Hepatitis in children: What’s behind the outbreaks?BMJ 2022; 377 doi: https://doi.org/10.1136/bmj.o1067 (Published 26 April 2022) Cite this as: BMJ 2022;377:o1067
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I would like to state the hypothesis that acute hepatitis of unknown cause in children is caused by adeno-associated virus type 2.
Gastrointestinal symptoms such as diarrhea and nausea were commonly reported prior to admission, which is consistent with the typical clinical presentation of type41 infection, an intestinal adenovirus [1,2]. Adenovirus DNA levels in blood and serum have been noted to be approximately 12 times higher in liver transplant recipients than in non-transplant recipients. Normally, however, adenoviruses do not cause hepatitis in children with healthy immunity. In immunodeficiency, some serotypes of adenovirus have been reported to cause hepatitis, but even then, serotype 41 is not common. In the case of adenovirus, there is a "threshold effect" that prevents the virus from reaching the hepatocyte unless adenovirus capture by liver Kupffer cells is saturated. Therefore, a small amount of adenovirus in the blood does not easily infect hepatocytes, and if it does, there should be at least a finding that the Kupffer cells are saturated with adenovirus. However, liver biopsies from six U.S. patients showed no immunohistochemical evidence of adenovirus and no electron microscopic evidence of viral particles. Therefore, it is unlikely that the adenovirus is infecting the hepatocytes and causing hepatitis.
On the other hand, metagenomic analyses of blood and liver tissue have detected large amounts of adeno-associated virus type 2 (AAV-2) . Adeno-associated virus (AAV) is used as a vector for gene therapy targeting hepatocytes and has the property of reaching hepatocytes efficiently. AAVs are generally considered non-pathogenic, but in a high-dose gene therapy trial with the AAV type 8 vector, two patients died due to progressive liver dysfunction. Temporary liver inflammation and transient elevation of liver enzymes following intravenous administration of AAV-2 are reported.
Possible mechanisms of hepatotoxicity following high-dose intravenous administration of AAV may point to complement activation. It is possible that inadequate immunity to AAV-2 or large amounts of AAV-2 can cause liver dysfunction. Since AAV is a virus that can multiply only in the presence of helper viruses such as adenovirus, it is reasonable to assume that AAV-2, detected in large quantities in blood and liver, multiplied as a result of adenovirus type 41 infection.
Adenovirus type 41 is transmitted through the fecal-oral route. Countries where hepatitis of unknown origin in children is seen tend to be those with good sanitary conditions, such as Europe, the United States, and Japan. Prevalence of serum neutralizing antibodies to adenovirus type 41 in Chinese children is associated with age and sanitary conditions. The younger the age and the better the sanitary conditions, the lower the prevalence. The difference in adenovirus 41 neutralizing antibody titers diminished in children over 3 years of age. These results indicate that childhood sanitary conditions is an important factor affecting adenovirus 41 neutralizing antibody titers. Neutralizing antibodies Prevalence of AAV-2 in adults is also low in the United States (30%) and Europe (about 35%), where sanitary conditions are considered good, and as high as 70% in Africa . Positive rates of neutralizing antibodies to AAV-2 have also been reported to increase with age[11,12].
A possible link between waned immunity to respiratory syncytial virus in the COVID-19 pandemic and the interseasonal re-emergence of RSV cases seen worldwide has been raised. . In countries with good sanitation, the proportion of children with low immunity to adenovirus and AAV-2 was originally high and may have been further exacerbated by the measures taken against COVID-19. If an outbreak of adenovirus 41 and AAV-2 were to occur among such children, it is possible that some children would develop hepatitis.
1. UK Health Security Agency. Investigation into acute hepatitis of unknown aetiology in children in England Technical briefing 2. London, United Kingdom: Department of Health and Social Care, UK Health Security Agency; 2022. https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
2. Baker JM, Buchfellner M, Britt W, et al. Acute Hepatitis and Adenovirus Infection Among Children - Alabama, October 2021-February 2022. MMWR Morb Mortal Wkly Rep. 2022 May 6;71(18):638-640. doi: 10.15585/mmwr.mm7118e1. PMID: 35511732.
3. UK Health Security Agency. Investigation into acute hepatitis of unknown aetiology in children in England Technical briefing. London, United Kingdom: Department of Health and Social Care, UK Health Security Agency; 2022.
