2022.06.10 阴性的COVID测试从未如此毫无意义

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A Negative COVID Test Has Never Been So Meaningless
A string of negatives can still presage a clear-as-day positive.

By Katherine J. Wu
a series of blue coronavirus splotches, the last of which is pink
Getty; The Atlantic
JUNE 10, 2022, 7 AM ET
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In early May, 27-year-old Hayley Furmaniuk felt tired and a bit congested, but after rapid-testing negative for the coronavirus two days in a row, she dined indoors with friends. The next morning, her symptoms worsened. Knowing her parents were driving in for Mother’s Day, she tested again—and saw a very bright positive. Which meant three not-so-great things: She needed to cancel with her parents; she had likely exposed her friends; a test had apparently taken three days to register what her vaccinated body had already figured out.

Tests are not and never have been perfect, but since around the rise of Omicron, the problem of delayed positivity has gained some prominence. In recent months, many people have logged strings of negatives—three, four, even five or more days in a row—early in their COVID-symptom course. “I think it’s become more common,” says Amesh Adalja, an infectious-disease physician at the Johns Hopkins Center for Health Security.


Read: COVID tests weren’t designed for this

No one can yet say how common these early negatives are, or who’s most at risk. But if SARS-CoV-2 is rewriting the early-infection playbook, “that makes it really scary,” says Susan Butler-Wu, a clinical microbiologist at USC’s Keck School of Medicine. “You can’t test and get a negative and actually know you’re negative.” Misleading negatives could hasten the spread of the virus; they could delay treatments premised on a positive test result. They also buck the current COVID dogma: Test as soon as you feel sick. The few days around the start of symptoms are supposed to be when the virus inside you is most detectable and transmissible; we built an entire edifice of testing and isolation on that foundation.

Experts aren’t sure why delayed positives are happening; it’s likely that population immunity, viral mutations, and human behavior all have some role. Regardless, the virus is “acting differently from a symptom perspective for sure,” says Emily Martin, an infectious-disease epidemiologist at the University of Michigan. That’s worth paying attention to. The start of symptoms has always been a bit of a two-step: Is it COVID, or not? If SARS-CoV-2 is re-choreographing its moves, we must too—or risk losing our footing.




Right now, experts are operating in a vacuum of evidence: “I don’t even know of any data that systematically evaluates this,” says Yonatan Grad, who’s studying the viral dynamics of SARS-CoV-2 at Harvard’s School of Public Health. But several phenomena could plausibly be muddying the testing timeline.

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First, the immunity hypothesis, the most popular idea floated by the experts I spoke with. Perhaps symptoms are preceding test positivity, less because the virus is peaking late, and more because illness is arriving early, thanks to the lightning-fast reflexes of people’s primed immune systems. Sometimes, sickness is direct damage from a virus. But a runny nose, muscle and joint aches, chills, fevers, fatigue—which are common across many respiratory infections—can also be “signs that the immune system is being activated,” says Aubree Gordon, an infectious-disease epidemiologist at the University of Michigan. When the pandemic began, infections happened exclusively in people who’d never encountered the coronavirus before; illness took several days to manifest, as the virus churned itself into a frenzy and the immune system struggled to catch up. “Once people are vaccinated, though, their immune systems kick in right away,” says Emily Landon, an infectious-disease physician at the University of Chicago. (Prior infection, too, could have an impact.) If the body makes fast work of the invader, some people may never end up testing positive, especially on antigen tests. (PCRs are generally more sensitive.) Others may see positives a few days after symptoms start, as the virus briefly gains a foothold.

But some of the experts I spoke with were a little hesitant to give the immune system all the credit. Some unimmunized people have experienced early negativity, too, and many people who have gotten their shots still test positive before falling ill.


SARS-CoV-2 traits, too, could be flipping the sickness script, which brings us to the virus hypothesis. Any member of the Omicron cohort is “just a different beast,” says Ryan McNamara, a virologist at Massachusetts General Hospital. It struggles to penetrate deep into the lower airway, and may not accumulate to the densities that Delta did in the nose, which could make false negatives more likely. A couple of studies have also found that Omicron may, in some people, be detected in the mouth or throat before the nostrils.

