现场视频：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

冠状病毒在患者体内的行为如何？

我们已经计算出病毒在各个民族之间的传播；现在我们需要在人们内部进行计数。

悉达多·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

测量将有助于确定影响covid-19病例严重程度的因素.Alexander Glandien的插图

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月的第三个星期，由于covid-19流行病仍在中国蔓延，我到达了印度加尔各答。我醒来到一个闷热的早晨-旅馆房间外面的黑色风筝在高高的气流的作用下向上盘旋-然后我去了神殿的希塔拉神社。她的名字的意思是“很酷”。就像神话一样，她从牺牲之火的冰冷灰烬中复活。她应该散发的热量不仅是6月中旬袭击这座城市的盛怒，而且是发炎的内在热量。她的目的是保护儿童免受天花伤害，治愈感染天花的人的痛苦并减轻痘病毒流行的愤怒。

这座神社是一座寺庙内的小建筑物，距离加尔各答医学院只有几个街区。里面有一个女神雕像，坐在驴上，背着一罐冷却液，就像她描绘千年的样子一样。寺庙告诉我，这座寺庙已有250年的历史。这可以追溯到大约首次出现一个婆罗门人神秘教派在恒河平原上空徘徊以普及提卡的实践的时候，这是早期的接种尝试。这涉及从天花病人的脓疱（活病毒的蛇窝）中取出物质，然后将其涂在未感染者的刺破皮肤上，然后用亚麻碎布覆盖该部位。

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.”

印度的提卡修炼者很可能是从阿拉伯医师那里学到的，而阿拉伯医师是从中国人那里学到的。早在1100年，中国的医学治疗师就意识到那些幸存了天花的人再也没有染上这种疾病（该疾病的幸存者被邀请照料新的受害者），并推断身体暴露于某种疾病下可以保护它从该疾病的未来情况。中国医生会把天花疮ab磨成粉末，然后用一根长长的银管将其注入孩子的鼻孔。

用活病毒进行疫苗接种是徒劳的：如果粉末中的病毒接种量过多，孩子将丧生于该疾病的全面版本-可能发生了一百次灾难。如果一切顺利，孩子将对该病有轻微的经历，并可以终生免疫。到了一百七十年代，这种习俗已经传播到整个阿拉伯世界。在十七六十年代，苏丹的妇女练习了tishteree el jidderee（“买痘”）：一位母亲与另一位母亲讨价还价，她要为自己的儿子或女儿购买多少个生病的脓疱。这是一门考究的技巧：最精明的传统治疗师意识到可能只产生足够病毒物质但不会产生太多病毒的病灶。该疾病的欧洲名称为天花，源自拉丁语的“斑点”或“粉刺”。对痘进行免疫的过程称为“变痘”。

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.

英国驻君士坦丁堡大使的妻子玛丽·沃特利·蒙塔古夫人（Mary Wortley Montagu）于1715年被该病折磨，完美的皮肤上留下了疤痕。后来，在土耳其的乡下，她亲眼目睹了静脉曲张的病情，并惊奇地写信给她的朋友，描述了一位专家的工作：“这位老妇人简直是疯了，痘痘，问你想要打开什么静脉，”于是她“尽可能多地把静脉置于针头上。”蒙塔古夫人指出，患者因发烧而在床上休息了两天，而她却毫发无损。 “他们的脸上很少有二十或三十岁以上的人，他们从来没有留下过痕迹。在八天的时间里，他们和生病之前一样。”她报告说，每年有成千上万的人安全地接受了手术，该地区基本上已经控制了这种疾病。她补充说：“您可能会相信我对这个实验的安全性感到满意，因为我打算在我亲爱的小儿子身上尝试一下。”她的儿子从未得过痘。

自蒙塔古夫人对接种的功效赞叹不已以来的几个世纪，我们在传染病的生物学和流行病学方面取得了不可思议的发现，但covid-19大流行却不容小s。为什么它在野外像野火一样在距其最初震源数千英里的意大利武汉扩散，而到目前为止印度似乎在很大程度上已幸免于难？哪些动物物种将原始感染传播给人类？

