Acute hepatitis of unknown origin in children: Should we move the discussion from a purely infectious origin also to other plausible causes?

KEYWORDS:

• Acute hepatitis of unknown/undetermined origin
• human adenovirus type 41
• adeno-associated virus type 2
• paracetamol
• counterfeit medicines

Dear Editor

We read with interest the article by Dr. Grand which appeared in a recent issue of the Journal, where he reviews in great detail the updated literature on a) the general features of human adenoviruses (HAdVs) and adeno-associated viruses type 2 (AAV2), and b) these two viruses’ possible association with the last year paediatric outbreak of severe acute hepatitis of unknown/undetermined origin (AHUO) [1].

We commend the author for taking on this huge task, the conclusions of which, however, appear still largely open. In fact it turns out that HAdV-F41 (eventually become more virulent due to the COVID-19 restrictions associated immunity gap, and/or due to the host’s genetically determined susceptibility) has not been reported to infect the liver, and AAV-2 has generally been considered harmless [1].

Therefore, we wonder whether the author’s opinion/further elaboration on possibly overlooked contributing factors, mentioned but not commented on further, might help the readers gain more from the article and perhaps help move the discussion from a purely infectious origin of AHOU also to other possibilities.

On this matter, we would like to specifically recall the possible role of paracetamol. There is no doubt that the dconcurrent use of products containing paracetamol may result in inadvertent exposure to supratherapeutic doses of the drug responsible for drug-induced liver injury (DILI) [2]. Nevertheless, sound data on paracetamol-protein adduct testing, a valuable tool for identifying paracetamol toxicity, were not overtly cited in any of the previous studies reporting severe AHUO cases [3,4]. Anyhow, if paracetamol were a culprit, one should acknowledge that the big question still remains as to why accidental overdose of paracetamol resulted in clusters of severe DILI just in these children and in some parts of the world? Furthermore, the question arises also why did the outbreak slow down, then stagnate and eventually probably disappear?

In this respect, we have recently suggested to take into consideration also the possible role of the uncontrolled global spread of counterfeit medicines, with paracetamol undoubtedly being a relevant protagonist, mainly due to diethylene glycol (DEG) contamination as a paracetamol solvent in paediatric liquid formulations, in place of the more expensive propylene glycol. This phenomenon has often been recognized being responsible for several past and current epidemic deaths [5,6]. Given existing data that in addition to being nephrotoxic DEG is also hepatotoxic [7–9], one may therefore wonder whether AAV2 ± adenovirus or other viruses caused minor hepatitis which was exacerbated by batches of low-quality/counterfeit paracetamol a) with DEG or other contaminants, and/or b) with uncontrolled higher concentrations of the active ingredient, eventually administered to children with HLA predisposition.

Overall, we recommend that in future cases of severe AHUO, in addition to virological studies, the doses of paracetamol given are also substantiated by measurements of paracetamol exposure biomarkers, and that the type and origin of formulations used should be examined in more detail.

Author contributions statement

Authors Pietro Vajro, Claudia Mandato and Björn Fischler contributed equally to this work.

Disclosure statement

No relevant financial or non-financial competing interests to report.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.