Health

Emerging data raise questions about antigen tests and nasal swabs

The study, which has not yet been peer-reviewed,
focused on 30 people infected with the virus at five workplaces that
experienced what were most likely outbreaks of the omicron variant in December.
The people received both saliva-based PCR tests and rapid antigen tests using
nasal swabs.

It took three days, on average, for people to test
positive on a rapid antigen test after their first positive PCR result. In four
cases, people transmitted the virus to others while the rapid test showed the
negative result, according to the study, which was conducted by several members
of the COVID-19 Sports and Society Working Group.

It is not clear whether the infections were missed
because the antigen tests are inherently less sensitive to omicron or because
saliva tests may be better at detecting the new variant.

But the results are consistent with other preliminary
evidence that the at-home tests that many Americans have come to rely on — at
least as currently administered, with a nasal swab — may fail to detect some
omicron cases in the first days of infection.

The researchers said they shared their results with federal
officials — including at the White House, the Food and Drug Administration and
the Centers for Disease Control and Prevention — in real-time, as the outbreaks
were occurring last month.

“They’re aware that there are flaws with antigen
testing,” said Dr Robby Sikka, an author of the study and chairman of the
working group.

The study comes a week after the Food and Drug
Administration released its own update on the effectiveness of the rapid
antigen tests. “Early data suggests that antigen tests do detect the omicron
variant but may have reduced sensitivity,” the agency said.

Many of the studies are early and small, and much more
data is needed. The tests, which can deliver results at home in minutes, remain
an important public health tool, and positive results are especially likely to
be informative, many scientists said. (The wait for PCR results can stretch for
days.)

“The message is not that we should stop using these
tests,” said Isabella Eckerle, a clinical virologist at the University of Geneva
in Switzerland.

But people should be cautious about interpreting
negative results, especially when they have symptoms or believe they may have
been exposed to the virus.

“It’s not a ticket that allows you to go back to
normal or to drop any other measures,” Eckerle said.

Assessing Sensitivity

Antigen tests are designed to detect proteins on the
surface of the coronavirus. If mutations in the virus change the structure of
these proteins, antigen tests might fail to detect the variant.

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The omicron variant has about 50 mutations, including
more than 30 on the spike protein alone. Most rapid antigen tests are designed
to detect more stable targets, which are far less mutated in omicron.

Still, even minor-seeming mutations can affect a
virus’s surface proteins, “sometimes in nonobvious ways,” said John Moore, a
virus expert at Weill Cornell Medicine. “Only experimental data can determine
whether there is an impact or not.”

The FDA in September told makers of rapid tests that
they would be required to continue to test their products as new variants
emerged, and, if asked, to share those results with the agency.

Many companies have announced that their tests can
detect omicron, and several independent scientists said that they believed the
tests should be capable of recognizing the variant, especially when present at
high levels. But a few new studies raise questions about the tests’
sensitivity.

The FDA’s update stemmed from an evaluation it is
doing with the National Institutes of Health, said Bruce Tromberg, director of
the National Institute of Biomedical Imaging and Bioengineering. The scientists
evaluated the antigen tests using pooled samples of nasal mucus collected from
multiple people with omicron, as well as similar pooled samples from delta patients.

Scientists then diluted each of these pooled samples
until the antigen tests no longer detected the virus. The tests were able to
detect more dilute solutions of delta samples than omicron samples, suggesting
that the tests may be less sensitive to the new variant, Tromberg said. Still,
he added, in real-world settings, “it may not translate into any different
sensitivity.”

An FDA spokeswoman, Stephanie Caccomo, said last week
that studies were underway “to confirm the reason for the apparent decreased
sensitivity.”

“Once that is known,” she said, “adjustments to
existing tests can be undertaken by each developer with support from the FDA,
if appropriate.”

The FDA update was not the first hint that some
antigen tests may be less sensitive to omicron. Eckerle and her colleagues
recently evaluated the performance of seven antigen tests against samples of
the virus grown from specimens taken from people infected with omicron.
Overall, the researchers found, the tests were less sensitive to omicron than
to previous variants.