但是，三个问题值得特别注意，因为它们的答案可能会改变我们隔离，治疗和管理患者的方式。首先，我们可以了解初次感染的“剂量反应曲线”，即，当人们暴露于更高剂量的病毒时，我们能否量化感染风险的增加？其次，病毒的初始“剂量”与疾病严重程度之间是否存在关系，即更多的接触是否会导致严重疾病？第三，是否存在定量方法来衡量病毒在受感染患者中的行为（例如，您体内病毒载量的峰值，其上升和下降的方式）可以预测疾病的严重程度以及它们对他人的传染性？到目前为止，在covid-19大流行的早期阶段，我们一直在测量病毒在人与人之间的传播。随着大流行速度的加快，我们还需要开始测量人体内的病毒。

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.

鉴于缺乏数据，大多数流行病学家被迫模拟新冠状病毒的传播，就好像它是一种二元现象：个体是暴露的或未暴露的，感染的或未感染的，有症状的患者或无症状的携带者。最近，《华盛顿邮报》发布了一个特别引人注目的在线模拟，其中将城市中的人们描绘成在空间中自由移动的点-灰色未感染的点，红色感染的点（随着免疫力的增强，然后变为粉红色）。每次红点碰到灰点，都会传播感染。在没有干预的情况下，整个点域从灰色稳定地变为红色。社会上的疏离和孤立使这些点之间无法相互碰撞，并减缓了红色在屏幕上的传播。

这是病毒在整个人群中传播的鸟瞰图，被视为“开关现象”。我的医生和医学研究人员-作为一名研究生，曾接受过病毒免疫学的培训-想要知道点点滴的情况。该红点内有多少病毒？在此点复制的速度有多快？接触时间（“触摸时间”）与传播机会有什么关系？红点保持红色状态持续了多长时间-也就是说，个人的感染力会随着时间变化吗？每种情况下的疾病严重程度如何？

我们了解到的其他病毒（包括引起辅助病毒，sars和天花的病毒）建议对这种疾病，其发病率和遏制策略有更复杂的认识。在十九世纪九十年代，研究人员学会了测量多少H.I.V.在病人的血液中，出现了独特的模式。感染后，血液中的病毒数量会上升到最高点，称为“峰值病毒血症”，病毒血症高峰期最高的患者通常会更快发病。他们抵抗病毒的能力最差。比峰值病毒载量更具预测性的是所谓的设定点-某人的病毒计数在其初始峰值后稳定下来的水平。它代表了病毒与其人类宿主之间达到的动态平衡。设定值高的人往往会更快地发展到艾滋病。设定值低的人经常被证明是“进展缓慢”。病毒载量（一个连续的而非二进制值）有助于预测疾病的性质，病程和传染性。可以肯定的是，每种病毒都有其自己的特征，并且H.I.V.具有使病毒载量特别显着的特征：它会引起慢性感染，而特异性地针对免疫系统的细胞。然而，其他病毒也观察到了类似的模式。

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，从免疫学上来说，这并不奇怪。如果您的系统由于年龄，遗传学和其他免疫能力指标的原因，能够有效地抵抗病毒复制，那么您的设定值将更低。与接受替卡治疗的儿童一样，较低的初始暴露量是否也可以导致较低的设定点？面对较小的挑战，免疫系统控制病原体的机会更大。相反，如果您被大量的高剂量暴露所淹没，那么迅速复制的入侵者可能会发现免疫系统可能很难被重新征服。

西雅图的弗雷德·哈钦森癌症研究中心和华盛顿大学的一个小组对人体中病毒暴露强度与传染性之间的关系进行了巧妙的研究。 2018年，一位名叫布莱恩·梅耶（Bryan Mayer）的流行病学家和统计学家加入了一组医生和生物学家，他们正在研究一个表面上看来几乎无法解决的问题。迈耶（Mayer）三十多岁，说话口才又精准：他用词谨慎，说话时语速慢。他告诉我：“即使是研究生，我对一定剂量的病毒或病原体也很感兴趣。” “但是问题是初始剂量通常无法捕获，因为您只知道一个人被感染后才被感染。”大多数传染病只能在后视镜中查看：当患者成为患者时，传播的关键时刻已经过去。

