猴痘——過去的序幕
資料來源：H. Clifford Lane, M.D. & Anthony S. Fauci, M.D. / N engl j med 387;8 nejm.org / 2022 /0 8 / 25 / 財團法人台灣紅絲帶基金會編譯
在新英格蘭醫學期刊本期當中，Thornhill 等人報告了來自五大洲 16 個國家的 528 名猴痘患者。作者提供了在具有全球重要性的新興傳染病爆發中最新、最大患者世代之重要的人口統計學、流行病學和臨床細節報告。診斷依賴於取自病變部位（主要是皮膚、肛門生殖器區域、鼻子或喉嚨）的拭子樣本進行聚合酶鏈反應 (PCR) 分析。作者注意到一系列不同的皮膚病變和口咽臨床表現，在許多情況下可能與多種其他疾病相混淆，包括幾種性傳播感染。大多數患者有 10 個或更少的病變，10% 有單個生殖器病變，結果與其他早期報告一致。病變的外觀範圍從斑丘疹到水皰膿皰到結痂，最常見的部位是肛門生殖器區域。文章的補充附錄（可在 NEJM.org 上與文章全文一起獲得）包含一組極好的病變圖像，以幫助識別病例。儘管世代中沒有死亡病例，但 13% 的感染者因疼痛或繼發感染而住院治療。
自 1970 年以來，猴痘已被確認為中非和西非的一種地方病，當時在剛果民主共和國的一名 9 個月大的兒童中被診斷出該病，該兒童尚未接種過天花疫苗。從那時起，中部和西部非洲都有病例報告，可以根據分子特徵分為兩大類，通常稱為剛果盆地（進化枝 I）和西非（進化枝 IIa 和 IIb [以前的進化枝 2和 3]) 。目前在該疾病原未流行國家中出現的暴發與西非進化枝引起的疾病最類似，而剛果盆地進化枝則引起更嚴重的疾病，相關的死亡率為 10%。早期基因組分析顯示，當前的全球爆發是由進化枝 IIb 病毒引起的，類似於 2017 年和 2018 年導致奈及利亞爆發的那些病毒，其中包括 2018 年和 2019 年出口到英國、以色列和新加坡的病例；當前爆發的病毒的特徵在於可能由載脂蛋白 B 信使 RNA 編輯催化多肽樣 3 (APOBEC3) 酶驅動的進化變化模式。值得注意的是，最近非洲猴痘的流行病學特徵似乎發生了變化，病例現在出現在新的地理區域，這可能是由於氣候變化和森林砍伐導致人與動物貯藏宿主或貯存窩之間的環境界面發生變化而促成的。
這些病例的新出現的流行病學模式與早期的愛滋病毒/愛滋病例有著驚人的相似之處。在本研究中，被認定為同性戀或雙性戀的男性佔病例的 98%。猴痘病毒感染的典型傳播方式被認為是病灶與皮膚的直接接觸。到目前為止，除了照護人員之外，幾乎沒有任何形式的猴痘在家庭中傳播的證據，這顯示這種感染不會透過偶然接觸傳播，可能需要長時間或反復接觸會排放病毒之病變。在本研究中，32 份精液樣本中有 29 份發現 PCR 陽性，23% 的感染者存在孤立於口咽部的病變，並且觀察到世代中 73% 的人在肛門生殖器處區域有病變，提示性傳播也可能起作用。鑑於我們對當前疫情的流行病學特徵知之甚少，謹慎地注意在愛滋病毒/愛滋病大流行的第一年所做的觀察：「 . .任何認為它仍將僅侷限於我們社會特定部分的假設都是沒有科學根依據的假設」。因此，額外詳細的流行病學和觀察性世代研究、血清調查以及對新病例的持續監測至關重要。
如果將 AIDS、Covid-19 和當前全球猴痘爆發時的情況進行比較，就會發現顯而易見的某些有趣的相似之處和不同之處。在愛滋病的情況下，病因不明，沒有有效的具體對策；今天，我們知道了病因，有了有效的治療方法；然而，到達目前這一點前我們花了許多年時間，而且我們直到現在仍然缺乏疫苗。在 Covid-19 的案例中，我們迅速確定了病原體；但是，我們缺乏有效的應對措施；今天，經過大約一年的緊張研究和開發，我們擁有了有效的診斷方法、疫苗和療法。相比之下，在猴痘的情況下，病原體已為人所知數十年。一種獲得許可的猴痘疫苗——非複制性改良痘苗 Ankara（Jynneos [在加拿大稱為 Imvamune，在歐洲稱為 Imvanex]，巴伐利亞北歐生技公司）——以及一種在 FDA 擴大取得研究新藥機制下可用於猴痘的疫苗（活病毒痘苗 [ACAM2000 , Emergent BioSolutions]) 在國家戰略儲備中。此外，兩種藥物（tecovirmat 和 brincidofovir）已經通過「動物規則」獲得許可，用於治療密切相關的天花病毒（導致天花）。對猴痘及其動物宿主的研究一直在非洲進行，一項隨機、安慰劑對照的 tecovirimat 試驗即將在剛果民主共和國開始。因此，在緊急響應期間，公共衛生和研究界面臨的挑戰是，確保有效和公平地向有需要的人提供和分發現有的相關對策，同時進行必要且嚴格的研究，以確定什麼是可能的臨床療效、了解任何潛在的安全問題，並指導正確使用。
