現場視頻：湖北解封 車站擠滿出省務工人潮

How Does the Coronavirus Behave Inside a Patient?

We』ve counted the viral spread across peoples; now we need to count it within people.

By Siddhartha Mukherjee

March 26, 2020

冠狀病毒在患者體內的行為如何？

我們已經計算出病毒在各個民族之間的傳播；現在我們需要在人們內部進行計數。

悉達多·穆克吉（Siddhartha Mukherjee）

2020年3月26日

Measurement will help identify factors affecting the severity of covid-19 cases.Illustration by Alexander Glandien

測量將有助於確定影響covid-19病例嚴重程度的因素.Alexander Glandien的插圖

In the third week of February, as the covid-19 epidemic was still flaring in China, I arrived in Kolkata, India. I woke up to a sweltering morning—the black kites outside my hotel room were circling upward, lifted by the warming currents of air—and I went to visit a shrine to the goddess Shitala. Her name means 「the cool one」; as the myth has it, she arose from the cold ashes of a sacrificial fire. The heat that she is supposed to diffuse is not just the fury of summer that hits the city in mid-June but also the inner heat of inflammation. She is meant to protect children from smallpox, heal the pain of those who contract it, and dampen the fury of a pox epidemic.

The shrine was a small structure within a temple a few blocks from Kolkata Medical College. Inside, there was a figurine of the goddess, sitting on a donkey and carrying her jar of cooling liquid—the way she has been depicted for a millennium. The temple was two hundred and fifty years old, the attendant informed me. That would date it to around the time when accounts first appeared of a mysterious sect of Brahmans wandering up and down the Gangetic plain to popularize the practice of tika, an early effort at inoculation. This involved taking matter from a smallpox patient』s pustule—a snake pit of live virus—and applying it to the pricked skin of an uninfected person, then covering the spot with a linen rag.

在2月的第三個星期，由於covid-19流行病仍在中國蔓延，我到達了印度加爾各答。我醒來到一個悶熱的早晨-旅館房間外面的黑色風箏在高高的氣流的作用下向上盤旋-然後我去了神殿的希塔拉神社。她的名字的意思是「很酷」。就像神話一樣，她從犧牲之火的冰冷灰燼中復活。她應該散發的熱量不僅是6月中旬襲擊這座城市的盛怒，而且是發炎的內在熱量。她的目的是保護兒童免受天花傷害，治癒感染天花的人的痛苦並減輕痘病毒流行的憤怒。

這座神社是一座寺廟內的小建築物，距離加爾各答醫學院只有幾個街區。裡面有一個女神雕像，坐在驢上，背著一罐冷卻液，就像她描繪千年的樣子一樣。寺廟告訴我，這座寺廟已有250年的歷史。這可以追溯到大約首次出現一個婆羅門人神秘教派在恆河平原上空徘徊以普及提卡的實踐的時候，這是早期的接種嘗試。這涉及從天花病人的膿皰（活病毒的蛇窩）中取出物質，然後將其塗在未感染者的刺破皮膚上，然後用亞麻碎布覆蓋該部位。

The Indian practitioners of tika had likely learned it from Arabic physicians, who had learned it from the Chinese. As early as 1100, medical healers in China had realized that those who survived smallpox did not catch the illness again (survivors of the disease were enlisted to take care of new victims), and inferred that the exposure of the body to an illness protected it from future instances of that illness. Chinese doctors would grind smallpox scabs into a powder and insufflate it into a child』s nostril with a long silver pipe.

Vaccination with live virus was a tightrope walk: if the amount of viral inoculum in the powder was too great, the child would succumb to a full-fledged version of the disease—a disaster that occurred perhaps one in a hundred times. If all went well, the child would have a mild experience of the disease, and be immunized for life. By the seventeen-hundreds, the practice had spread throughout the Arab world. In the seventeen-sixties, women in Sudan practiced tishteree el jidderee (「buying the pox」): one mother haggling with another over how many of a sick child』s ripe pustules she would buy for her own son or daughter. It was an exquisitely measured art: the most astute traditional healers recognized the lesions that were likely to yield just enough viral material, but not too much. The European name for the disease, variola, comes from the Latin for 「spotted」 or 「pimpled.」 The process of immunizing against the pox was called 「variolation.」

印度的提卡修鍊者很可能是從阿拉伯醫師那裡學到的，而阿拉伯醫師是從中國人那裡學到的。早在1100年，中國的醫學治療師就意識到那些倖存了天花的人再也沒有染上這種疾病（該疾病的倖存者被邀請照料新的受害者），並推斷身體暴露於某種疾病下可以保護它從該疾病的未來情況。中國醫生會把天花瘡ab磨成粉末，然後用一根長長的銀管將其注入孩子的鼻孔。