但是研究人员发现了一种不寻常的资源：乌干达坎帕拉的一群新母亲及其子女。几年前，一位名叫索伦·甘特（Soren Gantt）的儿科医生和一组医生对这些妇女进行了检查，并要求她们提供一年的口腔拭子检查。然后，他们测量了这些妇女散发了多少种名为HHV-6的病毒，该病毒通常通过口腔分泌物传播给出生后的婴儿，并引起发烧和红色全身疹子。现在，有可能调查脱落病毒的量（即暴露的“剂量”）如何影响新生儿被感染的可能性。甘特（Gantt），梅耶（Mayer）及其同事从一开始就想出了一种方法来监听人类病毒感染的传播动态。梅耶告诉我：“我们的数据证实HHV-6的病毒传播存在剂量反应关系。” “您释放的病毒越多，您感染他人的可能性就越大。”他设法扭转了流行病学的后视镜。

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，传播和疾病还有另一个方面：宿主的免疫反应。病毒攻击和免疫系统的防御是两个相反的力量，始终处于矛盾状态。俄国免疫学家Ilya Metchnikoff在一百九十年代初期工作，在他的德语版本中将这种现象描述为“斗争”，即Kampf。梅奇尼克诺夫（Metchnikoff）想像微生物与免疫力之间的持续斗争。坎普夫问题是得失的基础。微生物存在的总“力”是什么？哪些宿主因素（遗传，先前接触，基线免疫能力）限制了微生物的入侵？然后：初始平衡趋向于病毒还是宿主？

这就提出了第二个问题：更大的病毒“剂量”会导致更严重的疾病吗？从记忆中抹去李文亮的画像是不可能的，她是三十三岁的中国眼科医生，在他最后的病情中，他对第一批covid-19病例发出了警报。一张照片显示，在他去世前不久，他脸红，汗水且努力呼吸着口罩。然后是武汉联合江北医院二十九岁的医生夏思思的意外死亡，他有一个两岁的孩子，据《泰晤士报》报道，他爱四川火锅。另一名中国卫生保健工作者，武汉的一名二十九岁护士，病危重重，开始幻觉。后来，她将自己形容为“走在死亡边缘”。

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.

他们疾病的惊人严重程度-二十岁和三十岁的covid-19患者通常会经历一种自限性，类似流感的疾病-与他们最初接触的病毒量有关吗？在美国，至少有两位E.R.医生在大流行的第一线，也都患了重病；其中之一，仅在华盛顿州，才四十岁。根据武汉和意大利的可用数据，医护人员的病死率不一定更高，但是他们是否会最严重地遭受这种疾病的折磨？ “我们知道老年人的高死亡率，”贝勒医学院的传染病专家和疫苗科学家彼得·霍特兹告诉美国有线电视新闻网。 “但是，由于我们不了解的原因，一线卫生保健人员尽管年龄较小，但仍面临严重疾病的巨大风险。”

已经对其他病毒进行了一些有启发性的研究。在流行性感冒的动物模型中，可以精确地量化暴露强度，并且被给予更高剂量的某些流行性感冒病毒的小鼠会患上这种疾病的更严重形式。然而，从一种流感到另一种流感，剂量和疾病严重程度之间的相关程度差异很大。 （奇怪的是，在一项研究中，呼吸道合胞病毒的初始负荷较高，这可能引起肺炎，尤其是在幼儿中，与严重疾病呈负相关-尽管另一项研究表明，与患病率最高的学步儿童呈正相关。）

