Gurdasani Deepti, Trent Mallory, Ziauddeen Hisham, Mnatzaganian Emmanuel, Turville Stuart, Chen Xin, Kunasekaran Mohana Priya, Chughtai Abrar Ahmad, Moa Aye, McEniery Julie, Greenhalgh Trisha, MacIntyre Chandini Raina
William Harvey Research Institute, Queen Mary University, London, UK.
Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.
BMJ Paediatr Open. 2024 Dec 9;8(1):e002410. doi: 10.1136/bmjpo-2023-002410.
The cause of acute paediatric hepatitis of unknown aetiology (2022) has not been established despite extensive investigation.
To summarise the evidence for and against a causal role for human adenovirus (HAdv), adeno-associated virus 2 (AAV-2) and SARS-CoV-2 in outbreaks of paediatric hepatitis in 2022.
We appraised and summarised relevant evidence for each of the Bradford Hill criteria for causality using quantitative (statistical modelling) and qualitative (narrative coherence) approaches. Each team member scored the evidence base for each criterion separately for HAdv, AAV-2 and SARS-CoV-2; differences were resolved by discussion. We additionally examined criteria of strength and temporality by examining the lagged association between SARS-CoV-2 positivity, respiratory HAdv positivity, positive faecal HAdv specimens and excess A&E attendances in 1-4 years for liver conditions in England.
Assessing criteria using the published literature and our modelling: for HAdv three Bradford Hill criteria (strength, consistency and temporality) were partially met; and five criteria (consistency, coherence, experimental manipulation, analogy and temporality) were minimally met. For AAV-2, the strength of association criterion was fully met, five criteria (consistency, temporality, specificity, biological gradient and plausibility) were partially met and three (coherence, analogy and experimental manipulation) were minimally met. For SARS-CoV-2, five criteria (strength of association, plausibility, temporality, coherence and analogy) were fully met; one (consistency) was partially met and three (specificity, biological gradient and experimental manipulation) were minimally met.
Based on the Bradford Hill criteria and modelling, HAdv alone is unlikely to be the cause of the recent increase in hepatitis in children. The causal link between SARS-CoV-2, and to a lesser degree AAV-2, appears substantially stronger but remains unproven. Hepatitis is a known complication of multisystem inflammatory syndrome in children following COVID-19, and SARS-CoV-2 has been linked to increased susceptibility to infection post-COVID-19, which may suggest complex causal pathways including a possible interaction with AAV-2 infection/reactivation in hosts that are genetically susceptible or sensitised to infection.
尽管进行了广泛调查，但2022年病因不明的急性儿童肝炎的病因仍未确定。
总结支持和反对人类腺病毒（HAdv）、腺相关病毒2（AAV-2）和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在2022年儿童肝炎暴发中起因果作用的证据。
我们使用定量（统计建模）和定性（叙事连贯性）方法，对布拉德福德·希尔因果关系标准中的每一项相关证据进行评估和总结。每个团队成员分别对HAdv、AAV-2和SARS-CoV-2的每项标准的证据基础进行评分；通过讨论解决分歧。我们还通过研究SARS-CoV-2阳性、呼吸道HAdv阳性、粪便HAdv标本阳性与英格兰1至4年内肝病急诊就诊人数增加之间的滞后关联，来检验强度和时间性标准。
使用已发表的文献和我们的模型评估标准：对于HAdv，部分满足三个布拉德福德·希尔标准（强度、一致性和时间性）；最低限度满足五个标准（一致性、连贯性、实验性操作、类比和时间性）。对于AAV-2，完全满足关联强度标准，部分满足五个标准（一致性、时间性、特异性、生物学梯度和合理性），最低限度满足三个标准（连贯性、类比和实验性操作）。对于SARS-CoV-2，完全满足五个标准（关联强度、合理性、时间性、连贯性和类比）；部分满足一个标准（一致性），最低限度满足三个标准（特异性、生物学梯度和实验性操作）。
根据布拉德福德·希尔标准和模型，仅HAdv不太可能是近期儿童肝炎增加的原因。SARS-CoV-2之间的因果联系，以及在较小程度上AAV-2之间的因果联系，似乎要强得多，但仍未得到证实。肝炎是儿童感染新冠病毒后多系统炎症综合征的已知并发症，并且SARS-CoV-2与新冠病毒感染后易感性增加有关，这可能暗示了复杂的因果途径，包括在对感染具有遗传易感性或致敏性的宿主中可能与AAV-2感染/再激活的相互作用。
