Five years after the pandemic hit, questions remain about how and why millions of Americans are still struggling with long-term disease.
Michele G. Sullivan, Health Central
According to a June 2024 report by the Centers for Disease Control and Prevention (CDC), about 20% of adults with long COVID report health problems that significantly limit their daily activities. Children, too, can and do develop long COVID; an estimated 5.8 million American school-age kids have been diagnosed with it since 2021. And, as with adults, long COVID in children can affect virtually every body system, including the brain, gut, muscles, and even behavior.
It’s true that COVID hospital admissions and deaths are way down since the pandemic peaks of 2020 and 2021, due in large part to the 80% vaccine coverage rate in the U.S. But long COVID remains a real and ongoing concern, says David Hill, M.D., the chairman of the American Lung Association‘s board of directors and a pulmonologist based in Waterbury, CT. “While many people who get COVID have mild symptoms, some experience severe respiratory distress, chest pain, organ failure, and other significant complications from the disease,” Dr. Hill says. “This is especially concerning for older adults, people with chronic lung disease, people with a weakened immune system, and people who smoke or used to smoke.” What’s more, “a substantial number will have persistent respiratory symptoms,” he adds. “Especially, cough or shortness of breath, lasting months after infection—more likely in those with severe disease and the unvaccinated.”
Despite their enormous numbers, people with long COVID have struggled to carve out a legitimate niche in the world of research and clinical medicine, notes Lisa Sanders, M.D., the medical director of the Long COVID Multidisciplinary Care Center at Yale Medical Center in New Haven, CT. “When I first started seeing patients three years ago, a lot of people came to me saying, ‘Nobody believes in long COVID … I can’t get any help because people just think I’m nuts or lazy,’” she reports. “Now, I hear that less often. Long COVID has been around long enough to get greater buy-in from the medical community.”
On the five-year anniversary of a pandemic that so profoundly disrupted our lives and health, we asked leading experts to unpack the current state of long COVID, including the latest scientific findings on distinguishing these symptoms into four categories that reflect distinct disease outcomes—the first step, researchers hope, toward developing targeted diagnostics and treatments.
Many Experiences
One Disease, Many Experiences
These days, most of us recover fairly uneventfully from a bout of COVID. But recent research shows that 22% of cases do not resolve within 90 days. In fact, the average duration of long COVID symptoms is about nine months in those who’d been hospitalized for acute infection, and four months among the nonhospitalized. Roughly 15% of people report symptoms a year later.
Meaning, such lingering disease outcomes meet the official, clinical long COVID timeline, first outlined by experts in 2024. The disorder, the same experts note, can be continuous, progressive, or relapse and recur. Long COVID can wreak havoc throughout the body. It can make existing health problems worse or create multiple new ones.
New Long COVID Newsletter Available!
Get the latest long COVID research and recovery tips —delivered right to your inbox. Your Email…Your privacy is important to us.
Admittedly, this covers a lot of ground. “Long COVID is a condition that is known to have over 200 manifestations that can affect virtually every system in the body,” explains Dr. Sanders. Some can be seen and measured—like irregular heartbeat and fluctuating blood pressure. “Others—such as brain fog, fatigue, and depression—are invisible but still seriously impair quality of life,” she adds. “The sheer diversity of symptoms is overwhelming.”
A 2024 review outlines long COVID’s shapeshifting personality. Examining the findings of 47 prior studies, the paper confirmed that long COVID can cause—among dozens of other health woes—impaired smell and taste; neurocognitive issues; chronic respiratory problems; migraine; muscle aches and weakness; and damage to the heart, kidneys, joints, and gastrointestinal (GI) tract. According to the paper, the most common symptoms were fatigue (23%), memory problems (14%), breathing difficulty (13%), sleep problems (11%), and joint pain (10%.)
