An enduring coronavirus mystery: Why do only some get sick?

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 did not get sick and had no symptoms have been one of the most confounding factors of the ongoing public health emergency. The United States currently 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 these individuals contribute to the spread of the virus and whether asymptomatic patients have developed antibodies or other protections that would confer some type of immunity against reinfection.

Dr. Jorge Mercado, a pulmonologist and critical care doctor at New York University’s Langone Hospital Brooklyn, said most of these questions stem from the fact that 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 still 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.

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Early on, many asymptomatic cases went unnoticed because states were dealing with dire shortages of test kits and supplies that limited testing capacity to only the sickest patients. As such, 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 of those categories — including those who are presymptomatic — can transmit the virus, though there was again some confusion on 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, Dr. Maria Van Kerkhove, stated that 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 explained that her response was based on several studies that had not undergone peer review and made 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 these individuals are contributing to the outbreaks.

“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 to the coronavirus, 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 individuals in China’s Wanzhou district and compared them to 37 people who had symptoms.

Though it was a small study, the scientists found that the asymptomatic patients did develop antibodies, which are protective proteins that are produced by the immune system in response to an infection. But the researchers discovered that antibody levels among these individuals diminished within two to three months.

It’s not yet known if COVID-19 antibodies confer any kind of immunity, but if they do, the recent results suggest that those 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, though 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.

Dr. Daniel Kuritzkes, chief of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston, said it’s not altogether surprising that asymptomatic patients would have a more modest immune response. But, he noted one intriguing finding from the Nature Medicine study that further muddies the definition of “asymptomatic” coronavirus patients.

In CT scans of all 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, according to Kuritzkes.

“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 the recent study, though small, reveals some insights into the immune responses of asymptomatic patients, but 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.”