Over the past two years, diagnosing a coronavirus infection has often required a probing of the nose. Healthcare professionals have inserted slender cotton swabs deep into the recesses of American nasal passages, while test kits at home have asked us to master the superficial double-nostril vortex.
"The traditional approach to diagnosing respiratory infections has been to go after the nose," said Dr. Donald Milton, an expert in respiratory virus at the University of Maryland.
But the rapid spread of the omicron variant and questions about the sensitivity of home tests have revived a debate over whether the best way to detect the virus is to try somewhere else: the mouth.
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"The virus first shows up in your mouth and throat," Milton said. "That means the approach we take to testing has problems."
Collecting saliva samples, or swabbing the inside of the mouth, can help identify people who are infected with the virus days earlier than nasal swabs do, some studies suggest.
Science is still evolving, and the data paints a complex picture that suggests saliva-based tests have their own limitations. Many laboratories are not currently set up to treat saliva, and the home antigen tests available in the United States are not approved for it either.
But even saliva skeptics recognize that oral tests have some unique benefits. And with omicron on the march, some experts say test companies, labs and federal officials should work more urgently to determine the best test sites and types for the virus.
"We need to be adaptable," said Anne Wyllie, a microbiologist at the Yale School of Public Health, who is one of the developers of SalivaDirect, a non-commercial polymerase chain reaction (or PCR) test protocol. "I see so many either laboratories or governments that are so fixated on a particular type of sample or a particular test that even with changed data or test preferences, they do not make the necessary adjustments to their testing programs."
The matter of saliva
Researchers began examining saliva tests in the first months of the pandemic. They were eager to find a test method that would be more comfortable than the deep nasopharyngeal grafts that were standard at the time and that would not require trained health professionals or nasal grafts, both of which were in short supply. With saliva, people could simply spit into a tube and hand it over for treatment.
Some laboratory professionals were skeptical that saliva testing would be a reliable way to detect infection.
"There was initial concern that saliva was not the gold standard sample, that it was not the most sensitive sample," said Glen Hansen of the Laboratory of Clinical Microbiology and Molecular Diagnostics at Hennepin County Medical Center in Minnesota.
But by the fall of 2020, dozens of studies had suggested that saliva was an appropriate sample for testing.
"There's been a growing body of evidence that saliva at least works well - it's as good as, if not better, when collected properly, when treated properly," Wyllie said.
Evidence also emerged that the virus tended to appear in saliva before it built up in the nose, suggesting that saliva samples may be the best way to detect infections early.
Milton and his colleagues recently found that saliva samples in the three days before symptoms occur and the two days after contained about three times as much virus as nasal samples and were 12 times as likely to give a positive PCR result. After that, however, more viruses began to accumulate in the nose, according to the study, which has not yet been published in a scientific journal.
The Food and Drug Administration has now approved several saliva-based PCR tests, which have proven popular for screening students in schools.
"Saliva has really proven to be a valuable sample type and one that has increasingly been recommended as a primary test sample," Hansen said.
Saliva's benefits may be more pronounced with omicron, which appears to replicate faster in the upper respiratory tract and has a shorter incubation time than previous variants. Any test method that can reliably detect the virus in the past is particularly valuable, experts said.
"I think omicron has really changed the test game because of how fast the virus replicates and how fast it spreads," said Dr. Robby Sikka, chairman of the COVID-19 Sports and Society Working Group, who helped bring saliva tests to the NBA in 2020. (Both Sikka and Wyllie serve as unpaid board members of SalivaDirect.)
Some experts have also theorized that omicron may be better at replicating in the cells of the mouth and pharynx than other variants have been.
A team of South African researchers recently found that while nose grafts performed better than saliva samples when they detected the delta variant, the opposite was true for omicron. (The study, which used PCR tests, has not yet been reviewed by experts.)
More research is needed, and another small new study, conducted at a test site in San Francisco during an omicron rise, was less encouraging. Of the 22 individuals who tested positive on a rapid antigen test with standard nasal inoculations, only two tested positive when their inner cheeks were inoculated. Researchers are currently investigating whether throat swabs work better.
Saliva also has trade-offs. While the virus appears to build up early in saliva, the nose may be a better place to detect it later in the course of the infection.
Researchers at the California Institute of Technology found that while the virus often rose first in saliva, it eventually rose to higher levels in the nose. Their results suggest that highly sensitive tests, such as PCR tests, may be able to detect infections in saliva days earlier than they do in nasal inoculations, but that less sensitive tests, such as antigen tests, may not.
The data on saliva are still mixed, some experts noted.
"There are these few studies that I have found really very interesting," said Dr. Mary K. Hayden, an infectious disease physician and clinical microbiologist at Rush University Medical Center in Chicago.
But Hayden said she interpreted the new studies cautiously because "this year and year and year," research has suggested that nasal swallow samples are best for detecting respiratory viruses.
Some scientists also have practical concerns. The mouth is "a little more of an uncontrolled environment compared to the nasal passages," said Joseph DeRisi, a biochemist at the University of California, San Francisco who is president of the Chan Zuckerberg Biohub and author of the cheek swab paper. . “Did you drink a coke just before you took the test? The pH will be different. And those things matter. "
Saliva can be "viscous and difficult to work with", especially when patients are sick and dehydrated, said Dr. Marie-Louise Landry, director of the Clinical Virology Laboratory at Yale New Haven Hospital, in an email.
Ultimately, different approaches may be needed under different circumstances. For people who have had symptoms for several days, nasal swabs may be a good choice, while saliva may be best suited for large-scale surveillance screening of asymptomatic people, Hansen suggested. "We have to get the right test in the right places," he said.
In the UK, some home tests require wiping both the throat and nose, an approach that may be worth pursuing, experts said.
"Sampling multiple sites will always give you an advantage," Hayden said.
However, if test manufacturers want to add saliva samples or pharyngeal samples, they will need to validate their tests with these samples and submit the data to regulators. At a hearing in the Senate on Tuesday, Dr. Janet Woodcock, acting commissioner for the FDA, said manufacturers may also need to reconfigure their tests to accommodate the larger grafts designed for the neck.
It is not yet clear if any of the major home testing companies have plans to do so. "We continue to monitor and evaluate," said John M. Koval, a spokesman for Abbott Laboratories, which conducts rapid antigen testing. "Our test is currently indicated for nasal use only."
Even scientists who were convinced of the potential of saliva were reluctant to recommend people to wash their mouths or throat with tests that are not approved for that purpose. (The FDA has also warned against this.) The biochemistry of the mouth is different from the nose and can affect test results, which could potentially yield false positive results, scientists said.
"It's not as easy as just saying, 'Hey, just use a quick antigen for saliva,'" Hansen said.
But experts said they hoped laboratories, test manufacturers and regulators would move quickly to evaluate whether any currently available tests could work better on other sample types.
Ultimately, the country will be well served by having a wide range of test options and the ability to switch between them, as circumstances dictate, scientists said.
"For future pandemics, and even perhaps as omicron evolves," Hayden said, "we need flexibility in our testing systems."
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