Newscasts and social media are alive these days with images of frontline medical workers receiving much-needed COVID-19 vaccines. But for most of us, vaccination is still a ways off, and navigating our pandemic world safely is more important than ever—especially as infections spike around the country and winter makes it more difficult to do things outside.
Let’s say you’ve been exposed to COVID-19. Maybe a colleague at the grocery store where you work develops symptoms after you spent a full shift together yesterday. Maybe one of your kids’ classmates gets sick. You think you should get tested, and you’ve heard you shouldn’t do it right away, but you’re not exactly sure why that is or what the best approach might be. That brings us to a question I’ve heard many people ask—and asked myself—in the last several months.
#CovidQ: If I think I’ve been exposed to COVID-19, when should I get tested?
What’s the difference between exposure and infection?
As with many complicated topics, it’s best if we start by defining our terms. What does it mean to be “exposed” to a virus? For purposes of contact tracing in the U.S., an “exposure” to COVID-19 involves having spent more than 10 minutes at less than 6 feet from someone who is infected while wearing no personal protection, says Ilhem Messaoudi, a viral immunologist at the University of California, Irvine.
“When contact tracers go around and assess risk, that’s the kind of question they’ll ask: Where were you, how long did you interact, were you wearing a mask?” she says. That’s because being exposed to a virus does not mean you will become infected (i.e. sick) with it. And the likelihood of that happening is directly linked to how far you were from that person and whether you had taken measures to protect yourself. (Though it’s useful for epidemiological purposes, note that this contact-tracing definition of exposure doesn’t encompass every possible way that infection can occur. Studies of fluid dynamics as well as individual COVID-19 cases have suggested that, under specific conditions, the virus can travel significantly farther than 6 feet, and possibly even infect new hosts in as little as five minutes.)
You probably know this much already. But here’s where things get complicated. What does a viral infection actually mean, and what determines if you’ll get one when you’re exposed?
“It’s actually really difficult to be a virus,” Messaoudi says. “You’re not a living organism, so you’re completely dependent on having access to what we call a ‘susceptible’ cell, or one that can be infected and support your replication.” Even if a human breathes some amount of virus in—or rubs some in her eyes, or licks some off her fingers—that doesn’t always happen.
To start, a virus entering a body faces many physical obstacles. “Our body is not a hospitable environment,” Messaoudi says. “There’s mucus everywhere, plus we’re breathing in and out.” Built-in systems like our mucociliary escalator, made up of the tiny hairs in our nose and throat, work hard to keep out intruders, in this case beating upward to slowly force bits of dirt and microbes out.
Even if it makes it past this biological gauntlet, in order to survive, a virus particle (also known as a virion) needs to find a cell that’s both “accessible” and “permissive.” That means that A) it will allow the virus inside and that, B) once the virus is inside, the cell’s innards can be taken over to create a factory for more viruses.
That’s not always a given. In the case of SARS-CoV-2, the virus that causes the COVID-19 disease, the spiky outside proteins allow it to attach to a human cell by linking to a protein that sits on the outside of many cells called ACE2. (The new, more transmissible SARS-CoV-2 variant out of the U.K. may owe some of its advantage to differences in its spike proteins that make it particularly effective at binding to ACE2, and thus at entering cells.) But both the virus and the cell are still separate at that point, each inside its own fatty membrane. Those membranes naturally repel each other, like oil and water, says Benhur Lee, a virologist at the Icahn School of Medicine at Mount Sinai. For the two to fuse, and the virus to access the cell, a special enzyme must be present at the site to help the process along. If the enzyme isn’t there, the virus may only make it this far.
If that enzyme is present, SARS-CoV-2 can fuse with its host cell and move inside. “When it enters the cell, it kind of disrobes,” Messaoudi says, releasing its genetic material, called RNA. After gathering proteins to build a template of itself, it then hijacks every possible process in that cell—the processes that make it a liver cell, say, or a lung cell—and turns it into a virus factory.
But not every cell has machinery that’s suitable for reproducing viruses. If it happens to have found a cell that can’t do that work—isn’t permissive—then SARS-CoV-2 is out of luck again.