While this study didn’t home in on cardiovascular complications, other research has, including a 2022 Veterans Administration study that found a 60% increase in the risk of heart complications among long COVID patients. Another recent study determined that those who developed COVID early in the pandemic faced double the risk for cardiovascular events, including heart attack and stroke, for up to three years post-infection, compared to those without a COVID infection history.
Emerging evidence also suggests that a COVID infection (especially one that led to hospitalization) may increase the risk of new-onset diabetes. In some people, the strong immune response associated with COVID can destroy the pancreatic cells that produce insulin (a.k.a., beta cells). Several studies have found up to a 5% increase in new type 2 diabetes after COVID infection, compared to people who never had the virus.
No Definitive Diagnostics
No Definitive Long COVID Diagnostics—Yet
Unfortunately, while some of those symptoms can be individually measured, there’s still no way to prove that any of them are long COVID, specifically. That’s because no blood or imaging test for COVID fallout yet exists—”nothing that is reliable and universal enough for me to say, ‘OK, you have long COVID,’” says Dr. Sanders. “In a very practical sense, it’s a clinical diagnosis. You have to go with the symptoms people are experiencing.”
A recent study by the National Institutes of Health (NIH) illustrates this frustrating problem. Of the 10,000 people in the study, about 9,000 had a history of COVID infection and 1,880 had a clinical diagnosis of long COVID. Every participant was given 25 standard diagnostic lab tests—and not a single test differentiated those with long COVID from those without it.
Even more confusing? While a COVID infection is at the root of all long COVID cases, the virus affects different bodies differently, Dr. Sanders adds—and likely for varying reasons. “Some symptoms, like respiratory and heart problems, may be because the virus actually damaged the organs,” she explains. “Others are caused by viral reservoirs—populations of the SARS-CoV-2 virus that are still hanging around in the body. Some are because the body’s inflammatory response is still hyperactive, and some seem to be [due to] autoimmune responses.”
Meaning, each case is clinically different, making it difficult to classify long COVID patients, Dr. Sanders says. But a novel approach is attempting to do just that, one that offers the potential of definitive tests and effective treatments.
Phenotypes
Long COVID Phenotypes
For any medicine to be effective, it has to be given under the right circumstances and to the right person. So, scientists are trying to distinguish long COVID phenotypes—meaning, the physical and biochemical characteristics that mark common presentations of the disorder. This is the beginning of creating specific long COVID tests and treatments, says Michael Peluso, M.D., an assistant professor of medicine and infectious disease clinician at the University of California, San Francisco.
The goal is to group long COVID patients by their physical symptoms and find chemical signals in their blood, called biomarkers, which are common and specific to those groups, Dr. Peluso explains. To that end, the NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative has identified four different physical clusters, each with a distinct patient profile. They are:
- Group 1 includes people with long COVID-related heart and kidney problems. These folks are more likely to be older, male, and have preexisting conditions of the blood and circulatory system, like anemia and heart arrythmias.
- Group 2 experiences respiratory, sleep, and anxiety disorders and are more likely to be women with preexisting respiratory disorders, such as asthma and chronic obstructive pulmonary disease (COPD).
- Group 3 reports musculoskeletal and nervous system problems, again skewing female, with higher pre-infection rates of rheumatoid arthritis and asthma, as well as allergies.
- Group 4 consists of people with digestive system disorders (nausea and vomiting, gastritis, pelvic pain) and respiratory conditions (breathing difficulties, and chest pain). They also tend to be women, just with fewer underlying medical problems before becoming infected with COVID.
Protein Signatures
Protein Signatures May Hold the Key
Currently, researchers are further distinguishing these four phenotypes into subtypes by identifying specific molecular patterns in the blood of people with different disease outcomes. The study found that people with long COVID with heart and lung problems had a completely different biomarker profile than those with GI symptoms. Those with cognitive impairment showed changes in markers of nerve tissue repair, while those with GI issues tested positive for proteins that are associated with an autoimmune response.
