解釋兒童不明原因的肝炎

解釋兒童不明原因的肝炎

資料來源:www.thelancet.com/infection Vol 22 June 2022;財團法人台灣紅絲帶基金會編譯

 

圖片:2022 年 5 月 12 日線上發布 https://doi.org/10.1016/ S1473-3099(22)00296-1

 

    隨著本期《刺胳針傳染病》的出版,世界各地正在調查 300 多例先前健康的兒童罹患急性肝炎的可能病例。大多數病例來自英國(截至 5 月 3 日為 163 例),但來自 20 個國家/地區的病例較少。 5 月 5 日,美國疾病控制和預防中心宣布,它正在調查過去 7 個月內在 25 個州和地區報告的 109 例原因不明的小兒肝炎病例。到目前為止,已有 20 多名兒童需要進行肝移植,其中數人已經死亡。確定病因的調查正在進行中,但兒童急性肝炎最常見的病因,包括A型肝炎病毒 - E型肝炎病毒,已被排除。

    腺病毒已成為調查的主要焦點,因為大量病例(根據世衛組織 5 月 10 日的媒體簡報顯示,約有 70% 的病例)的檢測結果呈陽性。腺病毒是常見的病原體,通常會引起輕微的呼吸道症狀,儘管它們在過去與免疫功能低下的兒童,以及在最近,與一位免疫功能正常的成年人的肝炎有關。對於腺病毒的發病機制可能如何改變,從而導致原本健康的兒童發生肝炎,已經提出了幾種假設。其中包括在 COVID-19 大流行期間由於缺乏接觸病原體而導致的兒童免疫缺陷使他們更容易受到腺病毒感染和感染的罕見結果。或者,正如其他呼吸道病毒所見,大流行限制的放寬可能導致大量腺病毒感染,從而檢測到更罕見的感染結果。另一種假設是,過去的感染或共同感染(與 SARS-CoV-2 或其他病原體),或者是暴露於毒素、藥物或環境因素,已經改變了宿主對腺病毒感染的反應。或者,我們看到的是一種能夠導致兒童嚴重肝病的新型腺病毒。

    主要嫌疑是腺病毒 41 亞型。英國衛生安全局 (UKHSA) 5 月 6 日的技術簡報報告稱,英國所有 18 例接受腺病毒分型的病例均為 41 亞型。同樣,Baker 及其同事報告稱,於2021 年 10 月至 2022 年 2 月期間,在阿拉巴馬州一家兒童醫院發現有 5 名罹患不明原因肝炎的兒童,患者在分型時具有腺病毒 41 亞型。

    並非所有人都相信腺病毒假說。腺病毒41亞型以前只與輕度至中度胃腸道症狀有關。並非所有兒童的腺病毒檢測都呈陽性,那些檢測呈陽性的兒童通常只在全血中檢測到(肝臟和血漿樣本大部分為陰性),並且在全血中的濃度很低——因此排除了去執行能更好地描述病毒和任何可能解釋這一新現象的基因組變化的全基因組測序。腺病毒是感染的常見原因,因此可能是附帶地被發現;英國正在進行的一項病例對照研究試圖解決這個問題。

    其他的感染原因亦正在調查,包括 SARS-CoV-2 的作用。在英國,5 月 6 日之前的 2 週內,新發不明原因兒科肝炎病例的報告減少,而 SARS-CoV-2 病例的減少亦恰逢其時。然而,英國衛生安全局警告肝炎病例的報告有滯後之時間差,並表示蘇格蘭仍在記錄新病例,而英格蘭的許多病例正在等待分類。此外,迄今為止,很少有報告的病例對 SARS-CoV-2 感染呈陽性反應。對過去感染的調查範圍有多廣尚不清楚; 英國衛生安全局報告說,血清學調查正在進行中,Baker 及其同事報告說,阿拉巴馬州的所有兒童都沒有記錄在案的 SARSCoV-2 感染史。這些兒童肝炎病例是否是 SARS-CoV-2 的感染後之後遺症仍有待觀察,可能屬於多系統炎症性疾病的範疇。

    疫情的起因受到了廣泛關注。社交媒體上的陰謀論比比皆是,有些人將這些病例歸因於 COVID-19 疫苗。然而,COVID-19 疫苗已被斷然排除,因為大多數患有不明原因肝炎的兒童因太小而無法接種 COVID-19 疫苗。雖然確定根本原因很重要,但考慮到兒童身體的狀況是如此不佳以及肝移植只能在高度專業化的醫學中心進行,重點關注早期病例辨識和尋找可以阻止疾病進展的有效治療方法也很重要。 

