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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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Common bacterial toxins are a possible contributing factor to hepatitis in children.

Dear Editor,

Viral infections of the respiratory and gastrointestinal mucosa perturb the mucosal bacterial flora and can lead to secondary bacterial infection [1]. 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 [2]. 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 [3]. 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 [2].

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 [4]. Furthermore, a wide range of pathogenic bacteria produce toxin laden extracellular vesicles which circulate in the blood and can cause systemic damage [5]. 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

01 May 2022
James Morris
Consultant Pathologist (retired)
Carnforth