These “protein signatures”—biochemical patterns that are associated with specific symptoms—could eventually become the basis of two desperately needed long COVID innovations, says Zyad Al-Aly, M.D., the senior clinical epidemiologist at Washington University in St. Louis. They include long COVID lab tests that predict risk and confirm diagnosis, as well as treatments that are tailored to each specific phenotype. Because they are complementary, the two areas should proceed in tandem.
“This is important because it will allow us to classify people into these categories, based on the type of long COVID they have, as well as the underlying mechanism,” says Dr. Al-Aly. “Then we’ll be able to figure out who is most likely to respond to specific agents, which will allow us to make advances in trials.”
Dr. Al-Aly likens this scientific push to the successful development of targeted cancer treatments. “We don’t treat skin cancer, breast cancer, and colon cancer all the same way,” he notes. “We identify clear diagnostic biomarkers, objective measures of disease activity and underlying mechanisms, and then develop promising therapeutics to try on them.”
Research
Still Searching for Answers Through Research
Five years in, we are still without a universal treatment for long COVID. Doctors manage symptoms based on the person’s individual array of symptoms, and the physician’s clinical experience with what works and what doesn’t, says Albert Rizzo, M.D., the chief medical officer of the American Lung Association and a pulmonologist at ChristianaCare Pulmonary Associates in Newark, DE.
“Because there are several possible mechanisms [behind] the development and persistence of long COVID symptoms, a universal treatment is hard to identify,” Dr. Rizzo says. “For now, long COVID treatments will need to target different mechanisms, such as abnormal immune responses, abnormalities in the blood-clotting mechanism, the persistence of viral particles, the development of autoimmunity, and related ongoing inflammation—and these may all be intertwined.”
Enter the Yale Paxlovid for Long COVID trial (PAX LC)—a highly anticipated study of extended Paxlovid treatment in people with long COVID. PAX LC has now wrapped up, with its results due to be published this summer. This research randomized 100 people with long COVID to 15 days of Paxlovid treatment (a combination of nirmatrelvir and ritonavir) or to placebo plus ritonavir. The aim: To eliminate any residual SARS-CoV-2 virus that might be lingering within cells and causing long-term problems.
Like many formal studies of existing drugs, this one was sparked by doctors who, lacking any other options, treated long COVID with an antiviral drug already known to knock down the virus. “The first foray into the arena of treating viral persistence was really the case reports that came out as far back as 2022, in which some people with long COVID took Paxlovid and said that their symptoms improved,” Dr. Peluso explains. “This led to a massive push toward clinical trials targeting viral persistence.”
The first results on this approach in 2024, from a trial called STOP-PASC, were negative. But that doesn’t necessarily mean that Paxlovid is a failure for treating long COVID, Dr. Al-Aly points out. Instead, it likely means that not everyone in the study had long COVID caused by viral persistence. “They may have had another biological mechanism instead,” and for those people, Paxlovid would be useless. “So, this doesn’t necessarily close the door on the idea that antivirals could be helpful [for some people with long COVID]. It just tells us we need to target the right patients for this treatment.”
What’s more, Dr. Peluso says that STOP-PASC may help provide valuable information by identifying specific protein biomarkers that are associated with a beneficial treatment response.
In addition, “the massive NIH RECOVER-VITAL trial, with 900 participants randomized to either Paxlovid or placebo, will further build on both of these [findings],” says Dr. Peluso, adding that the results are due later this year. “VITAL also enrolled large numbers of individuals with specific phenotypes of long COVID, which will be really important in determining whether a particular subgroup benefits from this treatment approach.”
RECOVER-VITAL is just one initiative from RECOVER, NIH’s large-scale long COVID research program. In addition to the Paxlovid study, RECOVER is carrying out studies aimed at long COVID-related neurocognitive problems, sleep issues, autonomic dysfunction (fast heart rate, dizziness, and fatigue), and exercise intolerance.