In practice, “it’s really hard to separate if all of this is a property of the virus, or a property of the immune system, or both,” says Roby Bhattacharyya, an infectious-disease physician at Massachusetts General Hospital. Take Omicron’s symptom profile, for instance. This variant seems to more often prompt sneezier, head-cold-esque symptoms than those that came before it, and less often causes loss of taste and smell. And, on average, people infected in recent surges have been showing symptoms three days after exposure, far faster than the incubation period of five or six days that was the norm in the pandemic’s early days. But those patterns could be attributable to either the peculiarities of the Omicron clan, or how much more immune the average Omicron host is.

Read: Next winter, what if we test for even more viruses?


And testing and sickness severity involve “just so many variables,” says Ali Ellebedy, an immunologist at Washington University in St. Louis, similar to the diversity in reactions to vaccines—some people feel side effects, others don’t—or virus exposures. Some people never get infected, even after spending days with infectious people, while others seem ultra-susceptible. People’s vaccination status, age, genetics, even the dose of virus, can affect if, when, or how they feel ill, and whether their infection registers on a test.

Symptoms and test accuracy are also both subject to human bias. People can’t always remember when they started feeling sick. And user error can muddle diagnostics. “Are people really doing 15 seconds in each nostril, and really scrubbing each time?” Landon said. Even super-sensitive tests will miss the virus some of the time. A good portion of the specimens taken from sick people in medical settings “come back negative for everything,” Martin told me.

Coinfections are also possible: People who feel sick and test positive “late” may have actually caught something else first, only to develop COVID later on. “There are easily five to eight other viruses circulating right now,” says Melissa Miller, a clinical microbiologist at the University of North Carolina at Chapel Hill. It’s also allergy season in much of the U.S. And coronavirus tests can spit out false positives—though they’re unlikely to do so several days in a row.


Without more data, it’s hard to know how to best address early negatives. For more clarity, “you’d probably need a human challenge experiment,” in which vaccinated and unvaccinated volunteers are deliberately infected with SARS-CoV-2, then repeatedly tested and monitored for symptoms over time, Gordon said. But based on the stories emerging, the issue doesn’t really seem rare. “I think I’ve had maybe 20 friends in the last five weeks” catch the virus, Jesse Chen, a vaccinated 27-year-old in New York, told me; most of them experienced delayed positivity, including Chen herself.

If this is happening more, then “you cannot trust a negative rapid test at the beginning of illness,” Landon told me. And while the CDC and test makers have long said that negative results can’t rule out a SARS-CoV-2 infection, it’s not clear how these early-illness testing issues fit into diagnostic guidance. Kimberly Modory, a spokesperson for Abbott, which makes the widely used BinaxNOW SARS-CoV-2 test, wrote in an email that “people should continue to follow our test instructions, which is to test twice over 3 days, at least 24 hours (and no more than 48 hours) apart.” Another popular brand, iHealth, offers similar instructions. (CDC and iHealth did not respond to a request for comment.)


Many of these protocols, though, were developed when far fewer people had been vaccinated or infected, and Omicron and its offshoots weren’t yet dominant. And they have missed some recent infections. Furmaniuk, for instance, green-lit herself for dinner with two iHealth tests. And Ellen Krakow, a triply-vaccinated 58-year-old from Long Island, didn’t get a positive antigen result until she took her third BinaxNOW, on her fourth day of symptoms. (A PCR test, collected on her third day, did turn positive first.)

Until experts know more, several researchers recommended that people test with caution. Positives are still reliable, Landon told me. But people who are symptomatic and recently exposed might have good reason to be skeptical of negatives. “If you’re turning symptomatic, assume you’re infectious,” Grad told me—with something, even if it turns out not to be SARS-CoV-2. “People forget that, baked into all the recommendations, is that as soon as you turn symptomatic, you’re supposed to be behaving differently,” Martin told me. “A negative test shouldn’t be a pass to go out.”

Landon also raised concerns about the implications of early negatives for the duration of isolation. In January, the CDC cut recommended COVID isolation time in half, saying that people could stop sequestering themselves after just five days, counting out from when their symptoms started, as long as they masked for the five days following. The agency justified its decision by noting that a majority of people were no longer infectious by that point—but used data that almost entirely predated the Omicron surge.


