它不會結束，直到它真正結束。..但它永遠不會結束—新興與再浮現的傳染病
資料來源：Anthony S. Fauci，醫學博士 / n engl j med 387;22 nejm.or / 2022 年 12 月 1 日 / 財團法人台灣紅絲帶基金會編譯
當我準備辭去國家過敏和傳染病研究所 (NIAID) 的雙重職位時，我在該研究所擔任了 54 年的醫師兼科學家和 38 年的主任，不可避免地要進行一些反思。當我回顧我的職業生涯時，最突出的是傳染病領域的顯著發展，以及學術界和公眾對該領域的重要性和相關性看法上的不斷變化。
我於 1968 年完成了內科住院醫師培訓，並決定在 NIAID 進行為期 3 年的傳染病和臨床免疫學聯合研究。作為一名年輕的醫生，我並不知道 1960 年代的某些學者和權威人士認為，隨著針對許多兒童疾病的高效疫苗的出現和越來越多的抗生素，傳染病的威脅——或許，隨之而來的是，對傳染病專家的需求正在迅速消失。儘管我對我進入的領域充滿熱情，但如果我知道這種對該學科未來的懷疑，我可能會重新考慮我對次專業的選擇。當然，當時瘧疾、肺結核和其他低收入和中等收入國家的疾病每年奪去數百萬人的生命。忘記了這種內在的矛盾，我愉快地追求我在宿主防禦和傳染病方面的臨床和研究興趣。
1976 年，當我離開訓練 5 年後時，當傳染病領域的標誌性人物羅伯特·彼得斯多夫博士在雜誌上發表了一篇挑釁性的文章，暗示傳染病作為一個次專業時，我有些吃驚內科醫學逐漸被遺忘。在一篇題為「醫生的困境」的文章中，他談到了接受各種內科醫學次專業培訓的年輕醫生的數量，「即使我個人對傳染病非常忠誠，我無法想像還需要 309 名傳染病專家，除非他們花時間互相培養」。
當然，我們都渴望成為一個充滿活力的領域的一部分。我選擇的領域現在是靜態的嗎？ Petersdorf 博士（他後來成為我的朋友和兼職導師，因為我們和其他人共同編輯了 Harrison 的《內科醫學原理》）發表了一個共同的觀點，該觀點缺乏對傳染病真正動態特性的充分理解，特別是關於新興和再浮現的感染的可能性。在 1960 年代和 70 年代，大多數醫生都意識到流行病的可能性，因為1918 歷史性流感大流行以及最近的 1957 年和 1968 年流感大流行的熟悉先例。然而，出現一種可能對社會產生巨大影響的真正新傳染病仍然是一個純粹的假設概念。
這一切都在 1981 年夏天發生了變化，因為第一批愛滋病病例得到承認。這種疾病的全球影響是驚人的：自大流行開始以來，已有超過 8,400 萬人感染了 HIV，這種病毒會導致愛滋病，其中 4,000 萬人已經死亡。僅在 2021 年，就有 65 萬人死於愛滋病相關疾病，新增感染人數達 150 萬人。今天，超過 3,800 萬人感染了愛滋病毒。
儘管尚未開發出安全有效的 HIV 疫苗，但科學的進步導致了高效能抗反轉錄病毒藥物的開發，這些藥物已將 HIV 感染從幾乎總是致命的疾病轉變為可控的慢性疾病與幾乎有正常的預期壽命。鑑於這些救命藥物的可及性在全球範圍內缺乏公平性，愛滋病毒/愛滋病在首次發現 41 年後仍在繼續，並在發病率和死亡率方面造成可怕的損失。
如果 HIV/AIDS 的出現有任何一線希望，那就是這種疾病大大增加了進入醫學領域的年輕人對傳染病的興趣。事實上，隨著 HIV/AIDS 的出現，我們非常需要 Petersdorf 博士關心的那 309 名傳染病實習生——還有更多。值得讚揚的是，在他的文章發表多年後，Petersdorf 博士欣然承認他沒有完全意識到新興的感染的潛在影響，並成為年輕醫生從事傳染病職涯的啦啦隊隊長特別是 HIV 領域/愛滋病實踐與研究。
當然，新興感染的威脅和現實並沒有因愛滋病毒/愛滋病而停止。在我擔任 NIAID 主任期間，我們面臨著許多傳染病的出現或重新出現的挑戰，這些疾病具有不同程度的區域或全球影響（見時間表）。其中包括首例已知的 H5N1 和 H7N9 流感人類病例；由A型H1N1流感引起的21世紀（2009年）第一次大流行；非洲多次爆發伊波拉病毒；美洲的玆卡病毒；由新型冠狀病毒引起的嚴重急性呼吸系統綜合症（SARS）；由另一種新冠病毒引起的中東呼吸道症候群（MERS）；當然還有 新冠肺炎(Covid-19)，這是一個多世紀以來對我們易受新興傳染病爆發的影響發出的最響亮的警鐘。
Covid-19 在全球造成的破壞具有真正的歷史意義，並凸顯出世界總體上缺乏公共衛生準備達一定量級。然而，應對 Covid-19 的一個非常成功的因素是快速發展——透過多年對基礎和應用研究的投資——高度適應性的疫苗平台，如 mRNA（以及其他）和結構生物學的使用設計疫苗免疫原的工具。安全高效的 Covid-19 疫苗的開發、證明有效和分發的速度前所未有，挽救了數百萬人的生命。多年來，許多醫學次專業都從驚人的技術進步中受益匪淺。現在可以說傳染病領域也是如此，特別是我們現在擁有的應對新興傳染病的工具，例如病毒基因組的快速和高通量測序；開發快速、高度特異性的多重診斷；以及基於結構的免疫原設計與新型疫苗平台的結合使用。
如果有人對傳染病的動態特性，進而對傳染病的學科有任何疑問，我們自從承認愛滋病以來四十多年的經驗應該完全消除這種懷疑。今天，沒有理由相信新興感染的威脅會減少，因為它們的根本原因已經存在，而且很可能還在增加。新感染的出現和舊感染的重新出現在很大程度上是人類與自然相互作用和侵占自然的結果。隨著人類社會在一個日益相互關聯的世界中擴張，人與動物之間的界面受到干擾，創造了機會，通常在氣候變化的幫助下，不穩定的傳染源出現、跨越物種，並在某些情況下適應在人類之間傳播。
我對傳染病領域的演變進行反思的一個必然結論是，多年前的權威人士的看法是不正確的，學科當然不是靜止的；它是真正動態的。除了明顯需要繼續提高我們應對瘧疾和肺結核等既定傳染病的能力外，現在很明顯，新出現的傳染病確實是一個永恆的挑戰。正如我最喜歡的專家之一 Yogi Berra 曾經說過的那樣，「它不會結束，直到它真正結束」。顯然，我們現在可以擴展這個公理：當涉及到新興傳染病時，它永遠不會結束。作為傳染病專家，我們必須時刻做好準備並能夠應對永恆的挑戰。
