To get the US pandemic under control, a growing number of health and medical experts are making a clarion call for an additional testing approach to Covid-19.<\/p>\n
What we need, they argue, are at-home rapid tests that look for antigens, proteins the live virus makes. These kits would allow anyone to test themselves for the coronavirus any time (and anywhere) for between $1 and $5, and get results in about 15 minutes. No doctors, labs, expensive machines, or special chemicals required.<\/p>\n
\u201cI see these [antigen] tests as a solution that\u2019s literally sitting in front of us,\u201d says Michael Mina, an epidemiologist at the Harvard T.H. Chan School of Public Health, who has led an effort to get these rapid tests authorized by the Food and Drug Administration. \u201cWe could be getting massive outbreaks down to nothing. … It\u2019s a no-brainer to me.\u201d<\/p>\n
Back in April, Deborah Birx, the White House coronavirus response coordinator, actually called for just this sort of solution in an interview on Meet the Press<\/em>. \u201cWe have to have a breakthrough innovation in testing,\u201d she said. \u201cWe have to be able to detect antigen.\u201d<\/p>\n Several small companies have been developing these simple tests, and the conglomerate 3M is working with MIT on another one. (The new BinaxNOW test from Abbott, authorized August 26, is different \u2014 it requires a health professional to administer it, and the patient must have symptoms to get a prescription.)<\/p>\n And some of these at-home tests are ready to go. But they have been sitting on the shelf, unused, for months. Why?<\/p>\n The holdup is that rapid, over-the-counter antigen tests are not nearly as sensitive to the coronavirus as the molecular PCR (polymerase chain reaction) tests currently used for most Covid-19 testing. In fact, by PCR standards, some at-home antigen tests might catch only half or a third of people who test positive on a PCR test.<\/p>\n But that\u2019s because they\u2019re looking for different things in different ways. A PCR test, designed to diagnose an individual with infection, can catch very low levels of viral material before or after a person spreads the virus. An over-the-counter antigen test, meanwhile, relies on high levels of the virus to be able to detect it. These high levels, though, also happen to coincide with when a person is most likely to transmit the virus to others.<\/p>\n \u201cThe antigen test is maximally sensitive at the same time that you are maximally infectious,\u201d says David Paltiel, a professor of public health and health policy at the Yale School of Public Health. \u201cThe antigen test is picking up the infections I want. Because I don\u2019t care about infections, I care about infectiousness.\u201d<\/p>\n Since at-home antigen tests would be fast and cheap, they could allow people to test themselves regularly. Currently, PCR testing is relatively expensive (about $100) and often experiences processing delays that hamstring efforts to stop transmission.<\/p>\n PCR tests\u2019 sensitivity, however, is the current benchmark by which the FDA judges new tests for emergency authorization.<\/p>\n This pre-pandemic framework, Mina and others argue, is a problem as we look for the most effective tools to fight the coronavirus right now. So they are calling for a new way to evaluate these tests, one based in public health terms rather than individual diagnostic ones \u2014 in other words, widely accessible tests that are well tuned to find those who are most likely to spread the virus.<\/p>\n Let\u2019s take a look at how and why this potential solution has gotten sidelined in the pandemic battle \u2014 and what might be done to get these tests off companies\u2019 shelves and out to the public.<\/p>\n A test to find infectiousness,<\/em> not infection<\/p>\n To understand the stalemate around antigen tests, it\u2019s helpful to first understand what they are, how they differ from classic PCR tests, and the trajectory of coronavirus infections. <\/p>\n First: An antigen test looks for a particular protein from a live virus. (Not to be confused with an antibody test, which finds immune cells your body has made after mounting a defense against the virus.) These tests need a lot of viral material to generate a positive result. <\/p>\n Second: A PCR test looks for the virus\u2019s genetic material \u2014 its RNA \u2014 making copies of itself until it reaches a detectable level. As a result, it has a fairly low (although not perfect) false-negative rate, or the proportion of time it would tell someone who has the virus that they don\u2019t.<\/p>\n Finally: One of this new coronavirus\u2019s superpowers is its ability to spread from people before they start to experience symptoms. In fact, people tend to carry the most live virus the day or so before they begin feeling sick, and the amount tends to quickly trail off in the several days after symptom onset.