用活病毒進行疫苗接種是徒勞的：如果粉末中的病毒接種量過多，孩子將喪生於該疾病的全面版本-可能發生了一百次災難。如果一切順利，孩子將對該病有輕微的經歷，並可以終生免疫。到了一百七十年代，這種習俗已經傳播到整個阿拉伯世界。在十七六十年代，蘇丹的婦女練習了tishteree el jidderee（「買痘」）：一位母親與另一位母親討價還價，她要為自己的兒子或女兒購買多少個生病的膿皰。這是一門考究的技巧：最精明的傳統治療師意識到可能只產生足夠病毒物質但不會產生太多病毒的病灶。該疾病的歐洲名稱為天花，源自拉丁語的「斑點」或「粉刺」。對痘進行免疫的過程稱為「變痘」。

Lady Mary Wortley Montagu, the wife of the British Ambassador to Constantinople, had herself been stricken by the disease, in 1715, leaving her perfect skin pitted with scars. Later, in the Turkish countryside, she witnessed the practice of variolation, and wrote to her friends in wonder, describing the work of one specialist: 「The old woman comes with a nut-shell full of the matter of the best sort of small-pox, and asks what vein you please to have opened,」 whereupon she 「puts into the vein as much matter as can lie upon the head of her needle.」 Patients retired to bed for a couple of days with a fever, and, Lady Montagu noted, emerged remarkably unscathed. 「They have very rarely above twenty or thirty in their faces, which never mark; and in eight days』 time they are as well as before their illness.」 She reported that thousands safely underwent the operation every year, and that the disease had largely been contained in the region. 「You may believe I am well satisfied of the safety of this experiment,」 she added, 「since I intend to try it on my dear little son.」 Her son never got the pox.

In the centuries since Lady Montagu marvelled at the efficacy of inoculation, we』ve made unimaginable discoveries in the biology and epidemiology of infectious disease, and yet the covid-19 pandemic poses no shortage of puzzles. Why did it spread like wildfire in Italy, thousands of miles from its initial epicenter, in Wuhan, while India appears so far to have largely been spared? What animal species transmitted the original infection to humans?

But three questions deserve particular attention, because their answers could change the way we isolate, treat, and manage patients. First, what can we learn about the 「dose-response curve」 for the initial infection—that is, can we quantify the increase in the risk of infection as people are exposed to higher doses of the virus? Second, is there a relationship between that initial 「dose」 of virus and the severity of the disease—that is, does more exposure result in graver illness? And, third, are there quantitative measures of how the virus behaves in infected patients (e.g., the peak of your body』s viral load, the patterns of its rise and fall) that predict the severity of their illness and how infectious they are to others? So far, in the early phases of the covid-19 pandemic, we have been measuring the spread of the virus across people. As the pace of the pandemic escalates, we also need to start measuring the virus within people.

英國駐君士坦丁堡大使的妻子瑪麗·沃特利·蒙塔古夫人（Mary Wortley Montagu）於1715年被該病折磨，完美的皮膚上留下了疤痕。後來，在土耳其的鄉下，她親眼目睹了靜脈曲張的病情，並驚奇地寫信給她的朋友，描述了一位專家的工作：「這位老婦人簡直是瘋了，痘痘，問你想要打開什麼靜脈，」於是她「儘可能多地把靜脈置於針頭上。」蒙塔古夫人指出，患者因發燒而在床上休息了兩天，而她卻毫髮無損。 「他們的臉上很少有二十或三十歲以上的人，他們從來沒有留下過痕迹。在八天的時間裡，他們和生病之前一樣。」她報告說，每年有成千上萬的人安全地接受了手術，該地區基本上已經控制了這種疾病。她補充說：「您可能會相信我對這個實驗的安全性感到滿意，因為我打算在我親愛的小兒子身上嘗試一下。」她的兒子從未得過痘。

自蒙塔古夫人對接種的功效讚嘆不已以來的幾個世紀，我們在傳染病的生物學和流行病學方面取得了不可思議的發現，但covid-19大流行卻不容小s。為什麼它在野外像野火一樣在距其最初震源數千英里的義大利武漢擴散，而到目前為止印度似乎在很大程度上已幸免於難？哪些動物物種將原始感染傳播給人類？

但是，三個問題值得特別注意，因為它們的答案可能會改變我們隔離，治療和管理患者的方式。首先，我們可以了解初次感染的「劑量反應曲線」，即，當人們暴露於更高劑量的病毒時，我們能否量化感染風險的增加？其次，病毒的初始「劑量」與疾病嚴重程度之間是否存在關係，即更多的接觸是否會導致嚴重疾病？第三，是否存在定量方法來衡量病毒在受感染患者中的行為（例如，您體內病毒載量的峰值，其上升和下降的方式）可以預測疾病的嚴重程度以及它們對他人的傳染性？到目前為止，在covid-19大流行的早期階段，我們一直在測量病毒在人與人之間的傳播。隨著大流行速度的加快，我們還需要開始測量人體內的病毒。

Most epidemiologists, given the paucity of data, have been forced to model the spread of the new coronavirus as if it were a binary phenomenon: individuals are either exposed or unexposed, infected or uninfected, symptomatic patients or asymptomatic carriers. Recently, the Washington Post published a particularly striking online simulation, in which people in a city were depicted as dots moving freely in space—uninfected ones in gray, infected ones in red (then shifting to pink, as immunity was acquired). Each time a red dot touched a gray dot, the infection was transmitted. With no intervention, the whole field of dots steadily turned from gray to red. Social distancing and isolation kept the dots from knocking into one another, and slowed the spread of red across the screen.

