To the Editor: According to the data released by the World Health Organization (WHO) on July 12, 2022, around 1010 cases of children with acute hepatitis of unknown etiology have been reported in five regions and 35 countries globally; these reports include new and retrospectively identified cases since October 1, 2021. Most patients presented with acute severe hepatitis and significantly high transaminase levels; the most common symptoms and signs were nausea or vomiting (60%), jaundice (53%), general weakness (52%), and abdominal pain (50%), which are typical symptoms of acute severe hepatitis. Among the possible cases, 5% (n = 46) of children required transplantation, while 2% (n = 22) of deaths were reported to the WHO. Although the case growth rate in the past months showed a downward trend, the actual number of cases might have been underestimated.
Almost half of the cases were from the European region (n = 484, including 272 cases from the United Kingdom [UK]), and the rest were from the American region (n = 435, including 334 cases in the United States of America), the Western Pacific Region (n = 70), the South-East Asia Region (n = 19), and the Eastern Mediterranean Region (n = 2), according to the incomplete WHO statistics. No regional characteristics of case distribution were reported, and no significant epidemiological link was found between the cases (except for two pairs of cases reported in Scotland and linked cases in the Netherlands). In addition, current data show that the main susceptible population is previously healthy children, most of whom are aged <5 years. Additionally, no significant differences in sex and ethnicity were reported [Figure 1].
Is adenovirus guilty? Currently, detailed investigations are underway, and the etiology of acute hepatitis remains unclear. Hepatitis A–E viruses, or an expected presentation of metabolic, inherited, genetic, congenital, or mechanical causes, have been rolled out in all cases. At present, adenovirus is the most frequently detected potential pathogen, with the majority found in blood samples, followed by respiratory and fecal samples. Of 260 cases in the UK, 241 were tested for adenovirus, of which the virus was detected in 156 (64.7%) cases. In an early investigation in England, adenovirus was detected in 91 of 122 available cases (75%). Thirty-five cases were successfully subtyped, of which 27 (77%) were of type 41F. Seven patients who required liver transplantation underwent blood sample testing for adenovirus and all of them tested positive. Among them, five were successfully genotyped as 41F. Adenoviral DNA levels in blood or serum samples were approximately 12-fold higher in patients who underwent liver transplantation than in those who did not. Similarly, adenovirus was detected in 45% of 252 patients under investigation reported by the Centers for Disease Control and Prevention, regardless of the specimen type (whole blood, plasma, serum, respiratory, or stool), and 13 of 20 were detected as 41F types [Supplementary Table 1, https://links.lww.com/CM9/B327].
Most adenoviruses cause mild and self-limiting diseases that present with flu-like symptoms. Adenovirus type 41F, the apparently implicated adenovirus type, typically presents with diarrhea, vomiting, and fever, often accompanied by respiratory symptoms, rarely causing hepatitis, and occurs mainly in children with severe disseminated disease or in children/adults with an immunocompromised status. Therefore, acute unknown hepatitis cannot be reasonably explained by previous experience.
One possible conjecture is that the disease might be related to a special response to human adenoviruses caused by one or a few co-factors. There was an adenovirus infection peak among young children in the UK. At the end of 2021, the detection rate of adenovirus at all sites (including the digestive tract and respiratory tract) had far exceeded that of previous years in younger children, but not in older children or adults. The prevalence of other respiratory and non-respiratory viruses (including norovirus, rotavirus, enterovirus, rhinovirus, and human metapneumovirus) has also increased due to changes in social behavior. In addition, the action of a novel variant of adenovirus with the contribution of a few co-factors may be a possible pathogenic mechanism. The majority of patients aged <5 years had less exposure to external pathogens during the coronavirus disease 2019 pandemic, and their immune system might be slightly different from that of children growing in normal environments. This also explains why these diseases tend to affect younger children.
Is severe acute respiratory syndrome (SARS-CoV-2) playing a role? It is also difficult to ignore SARS-CoV-2 given the global impact of the Omicron variant and detection results. Nishiura et al found that countries with a greater frequency of Omicron infection were more likely to experience one or more hepatitis cases. A predisposing SARS-CoV-2 infection may be a co-factor that triggers severe acute hepatitis. The latest data suggest that in the European region, the rate of SARS-CoV-2 positivity is 16% and is detected in 54 of 335 cases with available polymerase chain reaction results. Based on the preliminary reports from the United States of America, 15 of 197 cases tested positive for SARS-CoV-2. The same results were revealed in five of 59 cases (8%) in the Japanese data. However, serological evidence for the SARS-CoV-2 antibody is still lacking [Supplementary Table 1, https://links.lww.com/CM9/B327].
