Acute hepatitis of unknown origin in childrenBMJ 2022; 377 doi: https://doi.org/10.1136/bmj.o1197 (Published 17 May 2022) Cite this as: BMJ 2022;377:o1197
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Should anyone still believe the saga of fake news is behind our shoulders after the Covid-19 pandemic - for which the expression "infodemic" was coined by the World Health Organization -, let me respectfully inform you this is completely untrue!
Almost simultaneously, in fact, two giant fake news have added themselves to the impressive number of those already populating the media arena of emerging infectious diseases (EIDs).
According to the first, dogs could be the source of the hitherto unknown pathogen - a virus, most likely - responsible for the recent outbreak of "severe acute hepatitis" detected among pediatric patients from UK and other European (including Italy) and non-European (including USA) Countries. And, since hepatitis-affected children from UK would belong in 70% of the cases to families owing a dog, this has formed the totally unproven basis for dogs being the source of the agent causing the aforementioned hepatitis. It seems astonishing that, when making this assumption, no attention has been paid to the fact that at least half of the families living in UK as well as in many other European and non-European Countries are owners of dogs, cats or other companion animals!
The second fake news on which I would like to draw your attention still blames dogs as potential carriers and shedders of monkey poxvirus (MPXV), a zoonotic pathogen which is a matter of serious concern for the public health Authorities of many European and extra-European Countries, given the over 800 cases hitherto diagnosed in people outside the African Continent within a short timeframe. In this case, the "confounding element" is represented by the prairie dog, a squirrel-like rodent listed among the animal species truly susceptible to MPXV and sharing with our canine friends only the name!
Said in other words, there seems to be nothing new under the sun after the Covid-19 pandemic, with fake news continuing to bloom endlessly in the EID arena!
And, still noteworthy, provided that no less than 70% of EIDs have either a proven or suspect animal origin, why not leaving the floor to veterinarians much more often than it usually happens, at least in Italy (and also in many other Countries, I suppose)?
Indeed, as the Covid-19 pandemic has taught us, human, animal and environmental health are mutually and inextricably linked to each other, a concept efficiently summarized by the "One Health" principle.
Competing interests: No competing interests
Hepatitis with an unknown cause in children might be a consequence of mass vaccination with adenovirus vector vaccines in combination with lockdown
Adenovirus infections might cause the acute hepatitis in children observed. It is present in 70% of the affected children in comparison to SARS-CoV-2 present in only 15% . Furthermore, SARS-CoV-2 has spread worldwide for more than two years without cases appearing earlier. Adenovirus infections do not normally cause hepatitis in healthy children suggesting that a completely new type of adenovirus might have been introduced into the human population. The question one must ask in this case is what factors and events have occurred recently that distinguish the UK from other countries since it seems to be the origin and where most children have been affected by hepatitis with an unknown cause.
A substantial proportion of the population in the UK has received Vaxzevria which is an adenovirus vector vaccine from AstraZeneca developed by the Jenner Institute in Oxford . The chimpanzee viral vector was selected due to the low herd immunity in the human population and originates from an adenovirus purified from the faeces of chimpanzee cubs . The vector is genetically modified so that it cannot multiply, and genes of interest can be added. In Vaxzervria, the DNA sequence expressing the spike protein from the original Wuhan SARS-CoV-2 virus has been inserted . Could the adenovirus vector vaccine have contributed to a new recombinant virus? Even if the virus vector does not multiply there is an obvious risk exposing such a large number of individuals that recombination with an adenovirus could occur.
Multiplicity reactivation (MR) is a survival mechanism that was discovered for adenoviruses in 1971 by Yamamoto and Shimojo . It is a process where damaged adenovirus genomes can interact with other adenoviruses present in the cell forming a new viable viral genome. The mechanism is described as an early variant of a reproductive (sexual) process that can occur in microorganisms . A proportion of the population, especially individuals with a compromised immune system, is carrying latent adenoviruses. In Sweden, approximately 20% of adults and 50% of kindergarten children are carriers. This safety issue of viral-vector delivery systems was often discussed in the beginning of the development of these medical tools. It is the first time in history that so many individuals have been exposed to adenovirus vector vaccines. The risk for recombination’s with adenoviruses is therefore increased.
Lockdown, closing the society aiming to stop the spread of coronavirus, recently also occurred in the UK. The susceptibility for all kind of infections will unfortunately increase afterwards due to less herd immunity, particularly in young children. They are relatively unexposed to different viruses and need to build up immunity against different pathogens. A new adenovirus therefore can spread more quickly after isolation measures because there is an immunity debt in the population. The virus load can become high in susceptible individuals causing more severe infections and damage to the gastrointestinal area that might lead to viral hepatitis.