What’s happening in my body at the beginning of a viral infection?
If SARS-CoV-2 does succeed in hijacking a cell's machinery, then it’s well on its way to infection. This first period, where a virus is gathering materials for replication, then creating initial copies of itself and releasing those copies to infect cells on either side, is known in some virology circles as a “latent period.” It’s a given amount of time where a virus is busy finding accessible, permissive cells and setting up infrastructure to replicate itself and is therefore undetectable.
In a lab, “when you infect a cell line and look at what comes out, you’ll not see anything for a fixed amount of time,” Lee says. “Eight hours, 16 hours, then it crosses a critical threshold and starts going up.” Once SARS-CoV-2 has established its first few cellular factories, things begin to move quickly. “Viruses replicate exponentially,” Lee says. “Infecting two cells doesn’t mean twice the amount of virus. It can mean 100 or 1,000 times the amount.”
(Messaoudi is careful to note that people in her community don’t talk about latent periods because “latency” in HIV and other similar viruses refers instead to the time a virus can survive undetected in a body after infection. “There’s no international committee on viral language,” Lee says with a laugh.)
All this is happening under the immune system’s radar. In the case of SARS-CoV-2, the virus often goes undetected by the immune system for more than three days. But crossing that “critical threshold” of exponential replication prompts the cells in the infected area to send out an alarm, alerting neighbors to a possible intruder. This alarm comes in the form of type-1 interferon, a protein that triggers the arrival of powerful immune cells that can chop up viral RNA and deprive the virus of proteins essential to its replication. And though we still don’t understand everything about how interferon interacts with SARS-CoV-2, this alarm is important enough that there’s some indication that patients’ type-1 interferon levels may influence the severity of their COVID cases.
When it comes to most of the viruses in our body, this is usually the end of the story. “Most of the time, we don’t even know we’re infected with something,” Messaoudi says. “We do battle, we win, and the immune system cleans up the area. We go on as if nothing happened.”
What does it really mean to ‘shed’ the virus?
This is also the point in the viral cycle at which a test could potentially pick up the presence of a virus: about four to seven days after exposure. Before this stage, the number of viruses in a person’s system (their “viral load”) is likely too low to be detected by a test. Once those numbers shoot up, that patient will also start “shedding” the virus. Shedding a virus means that there is a sufficient amount of virus circulating in your system—in the case of SARS-CoV-2, in your mucus and saliva—that it might escape your body and go elsewhere.
One way of shedding is by leaving those bodily fluids on surfaces. “You’re unknowingly touching parts of your body fluid throughout the day: wiping your nose, licking your fingers, rubbing your eyes. These are all ways to potentially get virus on yourself,” says Yale University epidemiologist Virginia Pitzer. You can also shed virus through now-much-discussed “aerosols,” tiny droplets that fly out of your mouth when you breathe or speak.
The three experts interviewed for this article recommended getting tested twice, which allows for the inherent variability in viral load and in everyone’s immune systems, and for false negatives.
Viral replication is hard on cells and can cause early death and disintegration, leaving infectious viruses floating freely in your system to look for new targets. Aerosols can contain both entire infected cells and even those loose viruses, flung out into the air when we breathe, cough, or sneeze, or talk. “Just talking, we generate thousands of aerosols,” Lee points out. “I’ve been in the front row of Broadway shows before. It’s so obvious!”
Still, unless you’re at peak infectiousness, “if you’re keeping your mouth closed and wearing a mask, it’s likely you shed a lot less than if you’re actively sneezing, coughing, singing, shouting,” Pitzer says. It’s about the physics of those actions—the propulsive air is necessary. “It’s not just pouring out of you.”
All of this is to say that a person who thinks they might have been exposed to the coronavirus should wait a few days, to give the hypothetical virus time to develop through its latent period. The three experts interviewed for this article recommended getting tested twice, which allows for the inherent variability in viral load and in everyone’s immune systems, and for false negatives. The recommended timeline of those two tests varies a bit—but we’ll get to that.
Why are there false negatives?
