in the entire population because HBV mass vaccination has been implemented in Italian infants for many decades and HCV rarely shows an acute course.
      • Stroffolini T.
      • Morisco F.
      • Ferrigno L.
      • Pontillo G.
      • Iantosca G.
      • Cossiga V.
      • et al.
      Effectiveness of hepatitis B vaccination campaign in Italy: towards the control of HBV infection for the first time in a European country.
      Four of 31 (12.9%) patients were vaccinated for SARS-CoV-2 (3 with 2 doses) supporting the absence of a role of the vaccine in triggering this condition. 38.2% had history of COVID-19 of whom 53.8% had it within the 3 months prior to observation.
      Infectious agents were detected in 21/34 (61.8%) cases of which 12 (57.1%) showed multiple infections. In 9/21 patients, one or more potentially hepatotropic agents were identified: cytomegalovirus, Epstein-Barr virus, Leishmania, E. Coli, HHV6 and 7, Norovirus, Rotavirus. SARS-CoV-2 was positive in 4 (11.8%) patients. 26 patients were tested for Adenovirus and 6 (23.1%) were infected. None had SARS-CoV-2/Adenovirus co-infection. The other agents identified were Rhinovirus, Parvovirus, Metapneumovirus, Paraechovirus, Enterovirus, Influenza A, Coronavirus OC43, Salmonella paratyphi, C. Difficile, and S. Pneumoniae.
      The results from our study suggest a poor association of SARS-CoV-2 and Adenovirus infection with severe acute hepatitis. This fits with the relatively small number of cases of severe acute hepatitis compared to the millions of people who have had COVID-19 in the context of the pandemic. The finding of multiple infectious agents in our patients with severe acute hepatitis, on the one hand, may reflect greater attention to the problem and, on the other, could be explained by an increased circulation of infections after 2 years of social restrictions. SARS-CoV-2, Adenovirus, Norovirus, Herpesvirus and other viruses have already been reported as possible causes of acute hepatitis, even if not so commonly.
      • Lee Y.
      • Yi D.Y.
      • Lee Y.M.
      • Choi S.Y.
      • Choi Y.J.
      • Lee K.J.
      A multicenter study of real-world practice for management of abnormal liver function tests in children with acute infectious diseases.
      Furthermore, Italian experience does not seem to support the hypothesis that previous COVID-19 causes an aberrant immune response to common circulating viruses in naive children.
      • Paraskevis D.
      • Papathedoridis G.
      • Sypsa V.
      • Sfikakis P.
      • Tsiodras S.
      • Zaoutis T.
      A proposed etiology for an aberrant response to enteric adenovirus infection in previously SARS-CoV-2-infected children with acute hepatitis.
      Since children commonly have severe elevations of aminotransferases from non-infectious causes, patients were investigated for myopathies, AIH, coeliac disease, α1-antitrypsin deficiency and Wilson disease. Further data on diagnostic work-up performed in our patients are reported in Table 1.
      Table 1Diagnostic work-up performed in 34 children with severe acute hepatitis and results.
      Diagnostic TestNumber of patients in which the test has been performedPositive test result
      SARS-CoV-2 nasopharyngeal swab34 (100%)4 (11.8%)
      Adenovirus testing26 (76.5%)6 (23.1%)
       Nasopharyngeal swab155 (33.3%)
       Blood101 (10%)
       Faeces122 (16.7%)
       Serology82 IgM + (25%)
      Multiplex PCR nasopharyngeal swab15 (44.1%)12 (80%)
      Multiplex PCR whole blood14 (41.2%)5 (35.7%)
      Multiplex PCR faeces10 (29.4%)5 (50%)
      Creatine phosphokinase23 (67.6%)0
      Antitransglutaminase IgA17 (50%)0
      Ceruloplasmin14 (41.2%)2 (14.3%)
      Both patients were under 3 years of age with acute liver failure possibly causing mild hypoceruloplasminemia and without other signs of Wilson's Disease.
      α1-antitrypsin17 (50%)0
      Liver autoantibodies20 (58.8%)6 (30%)
      No patients fulfilled diagnostic criteria for autoimmune hepatitis.
      Both patients were under 3 years of age with acute liver failure possibly causing mild hypoceruloplasminemia and without other signs of Wilson's Disease.
      ∗∗ No patients fulfilled diagnostic criteria for autoimmune hepatitis.
      None of the enrolled patients satisfied criteria for drug-induced liver injury. The attention to these non-infectious causes is probably a strong point of this survey. Overall, no putative cause of hepatitis was found in 15 (44.1%) patients. At the last follow-up (data on 26 patients), 20 (76.9%) recovered without complications, 5 (19.2%) showed the following abnormalities: aplastic anaemia (1), bone marrow aplasia (1), persistent or relapsing elevation of aminotransferases (3). Only 1 patient was liver transplanted 20 days after symptoms onset without a defined cause. None of the centres reported an increased number of severe hepatitis cases compared to the past 3 years. The number of severe acute hepatitis cases was also compatible with those notified to the European Centre for Disease Prevention and Control in recent months.

      European Centre for Disease Prevention and Control (ECDC) 2022. Epidemiological update issued 19 May 2022: hepatitis of unknown aetiology in children (Epidemiological update 19 May 2022). Available at: https://www.ecdc.europa.eu/en/news-events/epidemiological-update-issued-19-may-2022-hepatitis-unknown-aetiology-children.

      In conclusion, although 44 cases were initially reported in Italy, only 15 had severe acute hepatitis without any putative cause and with a favourable outcome in almost all cases with only 1 patient requiring a liver transplant. The data are similar to those observed in the past years in Italian children.

      Financial support

      No financial support was provided for this study.

      Authors’ contributions

      Fabiola Di Dato: Substantial contributions to the conception or design of the work; Acquisition, analysis, or interpretation of data for the work AND Drafting the work; AND Final approval of the version to be published. Angelo Di Giorgio: Substantial contributions to the conception or design of the work AND Acquisition, analysis, or interpretation of data for the work; AND Final approval of the version to be published. Claudia Mandato: Substantial contributions to the design of the work AND revising it critically for important intellectual content; AND Final approval of the version to be published. Giuseppe Maggiore: Substantial contributions to the design of the work; AND revising it critically for important intellectual content; AND Final approval of the version to be published. Raffaele Iorio: Substantial contributions to the conception or design of the work; AND Drafting the work; AND revising it critically for important intellectual content; AND Final approval of the version to be published.

      SIGENP Acute Hepatitis Group

      Marina Aloi, Roberto Antonucci, Claudia Banzato, Valentina Buccella, Pier Luigi Calvo, Angelo Campanozzi, Mara Cananzi, Simonetta Cherubini, Fernanda Cristofori, Lorenzo D’Antiga, Marco Deganello Saccomani, Anna De Giorgi, Valeria Dell’Omo, Federica Ferrari, Ruggiero Francavilla, Maurizio Giuseppe Fuoti, Paola Gaio, Francesco Graziano, Giuseppe Indolfi, Ramona Inferrera, Annalisa Madeo, Alessio Mesini, Fulvio Moramarco, Valentina Motta, Barbara Parma, Michele Pinon, Silvia Provera, Giusy Ranucci, Anna Tulone, Piero Valentini, Silvio Veraldi, Antonietta Villirillo.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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