4. Hierholzer JC. Adenoviruses in the immunocompromised host. Clin Microbiol Rev 1992;5:262–74. https://doi.org/10.1128/CMR.5.3.262external icon
5. Tao N, Gao GP, Parr M, et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther. 2001 Jan;3(1):28-35. doi: 10.1006/mthe.2000.0227. PMID: 11162308.
6. Morales L, Gambhir Y, Bennett J, Stedman HH. Broader Implications of Progressive Liver Dysfunction and Lethal Sepsis in Two Boys following Systemic High-Dose AAV. Mol Ther. 2020;28(8):1753-1755. doi:10.1016/j.ymthe.2020.07.009
7. Wang L, Wang H, Bell P, et al. Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther. 2010;18(1):118-125. doi:10.1038/mt.2009.246
8. Flotte TR Editor-in-Chief. Revisiting the "New" Inflammatory Toxicities of Adeno-Associated Virus Vectors. Hum Gene Ther. 2020 Apr;31(7-8):398-399. doi: 10.1089/hum.2020.29117.trf. PMID: 32302233.
9. Yang WX, Zou XH, Jiang SY, et al. Prevalence of serum neutralizing antibodies to adenovirus type 5 (Ad5) and 41 (Ad41) in children is associated with age and sanitary conditions. Vaccine. 2016 Nov 4;34(46):5579-5586. doi: 10.1016/j.vaccine.2016.09.043. PMID: 27682509; PMCID: PMC7115419.
10. Roberto Calcedo, Luk H. Vandenberghe, Guangping Gao, et al. Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses, The Journal of Infectious Diseases, Volume 199, Issue 3, 1 February 2009, Pages 381–390, https://doi.org/10.1086/595830
11. Calcedo R, Morizono H, Wang L, et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol. 2011;18(9):1586-1588. doi:10.1128/CVI.05107-11
12. Mimuro J, Mizukami H, Shima M, et al. The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals. J Med Virol. 2014 Nov;86(11):1990-7. doi: 10.1002/jmv.23818. Epub 2013 Oct 17. PMID: 24136735.
13. Frederic Reicherz, Rui Yang Xu, Bahaa Abu-Raya, et al. Waning immunity against respiratory syncytial virus during the COVID-19 pandemic, The Journal of Infectious Diseases, 2022;, jiac192, https://doi.org/10.1093/infdis/jiac192
Competing interests: No competing interests
We read with keen interest the recent article in The BMJ about cases of idiopathic hepatitis in children around the world. We are concerned that the gains of multi-sectoral mitigation responses to COVID-19 is under threat by this evolving situation. Cases of idiopathic acute hepatitis were first identified in Scotland among 11 children aged one to five years between January to March 2022. The World Health Organization (WHO) was notified of these cases on April 5, 2022.  The outbreak in Scotland triggered retrospective investigations across the UK, leading to identification of 74 cases in children admitted to hospitals in since January 2022.  This coordinated case finding effort involved assessment of exposure history, toxicological testing and additional laboratory tests. By April 8, 2022, the WHO was notified of the 74 cases that fulfilled the case definition (49 cases in England, 13 in Scotland inclusive of 11 cases above, and 12 in Wales and Northern Ireland). 
By April 11, 2022, the usual causes of infectious hepatitis (hepatitis A to E) had been excluded from all 74 cases of hepatitis, while the coronavirus and/or adenovirus had been detected in several of the children. By April 29, 2022, the total number of cases had risen to 145: 108 in England, 17 in Scotland, 11 in Wales and 9 in Northern Ireland. A total of 10 of the 145 affected children have required liver transplantation and they will require immunosuppressive drugs for the rest of their lives, which will put them at risk of other infections. Findings suggest that these cases may be linked to adenovirus type 41 infection , however, several potential causes such as drugs, toxins, or environmental exposure are still under investigation. Parents are advised to watch out for symptoms of hepatitis such as high fever, jaundice, dark urine and pruritus whilst supervising good handwashing and hygiene at home.
Initially there were concerns that these new hepatitis cases could be linked to COVID-19 vaccination. However, this is unlikely to be the case as the COVID-19 vaccine is only offered to children over 5 years in the UK.  The UK Heath Security Agency (UKHSA) has stated that there is no link between these hepatitis cases and COVID-19 vaccination.  It is interesting to note the alternative causal hypothesis of a yet-to-be-identified non-native virus that is reflected in the article in The BMJ (https://www.bmj.com/content/377/bmj.o1067).
