By Katherine J. Wu
That’s long been the dogma of infectious disease diagnostics, experts say, since it helps ensure that cases won’t be missed. During this pandemic, that has meant relying heavily on PCR testing, an extremely accurate but time- and labor-intensive method that requires samples to be processed at laboratories.
But as the virus continues its rampage across the country and tests remain in short supply in many regions, researchers and public health experts have grown increasingly vocal about revising this long-held credo. The best chance to rein in the sprawling outbreaks in the United States now, experts say, requires widespread adoption of less accurate tests, as long as they’re administered quickly and often enough.
“Even if you miss somebody on Day 1,” said Omai Garner, director of clinical microbiology in the U.C.L.A. Health System. “If you test them repeatedly, the argument is, you’ll catch them the next time around.”
Such a considerable shift would likely be a welcome change for a country where the status quo of testing was just described as “unacceptable, period” by Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, in an interview Wednesday on CNN.
“If you had asked me this a couple months ago, I would have said we just need to be doing the PCR tests,” said Susan Butler-Wu, a clinical microbiologist at the University of Southern California. “But we are so far gone in this country. It is a catastrophe. It’s kitchen sink time, even if the tests are imperfect.”
Of the dozens of coronavirus tests that have been granted emergency use authorization by the Food and Drug Administration, most rely on complex laboratory procedures, like PCR, to detect the coronavirus’s genetic material.
Only a handful are quick and simple enough to be run in what is called a point-of-care setting, like a doctor’s office or urgent care clinic, without the need for lab equipment. And these tests are still relatively scarce nationwide. Government officials have pledged to astronomically scale up the number of point-of-care tests by fall, increasing by millions the weekly tally of tests conducted.
“We can’t have these in every household,” said Michael Mina, an epidemiologist at Harvard University’s School of Public Health and a vocal proponent of speedy testing.
These tests could be done at a doctor’s office, or even at home — no fancy machines or specially trained personnel required — and cost just a few dollars a pop, perhaps even less. And there would be no delays of a week or longer. Companies like the Massachusetts-based E25Bio are currently cooking up tests that might fit this need.
Such convenient setups could resolve some of the supply shortages that have plagued testing laboratories across the nation for months and caused a national embarrassment over inadequate, inaccessible testing. In many cities, people are still experiencing turnaround times of over a week, sometimes three or more — as people did at the beginning of the U.S. epidemics — for results from PCR-based tests, effectively rendering them useless for themselves and the people around them.
Hamstrung by a long delay, even an accurate test can morph into a useless one.
Natalie Magnus, who got tested in Winnebago County, Ill., on July 14, still didn’t have results 22 days later. Her brother and sister-in-law, who were each tested twice at separate facilities in Colorado on July 7 and July 8, have so far received only one set of results after a 17-day wait. One of them was positive for the coronavirus.
Antigen tests, on the other hand, can be low-tech and easy to manufacture en masse. Distributed weekly or even daily, they could painlessly screen people headed back into offices, schools and universities, delivering peace of mind to parents, teachers and employers. Everyone — not just those feeling ill — would have an easier way to assess their health status on a regular basis.
“The goal here is to detect as many infections as possible,” said Daniel Larremore, an applied mathematician who models infectious diseases at the University of Colorado, Boulder. “That means taking as many shots on goal as we can.”
Broad distribution of antigen tests might also ease the demand for PCR, which still has an important role in hospitals and vulnerable communities like nursing homes. As things stand, many doctors still can’t get their patients’ results within 24 hours.
In those settings, accuracy is crucial, said Melissa Miller, director of the Clinical Molecular Microbiology Laboratory for U.N.C. Hospitals. “You don’t want to miss that diagnosis.”
There are drawbacks. Antigen tests will miss some people who would test positive by PCR, which amplifies coronavirus RNA and picks up even tiny amounts of it. With antigen tests, proteins can’t be copied in the same way, making it easier to mistake some people who are carrying minute levels of the coronavirus in their bodies as pathogen-free. Some antigen tests used in the past miss up to half the infections they look for.
Early on, many experts balked because of these shortcomings. “As laboratorians, we wanted the most sensitive test, the most specific test, the most accurate test,” Dr. Miller said. “End of story.”
Virus levels vary from person to person, and can wax and wane in an individual over the course of an infection, typically peaking around the time symptoms first appear. People carrying — and thus probably shedding — gobs of germs will most likely turn up positive using every test on the market, Dr. Mina said. Those harboring less virus in their bodies might get more mixed results. Many of these individuals, however, probably aren’t the cases of most concern.
It’s another way to look at testing accuracy, Dr. Mina said: “Detecting the most infectious people.”
“If you test people all the time, you can account for lack of sensitivity,” Dr. Butler-Wu said. “But are you really going to test people all the time? If the answer is no, then that lack of sensitivity becomes more of a big deal.”
And many experts are still hesitant to trust negative antigen results, which may need to be backed up with a more sensitive test. That might not be very burdensome in the midst of an outbreak, when positivity rates are likely to be high, Dr. Babady said. In spots where infection rates are especially low, however, “that is not going to be the best approach to testing,” she said.
Cheap tests also aren’t the same thing as free tests. Even $1 tests can start to rack up quite a bill, especially for large families hoping to do daily checkups or nursing home aides required to get tested repeatedly. Left unregulated, the testing market could end up exacerbating the socioeconomic split that’s already disproportionately burdened some sectors of the population with the worst effects of Covid-19.
Concerns over accuracy bogged down the approval process for simple, speedy tests. F.D.A. guidelines stipulate that any new coronavirus test vying for emergency clearance from the agency must perform nearly as well as the gold standard of PCR.
The F.D.A.’s rules frustrate Dr. Mina, who noted that several companies on the verge of debuting antigen tests have found the regulatory hurdles daunting. “Many of them are not even bothering,” he said. “‘Our product might not be good enough. So what’s the point?’”
There probably isn’t one way to grapple with all these issues — and certainly not an obvious one, Dr. Butler-Wu said. What’s clear to her and others, though, is that the current situation is untenable.
“Our backs are against the wall, and it’s Hail Mary time,” Dr. Butler-Wu said. “We have to try something different.”