2022 年兒童急性肝炎——人類腺病毒 41?
資料來源:Saul J. Karpen, M.D., Ph.D/2022 年 7 月 13 日,NEJM.org。 /財團法人台灣紅絲帶基金會編譯
兒童急性肝炎當然不是新事物,而且可能令人擔憂。在過去的幾十年裡,成功的全球疫苗接種運動透過減少兩種病毒原因(A型肝炎病毒和B型肝炎病毒)的發病率和後果,顯著改善了公眾健康和福祉。許多其他病毒,有一些在兒童時期很常見,是嗜肝病毒,在少數患者中可能會導致病情加重。在這些情況下,肝損傷表現為血清肝酶水平升高,例如丙氨酸氨基轉移酶 (ALT) 和天冬氨酸氨基轉移酶 (AST),可迅速增加到正常範圍上限的 100 倍以上。在這些嚴重的病例中,患者的病情會迅速惡化,導致肝功能嚴重受損(例如凝血病、黃疸和腦病),進而可能導致肝功能衰竭。一些患者的轉氨酶水平沒有如此明顯的升高,主要是功能障礙。大部分患者都康復;然而,肝臟顯著的再生能力是有限度的,因此在進行性病例中,必須將兒童轉診到能夠提供肝移植的中心。
即使應用現代的基於基因和抗原的快速診斷方法,急性肝炎的根本原因也常常難以捉摸。當出現典型的呼吸道或胃腸道前驅症狀伴隨發熱時,病毒通常被認為是根本原因。在 1999 年至 2004 年因肝功能衰竭住院的大量兒童中,最常見的診斷是「不確定」,佔 49%,今天仍然如此。鑑於患者年齡較小,需要尋找遺傳基礎和(在極少數情況下)環境原因。顯然,我們必須繼續尋找導致急性肝炎,特別是導致肝功能衰竭的肝炎之原因,以便我們能夠有效地照顧這些孩子。
兩份旨在填補這一空白的及時報告——一份來自英國伯明翰, 另一份來自美國阿拉巴馬州伯明翰——現已在《新英格蘭期刊》上發表。由於對阿拉巴馬州病例的最初報導引起了社交媒體、新聞機構、醫學協會和流行病學聯盟的參與,全世界都在強調兒童急性肝炎的識別和報告。英國則與美國不同,使用三個轉診中心(包括伯明翰的一個)來集中照護可能接受肝移植的患者。凱爾格里等人(Kelgeri et al.) 在伯明翰肝臟中心接受治療的 44 名兒童之報告,其病情符合英國衛生安全局的確診病例定義(例如,血清轉氨酶 [ALT 或 AST] 水平 >500 IU/L 的 ≤10 歲兒童,無代謝、遺傳或遺傳、先天或機械性原因的非 A–E 急性肝炎者);世代中患者的中位數年齡為 4 歲。大多數患者出現黃疸和胃腸道症狀。其中六名患者進展為肝功能衰竭並接受了肝移植。
在來自美國的研究中,Gutierrez Sanchez 等人報告了來自阿拉巴馬州不同地點的 9 名患者,他們在伯明翰的一家兒童醫院接受了治療,他們的體徵和年齡與英國世代相似,儘管美國作者使用了不同的轉氨酶水平標準(>250 U/L ALT 和 >440 U/L AST)。其中三名患者進展為肝功能衰竭,其中兩名患者接受了肝移植。
這裡有趣的是發現美國病例系列中的所有 9 名兒童和在英國研究中接受分子檢測的 30 名兒童中的 27 名對人類腺病毒 41 型檢測呈陽性,這一發現與其他報告一致。進展為肝功能衰竭的患者的血清病毒載量顯著高於自發恢復的患者。
有來自全球的此類報導,是否有足夠的證據顯示人類腺病毒 41 是導致小兒肝衰竭的新原因?目前還沒有完全令人信服的因果關係證據,因為至少在美國,報告的腺病毒肝炎病例並沒有增加。此外,沒有任何組織學評估顯示肝細胞有腺病毒感染的證據,正如我們這些主要照顧免疫功能低下的腺病毒性肝炎患者所預期的那樣。腺病毒感染在兒童時期極為常見,已知人類腺病毒 41 會引起急性胃腸炎,但與肝功能衰竭無關。幾名患者接受了西多福韋 (cidofovir) 治療,目前尚不清楚這是否會影響結果。在沒有腺病毒介導的組織損傷的證據的情況下,這些研究還不足以宣佈人類腺病毒 41 是可導致肝功能衰竭的急性肝炎的確切原因。需要考慮的替代方案包括人類腺病毒 41,它可能作為免疫激活劑,甚至作為無辜的、容易被發現的旁觀者。必須先解決關鍵的未知數,然後才能確定病因或提供有關開始治療的實踐指導。
此外,在許多病例中以及在英國系列中的 SARSCoV-2病例中發現了人類腺病毒和其他常見的兒科病毒(例如鼻病毒、腸道病毒和流感病毒)同時存在。如果沒有更廣泛的有關兒科或急診科就診的兒童其病毒的流行病學數據,這似乎並不意外,並應該盡量減少對多種病毒原因的反思。同樣,需要適當的研究和數據,才能對關於兒童疾病大流行相關免疫反應的改變之推測予以支持或駁斥。
最後,沒有人願意聽到當今世界上有一種潛在關注的新病毒。然而,目前尚不清楚這種腺病毒株是新的、增加發病率的,還是導致急性肝炎和小兒肝衰竭的原因,因為這些數據尚未在兒童中被前瞻性地收集。這兩份重要報告向兒科肝病學領域內外的人士顯示,急需兒童急性肝炎的登記和臨床研究;這些目前正在歐洲和北美開發。很可能隨著對急性肝炎兒患病例和生物樣本數據的收集更加關注,我們將能夠確定這種病毒,即人類腺病毒 41,是否與兒童中這種重要而嚴重的疾病有關。
本社論於 2022 年 7 月 13 日在 NEJM.org 上發表。