Following the notifications from the UK, cases of idiopathic hepatitis have been reported in 14 other countries including in Europe, American and Asia. This is eliciting concerns of cross-border spread.  It is therefore vital to leverage existing clinical and public health surveillance mechanisms that facilitated early detection and management of COVID-19 to unravel the cause of these cases of idiopathic hepatitis.
Greater priority should be given to viral hepatitis as it causes an estimated 1·34 million deaths annually, a figure comparable with deaths caused by infectious diseases such as HIV/AIDS, tuberculosis, and malaria.  Furthermore, the number of deaths from HIV, tuberculosis and malaria have all declined since 2008, while global deaths from chronic hepatitis show no sign of reducing. 
The World Health Assembly in 2016 passed a resolution to eliminate viral hepatitis as a public health problem, defined as: i) a reduction in hepatitis-related deaths by 65% and ii) new chronic hepatitis by 90%, by 2030.  However, achieving these targets require all countries to significantly scale-up interventions to prevent the transmission of hepatitis and improve access to testing and treatment. The current outbreak of viral hepatitis among children in 15 countries is a poignant reminder of what remains to be done to achieve these targets.
1. UK Health Security Agency. Increase in hepatitis (liver inflammation) cases in children under investigation. 12 April 2022. https://www.gov.uk/government/news/increase-in-hepatitis-liver-inflammat...
2. Wilson C. Mystery outbreak of hepatitis in children investigated in the UK. New Scientist. https://www.newscientist.com/article/2315740-mystery-outbreak-of-hepatit...
3. Reed J. Childhood hepatitis: Why are we seeing an unusual spike in cases? BBC News. 9 April 2022. https://www.bbc.co.uk/news/health-61025140
4. GOV.UK. Increase in hepatitis (liver inflammation) cases in children under investigation. Available at: https://www.gov.uk/government/news/increase-in-hepatitis-liver-inflammat...
5. World Health Organization (15 April 2022). Disease Outbreak News; Acute hepatitis of unknown aetiology - the United Kingdom of Great Britain and Northern Ireland. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/acute-hepatit...
6. Rob Brierley R. Elimination of viral hepatitis by 2030: ambitious, but achievable. The Lancet Gastroenterology & Hepatology 2019; Volume 4, Issue 2, 88 - 89
7. Cox AL, El-Sayed MH, Kao JH, et al. Progress towards elimination goals for viral hepatitis. Nat Rev Gastroenterol Hepatol 2020; 17, 533–542 (2020). https://doi.org/10.1038/s41575-020-0332-6.
8. Smith S, Harmanci H, Hutin Y. Global progress on the elimination of viral hepatitis as a major public health threat: An analysis of WHO Member State responses. 2017. JHEP Reports 2019: 1(2): 81-89
Competing interests: No competing interests
In normal times, I would have expected a rapid output of relevant clinical data and early research into the medical domain. This hasn't happened with the hepatitis outbreak, despite 114 of 169 total reported cases having occurred in UK. We surmise on thin and disparate evidence. My supremely unqualified view is based on information which I found on Twitter (!) (thanks to @farid_jalali ).
My guess is that it's a new specific presentation of MISC-C from infection with the BA.2 lineage now running riot in UK. I don't think Adenovirus-related acute co-infection, or even potentiation, is as likely.
The frequency of Covid in these patients may well be higher than is apparent from the 16% 'Covid not detected' cohort. SARS-Cov-2 test positivity was much higher anyway in patients with hepatitis (16%) than the background rate of 5-8%, but this was only from testing on admission - so Covid infections in the preceding six weeks may not have been detected, and a delay in onset of MISC-C is usual. Covid is very prevalent and MISC-C only occurs in children. In the UK study, there was similar blood positivity for Covid (n=10) as for Adenovirus (n=11).
Of 100 described cases of severe adenoviral hepatitis, all were severely immunocompromised and all liver biopsy samples had hepatocyte adenovirus inclusions on histopathology - none of which were serotype Ad 41. In the current Alabama study, none of the samples had any adenovirus inclusions or positivity within hepatocytes.
Serotype Ad 41 has never been known to cause hepatitis. Adenoviruses commonly inhabit tonsils/adenoids on a chronic ongoing basis and viraemia can then occur when the host is immunocompromised eg during an attack of hepatitis. 'Acute' infection can still produce live virus 3 months to >1 year later and replication can persist for years in healthy people. So Adenovirus 41 may be less co-factor and more freeloader.
