In the world's ongoing quest to respond to the Sars-CoV-2 coronavirus, one of the tools most often invoked and hailed is testing - testing for current infections, to determine who is ill and contagious, and testing for antibodies, a sign of past infection and possibly, too, of future immunity.
The goal is to identify people who might spread the virus and isolate them, and to allow anyone protected from reinfection to resume an active social and professional life.
Democrats in the United States Senate have proposed a plan for "fast, free testing in every community". At a recent news briefing, Mr Andrew M. Cuomo, the governor of New York state, declared: "The more testing, the more open the economy."
President Donald Trump's new business advisory council has warned that the American economy will not rebound until wide-scale screening takes place.
But there are major problems with this approach. Far too few tests are available in the United States. Some are shoddy. Even the ones that are precise aren't designed to produce the kind of definitive yes-no results that people expect.
The first type of test, the reverse transcription polymerase chain reaction (RT-PCR) test, diagnoses Sars-CoV-2 infections by analysing cells collected from the nose or back of the throat. It converts the cells' RNA into DNA and then, using polymerase enzymes, duplicates the DNA again and again, so that there's enough of the virus that it can be detected, if it is present at all. This process is known as "amplification".
As of Monday, about 5,593,000 such tests had been performed in the United States, according to the Covid Tracking Project.
That's far less testing, per capita, than in many other advanced countries, and it's not nearly enough, especially since people will need to be screened repeatedly: Anyone who tests negative for Sars-CoV-2 today could be exposed to it tomorrow, particularly in areas where the virus is spreading rapidly.
Yet, for all the calls and recommendations to get many more tests done, there is a more fundamental problem that is far less recognised: The accuracy of RT-PCR tests is inherently limited.
The US Food and Drug Administration (FDA) recommends 40 cycles of amplification, but even after that, too little of the virus' genetic material might be present to be detectable.
One consequence is that even when diagnostic tests aren't faulty and they are performed properly, some people who test negative for Sars-CoV-2 actually are infected - a reading known as a "false negative".
In a recent study by researchers at the Cleveland Clinic of five commonly used diagnostic tests, nearly 15 per cent of the results were false negatives. Chinese scientists published a study in February that found that the false negative rate of some tests conducted at the Third People's Hospital in Shenzhen, southern China, between Jan 11 and Feb 3 was as high as 40 per cent.
An article published earlier this month in Mayo Clinic Proceedings cautioned that "even with test sensitivity values as high as 90 per cent" (really rather precise), the danger posed by false negative results - that is, the health risk created by infected people mistakenly being told they are infection-free - was significant and that it would only increase as testing increases overall.
The second kind of test is serology, which detects the presence of antibodies to the virus in the bloodstream. Antibodies are evidence of the body's reaction to an infection, of the fact that a person was previously infected; their presence might also suggest that the person is now immune to the virus.
We say "might" and "suggest", not "prove", because the notion that immunity to Sars-CoV-2 can be acquired through infection is only, for now, an assumption based on past experience with other viruses. No scientific studies have confirmed this hypothesis yet.
Scientists worldwide are working to determine if, in the case of Sars-CoV-2, too, infection confers immunity, and if so, how effectively and for how long. But the first serological studies made public to date have been flawed or too easy to misinterpret.
In a much-discussed study of 3,330 residents of Santa Clara County, California, conducted early this month, 2.5 per cent to 4.2 per cent of the subjects tested positive for antibodies to Sars-CoV-2 - a finding suggesting that some 50 to 85 times more people in the community had been infected than the official figures stated.
The study, which had not been peer reviewed before publication, came under fire for various methodological flaws, including selection bias: Recruitment for the study was conducted via social media, and some subjects might have volunteered in order to get tested because they had reason to believe they had been infected.
One question that debate has highlighted is whether a study conducted in a suspected hot spot of infection - in Santa Clara County or anywhere - can hope to say something useful about the population as a whole or any other group beyond its own subjects.
Consider also this serological study conducted in the town of Gangelt, Germany: About 15 per cent of residents tested were found to have Sars-CoV-2 antibodies - but the town was the site of a carnival thought to have been a super spreader of infection.
As for the blood work itself, serological tests, like RT-PCR tests, have inherent limitations to do with accuracy. Even the most precise antibody tests don't produce neat, binary results.