This was a bird』s-eye view of a virus radiating through a population, seen as an 「on-off」 phenomenon. The doctor and medical researcher in me—as a graduate student, I was trained in viral immunology—wanted to know what was going on within the dots. How much virus was in that red dot? How fast was it replicating in this dot? How was the exposure—the 「touch time」—related to the chance of transmission? How long did a red dot remain red—that is, how did an individual』s infectiousness change over time? And what was the severity of disease in each case?

What we』ve learned about other viruses—including the ones that cause aids, sars, and smallpox—suggests a more complex view of the disease, its rate of progression, and strategies for containment. In the nineteen-nineties, as researchers learned to measure how much H.I.V. was in a patient』s blood, a distinct pattern emerged. After an infection, the virus count in the blood would rise to a zenith, known as 「peak viremia,」 and patients with the highest peak viremia typically became sicker sooner; they were least able to resist the virus. Even more predictive than the peak viral load was the so-called set point—the level at which someone』s virus count settled after its initial peak. It represented a dynamic equilibrium that was reached between the virus and its human host. People with a high set point tended to progress more rapidly to aids; people with a low set point frequently proved to be 「slow progressors.」 The viral load—a continuum, not a binary value—helped predict the nature, course, and transmissibility of the disease. To be sure, every virus has its own personality, and H.I.V. has traits that make viral load especially revealing: it causes a chronic infection, and one that specifically targets cells of the immune system. Yet similar patterns have been observed with other viruses.

鑒於缺乏數據，大多數流行病學家被迫模擬新冠狀病毒的傳播，就好像它是一種二元現象：個體是暴露的或未暴露的，感染的或未感染的，有癥狀的患者或無癥狀的攜帶者。最近，《華盛頓郵報》發布了一個特別引人注目的在線模擬，其中將城市中的人們描繪成在空間中自由移動的點-灰色未感染的點，紅色感染的點（隨著免疫力的增強，然後變為粉紅色）。每次紅點碰到灰點，都會傳播感染。在沒有干預的情況下，整個點域從灰色穩定地變為紅色。社會上的疏離和孤立使這些點之間無法相互碰撞，並減緩了紅色在屏幕上的傳播。

這是病毒在整個人群中傳播的鳥瞰圖，被視為「開關現象」。我的醫生和醫學研究人員-作為一名研究生，曾接受過病毒免疫學的培訓-想要知道點點滴的情況。該紅點內有多少病毒？在此點複製的速度有多快？接觸時間（「觸摸時間」）與傳播機會有什麼關係？紅點保持紅色狀態持續了多長時間-也就是說，個人的感染力會隨著時間變化嗎？每種情況下的疾病嚴重程度如何？

我們了解到的其他病毒（包括引起輔助病毒，sars和天花的病毒）建議對這種疾病，其發病率和遏制策略有更複雜的認識。在十九世紀九十年代，研究人員學會了測量多少H.I.V.在病人的血液中，出現了獨特的模式。感染后，血液中的病毒數量會上升到最高點，稱為「峰值病毒血症」，病毒血症高峰期最高的患者通常會更快發病。他們抵抗病毒的能力最差。比峰值病毒載量更具預測性的是所謂的設定點-某人的病毒計數在其初始峰值后穩定下來的水平。它代表了病毒與其人類宿主之間達到的動態平衡。設定值高的人往往會更快地發展到艾滋病。設定值低的人經常被證明是「進展緩慢」。病毒載量（一個連續的而非二進位值）有助於預測疾病的性質，病程和傳染性。可以肯定的是，每種病毒都有其自己的特徵，並且H.I.V.具有使病毒載量特別顯著的特徵：它會引起慢性感染，而特異性地針對免疫系統的細胞。然而，其他病毒也觀察到了類似的模式。

And, immunologically, that』s not surprising. If your system is able to combat viral replication with some efficiency—owing to your age, your genetics, and other indices of immune competence—you』ll have a lower set point. Could a lower initial exposure, as with children treated with tika, also lead to a lower set point? Faced with a smaller challenge, the immune system could have a greater chance of controlling the pathogen. In contrast, if you』re inundated with multiple high-dose exposures, the swiftly replicating invader could gain ground that the immune system might be hard-pressed to reconquer.