■ 刺胳針傳染病

 

 

 

 

 

Explaining the unexplained hepatitis in children

 

Published Online May 12, 2022 https://doi.org/10.1016/ S1473-3099(22)00296-1 

 

    As The Lancet Infectious Diseases went to press, more than 300 probable cases of acute hepatitis in previously healthy children were being investigated around the world. The majority of cases have been reported from the UK (163 as of May 3), but smaller numbers of cases have been reported from across 20 countries. On May 5, the US Centers for Disease Control and Prevention announced that it was investigating 109 cases of paediatric hepatitis of unknown cause reported in the past 7 months across 25 states and territories. So far, more than 20 children have required liver transplants and several have died. Investigations to identify a cause are ongoing, but the most frequent causes of acute hepatitis in children, including hepatitis viruses A–E, have been ruled out. 

    Adenoviruses have become the major focus of investigations as a substantial number of cases—around 70% of cases according to a WHO media briefing on May 10—have tested positive for them. Adenoviruses are common pathogens that typically cause mild respiratory symptoms, although in the past they have been implicated in hepatitis in immunocompromised children and, more recently, in an immunocompetent adult. Several hypotheses have been proposed for how the pathogenesis of adenoviruses might have changed to cause hepatitis in otherwise healthy children. These include that an immune deficit in children resulting from lack of exposure to pathogens during the COVID-19 pandemic has rendered them more susceptible to adenovirus infection and the rarer outcomes of infection. Alternatively, as has been seen with other respiratory viruses, relaxation of pandemic restrictions could have led to a massive wave of adenovirus infections, allowing a rarer outcome of infection to be detected. Another hypothesis is that past infection or coinfection (with SARS-CoV-2 or an alternative pathogen), or exposure to a toxin, drug, or an environmental factor, have altered the host response to adenovirus infection. 

Alternatively, what we are seeing is a novel adenovirus capable of causing severe liver disease in children.

    The main suspect is adenovirus subtype 41. A technical briefing from the UK Health Security Agency (UKHSA) on May 6 reported that all 18 cases in the UK that underwent adenovirus typing had subtype 41. Similarly, Baker and colleagues reported that five children with hepatitis of unknown cause identified at a children’s hospital in Alabama between October, 2021, and February, 2022, had adenovirus subtype 41 upon typing. 

    Not everyone is convinced by the adenovirus hypothesis. Adenovirus subtype 41 has previously only been linked to mild-to-moderate gastrointestinal symptoms. Not all children have tested positive for adenovirus, those who have tested positive have often done so only in whole blood (liver and plasma samples have been largely negative), and concentrations in whole blood have been low—thus precluding performance of whole-genome sequencing to better characterise the virus and any genomic changes that might explain this new phenomenon. Adenoviruses are a common cause of infection and so might be an incidental finding; an ongoing case-control study in the UK seeks to address this. 

    Other infectious causes are being investigated, including a role for SARS-CoV-2. In the UK, a decline in reports of new cases of paediatric hepatitis of unknown cause in the 2 weeks before May 6 coincided with a decline in cases of SARS-CoV-2. However, the UKHSA warned of lags in reporting of hepatitis cases and said that new cases are still being recorded in Scotland and many cases in England are pending classification. Moreover, few of the reported cases so far have tested positive for SARS-CoV-2 infection. How extensively past infection has been investigated is unclear; the UKHSA reported that serological investigations were ongoing, and Baker and colleagues reported that none of the children in Alabama had a documented history of SARSCoV-2 infection. It still remains to be seen whether these cases of hepatitis in children are post-infectious sequelae of SARS-CoV-2, potentially falling under the umbrella of multisystem inflammatory disease. 

    Much attention is being given to the cause of the outbreak. Conspiracy theories on social media abound, with some attributing the cases to COVID-19 vaccines. However, COVID-19 vaccines have been categorically ruled out, most of the children with unexplained hepatitis being too young to receive a COVID-19 vaccine. While identifying the underlying cause is important, considering how unwell the children are and that liver transplantation is possible in only highly specialised centres, it is also important to focus on early case identification and finding effective treatments that can halt progression of the disease. ■ The Lancet Infectious Diseases