Read: America’s COVID rules are a dumpster fire

Based on the evidence that’s emerged since, “five days is ridiculous optimism,” said Landon, who recently ran a study showing that a large fraction of people continue to test positive after their fifth isolation day, raising the possibility that they’re still shedding the virus in gobs. Rebecca Ennen, a vaccinated 39-year-old in D.C., didn’t even get her first positive result until Day Six of her illness, as her symptoms were on their way out. “It was just bizarre,” she told me. “I was on the mend.” So Ennen continued cloistering for another five days, until she finally tested negative again. Others, including Gordon and Furmaniuk, have also waited to test out of isolation; it’s what Bhattacharyya “would do too, if it were me.”

But such a mindset hardly seems sustainable, especially for people who are frequently exposed to respiratory microbes, including parents of very young kids, or who have bad allergies, or who don’t have rapid tests to spare. Isolation still takes people away from work (and income), school, and their families. It’s also emotionally harrowing. Krakow, of Long Island, didn’t test negative again until 14 days into her illness. “I was isolating for beyond two weeks,” she told me.


All of this means that our guidelines and perceptions of the virus may soon need to adjust—likely not for the last time. Butler-Wu, the USC clinical microbiologist, recently advised a friend who had received more than half a dozen negative test results—antigen and PCR—that her respiratory illness probably wasn’t COVID. The friend ended up visiting Butler-Wu, only to test positive shortly thereafter. “That really shook me,” Butler-Wu told me. “It flew in the face of everything I knew from before.” It was a reminder, she said, that the pandemic is still serving up plot twists. “I do this professionally,” she said, “and I still made the wrong call.”

Katherine J. Wu is a staff writer at The Atlantic.





阴性的COVID测试从未如此毫无意义
一连串的阴性结果仍然可以预示着一个明确的阳性结果。

作者：Katherine J. Wu
一系列蓝色的冠状病毒斑点，其中最后一个是粉红色的。
Getty; The Atlantic
2022年6月10日，美国东部时间上午7点
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5月初，27岁的海莉-弗曼纽克(Hayley Furmaniuk)感到疲惫，有点鼻塞，但在连续两天的冠状病毒快速检测呈阴性后，她与朋友在室内用餐。第二天早上，她的症状恶化了。她知道她的父母正开车来过母亲节，于是她再次进行了检测--看到了一个非常明亮的阳性。这意味着三件不太妙的事情。她需要取消与父母的通话；她很可能暴露了她的朋友；一个测试显然花了三天时间来记录她接种疫苗的身体已经知道的情况。

测试并不完美，也从来没有完美过，但是自从Omicron的兴起，延迟阳性的问题已经得到了一定程度的重视。最近几个月，许多人在其COVID症状过程的早期就记录了一连串的阴性结果--三、四、甚至五天或更多。"约翰霍普金斯大学健康安全中心的传染病医生阿梅什-阿达尔加说："我认为这已经变得更加普遍。


阅读。COVID测试并不是为这个而设计的

还没有人能够说这些早期阴性的情况有多普遍，或者谁的风险最大。但是如果SARS-CoV-2正在改写早期感染的剧本，"这使它变得非常可怕，"南加州大学凯克医学院的临床微生物学家苏珊-巴特勒-吴说。"你不能测试并得到一个阴性结果，而且实际上知道你是阴性的。" 误导性的阴性结果可能会加速病毒的传播；它们可能会推迟以阳性测试结果为前提的治疗。它们还违背了目前COVID的教条。一旦感到不适就立即测试。症状开始前的几天应该是你体内的病毒最容易被检测到和传播的时候；我们在这个基础上建立了整个测试和隔离的大厦。

专家们不确定为什么会出现延迟阳性；很可能人口免疫力、病毒变异和人类行为都有一些作用。密歇根大学的传染病流行病学家艾米丽-马丁说："无论如何，病毒 "从症状的角度看肯定会有不同的表现"。这是值得注意的。症状的开始一直是一个两步走的过程。它是COVID，或者不是？如果SARS-CoV-2正在重新编排它的行动，我们也必须这样做，否则就有可能失去我们的立足点。




现在，专家们是在证据真空的情况下工作。"在哈佛大学公共卫生学院研究SARS-CoV-2病毒动态的Yonatan Grad说："我甚至不知道有任何数据可以系统地评估这一点。但是有几种现象可能会使测试的时间线变得模糊不清。