An ingenious study on the relationship between the intensity of viral exposure and infectivity in human beings comes from a team at the Fred Hutchinson Cancer Research Center and the University of Washington, in Seattle. In 2018, an epidemiologist and statistician named Bryan Mayer joined a group of physicians and biologists who were researching a problem that seemed, on its face, almost impossible to tackle. Mayer, who is in his mid-thirties, is soft-spoken and precise: he uses words carefully, and speaks in long, slow sentences. 「Even as a graduate student, I was interested in the idea of a dose of a virus or a pathogen,」 he told me. 「But the problem is that the initial dose is often impossible to capture, because you only know a person is infected after he or she has been infected.」 Most infectious diseases can only be viewed in a rearview mirror: by the time a patient becomes a patient, that critical moment of transmission has already passed.

But the researchers found an unusual resource: a cohort of new mothers and their children in Kampala, Uganda. A few years earlier, a pediatrician named Soren Gantt and a team of doctors examined these women, and asked them to provide oral swabs for a year. Then they measured how much the women shed a virus called HHV-6, which is usually spread through oral secretions to an infant after birth, and which causes fever and a red whole-body rash. It was now possible to investigate how the amount of virus-shedding—the 「dose」 of exposure—affected the likelihood of a newborn infant becoming infected. Gantt, Mayer, and their colleagues had devised a way to eavesdrop on the dynamics of the transmission of a human viral infection from the very start. 「Our data confirmed that there』s a dose-response relationship in viral transmissions for HHV-6,」 Mayer told me. 「The more virus you shed, the more likely you are to infect others.」 He』d managed to turn around the rearview mirror of epidemiology.

而且，從免疫學上來說，這並不奇怪。如果您的系統由於年齡，遺傳學和其他免疫能力指標的原因，能夠有效地抵抗病毒複製，那麼您的設定值將更低。與接受替卡治療的兒童一樣，較低的初始暴露量是否也可以導致較低的設定點？面對較小的挑戰，免疫系統控制病原體的機會更大。相反，如果您被大量的高劑量暴露所淹沒，那麼迅速複製的入侵者可能會發現免疫系統可能很難被重新征服。

西雅圖的弗雷德·哈欽森癌症研究中心和華盛頓大學的一個小組對人體中病毒暴露強度與傳染性之間的關係進行了巧妙的研究。 2018年，一位名叫布萊恩·梅耶（Bryan Mayer）的流行病學家和統計學家加入了一組醫生和生物學家，他們正在研究一個表面上看來幾乎無法解決的問題。邁耶（Mayer）三十多歲，說話口才又精準：他用詞謹慎，說話時語速慢。他告訴我：「即使是研究生，我對一定劑量的病毒或病原體也很感興趣。」 「但是問題是初始劑量通常無法捕獲，因為您只知道一個人被感染后才被感染。」大多數傳染病只能在後視鏡中查看：當患者成為患者時，傳播的關鍵時刻已經過去。

但是研究人員發現了一種不尋常的資源：烏干達坎帕拉的一群新母親及其子女。幾年前，一位名叫索倫·甘特（Soren Gantt）的兒科醫生和一組醫生對這些婦女進行了檢查，並要求她們提供一年的口腔拭子檢查。然後，他們測量了這些婦女散發了多少種名為HHV-6的病毒，該病毒通常通過口腔分泌物傳播給出生后的嬰兒，並引起發燒和紅色全身疹子。現在，有可能調查脫落病毒的量（即暴露的「劑量」）如何影響新生兒被感染的可能性。甘特（Gantt），梅耶（Mayer）及其同事從一開始就想出了一種方法來監聽人類病毒感染的傳播動態。梅耶告訴我：「我們的數據證實HHV-6的病毒傳播存在劑量反應關係。」 「您釋放的病毒越多，您感染他人的可能性就越大。」他設法扭轉了流行病學的後視鏡。

There』s another aspect of transmission and disease, however: the host immune response. Viral attack and the immune system』s defense are two opposing forces, constantly at odds. The Russian immunologist Ilya Metchnikoff, working in the early nineteen-hundreds, described the phenomenon as 「the struggle」—or Kampf, in German editions of his work. Metchnikoff imagined an ongoing battle between microbe and immunity. The Kampf was a matter of ground gained or lost. What was the total 「force」 of the microbial presence? What host factors—genetics, prior exposure, baseline immune competence—were limiting the microbial invasion? And then: was the initial equilibrium tipped toward the virus, or toward the host?

That raises the second question—does a larger viral 「dose」 result in more severe disease? It』s impossible to erase from one』s memory the image of Li Wenliang, the thirty-three-year-old Chinese ophthalmologist who sounded the alarm on the first covid-19 cases, in his final illness; a photograph shows him crimson-faced, sweating, and struggling to breathe in a face mask, shortly before his death. Then there』s the unexpected death of Xia Sisi, a twenty-nine-year-old doctor from Union Jiangbei Hospital of Wuhan, who had a two-year-old child and, the Times reported, loved Sichuan hot pot. Another Chinese health-care worker, a twenty-nine-year-old nurse in Wuhan, fell so critically ill that she started hallucinating; later, she would describe herself as 「walking on the edge of death.」

