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Eric Topol was worried when he first saw images of the lungs of people who had been infected with COVID-19 aboard the Diamond Princess, a cruise ship that was quarantined off the coast of Japan in the earliest weeks of the pandemic.
A study of 104 passengers found that 76 of them had COVID but were asymptomatic. Of that group, CT scans showed that 54 percent had lung abnormalities—patchy gray spots known as ground glass opacities that signal fluid build-up in the lungs.
These CT scans were “disturbing,” wrote Topol, founder and director of the Scripps Research Translational Institute, with co-author Daniel Oran in a narrative review of asymptomatic disease published in the Annals of Internal Medicine. “If confirmed, this finding suggests that the absence of symptoms might not necessarily mean the absence of harm.”
The United States has recorded nearly 40 million COVID-19 infections since the beginning of the pandemic. One recent study estimated that a staggering 35 percent of all COVID-19 infections are asymptomatic. “That’s why it’s important to know if this is a vulnerability,” Topol says.
But Topol says he hasn’t seen any further studies investigating lung abnormalities in asymptomatic people in the more than a year and a half since the Diamond Princess cases were first documented. “It’s like we just gave up on it.”
He argues that asymptomatic disease hasn’t gotten the attention it should amid the race to treat severe disease and develop vaccines to prevent it. As a result, scientists are still largely in the dark about the potential consequences of asymptomatic infections—or how many people are suffering those consequences.
One stumbling block that scientists worry could keep them from truly understanding the scope of the problem is that it’s incredibly challenging to pinpoint how many people had asymptomatic infections. “There’s probably a pool of people out there who had asymptomatic disease but were never tested so they don’t know they had COVID at that time,” says Ann Parker, assistant professor of medicine at Johns Hopkins and a specialist in post-acute COVID-19 care.
Still, there is some evidence that asymptomatic disease can cause serious harm among some people—including blood clots, heart damage, a mysterious inflammatory disorder, and long COVID, the syndrome marked by a range of symptoms from breathing difficulties to brain fog that linger after an infection. Here’s a look at what scientists know so far about the effects of asymptomatic COVID-19 and what they’re still trying to figure out.
Heart inflammation and blood clots
Just as imaging scans have revealed damage to the lungs of asymptomatic individuals, chest scans have also shown abnormalities in the hearts and blood of people with asymptomatic infections—including blood clots and inflammation.
Thrombosis Journal and other publications have described several cases of blood clots in the kidneys, lungs, and brains of people who hadn’t had any symptoms. When these gel-like clumps get stuck in a vein, they prevent an organ from getting the blood it needs to function—which can lead to seizures, strokes, heart attacks, and death.
There have been relatively few of these case reports—and it’s unclear whether some patients might have had other underlying issues that could have caused a clot. But the Washington State researchers who reported on one case of renal blood clot write that it “suggests that unexplained thrombus in otherwise asymptomatic patients can be a direct result of COVID-19 infection, and serves as a call to action for emergency department clinicians to treat unexplained thrombotic events as evidence of COVID-19.”
Meanwhile, studies also suggest that asymptomatic infections could be causing harm to the heart. In May, cardiac MRI scans of 1,600 college athletes who had tested positive for COVID-19 revealed evidence of myocarditis, or inflammation of the heart muscle, in 37 people—28 of whom hadn’t had any symptoms, says Saurabh Rajpal, a cardiovascular disease specialist at the Ohio State University and lead author on the study.
Myocarditis can cause symptoms such as chest pain, palpitations, and fainting—but sometimes it doesn’t produce any symptoms at all. Rajpal says that while the athletes in the study were asymptomatic, “the changes on the MRI were similar to or almost the same as those who had clinical or symptomatic myocarditis.”
Although these chest scans are worrisome, Rajpal says that scientists don’t know yet what they ultimately mean for the health of asymptomatic patients. It’s possible that myocarditis might resolve over time—perhaps even before patients know they had it—or it could develop into a more serious long-term health issue. Long-term studies are necessary to suss that out.
The athletes’ heart inflammation might also be completely unrelated to their COVID-19 infection. Scientists would need to compare the scans with a set taken just before an individual was infected with COVID-19. So that, Rajpal says, will still need to be teased out.
Additionally, people with asymptomatic infections are at risk of becoming so-called COVID-19 long-haulers, a syndrome whose definition has been hard to pin down as it can include any combination of diverse and often overlapping symptoms such as pain, breathing difficulties, fatigue, brain fog, dizziness, sleep disturbance, and hypertension.
“There’s a myth out there that it only occurs with severe COVID, and obviously it occurs far more frequently in mild COVID,” Topol says.
Linda Geng, co-director of Stanford Health Care’s Post-Acute COVID-19 Syndrome Clinic, agrees. “There is actually not a great predictive factor about the severity of your illness in the acute phase and whether you will get long COVID,” she says. “And long COVID can be quite debilitating, and we don’t know the endpoint for those who are suffering from it.”
Studies attempting to assess how many asymptomatic infections account for long COVID symptoms have varied. FAIR Health, a national healthcare nonprofit, found from an analysis of healthcare claims that about a fifth of asymptomatic patients went on to become long-haulers. Another study, which is under peer review, used data from the University of California’s electronic health records and estimated that number could be as high as 32 percent.