Whether the hepatitis is a primary viral or secondary immune insult is an important starter question with regard to treatment approach. I'd have expected to have had at least some better information now, since both mechanisms are already known in viral hepatitis. Aside from the limited UKHSA/CDC publications, is it a reasonable question to ask if there might be a political angle to the seeming dearth of information in such an alarming situation? Are they just hoping it will go away without having had to explain it as a Covid-related harm in children?
Competing interests: No competing interests
The current article by Elisabeth Mahase discussing the sudden rise of severe non A-E hepatitis cases is quite informative.
In the light of current knowledge, I would like to highlight a few points.
The current approach to investigating these cases could be biased as we are only investigating the cases severe enough to get hospitalised. These cases are just the tip of the iceberg; there is an urgent need to uncover the prevalence of such viruses in children having a mild elevation of transaminases in the same vicinity.
Active search for the cofactor: From the recent report released by the UK Health Security Agency, i'ts quite evident that there is a co-factor in play since the suggested agent Adenovirus is not usually known to cause severe hepatitis in previously healthy children (1). However, given an immune-compromised state in a child recovering from COVID or some other novel virus, such a disease form might manifest. Such severe hepatitis cases have already been reported in HIV-affected and bone marrow transplant recipients (2). With the continuing current phase of the pandemic and given the tested COVID positivity was higher (16%) among the affected, versus the weekly positivity rate among the community (5-8%). However, we know that SARS-CoV-2 alone is unlikely to cause such severe liver disease since most cases wherever reported in children have been of mild elevation of transaminases (3).
A close look at the data also reveals that some other viruses like EBV, CMV and Human herpes viruses have been found in such cases, although in fewer numbers. Interestingly in some of such cases the main suspect Adenovirus is missing. In a recent study from India among children affected with severe hepatitis, positivity was found for other viruses like VZV and EBV in a similar fashion (4).
This leads us to a theory of primary insult followed by a secondary invasion of the liver, which in the case of the UK incidences is most likely to be Adenovirus. We should not forget that owing to a high number of many such viruses which are known to cause hepatitis in a host having a weakened immune system, which vary in their prevalence across the Globe, such active searches for these agents must be driven according to the affected area and not limited to testing for Adenoviruses alone.
1) Acute hepatitis: technical briefing [Internet]. GOV.UK. [cited 2022 May 3]. Available from: https://www.gov.uk/government/publications/acute-hepatitis-technical-bri...
2) Donald R. Carrigan P. Adenovirus Infections in Immunocompromised Patients. Am J Med. 1997 Mar 17;102(3):71–4.
3) Zhou YH, Zheng KI, Targher G, Byrne CD, Zheng MH. Abnormal liver enzymes in children and infants with COVID-19: A narrative review of case-series studies. Pediatr Obes. 2020;15(12):e12723
4) Rawat SK, Asati AA, Jain A, Mishra N, Ratho RK. COVID-19 Associated Hepatitis in Children (CAH-C) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon [Internet]. medRxiv; 2021 [cited 2022 May 3]. p. 2021.07.23.21260716. Available from: https://www.medrxiv.org/content/10.1101/2021.07.23.21260716v6
Competing interests: No competing interests
Viral infections of the respiratory and gastrointestinal mucosa perturb the mucosal bacterial flora and can lead to secondary bacterial infection . Indeed, when an otherwise mild viral respiratory tract infection turns nasty secondary bacterial infection is the usual cause. This can be overt in the case of bacterial pneumonia or bacterial sepsis, which are relatively easily diagnosed. But covert secondary bacterial infection due to bacterial toxins is less easy to diagnosis because there are no standard diagnostic tests. This concept of a viral/bacterial interaction leading to bacterial toxaemia should be considered in the present outbreak of hepatitis in children.
Reye’s syndrome was a disease of childhood in which a viral prodromal illness, commonly chicken pox or influenza, was followed by a severe toxaemic clinical picture with encephalopathy and hepatitis. This was not uncommon in the 1970s and 1980s but is now rare. The prescription of aspirin was an aggravating factor and following advice to avoid aspirin in childhood the disease became rare. The age profile of Reye’s syndrome, a childhood disease, however, is not explained by the viral cause or aspirin prescription . But it can be explained if common bacterial toxins had a role.