Acute Hepatitis in Children in 2022 — Human Adenovirus 41?
Saul J. Karpen, M.D., Ph.D / July 13, 2022, NEJM.org.
Acute hepatitis in children is certainly not new, and it can be worrisome. Successful worldwide vaccination campaigns over the past few decades have led to demonstrable improvements in public health and well-being by reducing the incidence and consequences of two viral causes — hepatitis A and B viruses. Many other viruses, some quite commonly encountered during childhood, are hepatotropic and in a minority of patients may cause illness that can escalate in severity. In these cases, liver damage manifests as elevations in serum levels of liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), that can increase rapidly to more than 100 times the upper limit of the normal range. In these severe cases, patients’ conditions can rapidly worsen, leading to substantial impairments in liver function (e.g., coagulopathy, jaundice, and encephalopathy) that may segue to liver failure. Some patients do not have such marked elevations in aminotransferase levels and have mainly functional impairments. The majority of patients recover. However, there are limits to the remarkable regenerative capabilities of the liver, and therefore in progressive cases it is imperative that children are referred to centers that are able to provide liver transplantation.
An underlying cause of acute hepatitis is often elusive even with the application of modern gene-based and antigen-based rapid diagnostic methods. Viruses are usually presumed to be the underlying cause when a typical respiratory or gastrointestinal prodrome with fever is present. In a large series of children hospitalized with liver failure in 1999 through 2004, the most common diagnosis was “indeterminate,” in 49%, and this is still the situation today. Given the young age of the patients, genetic underpinnings and (in rare cases) environmental causes are sought. Clearly, it is crucial that we continue the search for causes of acute hepatitis, especially hepatitis leading to liver failure, so that we can effectively care for these children.