关于冠状病毒的稀疏证据表明，它们可能会遵循流行性感冒中的模式。在2004年对引起sars的冠状病毒（引起covid-19的表亲的表亲）的一项研究中，来自香港的研究小组发现，较高的初始病毒载量（在鼻咽部，咽喉深处的腔中测得）高于您的上颚-与更严重的呼吸系统疾病相关。在为期两个月的随访中，发现几乎所有最初在鼻咽中携带低水平或无法检测到病毒的sars患者仍然存活。最高水平的人的死亡率为百分之二十至百分之四十。无论患者的年龄，基本情况等如何，这种模式都适用。对另一种急性病毒性疾病克里米亚-刚果出血热的研究得出了类似的结论：开始时病毒越多，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，可能会发现接触强度与后续疾病强度之间的最强关联。鹿特丹伊拉斯姆斯大学的病毒学家里克·德·斯瓦特（Rik de Swart）在讲话时警告说：“我想强调，麻疹和covid-19是由行为不同的病毒引起的不同疾病，但在麻疹中有几个明显的问题迹象表明疾病的严重程度与暴露剂量有关。这具有免疫学意义，因为病毒和免疫系统之间的相互作用是时间的竞赛。在病毒找到足够的目标细胞进行复制与旨在消除病毒的抗病毒反应之间，这是一个竞赛。如果您从大剂量开始使用该病毒，则会获得更高的病毒血症，更多的传播，更高的感染率和更严重的疾病。”

他描述了1994年的一项研究，研究人员给猴子提供了不同剂量的麻疹病毒，并发现更高的感染剂量与病毒血症的早期高峰有关。斯瓦特补充说，在人类中，最好的证据来自撒哈拉以南非洲的研究。他说：“如果您是通过家庭接触而得麻疹，而接触者的密度和剂量最高，那么您可能正与被感染的孩子同床共枕，那么通常您患上更严重疾病的风险就更高了，”他说。 “如果孩子通过操场或偶然接触感染该疾病，则该疾病通常较轻。”

我与哈佛病毒学家和免疫学家Dan Barouch讨论了感染的这一方面，他的实验室属于研究针对sars-CoV-2（引起covid-19的病毒）的疫苗的实验室之一。他告诉我，正在进行的猕猴研究正在调查sars-CoV-2病毒接种物的初始剂量与以后肺分泌物中病毒量之间的关系。他认为可能存在关联。他说：“如果将这种逻辑扩展到人类，我们将期待类似的关系。” “而且，从逻辑上讲，大量病毒应通过引起强烈的炎症反应来触发更严重的疾病。但这仍然是猜测。初始病毒剂量和严重程度之间的关系尚待观察。”

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?

为了回答第三个问题-是否可以以有助于我们预测疾病进程的方式跟踪covid-19患者的病毒载量-我们需要对患者体内sars-CoV-2计数进行更多的定量研究。一项德国未发表的研究测量了有症状和无症状个体的口腔拭子上的病毒载量。最初，据报道，没有症状的患者的负荷比患病的患者略高。结果很好奇。但是当时只研究了七名患者。负责这项研究的位于法兰克福的医学病毒学研究所所长桑德拉·切斯克（Sandra Ciesek）告诉我，随着开始对更多的患者人群进行抽样，两组之间没有出现显着差异。她告诉我：“在拭子中，我们不知道相关性。”她补充说，测量拭子中病毒载量的问题在于，它“受到分析前因素的影响，例如拭子的采集方式”。众所周知，口腔拭子的制作方式会有细微的变化。 “但是对于血液中的病毒载量，与严重疾病的相关性很可能是正确的。” Fred Hutchinson中心的临床病毒学家，HHV-6研究的合著者Joshua Schiffer报告说，对多种呼吸道病毒采用更严格的鼻拭子擦拭方法可产生一致，可靠的病毒载量，并且这些负荷通常可以很好地跟踪疾病症状和进展。在3月《柳叶刀传染病》在线发表的一篇论文中，香港大学和南昌大学的研究人员报告说，来自一组重度covid-19严重患者的鼻咽拭子中的病毒载量平均比普通人群高60倍。轻度疾病患者的负担。

随着病毒在全球范围内继续旋风传播，我们将开始找到这些问题的定量答案，这些问题是暴露强度和随后的病毒载量如何与covid-19的临床过程相关。我们将用蠕虫视图补充鸟瞰视图。这些见解将如何改变我们管理患者，医院和人群的方式？

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.