在作者擔任 NIAID 主任的四個十年任期之前和期間，傳染病出現的選定標誌性事件。
DRC表示剛果民主共和國，MERS表示中東呼吸道症候群，SARS表示嚴重急性呼吸道症候群，XDR表示廣泛耐藥。
作者提供的披露表可在 NEJM.org 獲取。
來自馬里蘭州貝塞斯達國家衛生研究院過敏和傳染病研究所。
本文於 2022 年 11 月 26 日發表在 NEJM.org。
It Ain’t Over Till It’s Over . . . but It’s Never Over — Emerging and Reemerging Infectious Diseases
Anthony S. Fauci, M.D. / n engl j med 387;22 nejm.org December 1, 2022
As I prepare to step down from my dual positions at the National Institute of Allergy and Infectious Diseases (NIAID), where I have been a physician-scienntist for 54 years and the director for 38 years, a bit of reflection is inevitable. As I think back over my career, what stands out most is the striking evolution of the field of infectious diseases and the changing perception of the importance and relevance of the field by both the academic community and the public.
I completed my residency training in internal medicine in 1968 and decided to undertake a 3-year combined fellowship in infectious diseases and clinical immunology at NIAID. Unbeknownst to me as a young physician, certain scholars and pundits in the 1960s were opining that with the advent of highly effective vaccines for many childhood diseases and a growing array of antibiotics, the threat of infectious diseases — and perhaps, with it, the need for infectious-disease specialists — was fast disappearing. Despite my passion for the field I was entering, I might have reconsidered my choice of a subspecialty had I known of this skepticism about the discipline’s future. Of course, at the time, malaria, tuberculosis, and other diseases of low- and middle income countries were killing millions of people per year. Oblivious to this inherent contradiction, I happily pursued my clinical and research interests in host defenses and infectious diseases.
In 1976, when I was 5 years out of my fellowship, I was somewhat taken aback when Dr. Robert Petersdorf, an icon in the field of infectious diseases, published a provocative article in the Journal suggesting that infectious diseases as a subspecialty of internal medicine was fading into oblivion. In an article entitled “The Doctors’ Dilemma,” he wrote regarding the number of young physicians entering training in the various internal medicine subspecialties, “Even with my great personal loyalties to infectious disease, I cannot conceive a need for 309 more infectious-disease experts unless they spend their time culturing each other.”