Additional long COVID trials are proliferating, too, Dr. Peluso notes. They include a small study of an antibody that binds to the SARS-CoV-2 spike protein so the virus can’t enter human cells. Another is testing a new antiviral as a treatment for acute COVID infection. One is examining larazotide, thought to “tighten” the gut barrier and keep persistent virus from re-entering circulation, while still another is looking at two anti-HIV drugs in the hopes that they’ll knock out residual SARS-CoV-2.
Two larger studies are targeting the persistent inflammation and autoimmune reactions that can occur in long COVID. And the Department of Defense is exploring the use of bezisterim, a synthetic steroid that crosses into the brain and acts as an anti-inflammatory and insulin-sensitizer, in hopes of reducing long COVID’s neurocognitive symptoms.
Vaccines
New Thinking on Vaccines
COVID vaccines have sparked debate, but these are the facts: If you get COVID after receiving the most up-to-date vaccine, you’re much less likely to have a serious case or one that lands you in the hospital. And remember, serious COVID illness is one of the biggest risk factors for developing long COVID, says Dr. Hill. “We know vaccination reduces your risk of getting COVID at all, and your risk of getting a serious case of COVID,” he says. “And less COVID equals less long COVID.”
The numbers say it all: A 2024 study found that people who had two doses of a COVID vaccine on board were 40% less likely to develop long COVID post-infection. Other studies have similar conclusions. The largest so far, a European study of 20 million people that was published in The Lancet Respiratory Medicine, found that vaccination cut the risk by up to 52%. And a just-released pediatric study concluded that the COVID vax reduced long COVID risk by up to 73% in kids aged 5 to 17.
Last year, a long-term study reviewed the incidence of new long COVID cases in 450,000 veterans during three periods of various COVID strains that were then circulating against vaccine availability during those same periods: the pre-Delta era (no vaccination available) and the Delta and Omicron eras (vaccination widely available). The rate of new cases declined during each era, and that decline was bigger among people who’d been vaccinated. About 70% of the total decline was due to vaccination, the researchers found.
Unfortunately, the COVID vaccine—especially those using newer messenger RNA (mRNA) technology—continues to get a global black eye from unfounded theories over the virus’s origin, vaccine ingredients, and risk of adverse effects, says Dr. Hill.
“Vaccine misinformation was weaponized during COVID,” he notes. “But vaccines have a higher level of regulation and safety testing and reporting than almost all other drugs,” he adds, sharing how adverse events are watched much more carefully in newer mRNA technology, with the risk of side effects being incredibly low. “We know COVID infection makes you sick. In healthy young people, it’s still worse than a cold and you feel miserable,” says Dr. Hill. “And if people have pre-existing risk factors or bad luck, COVID can make you sick enough to go to the hospital. It can lead to a case of long COVID—and it can still kill you.”
Looking Ahead
Where Does Long COVID Go From Here?
The strides scientists are making in better understanding long COVID may eventually yield targeted, effective diagnostics and treatments against the body-wide damage the virus can induce. Until then, though, experts say an annual, updated COVID vaccination remains the most effective armor to protect against long COVID disease and its potentially serious outcomes.
“Five years ago, COVID dominated nearly every aspect of our lives, consuming every news cycle, shifting most people to work from home, and shutting down schools,” says Dr. Rizzo. “Thanks to research and, most notably, the development of the COVID vaccine, fewer people are dying from this disease. However, COVID is still a very real health threat to many people.”
So, what might the world look like a full decade after COVID first burst onto the global scene? Will there be more treatments by 2030, less severity, and perhaps even a cure? Dr. Rizzo is hopeful.
“More research is needed to better understand COVID and long COVID, and to help people who are still significantly impacted by these diseases,” he says. “However, we’ve made tremendous progress since 2020. So I’m confident that we will continue to advance our knowledge and gain better insight, care, and treatment for long COVID five years down the road.”