Months into a pandemic that has caused more than 500,000 deaths worldwide, scientists are still trying to answer crucial questions about the coronavirus.
Chief among them: everything about asymptomatic patients.
People who contracted COVID-19 but didn't get sick and had no symptoms have been one of the most confounding factors of the public health emergency. The United States has more than 2.5 million confirmed coronavirus cases, but it's likely that many asymptomatic people have fallen through the cracks of official counts.
Now, scientists say that without a better understanding of how many people have been asymptomatically infected, it's difficult to know precisely how they contribute to the spread of the virus and whether they have developed antibodies or other protections that would confer some type of immunity against reinfection.
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Dr. Jorge Mercado, a pulmonologist and critical care doctor at New York University's Langone Hospital-Brooklyn, said scientists still aren't sure why some people who have been exposed to the virus get very sick, while others develop no symptoms.
"We really don't know much about this disease," he said. "We know a little more than we did three months ago, but there are still a lot of things we don't have answers to."
Public health officials are struggling to get a handle on the true number of people who have been infected. The Centers for Disease Control and Prevention said Thursday that the number of COVID-19 cases in the U.S. — including those that are asymptomatic — may be 10 times higher than what has been reported, meaning the true case count could be closer to 23 million.
"Our best estimate right now is that for every case that's reported, there actually are 10 other infections," Dr. Robert Redfield, director of the CDC, said Thursday.
Early on, many asymptomatic cases went unnoticed because states were dealing with dire shortages of test kits and supplies, which limited testing capacity to only the sickest patients. Many asymptomatic people likely had no idea they were ever positive, said Dr. Marybeth Sexton, an assistant professor of medicine at Emory University in Atlanta.
"We tend to pick up asymptomatic or mildly symptomatic people when we do contact tracing, so when we get someone who is positive and we start testing people they've been in contact with," she said. "I think it'll be a long time before we know for sure what the true percentage is."
Sexton added that the virus' long incubation period has also led to some confusion over how "asymptomatic" is defined. According to the CDC, it could take up to 14 days after exposure for someone to show any symptoms.
"There are people who are positive but truly have no symptoms, and there are people who go on to develop very mild or atypical symptoms, and then there are people who think they are asymptomatic until you query them about some of the more unusual manifestations of COVID-19," she said. "But sometimes, these all get lumped together as 'asymptomatic.'"
It's thought that people in all three categories — including those who are presymptomatic — can transmit the virus, although there was again some confusion about the nature of asymptomatic spread. In early June, the World Health Organization was forced to clarify that the coronavirus can be spread by people with no symptoms after one of the agency's top infectious disease epidemiologists, Maria Van Kerkhove, said she thought asymptomatic spread of COVID-19 was "very rare."
Van Kerkhove's assessment was roundly criticized by scientists around the world. A day later, she said her response had been based on several studies that hadn't undergone peer review, and she made it clear that the WHO's guidance still stands.
Yet even if scientists are sure that asymptomatic people can be so-called silent spreaders — transmitting COVID-19 even if they show no symptoms — it's not known to what degree they are contributing to the outbreaks.
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"It's been very hard thus far to nail down how much of transmission is due to asymptomatic people and how much is due to people who get quite sick," Sexton said.
Another big unknown is how asymptomatic people's immune systems respond and whether they will develop antibodies or other protections against the virus.
A study published June 18 in the journal Nature Medicine was the first to examine the immune responses in asymptomatic coronavirus patients. The researchers followed 37 asymptomatic people in China's Wanzhou district and compared them to 37 people who had symptoms.
Although it was a small study, the scientists found that the asymptomatic patients did develop antibodies, which are protective proteins the immune system produces in response to infections. But the researchers discovered that antibody levels among those people diminished within two to three months.
It's not yet known whether COVID-19 antibodies confer any kind of immunity, but if they do, the recent results suggest that the protections may not last long — particularly among those who are asymptomatic.
Mercado said it's possible that even low antibody levels could afford some protection, although more studies are needed to know for sure.
"There's a glimmer of hope that an antibody response can at least decrease the chances that you'll progress to a severe disease," he said.
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Dr. Daniel Kuritzkes, chief of the infectious diseases division at Brigham and Women's Hospital in Boston, said it's not altogether surprising that asymptomatic patients would have more modest immune responses. But he noted an intriguing finding from the Nature Medicine study that further muddies the definition of "asymptomatic" coronavirus patients.
In CT scans of the study participants, the researchers found signs of lung inflammation, known as pulmonary infiltrates, even in people who showed no symptoms. Signatures of inflammation were observed in 57 percent of the asymptomatic group, a "surprising" find because it's not common to conduct CT scans on people who aren't exhibiting symptoms of a respiratory infection, Kuritzkes said.
"It makes you wonder if they really were asymptomatic, because clearly they had some pneumonia," he said. "It just goes to show that the absence of symptoms is not the absence of infection."
Sexton said that the recent study, while small, reveals some insights into the immune responses of asymptomatic patients but that the results also show how much remains unknown about this population.
"Until we know how much transmission asymptomatic people are responsible for, it makes an incredible amount of sense to keep stressing that everyone should wear a mask," she said. "If you happen to be in that category and you're wearing a mask, that's going to keep you from infecting people and putting those viral particles out in the environment. And everyone else wearing a mask is doing the same for you."