但是，傳播和疾病還有另一個方面：宿主的免疫反應。病毒攻擊和免疫系統的防禦是兩個相反的力量，始終處於矛盾狀態。俄國免疫學家Ilya Metchnikoff在一百九十年代初期工作，在他的德語版本中將這種現象描述為「鬥爭」，即Kampf。梅奇尼克諾夫（Metchnikoff）想像微生物與免疫力之間的持續鬥爭。坎普夫問題是得失的基礎。微生物存在的總「力」是什麼？哪些宿主因素（遺傳，先前接觸，基線免疫能力）限制了微生物的入侵？然後：初始平衡趨向於病毒還是宿主？

這就提出了第二個問題：更大的病毒「劑量」會導致更嚴重的疾病嗎？從記憶中抹去李文亮的畫像是不可能的，她是三十三歲的中國眼科醫生，在他最後的病情中，他對第一批covid-19病例發出了警報。一張照片顯示，在他去世前不久，他臉紅，汗水且努力呼吸著口罩。然後是武漢聯合江北醫院二十九歲的醫生夏思思的意外死亡，他有一個兩歲的孩子，據《泰晤士報》報道，他愛四川火鍋。另一名中國衛生保健工作者，武漢的一名二十九歲護士，病危重重，開始幻覺。後來，她將自己形容為「走在死亡邊緣」。

Could the striking severity of their disease—twenty- and thirty-year-olds with covid-19 generally experience a self-limited, flu-like illness—be correlated with the amount of virus to which they were initially exposed? At least two E.R. doctors in the United States, both on the front lines of the pandemic, have also fallen critically ill; one of them, in Washington State, is only in his forties. To go by available data from Wuhan and Italy, health-care workers don』t necessarily have a higher fatality rate, but do they suffer, disproportionately, from the most severe forms of the disease? 「We know the high mortality in older people,」 Peter Hotez, an infectious-disease specialist and vaccine scientist at Baylor College of Medicine, told CNN. 「But, for reasons that we don』t understand, front-line health-care workers are at great risk for serious illness despite their younger age.」

Some suggestive research has been done with other viruses. In animal models of influenza, it』s possible to precisely quantify exposure intensity, and mice who were given higher doses of certain influenza viruses developed a more severe form of the disease. Yet the degree of correlation between dose and disease severity varied widely from one strain of the flu to the next. (Curiously, in one study a higher initial load of respiratory syncytial virus, which can cause pneumonia, especially in young children, correlated negatively with severe disease—although another study suggests that the correlation is positive with toddlers, the most affected patient population.)

What sparse evidence we have about coronaviruses suggests that they may follow the pattern seen in influenza. In a 2004 study of the coronavirus that causes sars, a cousin of the one that causes covid-19, a team from Hong Kong found that a higher initial load of virus—measured in the nasopharynx, the cavity in the deep part of your throat above your palate—was correlated with a more severe respiratory illness. Nearly all the sars patients who came in initially with a low or undetectable level of virus in the nasopharynx were found at a two-month follow-up to be still alive. Those with the highest level had a twenty- to forty-per-cent mortality rate. This pattern held true regardless of a patient』s age, underlying conditions, and the like. Research into another acute viral illness, Crimean-Congo hemorrhagic fever, reached a similar conclusion: the more virus you had at the start, the more likely you were to die.

他們疾病的驚人嚴重程度-二十歲和三十歲的covid-19患者通常會經歷一種自限性，類似流感的疾病-與他們最初接觸的病毒量有關嗎？在美國，至少有兩位E.R.醫生在大流行的第一線，也都患了重病；其中之一，僅在華盛頓州，才四十歲。根據武漢和義大利的可用數據，醫護人員的病死率不一定更高，但是他們是否會最嚴重地遭受這種疾病的折磨？ 「我們知道老年人的高死亡率，」貝勒醫學院的傳染病專家和疫苗科學家彼得·霍特茲告訴美國有線電視新聞網。 「但是，由於我們不了解的原因，一線衛生保健人員儘管年齡較小，但仍面臨嚴重疾病的巨大風險。」

已經對其他病毒進行了一些有啟發性的研究。在流行性感冒的動物模型中，可以精確地量化暴露強度，並且被給予更高劑量的某些流行性感冒病毒的小鼠會患上這種疾病的更嚴重形式。然而，從一種流感到另一種流感，劑量和疾病嚴重程度之間的相關程度差異很大。 （奇怪的是，在一項研究中，呼吸道合胞病毒的初始負荷較高，這可能引起肺炎，尤其是在幼兒中，與嚴重疾病呈負相關-儘管另一項研究表明，與患病率最高的學步兒童呈正相關。）

關於冠狀病毒的稀疏證據表明，它們可能會遵循流行性感冒中的模式。在2004年對引起sars的冠狀病毒（引起covid-19的表親的表親）的一項研究中，來自香港的研究小組發現，較高的初始病毒載量（在鼻咽部，咽喉深處的腔中測得）高於您的上顎-與更嚴重的呼吸系統疾病相關。在為期兩個月的隨訪中，發現幾乎所有最初在鼻咽中攜帶低水平或無法檢測到病毒的sars患者仍然存活。最高水平的人的死亡率為百分之二十至百分之四十。無論患者的年齡，基本情況等如何，這種模式都適用。對另一種急性病毒性疾病克里米亞-剛果出血熱的研究得出了類似的結論：開始時病毒越多，死亡的可能性就越大。