Most available COVID-19 tests are PCR or “polymerase chain reaction” tests. The tests work by using the polymerase enzyme to replicate the viral RNA present in a sample (without actually copying the virus itself) to the point where it can be detected. It’s a system with flaws and weaknesses like any other, Pitzer says. If the sample wasn’t stored at the right temperature, the genetic material might be too degraded to replicate. There might be an issue with the chemical reagents used in the test. And the swab that went up the patient’s nose or into their mouth might not have reached the spot where the virus was replicating—especially if that replication was happening deep in the lungs. All of these issues can lead to a false negative test result.
There’s another essential part to PCR tests that plays in here, as well: the “primers,” or short strands of genetic material added to a testing solution to help define which part of the virus’s RNA will be emphasized for replication. “It’s like how with a zipper, you need that bottom part to latch one side to the other,” Messaoudi says. “Polymerase is like the big piece, and the tiny piece it latches onto is the primer. If you don’t have that, you can’t zip your jacket.”
American PCR tests in particular focus on a narrower swath of viral RNA than other countries', she says. The problem is that the primers used to work with this part of the RNA tend to stick to each other instead of to the virus, preventing effective replication and leading to more false negatives. Other World Health Organization member countries have added different primers to their tests to try to circumvent this issue, but many of the labs running PCR tests in the U.S. haven’t done so yet.
When will I develop symptoms?
Confusing but true: At first, symptoms of an infection are caused by your immune system, not by the virus itself. If a viral infection is a battle, “when you start developing symptoms, that means the immune system is losing a little bit of ground,” Messaoudi says. The period between infection and symptom onset is known as an “incubation” period—different from a latent period.
“When you have a fever and aches, the actual feeling crappy is from the cytokines and immune molecules,” she adds. “Your body opens up its blood vessels to let those molecules through. Your bone marrow cranks out white blood cells, which takes a huge amount of energy, causing fever and fatigue.” You’re also expending a lot of energy to make your blood vessels more permeable so those immune cells can get in, she adds. Your muscles and bones are just “innocent bystanders” in this effort.
At a certain point, though, symptoms start coming both from the physiological stress of the battle your immune system is waging and from damage wrought by the virus itself. Your respiratory cells can start to fall apart, letting liquid and more virus into your lungs and starting a dangerous cycle of destruction. “If you get exposed and the virus replicates faster than the immune system can respond,” Messaoudi says, “then the virus is advancing and your immune system is working—it’s a double whammy.”
One of the things that has made dealing with COVID-19 so difficult is that many infected people shed lots of active, infectious virus before developing symptoms, or without developing symptoms at all—meaning they can silently spread the virus. So what determines when symptoms appear and how bad they are? “That’s the $64,000 question,” Lee says—a hard-to-define combination of viral load, how the immune system is calibrated, and underlying health factors.
All this is made doubly complicated because early research suggests that people who are pre-symptomatic—that is, who are infected but have not yet developed symptoms—contribute to around half of all COVID-19 transmission, Pitzer says, while those who will never develop significant symptoms (between 20% and 60% of COVID-19 cases) likely contribute less to the virus’s spread. But this latter group, of asymptomatic cases, is particularly tough to measure because these people may not ever realize they had the disease at all.
“It’s not really well understood if those individuals are potentially replicating virus to high levels, whether they’re infected for longer periods of time in comparison to symptomatic people,” Pitzer says. (Why some patients remain asymptomatic is another enduring COVID-19 mystery. One hypothesis suggests those individuals may be genetically predisposed to tolerate the disease, making small changes in the body’s mechanisms to counteract negative effects while the immune system fights the virus. Others focus on variations in ACE2 receptors among individuals.)
Asymptomatic infection is an area of continued debate among virologists. Lee argues that asymptomatic people don’t necessarily shed less virus than symptomatic people. “Disease is interplay between host and virus; it’s not just about underlying health factors,” he told me.
Messaoudi draws a more nuanced conclusion. Yes, asymptomatic people can be contagious, but they aren’t the ones doing most spreading of the virus, she says. She points out that 80% of transmissions are due to 20% of COVID-19 patients. “If your immune system is kick-ass enough that you’re not even feeling disease, it’s very unlikely that you have enough virus replicating in you to be very infectious to other people,” she says. “Nobody has bajillions of viruses in their respiratory tract and is not feeling it at all.”