从接触强度和感染之间的关系开始。暂时想一想我们如何监视辐射工作人员。使用辐射剂量法，我们可以量化某人的总暴露量，并对其设置限制。我们已经知道，通过使用防护设备（口罩，手套，礼服）来限制医生和护士对冠状病毒的暴露至关重要。但是，对于covid-19大流行前线的卫生保健工作者，尤其是在缺少防护装备的地方，我们也可能会跟踪总暴露量，并采取病毒剂量控制，以使一个人可以避免与某些具有高度传染性的患者反复互动。

在剂量和疾病严重程度之间建立关系可能反过来会影响患者的护理。如果我们能够确定可能暴露于最高剂量病毒的症状前患者，即与多个患病家庭成员同居或交往的人（例如新泽西州Freehold的近亲Fusco家庭，该家族已有四人死亡），或暴露于大量病毒散发的病人中的护士-我们可能会预测这种病的更为严重的经历，并在医疗资源有限的情况下优先考虑他们，以便可以更快，更早或更早地对其进行治疗。更集中地。

最后，如果我们开始跟踪病毒计数，那么covid-19患者的护理可能会改变。这些参数可以使用相当便宜且容易获得的实验室方法进行测量。想象一个分为两个步骤的过程：首先，确定感染的患者，然后量化鼻腔或呼吸道分泌物中的病毒载量，尤其是在可能需要最高水平治疗的患者中。将病毒计数和治疗措施与结果相关联可能会导致不同的护理或隔离策略。

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.

定量方法的价值也适用于临床研究。当对尚不严格的受试者进行临床药物试验时，通常能提供更多信息。一旦受试者达到该阶段，任何疗法都可能太少，太迟。而且，如果使用病毒载量指标来跟踪此类患者的病程，而不是仅通过跟踪症状来进行跟踪，则可以更轻松，准确地比较药物在不同试验中的效果。

我们还将希望能够识别从感染中恢复过来，对sars-CoV-2免疫并且不再具有传染性的人。这些人必须满足两个条件：必须在一定程度上没有病毒脱落，并且必须在血液中具有持续免疫的迹象（通过抗体检测很容易确定这一点）。正如中国人在十二世纪发现天花时那样，这些人，尤其是从事卫生保健工作的人，对医学特别有价值：除非免疫力下降，否则他们通常倾向于生病的病人而不会生病。

我的临床实践是肿瘤学。测量和枚举是我领域人们的主要药物：肿瘤的大小，转移的数量，化疗后恶性肿块的确切缩小。我们谈论“风险分层”（根据健康状况对患者进行分类）和“反应分层”（根据对治疗的反应对患者进行分类）。我能够与每个患者一起花费半小时或更长时间来描述风险，解释缓解的测量方式并仔细制定临床计划。

相反，大流行与恐慌并驾齐驱。混乱统治。意大利医生正在吊死临时病房中躺在临时婴儿床上的患者在临时杆上滴水。在这种情况下，测量（病毒负载测试）似乎不太可能。但是，这场危机将要求我们对风险进行分层和评估，并以最有效的方式部署不断减少的资源。

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. 

“流行病学”一词源自“ epi”和“ demos”，即“高于人民”。它是聚合的科学，是众多的科学。然而，当它与医学（一种科学）同步发展时，它最有效地发挥作用。早上，我参观了加尔各答的什塔拉神社，该地区的人口减少致病流行女神也曾是一位母亲的私人女神，这位母亲给孩子带来了一个为期一周的发烧。为了赢得对抗covid-19的坎普夫病毒，追踪病毒在人群中传播的过程至关重要。但同样重要的是要在单个患者中衡量其病程。一个变成很多。数一下；都算。