Perhaps the strongest association between the intensity of exposure and the intensity of subsequent disease is seen in measles research. 「I want to emphasize that measles and covid-19 are different diseases caused by very different viruses with different behaviors,」 Rik de Swart, a virologist at Erasmus University, in Rotterdam, cautioned when we spoke, 「but in measles there are several clear indications that the severity of illness relates to the dose of exposure. And it makes immunological sense, because the interaction between the virus and the immune system is a race in time. It』s a race between the virus finding enough target cells to replicate and the antiviral response aiming to eliminate the virus. If you give the virus a head start with a large dose, you get higher viremia, more dissemination, higher infection, and worse disease.」

He described a study from 1994 in which researchers gave monkeys different doses of the measles virus and found that higher infection doses were associated with earlier peaks in viremia. In human beings, de Swart added, the best evidence comes from studies in sub-Saharan Africa. 「If you acquire measles through household contacts, where the density and dose of exposure is the highest—you might be sharing a bed with an infected child—then you typically have a higher risk of developing more severe illness,」 he said. 「If a child contracts the disease through playground or casual contact, the disease is usually less severe.」

I discussed this aspect of infection with the Harvard virologist and immunologist Dan Barouch, whose lab is among those that are working toward a vaccine against sars-CoV-2, the virus that causes covid-19. He told me that ongoing studies with macaques are investigating the relationship between the initial dose of the sars-CoV-2 viral inoculum and the amount of virus in lung secretions at a later time. He believes that there may be a correlation. 「If we extended this logic to humans, we would expect a similar relationship,」 he said. 「And, logically, the larger amount of virus should trigger more severe disease by prompting a brisker inflammatory response. But that is still speculative. The relationship between initial viral dose and severity remains to be seen.」

在麻疹研究中，可能會發現接觸強度與後續疾病強度之間的最強關聯。鹿特丹伊拉斯姆斯大學的病毒學家裡克·德·斯瓦特（Rik de Swart）在講話時警告說：「我想強調，麻疹和covid-19是由行為不同的病毒引起的不同疾病，但在麻疹中有幾個明顯的問題跡象表明疾病的嚴重程度與暴露劑量有關。這具有免疫學意義，因為病毒和免疫系統之間的相互作用是時間的競賽。在病毒找到足夠的目標細胞進行複製與旨在消除病毒的抗病毒反應之間，這是一個競賽。如果您從大劑量開始使用該病毒，則會獲得更高的病毒血症，更多的傳播，更高的感染率和更嚴重的疾病。」

他描述了1994年的一項研究，研究人員給猴子提供了不同劑量的麻疹病毒，並發現更高的感染劑量與病毒血症的早期高峰有關。斯瓦特補充說，在人類中，最好的證據來自撒哈拉以南非洲的研究。他說：「如果您是通過家庭接觸而得麻疹，而接觸者的密度和劑量最高，那麼您可能正與被感染的孩子同床共枕，那麼通常您患上更嚴重疾病的風險就更高了，」他說。 「如果孩子通過操場或偶然接觸感染該疾病，則該疾病通常較輕。」

我與哈佛病毒學家和免疫學家Dan Barouch討論了感染的這一方面，他的實驗室屬於研究針對sars-CoV-2（引起covid-19的病毒）的疫苗的實驗室之一。他告訴我，正在進行的獼猴研究正在調查sars-CoV-2病毒接種物的初始劑量與以後肺分泌物中病毒量之間的關係。他認為可能存在關聯。他說：「如果將這種邏輯擴展到人類，我們將期待類似的關係。」 「而且，從邏輯上講，大量病毒應通過引起強烈的炎症反應來觸發更嚴重的疾病。但這仍然是猜測。初始病毒劑量和嚴重程度之間的關係尚待觀察。」

To answer the third question—whether we can track a covid-19 patient』s viral load in a way that helps us predict the course of the disease—we』ll need more quantitative research into sars-CoV-2 counts within patients. One unpublished German study has measured viral loads on oral swabs taken of both symptomatic and asymptomatic individuals. Initially, it was reported that patients who experienced no symptoms had slightly higher loads than those who fell ill. The results were curious. But at the time only seven patients had been studied. Sandra Ciesek, the director of the Institute of Medical Virology, in Frankfurt, who was running the study, told me that no significant differences between the two groups emerged as a larger patient population began to be sampled. 「In swabs, we don』t know of a correlation,」 she informed me. The problem with measuring viral loads in a swab is that it is 「affected by preanalytic factors, such as the way in which the swab is taken,」 she added. Oral swabs are notoriously affected by small variations in how they』re done. 「But a correlation with severe disease may well be true for the viral load in blood.」 Joshua Schiffer, a clinical virologist at the Fred Hutchinson Center, and a co-author of the HHV-6 study, reports that more stringent nasal-swabbing methods for a range of respiratory viruses have yielded consistent, reliable viral-load counts, and that these loads have generally tracked well with disease symptoms and progression. In a paper published online by The Lancet Infectious Diseases in March, researchers at the University of Hong Kong and Nanchang University reported that viral loads in nasopharyngeal swabs from a group of patients with severe covid-19 were sixty times higher, on average, than the loads among patients with a mild form of the disease.