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首先是免疫假说，这是与我交谈的专家们提出的最流行的想法。也许症状出现在测试阳性之前，与其说是由于病毒的高峰期较晚，不如说是由于疾病的提前到来，这要归功于人们的免疫系统的快速反应。有时，疾病是病毒的直接损害。但是流鼻涕、肌肉和关节疼痛、发冷、发烧、疲劳--这些在许多呼吸道感染中很常见--也可能是 "免疫系统被激活的迹象"，密歇根大学的传染病流行病学家奥布里-戈登说。当大流行开始时，感染只发生在那些以前从未遇到过冠状病毒的人身上；疾病需要几天的时间才能表现出来，因为病毒把自己搅得一团糟，而免疫系统却在努力追赶。"芝加哥大学的传染病医生艾米丽-兰登说："不过，一旦人们接种了疫苗，他们的免疫系统就会立即启动。(如果身体能快速解决入侵者的问题，一些人可能永远不会出现阳性反应，特别是在抗原测试中。(其他人可能在症状开始几天后看到阳性，因为病毒短暂地获得了一个立足点。

但是与我交谈的一些专家对把所有的功劳都归于免疫系统有点犹豫。一些没有免疫的人也经历了早期的阴性反应，而且许多已经打过针的人在生病之前仍然检测出阳性。


SARS-CoV-2的特征，也可能是翻开了生病的剧本，这就把我们带到了病毒假说。马萨诸塞州综合医院的病毒学家Ryan McNamara说，Omicron队列的任何成员都是 "不同的野兽"。它很难渗透到下呼吸道深处，而且可能不会积累到三角洲在鼻子里的密度，这可能使假阴性的可能性更大。一些研究还发现，在一些人中，Omicron可能会在鼻孔之前在口腔或喉咙中被检测到。

马萨诸塞州综合医院的传染病医生Roby Bhattacharyya说："在实践中，真的很难区分这一切是病毒的特性，还是免疫系统的特性，或者两者都是。以Omicron的症状特征为例。这个变体似乎比之前的那些变体更经常地引起打喷嚏、头疼的症状，而且不经常引起味觉和嗅觉的丧失。而且，平均而言，最近的感染者在接触后三天就出现了症状，远远快于该大流行病早期的5或6天的潜伏期。但是这些模式可能归因于Omicron氏族的特殊性，或者Omicron氏族的平均宿主有多大的免疫力。

阅读。下一个冬天，如果我们测试更多的病毒呢？


圣路易斯华盛顿大学的免疫学家Ali Ellebedy说，测试和疾病的严重程度涉及 "如此多的变量"，类似于对疫苗反应的多样性--有些人感到有副作用，有些人没有--或者病毒暴露。有些人从未被感染过，即使在与传染病患者相处数日之后，而其他人似乎极易受感染。人们的疫苗接种情况、年龄、遗传，甚至是病毒的剂量，都可能影响他们是否、何时或如何感到不适，以及他们的感染是否在测试中记录下来。

症状和测试的准确性也都会受到人类偏见的影响。人们并不总是记得他们何时开始感到不适。而用户的错误会使诊断变得混乱。"人们真的在每个鼻孔里做了15秒，而且每次都是真的擦洗吗？" 兰登说。即使是超级敏感的测试也会在某些时候错过病毒。马丁告诉我，从医疗环境中的病人身上提取的标本中，有相当一部分是 "阴性的"。

共同感染也是可能的。感到不适并在 "晚期 "检测出阳性的人可能实际上是先感染了其他东西，后来才患上COVID。"北卡罗来纳大学教堂山分校的临床微生物学家梅丽莎-米勒说："现在很容易有五到八种其他病毒在流通。在美国的大部分地区，现在也是过敏季节，而且冠状病毒测试可能会出现假阳性，尽管它们不太可能连续几天都这样。