If adenovirus infections are causing acute hepatitis in children, the severe cases could just be the tip of the iceberg and the majority infected by the adenovirus would have less severe symptoms. The virus may have spread to other countries from the UK, but it is also possible that adenovirus recombinations may have occurred independently elsewhere in the world where adenovirus vector vaccines also have been used. Development of a new more pathogenic adenovirus could be caused by using adenovirus vector vaccines in large populations, and it is consistent with the facts available. To investigate this important safety issue of viral vector vaccines, sequencing of entire adenovirus genomes from cases and comparisons with the vaccine viral vector is necessary to verify or dismiss this hypothesis.
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Competing interests: No competing interests
The experience of the COVID-19 pandemic will inevitably prompt investigators to propose viral causes for the extensive and severe international outbreak of hepatitis in children. However, as Cevik and colleagues point out, in their considered editorial (1), there are problems with the hypothesis of adenovirus infection as the cause. Only 91/126 (72%) of UK children tested were positive for the virus and histological findings were non-specific and not consistent with known viral causes of hepatitis. By contrast, "Mycotoxins are known to cause liver injury with a pathology like that seen in these patients" (2). Mycotoxins can also contaminate milk, apple juice, tomato concentrate, nuts and peanuts amongst other foods(3).
Although scarcely mentioned in any of the public or technical discourse, this outbreak resembles foodborne international outbreaks, in the past, although, admittedly, in these past episodes, conventional infectious organisms had been responsible (4). The age distribution suggests a soft digestible product, preferentially fed to young children, that might include among its base ingredients a foodstuff, potentially contaminated with mycotoxins, such as those listed above. Coincidentally, a salmonella outbreak in the United States and Canada has recently been linked to peanut butter promoting a continent wide recall (5)
In an age when the task of the epidemiologist is increasingly perceived, by the public, to be sitting in front of a computer screen, calculating an R number of variable usefulness, identifying a vehicle of infection requires an older tradition of epidemiological practice; field epidemiologists who follow Cevik et al's "well-trodden path" of outbreak investigation (1). This should involve, as a matter of urgency, rapid investigation by a small team of well trained personnel visiting, initially, in person, the households of the cases, possibly with a trawling questionnaire that could be standardised internationally so that histories can be compared, but certainly, with an open mind as to the possible causes of the outbreak..
Formerly, Director, Communicable Disease Surveillance Centre, Public Health Wales
Emeritus Professor of Public Health, Cardiff University
1. Cevik M, Rasmussen AL, Bogoch II, Kindrachuk J. Acute hepatitis of unknown origin in children. BMJ 2022;377:o1197
2. UKHSA. Investigation into acute hepatitis of unknown aetiology in children in England—technicalbriefing3.2022. pp26 https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
3. Panisset J-C, Dewailly E, Doucet-Leduc H. Contamination alimentaire in Gerin M, Gosselin P, Cordier S, Viau C, Quenel P, Dewailly E eds. Environnement et Sante Publique. Quebec 2003. Edisem pp379-380.
4. Salmon RL, Bartlett CLR. European surveillance systems. Reviews in Medical Microbiology. 1995. 6(4). 267-276
5. Salmonella outbreak linked to peanut butter. https://www.cdc.gov/salmonella/senftenberg-05-22/index.html. accessed 28 May 2022
Competing interests: No competing interests
I noticed that the appearance of a new variant of adenovirus is among current leading hypotheses to explain the development of acute hepatitis of unknown origin in children. I think this idea should be pursued accurately in view of the widespread distribution of non-human primate adenoviral vector-based anti-SARS-CoV-2 vaccines.
In fact, in vaccinees natural barriers against adenoviral particles have been overcome, and a non-human adenoviral genome might have been delivered not only in muscle cells but also, considering the very high number of adenoviral particles included in a vaccine dose, in cell types naturally susceptible to adenovirus infection. If vaccine-related adenoviral particles target a cell already infected with a human adenovirus, DNA recombination between different adenovirus species might occur. Since DNA recombination events are based on the recognition of stretches of identical sequences, and there is high sequence homology between human and non-human primate adenoviruses (> 95 %), the emergence of recombinant adenoviruses from vaccinated individuals could have been, although rare, a possible event (1).
New adenoviral species spreading from vaccinated people would be expected to target persons who have not developed an effective adenovirus-specific immunity yet, as in the case of children. I think that the availability of large liver samples, as from liver-transplanted children, would offer the possibility to attempt classic virus isolation and NGS sequencing using an appropriate set of primers with the aim to exclude such a devastating hypothesis.
1. Federico M. The conundrum of current anti-SARS-CoV-2 vaccines. Cytokine Growth Factor Rev. 2021 Aug;60:46-51. doi: 10.1016/j.cytogfr.2021.03.001. Epub 2021 Mar 6. PMID: 33714693; PMCID: PMC7936752.
Competing interests: No competing interests