Studies have shown that acute hepatitis is not a common feature of SARS-CoV-2 infection in children (of 3171 patients with SARS-CoV-2 infection and had alanine transaminase [ALT] measurement, only 13 had ALT >500 IU/L). However, recently, the Lancet Gastroenterol Hepatol proposed that this unknown hepatitis in children may be a multisystem inflammatory syndrome resulting from the immune activation by the SARS-CoV-2 superantigen motif (within the SARS-CoV-2 spike protein that bears a resemblance to Staphylococcal enterotoxin B). Children in their developmental period tend to tolerate the presence of pathogens to avoid systemic inflammatory responses. Thus, the SARS-CoV-2 virus persists in the gastrointestinal tract following infection, which causes recurrent release of superantigens from the damaged mucosal barrier. Subsequently, T cell immunity is extensively and indiscriminately activated. Reinfection with adenovirus or other pathogens can increase the susceptibility to toxic shock and liver injury caused by staphylococcal enterotoxin B.
The above findings lead us to surmise that a combination of a prolonged decreased exposure to paucisymptomatic viral infections during lockdown or prior infection with SARS-CoV-2 may have altered the immune response of children with a particular genetic background when they were exposed to an infectious agent, drug, toxin, or environmental agent, which subsequently led to liver immunopathology.
According to the technical briefing three from the UK Health Security Agency, 14 samples (including six blood samples and eight liver samples) were analyzed for metagenomic data, including one with insufficient viral reads for further analysis that were not included in the following data. Adeno-associated dependoparvovirus A viral reads were detected in 13 samples, four of which contained reads mapped to human adenovirus. In addition, all samples contained reads identified as human herpes virus, and four liver samples also contained human polyomavirus. Other viruses have also been detected in these cases, and a detailed classification is provided in the report. In addition, Epstein–Barr virus, enterovirus, cytomegalovirus, respiratory syncytial virus, and human herpes viruses 6 and 7 have also been identified in UK patients, although at lower frequencies. Administration of paracetamol, fluconazole, and few mycotoxins was found to be in excess in some cases, but there is no effective evidence to show that they are related to the disease.
The WHO detected the risk assessments at the global level as moderate based on the following reasons: the etiology of this severe acute hepatitis type remains unknown and under investigation; the available survey information is limited; the actual number of cases and geographical distribution may be underestimated; the source and mode of transmission have not been determined; and human-to-human transmission cannot be ruled out.
Based on the above, reported cases of acute severe hepatitis of unknown etiology seem to be related to the immune abnormalities in younger children, probably due to the intrinsic immune environment abnormalities or external infectious sources or co-factors. Although most patients improved or recovered after hospitalization, there was still a considerable number of children with acute liver failure who received liver transplantation or died. Active intervention and prevention of the continued spread of the disease are necessary for this condition. In the absence of relevant evidence, it is important to enhance hygiene habits and sanitization practices (eg, hand hygiene and surface disinfection) in settings where young children are enrolled, which may be a good practice to block the disease spread. Medical institutions should collect as many specimens as possible to assist with diagnosis and further investigate unknown etiologies. Institutions without testing capability should preserve specimens in accordance with the appropriate methods (the WHO guidelines on this topic can be used as a reference). Regional and national cooperation should be enhanced to ensure the timeliness and integrity of information for the early control of disease. Further results of epidemiological investigations, virological or microbiological detection, and toxicological tests need to be evaluated. Moreover, more data are urgently needed to confirm the suspected hypotheses and explain the outbreak of hepatitis.
Conflicts of interest
1. World Health Organization. Disease Outbreak News; Acute Hepatitis of Unknown Aetiology in Children – Multi-country, 2022. Available from: https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON400
. [Accessed on July 12, 2022].
2. UK Health Security Agency. Acute hepatitis: Technical briefing, 2022. Available from: https://www.gov.uk/government/publications/acute-hepatitis-technical-briefing
. [Accessed on June 17, 2022].
3. Aricò M, Caselli D. Acute, severe hepatitis of unknown origin: should we really be afraid of another obscure enemy of our children? Pediatr Rep 2022;14:217–219. doi: 10.3390/pediatric14020029.
4. Nishiura H, Jung SM, Hayashi K. High population burden of Omicron variant (B.1.1.529) is associated with the emergence of severe hepatitis of unknown etiology in children. Int J Infect Dis 2022;122:30–32. doi: 10.1016/j.ijid.2022.05.028.
5. Brodin P, Arditi M. Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens. Lancet Gastroenterol Hepatol 2022;7:594–595. doi: 10.1016/S2468-1253(22)00166-2.