Of course, we all aspire to be part of a dynamic field. Was my chosen field now static? Dr. Petersdorf (who would become my friend and part-time mentor as we and others coedited Harrison’s Principles of Internal Medicine) gave voice to a common viewpoint that lacked a full appreciation of the truly dynamic nature of infectious diseases, especially regarding the potential for newly emerging and reemerging infections. In the 1960s and 1970s, most physicians were aware of the possibility of pandemics, in light
of the familiar precedent of the historic influenza pandemic of 1918, as well as the more recent influenza pandemics of 1957 and 1968. However, the emergence of a truly new infectious disease that could dramatically affect society was still a purely hypothetical concept.
That all changed in the summer of 1981 with the recognition of the first cases of what would become known as AIDS. The global impact of this disease is staggering: since the start of the pandemic, more than 84 million people have been infected with HIV, the virus that causes AIDS, of whom 40 million have died. In 2021 alone, 650,000 people died from AIDS-related conditions, and 1.5 million were newly infected. Today, more than 38 million people are living with HIV.
Although a safe and effective HIV vaccine has not yet been developed, scientific advances led to the development of highly effective antiretroviral drugs that have transformed HIV infection from an almost-always-fatal disease to a manageable chronic disease associated with a nearly normal life expectancy. Given the lack of global equity in the accessibility of these lifesaving drugs, HIV/AIDS continues, exacting a terrible toll in morbidity and mortality, 41 years after it was first recognized.
If there is any silver lining to the emergence of HIV/AIDS, it is that the disease sharply increased interest in infectious diseases among young people entering the field of medicine. Indeed, with the emergence of HIV/AIDS, we sorely needed those 309 infectiousdisease trainees that Dr. Petersdorf was concerned about — and many more. To his credit, years after his article was published, Dr. Petersdorf readily admitted that he had not fully appreciated the potential impact of emerging infections and became something of a cheerleader for young physicians to pursue careers in infectious diseases and specifically in HIV/AIDS practice and research.
Of course, the threat and reality of emerging infections did not stop with HIV/AIDS. During my tenure as NIAID director, we were challenged with the emergence or reemergence of numerous infectious diseases with varying degrees of regional or global impact (see timeline). Included among these were the first known human cases of H5N1 and H7N9 influenza; the first pandemic of the 21st century (in 2009) caused by H1N1 influenza; multiple outbreaks of Ebola in Africa; Zika in the Americas; severe acute respiratory syndrome (SARS) caused by a novel coronavirus; Middle East respiratory syndrome (MERS) caused by another emergent coronavirus; and of course Covid-19, the loudest wake-up call in more than a century to our vulnerability to outbreaks of emerging infectious diseases.
The devastation that Covid-19 has inflicted globally is truly historic and highlights the world’s overall lack of public health preparedness for an oumagnitude. One highly successful element of the response to Covid-19, however, was the rapid development — enabled by years of investment in basic and applied research — of highly adaptable vaccine platforms such as mRNA (among others) and the use of structural biology tools to design vaccine immunogens. The unprecedented speed with which safe and highly effective Covid-19 vaccines were developed, proven effective, and distributed resulted in millions of lives saved. Over the years, many subspecialties of medicine have benefited greatly from breathtaking technological advances. The same can now be said of the field of infectious diseases, particularly with the tools we now have for responding to emerging infectious diseases, such as the rapid and high-throughput sequencing of viral genomes; the development of rapid, highly specific multiplex diagnostics; and the use of structure-based immunogen design combined with novel platforms for vaccines.
If anyone had any doubt about the dynamic nature of infectious diseases and, by extension, the discipline of infectious diseases, our experience over the four decades since the recognition of AIDS should have completely dispelled such skepticism. Today, there is no reason to believe that the threat of emerging infections will diminish, since their underlying causes are present and most likely increasing. The emergence of new infections and the reemergence of old ones are largely the result of human interactions with and encroachment on nature. As human societies expand in a progressively interconnected world and the human–animal interface is perturbed, opportunities are created, often aided by climate changes, for unstable infectious agents to emerge, jump species, and in some cases adapt to spread among humans.
An inevitable conclusion of my reflections on the evolution of the field of infectious diseases is that the pundits of years ago were incorrect and that the discipline is certainly not static; it is truly dynamic. In addition to the obvious need to continue to improve on our capabilities for dealing with established infectiou diseases such as malaria and tuberculosis, among others, it is now clear that emerging infectious diseases are truly a perpetual challenge. As one of my favorite pundits, Yogi Berra, once said, “It ain’t over till it’s over.” Clearly, we can now extend that axiom: when it comes to emerging infectious diseases, it’s never over. As infectious-disease specialists, we must be perpetually prepared and able to respond to the perpetual challenge.
Selected Landmark Events in Infectious-Disease Emergence Leading up to and during the Author’s Four-Decade Tenure as NIAID Director.
DRC denotes Democratic Republic of Congo, MERS Middle East respiratory syndrome, SARS severe acute respiratory syndrome, and XDR extensively drug-resistant.
Disclosure forms provided by the author are available at NEJM.org.
From the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
This article was published on November 26, 2022, at NEJM.org.