Infants and children build up immunity to common bacterial toxins and by adult life the vast majority of the population will have protective IgG antibodies. This means that maternal IgG will protect infants in the early months of life but then the risk of disease due to common bacterial toxins will rise. A mathematical model based on this idea shows a predicted age profile with a mode at 2 to 6 months but a long tail with a median from several months to several years depending on the rate of circulation of the toxigenic bacteria . The age distribution of Reye’s syndrome varied by social class, with a median of 6 months in social class 6, and 118 months in social class 1. This fits with the concept of toxigenic bacteria whose rate of circulation is influenced by general social conditions .
The current out break of hepatitis in children does not show the typical features of Reye’s syndrome but it is similar in some respects. The disease does have a viral prodrome, there is a toxaemic clinical picture which in some cases has resembled sepsis (but with negative blood cultures). The disease is much milder with a low mortality and hepatitis is the major feature. However, the age profile is similar, with most cases in young children, but the oldest 16 years.
Adenovirus and SARS-CoV-2 seem to be associated with the outbreak of hepatitis but there is no evidence, as presented so far, of a lytic viral infection of the liver. There is no common environmental toxin but the possibility of common bacterial toxins has not been excluded. A careful assessment of the nasopharyngeal flora should be undertaken. The last two years has been unusual, with multiple waves of SARS-CoV-2 disturbing the nasopharyngeal flora, widespread wearing of masks which could also influence re-breathing and bacterial carriage, and episodes of lockdown and social isolation reducing the rate of spread of both viruses and bacteria.
There are no readily available tests for bacterial toxins other than lipopolysaccharide. But it is possible to assay staphylococcal toxins . Furthermore, a wide range of pathogenic bacteria produce toxin laden extracellular vesicles which circulate in the blood and can cause systemic damage . The investigation of common bacterial toxins and their role in disease is long overdue.
1. Morris JA, Shepherd RJ, Diep-P-T, Gatheral T, Wray M, Rigby RJ. SARS-CoV-2 interacts with mucosal dysbiosis to cause the wide range of disease seen in Covid-19. Austin J Pulm Resp Med 2022; 9: 1086. https://austinpublishinggroup.com/pulmonary-respiratory-medicine/fulltex...
2. Morris JA, Shapiro DZ. Social class and age distribution in Reye’s syndrome. BMJ 1986; 292: 379. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1339356/pdf/bmjcred00220-00...
3. Morris JA, Haran D, Smith A. Hypothesis: common bacterial toxins are a possible cause of the sudden infant death syndrome. Medical Hypotheses 1987; 22: 211 – 222.
4. Harrison LM, Morris JA, Lauder RM, Telford DR. Staphylococcal pyrogenic toxins in infant urine samples: a possible marker of transient bacteraemia. J Clin Pathol 2009; 62: 735 – 738. http://dx.doi.org/10.1136/jcp.2008.057232
5. White JR, Dauros-Singorenko P, Hong J, Vanholsbeeck F, Phillips A, Swift S. The complex bidirectional role of extracellular vesicles in infection. Biochem Soc Trans 2021; 49: 881 – 891. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106493/
Competing interests: No competing interests
My recent experience is of staying with my son and being called in the middle of the night to assess my 15 month old granddaughter who had a pyrexia and was clearly distressed. My concern that she had cold extremities (though no rash) led me to instruct the parents to go straight to Children’s A&E where she quickly received iv support for sepsis and was subsequently found to have Covid19, Adenovirus and Paraflu. She recovered fully over the next 48 hours. I will be forever in debt to colleagues in Bristol.
It is dangerous to generalise from a single case but she had also been attending a nursery and so It is likely that herd immunity in nurseries (and primary schools) is in a post-lockdown low permitting parallel infections of common viruses because serial exposure has so far been denied. The situation is reminiscent of the stories of well meaning missionaries introducing pathogens to indigenous communities.
Not everyone has a GP in the spare bedroom but, in our case my granddaughter received prompt attention without the need for time consuming telephone triage or even waiting for an ambulance. Had she not, though not initially immunocompromised, the functional effect of multiple infections probably had the same impact on her immune system. It is not inconceivable that this could ultimately have led to clinical hepatitis.
It is probably not possible safely to increase toddler herd immunity though, if review of similar cases shows similar results, we might promote the value of teaching parents of young children red flags to which they should quickly respond and report to triage systems, perhaps via nurseries or even TV advertising as children ‘watch with mother’.
Competing interests: No competing interests