She attributes situations where asymptomatic spread occurred to specific, high-risk circumstances. On the aircraft carrier that hosted an outbreak last fall, for example, young sailors were sleeping on bunk beds, 20 to a room. “It’s how much virus you have, but it’s also the context in which you are,” she says. “Even if you take people who have mild disease who wouldn’t be the best transmitters and stick them in a tiny space, it’s going to spread.”
What if I’m asymptomatic and don’t know it? Could I spread the virus even beyond my 10-day quarantine?
There’s a lot we still don’t know about COVID-19, but the answer is: probably not. Although many infected people experience symptoms for two weeks or more, that doesn’t mean they’re contagious the entire time they feel sick. And even if they still have symptoms and continue to test positive for the virus, that doesn’t necessarily mean they’re contagious. I know that last part is particularly confusing. Let’s unpack it.
A viral infection ends once your body kills all remaining functioning viruses, putting an end to their replication. “Your immune system takes no prisoners when it goes to task,” Messaoudi says. After the interferon alarm goes off, what she calls the “heavy artillery” arrive: a dramatic burst of T-cells that go around killing all the cells in your body that are harboring virus. “You start out with 100 to 500 T-cells and in three to four days you expand to millions of cells,” she says. Quite the dramatic ramp-up.
For Pitzer, best practices would be getting tested on day 3 or 4 after an exposure and then again between days 7 and 10. Messaoudi and Lee recommend similar timelines.
Even if that attack is successful and there aren’t any more infected cells to kill, there’s plenty of bits of virus floating around in the chaos—manufacturing errors that won’t ever replicate, pieces of genetic material left over from the inside of cells that died.
Lee says he doesn’t know of a single study that found patients who were still infectious after 28 days. But a standard COVID-19 test (the PCR-based swab) can’t tell the difference between the battlefield debris—which is still recognizably RNA from SARS-CoV-2, even though it can’t make anyone sick—and a viable virus that can still infect someone. That’s why coronavirus patients often test positive for weeks or months after infection, but it doesn’t mean they’re still contagious. (That’s also, for the record, the reason behind news stories claiming viruses can survive for weeks on certain surfaces. “No, you haven’t found virus in cruise ships three weeks later, you found viral RNA,” Messaoudi says. “We’re just completely freaking everyone out unnecessarily.”)
That aftermath is also what causes symptoms to continue even after an infection is controlled. The repair process is long and tedious. “There’s a lot of destruction, a lot of clean-up that has to happen, she says.” That can leave you feeling lousy for weeks.
It’s natural that “people want to be given one number, but there’s no one number,” Lee says, “because we all receive different infectious doses.” Some people might test positive two days after exposure, others might wait 10 days.
So, what are testing best practices, then?
For someone showing symptoms, Pitzer, Lee, and Messaoudi suggest getting tested as soon as possible.
But as a general rule, “greater frequency is important; it scales with the risks,” Pitzer says. “The higher the likelihood of exposure, the more frequently you should be tested.” That makes it more likely you'll catch an infection early and be able to isolate during your presymptomatic period. In that way, testing can be a useful tool, especially in situations where you might have been exposed but you’re not sure. (Fortunately, current tests do detect the new variant that emerged in the U.K.)
For Pitzer, best practices would be getting tested on day 3 or 4 after an exposure and then again between days 7 and 10. “As an epidemiologist, to be on the safe side, I’d want to see two negative tests a few days apart before feeling free,” she says. Messaoudi and Lee recommend similar timelines. And a recent preprint study looking at strategies for shortening quarantine periods suggests that the optimal time for testing is day 6 or 7 after exposure.
But even as he gives his recommendation, Lee remains concerned about overgeneralization. It’s natural that “people want to be given one number, but there’s no one number,” he says, “because we all receive different infectious doses.” Some people might test positive two days after exposure, others might wait 10 days. And who’s to say people were exposed when they say they were? Humans are notoriously poor reporters of their own health status.
“What’s more informative is if you truly self-quarantined for 10 days,” Lee says. Ultimately, “it’s just a bit more sure.”