<\/p>\n<\/aside>\n So proponents of at-home antigen testing say that PCR tests, while useful in determining whether an individual is infected with Covid-19, are actually a poor tool in finding people who are most likely to spread the virus. That\u2019s because PCR tests are so sensitive, they are excellent at picking up traces of the virus even after someone has beat it back and is no longer infectious.<\/p>\n Thomas Tsai, a health policy expert at the Harvard T.H. Chan School of Public health, compares the two types of testing this way: PCR tests are reactive tests, usually used for people who either have symptoms, a close contact with the virus, or other reason to think they are likely to have caught it. Rapid, widespread antigen tests are proactive tests, designed to find cases before they spread the virus more widely.<\/p>\n And as the Center for Evidence-Based Medicine noted earlier this month, \u201cwhile an infectious stage may last a week or so because inactivated RNA degrades slowly over time, it may still be detected many weeks after infectiousness has dissipated.\u201d <\/p>\n To look a little bit deeper at how this works, an August 7 preprint report which hasn\u2019t been peer reviewed proposes that people with 10,000 copies of the virus detected in their airways are unlikely to spread the virus to someone else, even with sustained contact (according to their models, it would happen about 0.002 percent of the time). Once that viral load climbs to 10 million copies (which happens quickly, potentially in about a day), they have about a 40 percent chance of transmitting it to a close contact \u2014 and about 80 percent chance at 100 million viral copies (it\u2019s worth noting that when they first reach this level they still might not have any symptoms). <\/p>\n By the time someone has had Covid-19 symptoms for several days (which might currently be about the time they receive results from a PCR test), however, the amount of virus in their system has likely waned to the point of actually being less transmissible. As the authors of the study note, \u201ctransmission after the first week of infection is quite rare.\u201d <\/p>\n At that point, says Mina, it\u2019s more likely that \u201cthey just have residual [virus] RNA hanging about.\u201d So although many of these people would get a positive PCR test \u2014 and a negative at-home antigen test \u2014 they are much less likely to transmit the virus than someone who feels fine now but will develop symptoms in a day or two. <\/p>\n \u201cThe PCR is being fooled all the time,\u201d Paltiel says. \u201cThe PCR is just picking up strands of viral junk.\u201d If your goal is to slow an outbreak, he notes, this sort of data is not actually that useful. \u201cOutbreak control is all about figuring out who\u2019s actually spreading this stuff.\u201d <\/p>\n This could also help explain why so many people continue to get positive PCR test results weeks after getting over most of their symptoms. One small JAMA <\/em>study, for example, found that one in six former Covid-19 patients with no symptoms tested positive for the virus via PCR test four to 24 days after being discharged from the hospital. As an author of a commentary about that paper noted about these long-tail positive test results, \u201cthe clinical significance and infectivity are minimal. These PCR tests likely are responding to noninfective RNA fragments and do not represent detection of viable virus.\u201d <\/p>\n Antigen tests, however, need a much higher level of the virus to register a positive result because they don\u2019t rely on multiplying their target.<\/p>\n This, experts argue, make them well matched for finding people with Covid-19 at precisely their most infectious points rather than potentially long after symptoms have arrived and infectiousness has faded, as is more likely now with the long delays in PCR results and contact tracing. As Paltiel describes it, the concept is pretty simple: \u201cThe more viruses around your airway, the more likely you are to be a risk to others.\u201d <\/p>\n According to an analysis from the June preprint (on which Mina was a co-author), this crucial time period is precisely where the antigen test is most sensitive: detecting viral load at around 10,000 copies, which is just before someone\u2019s infectiousness skyrockets. PCR tests, on the other hand, can pick up about 1,000 copies of the virus, which gives them about a day\u2019s head start at finding the virus. Although with a lag of more than a day in returning results, that benefit is lost. <\/p>\n To put it in other terms, these tests could be \u201csuperspreading detectors,\u201d Mina says, locating many of those who would otherwise go on to unknowingly infect many other people before they know they have the virus. <\/p>\n<\/aside>\n \u201cTheir whole goal is to capture the 90 percent of people who might be transmitting the virus,\u201d Mina says. So if they were to be evaluated in this population \u2014 those with high levels of the virus \u2014 he says, the sensitivity for these