As the virus continues to cyclone across the world, we will begin to find quantitative answers to these questions of how exposure intensity and subsequent viral loads relate to the clinical course of covid-19. We will supplement the bird』s-eye view with the worm』s-eye view. How will these insights change the way we manage patients, hospitals, and populations?

為了回答第三個問題-是否可以以有助於我們預測疾病進程的方式跟蹤covid-19患者的病毒載量-我們需要對患者體內sars-CoV-2計數進行更多的定量研究。一項德國未發表的研究測量了有癥狀和無癥狀個體的口腔拭子上的病毒載量。最初，據報道，沒有癥狀的患者的負荷比患病的患者略高。結果很好奇。但是當時只研究了七名患者。負責這項研究的位於法蘭克福的醫學病毒學研究所所長桑德拉·切斯克（Sandra Ciesek）告訴我，隨著開始對更多的患者人群進行抽樣，兩組之間沒有出現顯著差異。她告訴我：「在拭子中，我們不知道相關性。」她補充說，測量拭子中病毒載量的問題在於，它「受到分析前因素的影響，例如拭子的採集方式」。眾所周知，口腔拭子的製作方式會有細微的變化。 「但是對於血液中的病毒載量，與嚴重疾病的相關性很可能是正確的。」 Fred Hutchinson中心的臨床病毒學家，HHV-6研究的合著者Joshua Schiffer報告說，對多種呼吸道病毒採用更嚴格的鼻拭子擦拭方法可產生一致，可靠的病毒載量，並且這些負荷通常可以很好地跟蹤疾病癥狀和進展。在3月《柳葉刀傳染病》在線發表的一篇論文中，香港大學和南昌大學的研究人員報告說，來自一組重度covid-19嚴重患者的鼻咽拭子中的病毒載量平均比普通人群高60倍。輕度疾病患者的負擔。

隨著病毒在全球範圍內繼續旋風傳播，我們將開始找到這些問題的定量答案，這些問題是暴露強度和隨後的病毒載量如何與covid-19的臨床過程相關。我們將用蠕蟲視圖補充鳥瞰視圖。這些見解將如何改變我們管理患者，醫院和人群的方式？

Start with the relationship between exposure intensity and infection. Think, for a moment, of how we monitor those who work with radiation. Using radiation dosimetry, we quantify someone』s total exposure, and we set limits on it. We already know how critical it is for doctors and nurses to limit exposure to the coronavirus by using protective equipment (masks, gloves, gowns). But for health-care workers on the front lines of the covid-19 pandemic, especially in places where protective equipment is scarce, we might also keep track of total exposure, and put in place viral-dosimetry controls, so that one individual can avoid repeated interactions with some set of highly contagious patients.

Establishing a relationship between dose and disease severity could, in turn, affect patient care. If we could identify pre-symptomatic patients who were likely exposed to the highest doses of viruses—someone cohabitating or socializing with multiple sick family members (as with the close-knit Fusco family of Freehold, New Jersey, which has had four deaths), or a nurse exposed to a set of patients shedding large amounts of the virus—we might predict a more severe experience of the disease, and give them priority when it came to limited medical resources, so that they could be treated faster, earlier, or more intensively.

And, finally, the care of covid-19 patients could change if we began to track virus counts. These parameters could be gauged using fairly inexpensive and easily available laboratory methods. Imagine a two-step process: first, identifying infected patients, and then quantifying viral loads in nasal or respiratory secretions, particularly in patients who are likely to require the highest level of treatment. Correlating virus counts and therapeutic measures with outcomes might result in different strategies of care or isolation.

從接觸強度和感染之間的關係開始。暫時想一想我們如何監視輻射工作人員。使用輻射劑量法，我們可以量化某人的總暴露量，並對其設置限制。我們已經知道，通過使用防護設備（口罩，手套，禮服）來限制醫生和護士對冠狀病毒的暴露至關重要。但是，對於covid-19大流行前線的衛生保健工作者，尤其是在缺少防護裝備的地方，我們也可能會跟蹤總暴露量，並採取病毒劑量控制，以使一個人可以避免與某些具有高度傳染性的患者反覆互動。

在劑量和疾病嚴重程度之間建立關係可能反過來會影響患者的護理。如果我們能夠確定可能暴露於最高劑量病毒的癥狀前患者，即與多個患病家庭成員同居或交往的人（例如新澤西州Freehold的近親Fusco家庭，該家族已有四人死亡），或暴露於大量病毒散發的病人中的護士-我們可能會預測這種病的更為嚴重的經歷，並在醫療資源有限的情況下優先考慮他們，以便可以更快，更早或更早地對其進行治療。更集中地。