當前猴痘的爆發給患者以及醫學和生物醫學研究界帶來了一系列新挑戰。當Thornhill 等人的文章在線上發表時，全球已報告約14,000例；而在撰寫這篇社論時（大約兩週後），這個數字翻了一番倍增。在應對 AIDS 和 Covid-19 期間吸取的經驗教訓應有助於我們調整對猴痘做出更有效益和更有效的應對，而對猴痘的應對反過來也應有助於告知我們，對於不可避免的下一次具有潛在大流行的新興或再浮現傳染病之應對。
作者提供的披露表與這篇社論的全文可在 NEJM.org 上獲取。來自馬里蘭州貝塞斯達國立衛生研究院國家過敏和傳染病研究所臨床研究部 (H.C.L.) 和主任辦公室 (A.S.F.)。本社論於 2022 年 8 月 25 日在 NEJM.org 更新。
Monkeypox — Past as Prologue
H. Clifford Lane, M.D., and Anthony S. Fauci, M.D. / N engl j med 387;8 nejm.org August 25, 2022
In this issue of the Journal, Thornhill et al. report on 528 persons with monkeypox in a cohort spanning 16 countries on five continents. The authors provide important demographic, epidemiologic, and clinical details on the largest reported cohort of patients in the latest emerging infectious disease outbreak of global importance. Diagnosis relied on polymerase-chain-reaction (PCR) assays of swab specimens taken from lesions, predominantly in the skin, anogenital region, nose, or throat. The authors note a diverse set of dermatologic and oropharyngeal clinical manifestations that in many instances could be confused with a variety of other illnesses, including several sexually transmitted infections. Most of the patients had 10 or fewer lesions, with 10% having a single genital lesion, findings consistent with other early reports. Lesions ranged in appearance from maculopapular to vesiculopustular to crusted, with the anogenital region the most common site. The Supplementary Appendix of the article (available with the full text of the article at NEJM.org) contains an excellent array of images of lesions to aid in case recognition. Although there were no fatalities within the cohort, 13% of the persons with infection were hospitalized for management of pain or secondary infections.
