With Covid-19 cases rising across the country, many people are once again relying on home testing to guide their decisions about going to work and sending their children to school and other activities.
Many of those tests will come back negative, even when a person is 100% sure they have Covid-19. They have had a known exposure, for example, or telltale symptoms they recognize from a previous attack.
That has led to speculation on social media that perhaps rapid tests have lost their ability to detect some of the newer variants of the coronavirus.
“Every time a new variant appears, I see this exact same conversation emerge on Twitter,” said immunologist and epidemiologist Dr. Michael Mina, chief scientific officer of the telehealth company eMed. Mina was an early advocate of selling rapid lateral flow tests to the public as a way to help people understand when they were contagious.
Mina says that people who notice this are not crazy. There are reasons why your test could be negative and why you actually have Covid.
For one thing, people are using rapid tests differently than they did before. Our immunity also plays a role. Almost all of us now have some kind of underlying immunity to the coronavirus, and that also affects the test’s performance.
But ultimately, the tests are still capable of detecting infections, said Todd Merchak, co-director of the RADx program at the National Institutes of Health. The program, whose name is short for “rapid diagnostic acceleration,” was created during the pandemic to quickly develop tests for the coronavirus.
“To date, the performance of currently marketed COVID-19 tests has not been negatively affected by any new variants,” Merchak said in a statement.
RADx works with the US Food and Drug Administration to monitor new variants and continually evaluates the performance of Covid-19 tests sold in stores.
The reason Covid-19 tests continue to work when other tools, like vaccines and monoclonal antibodies, don’t that have become ineffective over time, is that vaccines and antibodies target the spike proteins that protrudes from the round envelope of the virus. These spikes are under constant pressure from the environment to change, and they do.
Most rapid tests, on the other hand, target the nucleocapsid proteins, or N protein, of the coronavirus. N proteins do not change as much as spike proteins do.
If the N proteins change, researchers are prepared.
In a large study published in September 2022 in the journal Cell and funded by RADx, researchers developed a tool that is essentially a library of every imaginable change in the N protein over time. They used deep mutational scanning to predict how each of those changes would affect the ability of 17 antibodies used in 11 commercially available rapid tests to attach to the virus. Now, scientists can compare changes in each new virus variant to quickly assess whether a given test will continue to work.
If the FDA suspects that a test has stopped working to detect a common variant, it performs additional testing and may revoke the test’s authorization.
The CDC recommends that people get a rapid test five days after a known exposure to the virus.
“If you look at viral kinetics… on average, it normally takes three, four or five days for the virus to go from very low levels to levels high enough to be detected in any test,” Mina said.
That hasn’t changed, even with new variants, he said.
The new variants may copy a little faster in the body, but it’s a difference of hours, rather than days with the original virus, he said.
Now that our immune system recognizes the virus, Mina believes it begins to respond faster and therefore people are showing symptoms earlier than before.
That may be leading them to test earlier in their infections, before the virus has a chance to accumulate enough copies for a test to detect it.
“So now people are starting to test very quickly, like day one, day two after exposure, when we know that the average person is not going to get a high enough viral load to be detectable in PCR or viral tests. antigens until day 3, 4, 5 or 6,” Mina said.
“It’s a bias that occurs as a result of easy access to testing at home,” he said.
That’s why late last year, the FDA issued a safety statement to the public, advising anyone who uses a home test and gets a negative result to repeat it within 48 hours. In November, it added the same direction to emergency use authorizations for all at-home Covid-19 tests.
The advice to repeat the test came from another government-funded study. Researchers at the University of Massachusetts studied more than 5,000 people who had been recruited to find out how well home Covid-19 tests work in the real world. The study was carried out during the winter of 2021 and until 2022.
People who participated in the study underwent rapid home tests every 48 hours for 15 days. They also sent samples for PCR testing, which is a more sensitive way to detect infections.
“They can detect extremely small amounts of a virus, so they tend to work best in the early stages of an infection,” said study author Dr. Nathaniel Hafer, assistant professor of molecular medicine at the Chan School of Medicine in UMass.
During the study, 154 people tested positive in PCR tests; 57 had symptoms, but 97 did not.
Rapid home tests were more accurate in people who had symptoms. They detected the infection about 60% of the time when a single test was performed on the first day of infection when a person had symptoms. When the rapid test was repeated two days later, the tests detected an infection with symptoms about 90% of the time.
Rapid tests were less useful in people who did not have symptoms. A single test detected positive but asymptomatic cases only about 9% of the time. A second test two days later found people who tested positive but had no symptoms about 62% of the time. A third test, carried out two days later, detected more than 75% of positive cases without symptoms.
“At the beginning of an infection, the amount of virus can still be quite low. And PCR tests could detect the presence of the virus, but the rapid test is not sensitive enough,” Hafer said. “That’s why it’s so important to repeat testing every 48 hours.”
Another real-world study of rapid tests identified another reason why tests sometimes don’t work well: operator error.
The study followed more than 200 parents and 426 children treated at a family clinic in Taiwan as Covid-19 spread through their homes. Families received rapid home tests and instructions on how to use them. The average age of the children in the study was 5 years old, the parents were around 40 years old. More than 98% of adults were vaccinated, but most children were not because Taiwan had not recommended vaccination of children under 5 years of age at that time.
The Covid-19 cases were confirmed using PCR tests, which were useful in determining a person’s viral load.
The researchers then looked at how well the rapid tests worked at detecting those cases. Despite having more infections and more symptoms than their vaccinated parents, children’s rapid tests often come back negative. In this study, negative rapid tests correctly meant that a child was healthy only 38% of the time.
The researchers were baffled by this result. PCR tests showed that the infected children had viral loads that should have been high enough to test positive on rapid tests. What’s more, children who tested negative often had the same high viral loads as children who tested positive, giving researchers a clue to the problem: As many parents can attest, sometimes children weren’t exactly cooperative when It was about getting a good sample. .
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“This finding indicates that some parents find it difficult to obtain a good nasopharyngeal swab sample from their children, leading to false-negative results,” the study authors wrote.
Restless toddlers aside, Mina says she looks forward to the day when it’s common for rapid home tests to fail to show a positive result, even if the tests are repeated.
“We could actually call that a victory for our immune system, because it means that our immune system actually kept the virus at bay long enough that it never reached a high level” to test positive, he said. “I think for a lot of people, that’s really happening.”