tests would soar from 30 or 50 percent (as measured against PCR) up to 95 percent. (They also have very low false-positive rates, in which they would tell someone they had the virus when they actually didn\u2019t.) <\/p>\n Another selling point to antigen tests, proponents argue, is that they would give people their results much faster than PCR tests. Since delays of more than a day or so in getting PCR results back make containment and tracing much less effective, being able to have results back in 15 minutes or so would be a vast improvement. <\/p>\n Because these tests would be fast and affordable, people could also test frequently, which could help overcome worry about the tests being less sensitive than PCR \u2014 especially in the very small window early in an infection when a PCR test might catch the virus but an antigen test wouldn\u2019t. <\/p>\n And such frequent testing would be far superior to the still relatively rare PCR testing that we\u2019re currently doing, Paltiel says. \u201cOf all the variables that we control, the frequency of screening is the most important,\u201d he says. Even if the antigen-based test only caught half of all cases (regardless of infectiousness level), he says, if it\u2019s \u201cbetween a test that is missing 50 percent [but rapid and easy] and a test that is getting everyone that is so expensive or so cumbersome or has such a long turnaround time that it takes a week, I\u2019ll take what\u2019s behind door No. 1.\u201d <\/p>\n In the June preprint study, the researchers found the sensitivity of a test made little difference in the rate at which it could bring viral transmission down. For example, running either of these tests, PCR or at-home antigen testing, on a population weekly could lower the spread of the virus by about 60 percent, they posit. <\/p>\n So, Mina suggests, we shouldn\u2019t just be asking what level of sensitivity a test has, but rather, what it\u2019s sensitive to. PCR tests are great at finding traces of the coronavirus but, he says, \u201cit\u2019s going to have a 0 percent sensitivity to detect elephants.\u201d And if what we want is to start finding elephants \u2014 or people who are most infectious \u2014 we should look for new testing options, he argues.<\/p>\n The FDA\u2019s job is to help keep us safe, but it might lack a pandemic public health protocol<\/p>\n One of the FDA\u2019s essential responsibilities is to make sure dangerous medications, ineffective vaccines, or misleading diagnostic tests don\u2019t make it to US consumers. So it applies rigorous standards to make sure new products are reliable before they are allowed on the market. <\/p>\n And the FDA has applied this same rubric when it has evaluated new tests for the coronavirus this year. <\/p>\n \u201cTests are still being considered first and foremost as diagnostic tools,\u201d Mina says. This is evident in how the FDA has required antigen tests to perform at PCR-levels in detecting traces of the virus in people\u2019s systems, he notes. For example, a new test might need to detect the virus in 80 or 90 percent of emergency room patients who\u2019ve received a positive PCR test. <\/p>\n So when you compare the numbers and see a test that catches half or a third of the positive cases a PCR test does, it makes sense for the FDA to worry about a huge number of Covid-19-positive people thinking they are negative. <\/p>\n And Mina says he gets that. \u201cIf I\u2019m a doctor, which I am, and I have a patient in front of me, I would want the absolute best and most sensitive molecular test to make sure I don\u2019t miss something,\u201d he says. <\/p>\n But he is also an epidemiologist. \u201cFor public health, it\u2019s totally different. It requires a really different type of thinking.\u201d One that targets minimizing spread of the virus among people. <\/p>\n \u201cUnfortunately, the FDA just doesn\u2019t have that,\u201d he says. \u201cThey don\u2019t even have a lens with which to think about it.\u201d <\/p>\n And so, he says, they\u2019re still evaluating at-home antigen tests as individual medical diagnostic tools rather than \u201cas a virus control tool at the population level.\u201d <\/p>\n The FDA has already authorized four antigen-based tests, including ones from Quidel (in May), BD Veritor (in July), LuminaDX (in August), and the new one from Abbott. To meet the FDA\u2019s current sensitivity standards, however, the first three of these use proprietary machines to read results. (Some of these machines are now being allocated by the Centers for Medicare & Medicaid Services to nursing homes around the country.) <\/p>\n But an over-the-counter antigen test, the sort that Mina and others are advocating for, simply can\u2019t be authorized under the current standards.<\/p>\n This gets at the essential tension between the FDA\u2019s individual-based medical diagnostic framework and the broader public health needs of the pandemic. And, says Tsai, \u201cWe really need to shift gears.\u201d <\/p>\n