Melissa Pinto, a co-author of the latter study and associate professor in the Sue & Bill Gross School of Nursing at University of California Irvine, says the researchers examined healthcare records of people who tested positive for COVID-19 but hadn’t reported symptoms at the time of infection—only to come in later with symptoms associated with long COVID-19. To ensure they were identifying long-haulers, the researchers screened out anyone with a preexisting illness that could explain their later symptoms.
“This is not from another chronic disease,” she says. “These are new symptoms.”
But it’s unclear how accurate any of these estimates might be. Pinto says that some long-haulers are wary of seeking care after having their symptoms dismissed by physicians who weren’t familiar with long COVID-19 syndrome. That’s why she believes that the rates of asymptomatic infections among long-haulers are an underestimate.
Anecdotally, Geng and Parker both say that while they’ve seen plenty of patients with mild symptoms that initially went unrecognized, they’ve had little experience treating patients who were truly asymptomatic.
“We saw many patients who didn’t think they had symptoms except in retrospect because they found out that they had tested positive,” Geng says. “Because they’ve had these long unexplained symptoms of what’s presumed to be long COVID, they think, well, maybe that wasn’t allergies.”
But she thinks that most people who were truly asymptomatic are unlikely to have gotten tested and therefore wouldn’t think to consult a specialist in post-COVID-19 care if they started experiencing unexplained symptoms like brain fog and dizziness.
Parker says that ultimately physicians are still trying to understand the broad symptoms seen in long-haulers. “When a patient comes to see us, we do a very thorough evaluation because we still don’t know exactly what to attribute to COVID and what might be a pre-existing underlying syndrome,” she says. “The last thing I want to have happen is to say to a patient, yes, this is because you had COVID and miss something else that we could have addressed.”
Mysterious inflammation in children
Physicians have also seen troubling clinical manifestations of asymptomatic COVID-19 in children. Early in the pandemic, reports emerged of a rare and mysterious inflammatory syndrome similar to Kawasaki disease that typically sets in weeks after an initial infection.
“Six weeks down the line these people, especially children, will develop inflammation throughout their body,” Rajpal says.
The condition—now called multisystem inflammatory syndrome in children, or MIS-C—typically causes fever, rash, abdominal pain, vomiting, and diarrhea. It can have harmful effects on multiple organs, from hearts that have trouble pumping blood to lungs that are scarred. It is typically seen among children under 14, although adults have also been diagnosed with this syndrome.
MIS-C is incredibly rare. Kanwal Farooqi, assistant professor of pediatrics at Columbia University Vagelos College of Physicians and Surgeons, says that less than one percent of pediatric COVID-19 patients present with some type of critical disease—and MIS-C is just one of them. However, asymptomatic infections do play a role in the syndrome: A recent study of 1,075 children who had been diagnosed with MIS-C showed that three-quarters had originally been asymptomatic.
But there’s reason to hope that this syndrome might not cause long-term effects in patients, symptomatic or otherwise. Farooqi was the lead author on a recent study of 45 pediatric patients showing that their heart problems—which ranged from leaky valves to enlarged coronary arteries—mostly resolved within six months.
“That is reassuring,” Farooqi says. Still, she recommends administering follow-up MRI scans even to patients whose heart troubles seem to have resolved to make sure there’s no longer-term damage, such as scarring. She also says that it’s “really reasonable” to be cautious about asymptomatic infections and encourages parents to have their child evaluated if they have any persistent symptoms even if the original infection was mild or asymptomatic.
“What’s important is that we can’t right now say that there are no consequences,” she says.
Calls for more studies
Scientists caution that there’s still so much we don’t know about the potential harm of asymptomatic infections. Many have called for more rigorous studies to get to the bottom of the long-term effects of asymptomatic disease, why those effects occur, and how to treat them.
Rajpal points out that his study was only possible because the Big 10 athletic conference requires athletes to get tested every few days. Regular testing is key for uncovering asymptomatic cases, he says, which means that most data on asymptomatic disease is likely to come from healthcare workers, athletes, and other workplaces with strict testing protocols.
It’s also unclear what could be causing these lingering side effects. Scientists hypothesize that it could be an inflammatory response of the body’s immune system that persists long after an infection has been cleared. Others suggest there could be remnants of the virus lingering in the body that continue to trigger an immune reaction months after the COVID-19 infection peaked.
“This is all unchartered, unproven, just a lot of theories,” Topol says.
Yet even if asymptomatic infections aren’t linked in high rates to death and hospitalization, Pinto and others say it’s important to keep in mind that long COVID-19 symptoms can be debilitating to a patient’s quality of life.
“Even if people survive, we don’t want them to be having a lifelong chronic disease,” Pinto says. “We don’t know what this does to the body, so it’s not something that I would want to take my chances with.”
The bottom line
With so much we don’t know about the long-term effects of asymptomatic COVID-19, scientists insist it’s better to err on the side of caution.
“The full impact can take years to show,” Rajpal says. Although the chances are slim that an individual with asymptomatic infection will have a really bad outcome, he points out that the continuing high rate of infections means that more people are going to suffer.
“Even rare things can affect a lot of people,” he says. “From a public health perspective if you can reduce the number of people that get this infection, you will reduce the number of people who get severe outcomes.”
Parker agrees, adding that it’s particularly important to prevent infection now as the more transmissible Delta variant drives surges in cases and hospitalizations across the country.
“We have had an amazing breakthrough in terms of the rapid development of effective and safe vaccines,” she says. Although Parker and other scientists remain uncertain of the health effects of asymptomatic COVID-19, “we do know that vaccinations are safe and effective and available.”
Créditos: Comité científico Covid