Monkeypox has been recognized as an endemic disease in central and western Africa since 1970, when it was diagnosed in a 9-month old child in the Democratic Republic of Congo who had not been vaccinated against smallpox. Since then, cases have been reported from central and western Africa and can be classified on the basis of molecular characteristics into two major groups, often referred to as the Congo Basin (clade I) and West African (clades IIa and IIb [formerly clades 2 and 3]) groups.3,4 The West African clades cause disease most closely resembling the currently emerging outbreak in countries in which the disease is not endemic, whereas the Congo Basin clade causes a more severe disease, with an associated 10% mortality. Early genomic analyses suggest that the current global outbreak is caused by clade IIb viruses similar to those that caused a Nigerian outbreak in 2017 and 2018, which included cases that were exported to the United Kingdom, Israel, and Singapore in 2018 and 2019; the viruses in the current outbreak are characterized by a pattern of evolutionary changes potentially driven by apolipoprotein B messenger RNA–editing catalytic polypeptide-like 3 (APOBEC3) enzymes. It is noteworthy that there appears to have been a recent change in the epidemiologic characteristics of monkeypox in Africa, where cases are now occurring in new geographic areas, perhaps facilitated by climate change and deforestation leading to changes in the environmental interface between humans and the animal reservoir (or reservoirs).
The emerging epidemiologic pattern of these cases bears a striking resemblance to the early cases of HIV/AIDS. In the present study, men who identified as homosexual or bisexual accounted for 98% of cases. The classic mode of transmission of monkeypox virus infection is thought to be direct lesion-to-skin contact. Thus far, there has been very little evidence of household spread of any form of monkeypox other than among caregivers, which suggests that this infection is not spread through casual contact and probably requires prolonged or repeated exposure to virus shedding lesions. In the present study, the finding of PCR positivity in 29 of 32 semen samples, the presence of lesions isolated to the oropharynx in 23% of the persons with infection, and the observation that 73% of persons in the cohort had lesions in the anogenital area suggest that sexual transmission may also play a role. Given how little we know about the epidemiologic characteristics of the current outbreak, it is prudent to heed an observation made during the first year of the HIV/AIDS pandemic: “. . . any assumption that it will remain restricted to a particular segment of our society is truly an assumption without a scientific basis.” Thus, additional detailed epidemiologic and observational cohort studies, serosurveys, and ongoing surveillance for new cases are of critical importance.
If one compares the situations at the start of the AIDS, Covid-19, and current global monkeypox outbreaks, certain interesting similarities and differences are apparent. In the case of AIDS, the etiologic agent was unknown, and no effective specific countermeasures were available. Today, we know the cause and have effective therapies; however, it took years to get to that point, and we still lack a vaccine. In the case of Covid-19, we quickly identified the etiologic agent; however, we lacked effective countermeasures. Today, we have effective diagnostics, vaccines, and therapies, after approximately a year of intense research and development. In contrast, in the case of monkeypox, the etiologic agent has been known for decades. One licensed monkeypox vaccine — the nonreplicating modified vaccinia Ankara (Jynneos [called Imvamune in Canada and Imvanex in Europe], Bavarian Nordic) — and one vaccine that is available for monkeypox under the FDA Expanded Access Investigational New Drug mechanism (live virus vaccinia [ACAM2000, Emergent BioSolutions]) are in the Strategic National Stockpile. In addition, two drugs (tecovirimat and brincidofovir) had already been licensed through the “Animal Rule” for the closely related virus variola (which causes smallpox). Studies of the disease and its animal reservoirs had been ongoing in Africa, and a randomized, placebo-controlled trail of tecovirimat was close to starting in the Democratic Republic of Congo. Thus, the challenge to the public health and research communities during this time of emergency response is to ensure the efficient and equitable availability and distribution of existing countermeasures to those in need of them while at the same time conducting the rigorous studies needed to define what the clinical efficacy may be, understand any potential safety concerns, and guide proper utilization.
The current monkeypox outbreak provides a new set of challenges to patients as well as to the medical and biomedical research communities. At the time that the article by Thornhill et al. was published online, approximately 14,000 cases had been reported in the world; at the time this editorial was being written (approximately 2 weeks later), that number had doubled. Lessons learned during the responses to AIDS and Covid-19 should help us to marshal a more efficient and effective response to monkeypox, and the response to monkeypox should, in turn, help to inform our response to the inevitable next emerging or reemerging infectious disease of pandemic potential.
Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org. From the Division of Clinical Research (H.C.L.) and Office of the Director (A.S.F.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
This editorial was updated on August 25, 2022, at NEJM.org.