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“They missed samples with infectious virus, and they
missed samples that had quite a decent viral load,” Eckerle said. The work has
not yet been published in a scientific journal.

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But there was also vast variability in the performance
of the different tests, most of which are not available in the United States.
And an Australian study, which examined a mostly different collection of
antigen tests, found that the tests had a similar sensitivity to omicron and
delta.

More data are needed, experts said.

“Each test is going to have to be evaluated
independently any time there’s a new variant,” said David O’Connor, a virus
expert at the University of Wisconsin, Madison who urged people not to stop
using rapid tests. “And that takes some time.”

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Swabbing Sites

The new working group study focused on five New York
and California workplaces that had virus outbreaks in December. In 29 of 30
people, samples of the virus produced a telltale genetic pattern on PCR tests,
suggesting that these individuals were most likely infected with omicron.

Each participant took PCR and antigen tests daily over
a period of up to 10 days. The discordant results overwhelmingly came during
the first three days of infection.

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“A negative result may not actually be a negative
result,” said Anne Wyllie, a microbiologist at the Yale School of Public Health
and an author of the new study. “People should not ignore high risk exposures.
They should not ignore symptoms.”

The study’s other authors are Blythe Adamson, the
founder of Infectious Economics, a public health consulting company, and Dr.
Prem Premsrirut, the chief executive of Mirimus Laboratories, which offers
saliva-based PCR testing.

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An Abbott spokesman, John Koval, said on Wednesday
that the finding that a PCR test is more sensitive is “not new.”

“Due to immediate turnaround time, frequent rapid
antigen testing does slow transmission — and with a highly infectious variant
frequent testing is needed, which is not realistic with P.C.R.,” he wrote in an
email.

Quidel’s president, Douglas Bryant, said in a
statement that the company performed recent testing using samples from South
Africa and confirmed that its rapid tests are detecting the omicron variant.

A company spokesperson also said that it was not
surprising that saliva-based PCR tests detected the virus before nasal swabs
did, if the study accurately concluded that viral load peaks first in saliva.
The company noted that its rapid tests only have FDA clearance to collect nasal
swab specimens.

In a smaller analysis, of five participants who took
both nasal and saliva-based PCR tests, the researchers found that the levels of
virus peaked in saliva samples a day or two before they peaked in samples
collected from the nose.

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Those findings are consistent with a recent report
from South Africa, which has not yet been reviewed by experts. The researchers
found that PCR tests picked up a higher share of omicron infections when saliva
samples — produced by the rubbing of a swab inside the cheeks, around the gums
and tongue — were used instead of nasal samples. The reverse was true for
delta.

“Ideally, until we can directly compare the relative
sensitivity of the antigen tests, my suggestion would be to test both sites,”
Diana Hardie, a clinical virologist at the University of Cape Town, who led the
research, said in an email.

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One possible explanation for the findings is that
omicron replicates faster or earlier in the throat and mouth than in the nose.

“While we’ll have to wait to see if the science bears
out, that might be an indicator that that’s where the virus is growing first,”
said Gigi Gronvall, an immunologist and testing expert at Johns Hopkins
Bloomberg School of Public Health. “So if you’re going to look for the virus,
which is what the tests do, then you may find more of it faster in the throat
swab over the nose.”

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Anecdotal reports have also emerged that some people
who tested negative on antigen tests when they swabbed inside their noses
received a positive result when they instead swabbed the back of their throats.

“There’s a lot of chatter around this,” said Nathan
Grubaugh, a virus expert at the Yale School of Public Health. “Obviously, that
warrants further investigation.”

Some tests available in Britain call for swabbing both
the nose and the throat, but the antigen tests available in the United States
are not authorized for the collection of saliva or samples from the throat.

Omicron’s rapid replication also means that there is a
narrower window to catch the virus before it begins spreading, and that people
may need to test themselves sooner after a potential exposure and as close as
possible to an upcoming gathering or event, experts said. They may also need to
test themselves more frequently overall, a particular challenge when the tests
are in short supply.

People who may have been exposed to the virus should
take at least two antigen tests over the course of about two days, experts
said.

 

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