最後，如果我們開始跟蹤病毒計數，那麼covid-19患者的護理可能會改變。這些參數可以使用相當便宜且容易獲得的實驗室方法進行測量。想象一個分為兩個步驟的過程：首先，確定感染的患者，然後量化鼻腔或呼吸道分泌物中的病毒載量，尤其是在可能需要最高水賓士療的患者中。將病毒計數和治療措施與結果相關聯可能會導致不同的護理或隔離策略。

The value of a quantitative approach applies to clinical studies as well. Clinical drug trials are typically more informative when run on subjects who aren』t yet critical; once the subjects have reached that stage, any therapy might be too little, too late. And if the disease course in such patients is followed using viral-load metrics, rather than by tracking symptoms alone, the effect of a drug in different trials can be compared more easily and accurately.

We will also want to be able to identify people who have recovered from infection, have become immune to sars-CoV-2, and are no longer contagious. Such people must meet two criteria: they must have a measured absence of viral shedding, and they must have signs of persistent immunity in their blood (something readily determined by an antibody test). As the Chinese discovered with smallpox in the twelfth century, such individuals—especially those who are health-care workers—are of particular value to medicine: barring any decay in immunity, they can generally tend to the sickest patients without getting sick themselves.

My clinical practice is in oncology. Measurement and enumeration are the mainstays of medicine for people in my field: the size of a tumor, the number of metastases, the exact shrinkage of a malignant mass after chemotherapy. We talk about 「risk stratification」 (categorizing patients according to health status) and the 「stratification of response」 (categorizing patients according to their response to treatment). I am able to spend half an hour or more with every patient to describe risk, explain how a remission is measured, and carefully devise a clinical plan.

A pandemic, by contrast, goes hand in hand with panic. Chaos reigns. Italian doctors are hanging I.V. drips on makeshift poles for patients lying on makeshift cots in makeshift wards. Measurement—viral-load testing—can seem like an improbable indulgence under such circumstances. But this crisis will require that we stratify and assess risk, and deploy dwindling resources in the most effective manner.

定量方法的價值也適用於臨床研究。當對尚不嚴格的受試者進行臨床藥物試驗時，通常能提供更多信息。一旦受試者達到該階段，任何療法都可能太少，太遲。而且，如果使用病毒載量指標來跟蹤此類患者的病程，而不是僅通過跟蹤癥狀來進行跟蹤，則可以更輕鬆，準確地比較藥物在不同試驗中的效果。

我們還將希望能夠識別從感染中恢復過來，對sars-CoV-2免疫並且不再具有傳染性的人。這些人必須滿足兩個條件：必須在一定程度上沒有病毒脫落，並且必須在血液中具有持續免疫的跡象（通過抗體檢測很容易確定這一點）。正如中國人在十二世紀發現天花時那樣，這些人，尤其是從事衛生保健工作的人，對醫學特別有價值：除非免疫力下降，否則他們通常傾向於生病的病人而不會生病。

我的臨床實踐是腫瘤學。測量和枚舉是我領域人們的主要藥物：腫瘤的大小，轉移的數量，化療后惡性腫塊的確切縮小。我們談論「風險分層」（根據健康狀況對患者進行分類）和「反應分層」（根據對治療的反應對患者進行分類）。我能夠與每個患者一起花費半小時或更長時間來描述風險，解釋緩解的測量方式並仔細制定臨床計劃。

相反，大流行與恐慌並駕齊驅。混亂統治。義大利醫生正在弔死臨時病房中躺在臨時嬰兒床上的患者在臨時桿上滴水。在這種情況下，測量（病毒負載測試）似乎不太可能。但是，這場危機將要求我們對風險進行分層和評估，並以最有效的方式部署不斷減少的資源。

The word 「epidemiology」 is derived from 「epi」 and 「demos」—「above the people.」 It is the science of aggregation, the science of the many. Yet it works most effectively when it moves in step with medicine, the science of the one. On the morning I visited the Shitala shrine in Kolkata, the goddess of bygone population-decimating epidemics was also serving as the personal goddess of a mother who had brought a child with a weeklong fever. To win the Kampf against covid-19, it』s essential to trace the course of the virus as it moves through populations. But it』s equally essential to measure its course within a single patient. The one becomes the many. Count both; both count. 

「流行病學」一詞源自「 epi」和「 demos」，即「高於人民」。它是聚合的科學，是眾多的科學。然而，當它與醫學（一種科學）同步發展時，它最有效地發揮作用。早上，我參觀了加爾各答的什塔拉神社，該地區的人口減少致病流行女神也曾是一位母親的私人女神，這位母親給孩子帶來了一個為期一周的發燒。為了贏得對抗covid-19的坎普夫病毒，追蹤病毒在人群中傳播的過程至關重要。但同樣重要的是要在單個患者中衡量其病程。一個變成很多。數一下；都算。