没有更多的数据，就很难知道如何最好地处理早期的阴性结果。戈登说，为了更加明确，"你可能需要一个人类挑战实验，"在这个实验中，接种疫苗和未接种疫苗的志愿者被故意感染SARS-CoV-2，然后反复测试并监测一段时间内的症状。但是根据新出现的故事，这个问题似乎并不真正罕见。纽约一位27岁的疫苗接种者Jesse Chen告诉我，"我想在过去五周内我可能有20个朋友 "感染了病毒；他们中的大多数人都经历了延迟阳性，包括Chen本人。

如果这种情况发生得更多，那么 "你就不能相信在患病初期的阴性快速测试"，兰登告诉我。虽然疾病预防控制中心和检测设备制造商早就说过，阴性结果不能排除SARS-CoV-2的感染，但目前还不清楚这些早期疾病检测问题如何与诊断指南相适应。生产广泛使用的BinaxNOW SARS-CoV-2测试的雅培公司发言人Kimberly Modory在一封电子邮件中写道："人们应该继续遵循我们的测试说明，即在3天内测试两次，间隔至少24小时（不超过48小时）。" 另一个流行品牌iHealth也提供类似的说明。(CDC和iHealth没有回应评论请求)。


不过，这些方案中有许多是在接种过疫苗或被感染的人少得多的情况下制定的，而且Omicron和它的分支还没有占主导地位。而且它们还错过了一些近期的感染。例如，弗曼纽克(Furmaniuk)通过两项iHealth测试为自己的晚餐开了绿灯。而来自长岛的58岁的埃伦-克拉科（Ellen Krakow）在出现症状的第四天服用了第三次BinaxNOW后，才得到了抗原阳性的结果。(在她出现症状的第三天收集的PCR测试，确实首先变成了阳性）。

在专家们知道更多之前，一些研究人员建议人们谨慎地进行测试。兰登告诉我，阳性反应仍然是可靠的。但是有症状的人和最近接触的人可能有充分的理由对阴性结果持怀疑态度。格雷德告诉我："如果你出现了症状，就认为你被传染了，"他说，即使最后发现不是SARS-CoV-2。"马丁告诉我："人们忘记了，在所有的建议中，一旦你出现症状，你就应该有不同的表现。"阴性测试不应该成为外出的通行证。"

兰登还对早期阴性反应对隔离期的影响表示关注。今年1月，CDC将建议的COVID隔离时间减少了一半，说人们可以在仅仅五天后停止隔离，从他们的症状开始算起，只要他们在随后的五天内进行掩蔽。该机构为其决定辩护，指出大多数人到那个时候已经不再具有传染性--但使用的数据几乎完全是在Omicron激增之前。


阅读。美国的COVID规则是一场垃圾桶之火

根据此后出现的证据，"五天是可笑的乐观主义，"兰登说，他最近进行的一项研究显示，很大一部分人在第五个隔离日之后仍然检测出阳性，这提高了他们仍在大肆散播病毒的可能性。Rebecca Ennen是华盛顿特区的一名39岁的疫苗接种者，直到她患病的第六天才得到她的第一个阳性结果，因为她的症状正在逐渐消失。"她告诉我："这真是太奇怪了。"我当时正在康复中"。于是，恩宁又继续掐架了五天，直到她最终再次检测出阴性。其他人，包括戈登和弗曼纽克，也在等待测试，以摆脱隔离；这也是巴塔查里亚 "如果是我，也会这么做"。

但是这样的心态似乎很难持续下去，尤其是对于那些经常接触呼吸道微生物的人，包括年纪很小的孩子的父母，或者有严重过敏症的人，或者没有快速检测手段的人。隔离仍然使人们远离工作（和收入）、学校和他们的家庭。这在情感上也是令人痛苦的。长岛的克拉科夫在患病14天后才再次检测出阴性。"她告诉我："我被隔离了两个星期以上。


所有这些意味着我们的指导方针和对该病毒的看法可能很快需要调整--可能不是最后一次。南加州大学的临床微生物学家Butler-Wu最近建议一位收到半打以上阴性测试结果的朋友--抗原和PCR--说她的呼吸道疾病可能不是COVID。这位朋友最后去看望了Butler-Wu，但不久之后就检测出了阳性。"这真的震撼了我，"巴特勒-吴告诉我。"这与我以前所知道的一切都背道而驰。她说，这提醒了我，这种大流行病仍然在上演着情节的转折。她说："我是专业做这个的，"她说，"但我还是做了错误的决定。"