Measuring antibodies isn't like determining if a light has been switched on or off; it's more like gauging the intensity of a bulb controlled by a rheostat. One example: In the early days of an infection, while a patient's immune system is still revving up, his antibody levels might be too low to detect.
Serological tests also suffer from an internal contradiction, a structural tension. A very precise test is able to correctly identify both the presence of any antibodies if they are present (this is known as "sensitivity") and the absence of antibodies when they are not there (this is "specificity").
But sensitivity and specificity are somewhat at odds with each other, and they compete. For instance, the characteristics that make a test more sensitive, or better at turning out true positives, also make it more likely to yield false positives instead of what should be true negatives.
At the same time, it is also a principle of epidemiology that the lower the prevalence of an infection in a studied population, the greater the chance that testing for antibodies will yield false positive results. (That's because when testing in a population with few total cases of infection, the number of false positives will make up a larger share of all positive results.)
And the consensus among the leading epidemiologists and clinical lab experts we talk to regularly is that, to date, only between 5 per cent and 15 per cent of the population of the US has been infected with Sars-CoV-2.
These features are one reason an April 17 advisory from the FDA recommending the use of serological tests simultaneously warned that the agency "does not expect that an antibody test can be shown to definitively diagnose or exclude Sars-CoV-2 infection".
Last Friday, the World Health Organisation released a scientific brief that said: "There is currently no evidence that people who have recovered from Covid-19 and have antibodies are protected from a second infection."
Given these limitations, what, then, can be done to put in place an effective, large-scale testing programme in the US?
After the outcry over the initial failure of the Centres for Disease Control and Prevention to develop reliable RT-PCR tests, the FDA invoked emergency provisions to allow the use of Covid-19 test kits without their needing to undergo the agency's standard review for accuracy. As a result, coronavirus testing in the US is a Wild West, with at least 61 new RT-PCR tests and more than 136 unvetted antibody tests currently in use.
The FDA must bring order to this chaos and determine which tests work well. It should stick to its normal review process but expedite it by giving it top priority with its clinical reviewers and bringing in more reviewers as necessary.
The rush for widespread testing has also created unprecedented global demand for essential test components, like the reagents needed to process RNA and the swabs used to collect samples for RT-PCR tests. Major shortages could persist for months in the US and elsewhere: Demand is likely to outstrip even increased production, as more and more countries try to test an ever-larger share of their populations.
Governments throughout the world and the research, medical supply and clinical lab industries must unite to vastly increase global production of reagents and sampling equipment. Achieving this will take months and require building new capacity, presumably with public subsidies.
The time and costs involved will be considerable, but such an effort is the only way to test large populations for this infection (and for others in the future).
A blue-ribbon panel of public health, laboratory and medical experts, ethicists, legal scholars and elected officials should be convened immediately to set out a road map with realistic goals for testing and contact tracing.
It should also develop a national strategy for monitoring hot spots of cases and the cycles of troughs and spikes in infections that will almost certainly continue until an effective vaccine is widely available or much of the population has become immune to the virus.
In the meantime, and for as long as testing for Sars-CoV-2 is too limited or unreliable, the US must ramp up what public health professionals call "syndromic surveillance": the practice by medical personnel of observing, recording and reporting telltale patterns of symptoms in patients so that local health authorities, mayors and governors can anticipate and plan for the likely spread of a disease.
This system, supported by funding and technical assistance from the Centres for Disease Control and Prevention, has been put in place for seasonal infectious diseases like influenza and is currently being used to track Covid-19 symptoms. It should be expanded to include even more reporting locations.
Getting a handle on this pandemic will take many more months, and, in the US, as elsewhere, the effort will succeed only with the public's cooperation.
Much resolve will be needed to endure physical distancing measures over the long haul, including through the next waves of infection that are bound to hit. And people cannot be expected to accept the great economic and social costs required if they do not also understand the limitations of this campaign.
Informing the public involves clearly acknowledging what is still not known about this virus, and it involves stating what tests simply cannot do. It also means accepting this painful paradox: We turn to testing in the hope of managing the pandemic, but testing won't get better until the pandemic gets worse.
• Michael T. Osterholm is director of the Centre for Infectious Disease Research and Policy at the University of Minnesota. Mark Olshaker is a writer and documentary film-maker. They are the authors of Deadliest Enemy: Our War Against Killer Germs.
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