Why some people get coronavirus symptoms, but still test negative - San Francisco Chronicle

The first symptoms Brian Wilkes noticed were his loss of smell and taste.

They popped up on March 23, five days after the 39-year-old and his 9-year-old son flew into Hawaii and one week after Bay Area counties ordered a shelter-in-place. The pandemic was still nascent, but Wilkes, a general contractor who lives in Oakland, tried to be as diligent as he could about safety on the plane: sanitizing everything they touched, wearing masks, and even upgrading their seats to first class so they’d have more room.

But after noticing his senses weren’t working well, other symptoms began to crop up: he was light-headed, lethargic, and started feeling short of breath and chest tightness just from light conversation. When he got diarrhea, he decided to go into a nearby clinic in Hawaii, where he tested negative for the flu.

The following day, he got tested for the coronavirus at a drive-through clinic. Four days later, he got his results: negative.

“I told (the nurse), that’s bulls—, I know I have it,” Wilkes said.

Wilkes is one of the many across the world who believe they have gotten sick with the coronavirus but tested negative, despite symptoms and progression that point to the contrary.

A Redwood City resident among the passengers of the quarantined Diamond Princess cruise ship took seven coronavirus tests over a two-week period with results fluctuating between positive, negative and inconclusive. Dr. Joseph Fair, a virologist and epidemiologist, tested negative for COVID-19 four different times despite being hospitalized in New Orleans.

One of the most challenging aspects of the world’s response to the pandemic has been the reliance on testing, said Kelly Wroblewski, director of infectious diseases at the Association of Public Health Laboratories.

Even the experts and scientists racing to both produce more tests and analyze the virus know that testing a coronavirus as new as this one presents complications, and can’t be the only metric we rely on to shape policy and inform personal decisions, including when people see family and friends again, or go back to work.

“This heavy, heavy reliance on testing to not only diagnose patients but also to make public health decisions and public safety decisions is sort of unprecedented — and to put this expectation on tests is not realistic,” Wroblewski said. “There is no test that is 100% sensitive and 100% specific — those just don’t exist.”

Though data on false negative rates for the virus’ diagnostic tests seem to vary — and is still relatively scarce — experts agree that false negatives are a concern. Early research out of China stipulated the false negative rate could be around 30%. A study on Abbott ID Now, a diagnostic test that produces results in 15 minutes, was found to have a false negative rate of 15%.

But the rate greatly depends on the timing of the test. If testing was done at the optimal moment, that number may be closer to 5%, said Dr. John Swartzberg, clinical professor emeritus at UC Berkeley’s School of Public Health.

So when is the optimal time to get tested?

If someone is tested too early, one day after potential exposure, their viral load may be below the threshold of detection, rendering a negative result. Alternatively, if someone is tested too late — when they’re at the tail end of their infection, or if they’re only shedding a little bit of the virus — the viral load may also be too low to be detected.

But knowing what’s early or late for each person depends on the course of that person’s symptoms and sickness.

Generally speaking with viruses, viral load peaks around two to four days after symptom onset, said Wroblewski. However, this virus is not a typical virus. A Nature study showed peak viral load to be around two days before symptom onset. There have also been widely varied timelines given on how long it takes for symptoms to show up after exposure. On average, people start to get symptoms about five days after they’ve been infected, but some people are getting sick shortly after exposure, while others have seen two weeks pass before experiencing symptoms.

Many experts are encouraging people to get tested around three to six days after they think they may have been exposed.

A study from the American Society of Microbiology found that during the first five symptomatic days, both nasopharyngeal (deep nasal) and oropharyngeal (long throat) swabs had the highest viral loads and gave positive results, but by the fifth day, detection of the virus dropped to 40%.

Several other studies corroborate that the later a specimen is collected after symptoms begin, the higher the chance of a false negative.

Test sample collection may also be a factor in false negative results.

It’s possible that some false negative test results come about because of variability in swabbing technique, according to Dr. Anne Wyllie, an associate research scientist at Yale.

The deep nasal swab, which is the most common diagnostic test in use, requires a health care provider, who might be a trainee or an intern, to collect nasal secretions that are far back in the nose, and rotate the swab several times. It’s a test that requires some finesse to make sure the sample is collected from the right place; it’s also difficult for the patient to sit through.

There’s also the issue of how the virus moves in the body.

The outward appearance of the virus — neurological issues, blood clots, blue toes, pneumonia — can be as perplexing as its path inside the body. The virus tends to first begin in the nose and the throat, but can quickly spread into the lungs. It can also lodge itself along the lining of blood vessels and push even further, damaging and attacking different organs.

Depending on when a test is taken, it’s possible the virus may have already traveled beyond the original sites of entry, one’s nose or throat. Or, according to Swartzberg, the virus may be present in just one part of the upper respiratory tract, but not throughout.

Some scientists are beginning to consider whether saliva tests — where a patient spits into a cup — may be better equipped to detect the virus across the board, both in mild cases and reliably over a longer period of time. In a study of 49 patients and 98 health care workers, a Yale University team found that saliva samples provided “greater detection sensitivity and consistency” throughout the course of an infection than the broadly recommended deep nasal swab. One health care worker who tested variably using a deep nasal swab tested positive all three times from a saliva test.

However, saliva tests are not yet in widespread use, because nasal swabs and throat swabs are already the gold standards for many other viral panels, according to Wyllie, who led the Yale team’s study.

That study has yet to be peer-reviewed and there is not yet sufficient data to judge with certainty how saliva tests compare to the swab tests. But Swartzberg agrees that preliminary research suggests saliva tests may prove to be reliable.

Symptoms don’t always mean infection.

“The way a person sheds a virus isn’t always consistent and isn’t always on a defined schedule,” Wroblewski said.

Take the case of a UCSF doctor who has been testing positive for the coronavirus for nearly 90 days, though the worst of her symptoms are over. Her case is still something scientists are puzzled by, but experts maintain it’s highly likely that the virus isn’t active in the body for long periods after symptoms pass — even if someone is still testing positive.

On the other hand, there are people who continue to experience a wide range of symptoms and fall into relapses for months, despite testing negative. One explanation could be that, for some infected people, the virus kicks the immune system into overdrive, triggering long-lasting symptoms even after the virus itself is long gone, as Yale immunologist Akiko Iwasaki told the Atlantic.

If I get a negative test result, but I think I’m sick, what should I do?

The short answer: stay home.

“What we’ve seen and the data we have so far shows that two weeks out, most people are no longer shedding viable virus,” Wroblewski said.

For those who are still experiencing symptoms after two weeks, the safest option is to continue self-quarantining until all symptoms go away — or even a week or 10 days after that.

“Testing is one tool in the toolbox,” she said. “It often can’t tell us everything. But if your symptoms progress, the hospital should be the place to go, whether you’ve tested negative or positive.”

Annie Vainshtein is a San Francisco Chronicle reporter. Email: avainshtein@sfchronicle.com

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