Two timely reports aiming to fill this gap — one from Birmingham, United Kingdom, and the other from Birmingham, Alabama — have now been published in the Journal. Since the original accounts of the cases from Alabama resulted in the engagement of social media, news organizations, medical societies, and epidemiologic consortia, there has been a worldwide emphasis on the recognition and reporting of acute hepatitis in children. Unlike the United States, the United Kingdom uses three referral centers, including the one in Birmingham, to centralize the care of patients who may undergo liver transplantation. Kelgeri et al. report on 44 children who received treatment at the Birmingham liver center and whose conditions were consistent with the confirmed case definition of the U.K. Health Security Agency (e.g., non-A–E acute hepatitis without a metabolic, inherited or genetic, congenital, or mechanical cause in a child ≤10 years of age with a serum aminotransferase [ALT or AST] level >500 IU per liter); the median age of patients in the cohort was 4 years. The majority of the patients presented with jaundice and gastrointestinal symptoms. Six of the patients had progression to liver failure and underwent liver transplantation.
In the study from the United States, Gutierrez Sanchez et al. report on nine patients from various locations in Alabama who were treated at a children’s hospital in Birmingham and who had presenting signs and ages similar to those in the U.K. cohort, although the U.S. authors used different criteria for aminotransferase levels (>250 U per liter for ALT and >440 U per liter for AST). Three of the patients had progression to liver failure, and two of these patients underwent liver transplantation.
What is of interest here is the discovery that all 9 of the children in the U.S. case series and 27 of the 30 children who underwent molecular testing in the U.K. study tested positive for human adenovirus type 41, a finding consistent with other reports. Serum viral loads in the patients with progression to liver failure were substantially higher than those in the patients who spontaneously recovered.
With reports like these from around the globe, is there sufficient evidence that human adenovirus 41 is a new cause of pediatric liver failure? There is not yet completely convincing evidence of a causal link, since at least in the United States there has not been an increase in reported cases of adenoviral hepatitis. Moreover, none of the histologic evaluations have revealed evidence of hepatocellular adenoviral infection, as was expected by those of us who have cared for mainly immunocompromised patients with florid adenoviral hepatitis. Adenoviral infections are exceedingly common during childhood, and human adenovirus 41 is known to cause acute gastroenteritis, although not in association with liver failure. Several of the patients received cidofovir treatment, which is not known to have affected outcomes. Without evidence of adenovirus-mediated tissue damage, these studies are not yet sufficient to declare human adenovirus 41 a firm cause of acute hepatitis that can lead to liver failure. Alternatives to consider include human adenovirus 41 potentially serving as an immunologic activator or even as an innocent, readily detected bystander. Crucial unknowns must be resolved before etiologic guilt can be assigned or practice guidance regarding the initiation of therapy can be provided.
Moreover, human adenovirus was found along with other common pediatric viruses in a number of the cases (e.g., rhinovirus, enterovirus, and influenza virus) and, in the U.K. series, SARSCoV-2. Without broader epidemiologic data on viruses in children who present to pediatricians or emergency departments for any indication, this does not seem unexpected and should minimize reflections about multiple viral causes. Similarly, appropriate studies and data are needed before speculation about pandemic-related alterations in immunologic reactivity to childhood illnesses can be supported or refuted.
Finally, no one wants to hear of a potential new virus of concern in the world these days. However, it is not at all clear that this adenoviral strain is new, of increasing incidence, or causative of acute hepatitis and pediatric liver failure, since such data have not been prospectively collected in children. These two important reports indicate to those inside and outside the field of pediatric hepatology that registries and clinical studies of acute hepatitis in children are sorely needed; these are currently being developed in Europe and in North America. It is likely that with greater attention to collecting data on cases and biospecimens from children with acute hepatitis, we will be able to determine whether this one virus, human adenovirus 41, is of relevance to this important and serious condition in children.
This editorial was published on July 13, 2022, at NEJM.org.