Tens of millions of people worldwide are thought to have developed long-term symptoms and conditions in the wake of a SARS-CoV-2 infection. But this sometimes-debilitating phenomenon, often called long COVID, remains a puzzle to researchers. What causes it? Who gets it? And, perhaps, the most maddening one: What is it?

Long COVID patients have reported a wide spectrum of more than 200 symptoms. Some are common, like loss of smell, while others are rarer, like tremors. Some patients have familiar constellations of symptoms, others seem to have idiosyncratic assortments.

Researchers hypothesize that long COVID may simply be an umbrella term for a collection of variable—and potentially overlapping—post-COVID conditions that may have different causes. Those causes might include autoimmunity, immune system dysregulation, organ injury, viral persistence, and intestinal microbiome imbalances (dysbiosis).

As millions continue to struggle with the realities of their conditions, research on long COVID is, unfortunately, still in its infancy. But a study published Thursday in JAMA offers a hopeful small step toward understanding the condition. With data from 9,764 participants, researchers whittled down long COVID’s more than 200 symptoms to a weighted list of 12 core symptoms. The list is not a final definition of long COVID as it needs to be validated in further studies. But it’s a start. It could help direct further research, identify different subtypes of long COVID, and develop diagnostic tools, like biomarkers.

The study—part of the National Institutes of Health’s Researching COVID to Enhance Recovery (RECOVER) Initiative—surveyed symptoms and conditions among people with a past SARS-CoV-2 infection (8,646 people) and those without (1,118). Researchers looked at the frequency of each symptom identified and the symptoms that differentiated the infected from the uninfected.

They came to a core list of 12 symptoms and assigned each symptom a score that represented the odds of it being related to COVID-19. The scores for each of the 12 symptoms ranged from 1 to 8, and the researchers added up the symptom points for each person in the trial. Based on the spectrum of score totals seen among uninfected people, the researchers concluded that a score of 12 was a reasonable cutoff for determining if someone had long COVID. And that cutoff was validated when they looked at how it correlated with the participants’ reports of quality of life and health.

Here is the list of 12 symptoms and their scores:

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As people build up immunity to SARS-CoV-2 through vaccines, boosters, and infections, the most commonly reported symptoms of COVID-19 have shifted, making the deadly pandemic infection more difficult for many people to distinguish from standard cold-weather viruses.

That’s according to recent survey data collected in the ZOE COVID Study, an app-based study with over 4 million users that was created by researchers at Massachusetts General Hospital, Harvard University, King’s College London, and the health science company, ZOE.

Since COVID-19 emerged, the common symptoms that have topped standard lists include fever, chills, a persistent cough, and shortness of breath. As the virus spread around the planet, loss of taste and smell were also reported as telltale signs. But these days, those symptoms are almost completely absent from the top five.

According to the new survey data taken over several recent weeks amid the spread of omicron subvariants, for those who are fully vaccinated, the top five symptoms of a breakthrough infection are (in order): sore throat, runny nose, blocked nose, persistent cough, and headache. Only persistent cough hangs on from the original list of top symptoms, but it is down to the fourth most common symptom. A loss of smell came in as the sixth most common symptom, and fever trailed at number eight. Shortness of breath ranked 29th.

For those who are unvaccinated or who only got one vaccine dose, the top five symptoms are similar to those seen in the fully vaccinated. However, in both the unvaccinated and partially vaccinated groups, headache comes in as the most common symptom. Partially vaccinated people reported more sneezing (their fourth most common symptom), and the unvaccinated still listed fever as a common symptom. The data didn’t include information on how many times survey respondents had been infected with SARS-CoV-2.

The study authors suggest several reasons why the symptoms have shifted to milder, upper-respiratory complaints. The most obvious is that immune protection from previous vaccination and infection largely guards against severe disease. They also note that respondents who have fallen ill in recent weeks have tended to be younger—with the returns to schools, for example—and younger people tend to have less severe symptoms.

But, the authors noted concern that sneezing has risen in the ranks of COVID-19 symptoms, making the top five for the partially vaccinated. Sneezing—much like coughing—is a highly effective way to spread SARS-CoV-2. The authors warn that people should be cautious and get tested if they suddenly find themselves suffering from sneezing fits.

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Pfizer’s antiviral pill Paxlovid is among the most treasured tools for hammering COVID-19; it can knock back the relative risk of hospitalization and death by 89 percent in unvaccinated patients at high risk of severe disease. But, as use of the convenient drug has grown in the US, so have troubling reports of rebound cases—people who took the pill early in their infection, began feeling better, and even tested negative but then slid back into symptoms and tested positive again days later.

It’s still unclear just how common the phenomenon is, but it certainly happens in some proportion of Paxlovid-treated patients. In May, the Centers for Disease Control and Prevention even issued a health alert over the rebound reports.

But, amid the rising awareness, it has also become clear that patients who have not been treated with Paxlovid can also rebound. In fact, in Pfizer’s clinical trials of Paxlovid, researchers noted that about 1 percent to 2 percent of both treatment and placebo groups had rebounds.

Together, this has raised a slew of questions: Are the rebounds reignited infections? Are people still infectious? Do they need to resume isolation? Are they again at risk of severe disease? Did their immune systems fail to mount an effective response? Is the virus mutating to become resistant to Paxlovid? Is omicron causing more rebounds than previous variants?

So far, there’s limited data and mostly only anecdotal reports. But a new, small pre-print study led by researchers at the National Institutes of Health offers some encouraging news about COVID rebounds. The study, which included data on seven rebounding patients—six of whom were treated with Paxlovid and one who was not—found no evidence of Paxlovid-resistant mutations, viral replication gone wild, or faltering immune responses.

Intact immune responses

Instead, a detailed look at their immune responses found that rebounds were associated with a surge in antibody and cellular immune responses specific against SARS-CoV-2. At the same time, rebounds were accompanied by downward trends in markers of innate (non-specific) immune responses, as well as levels of SARS-CoV-2 nucleocapsid bits in the blood.

Together, the findings suggest that the rebounds could be partly due to reignited immune response as the body works to clear cellular debris and viral scraps from a quickly smothered infection. Or, as the authors put it: “rebound symptoms may in fact be partially driven by the emerging immune response against residual viral antigens possibly shed from dying infected cells due to cytotoxicity and tissue repair throughout the respiratory tract.”

In further support of this, the authors—co-led by infectious disease experts Brian Epling and Joe Rocco—note that while three of four controls had a recoverable, live virus during their acute infection, only one of the seven rebounding patients had a live virus at the time of their rebound. And that one patient also had underlying immune suppression, which may explain the finding. Further, none of the rebounding patients developed severe disease.

The study is, again, very small and may not be generalizable to all rebound cases. The authors call for rebound studies with larger cohorts. But some elements of the findings are already backed up. For instance, other studies have also failed to identify Paxlovid-resistant mutations. And on Tuesday, the CDC published a study of more than 5,000 Paxlovid-treated patients, finding that less than 1 percent of patients had emergency visits or hospitalizations in the 5-to-15 rebound period after treatment.

For now, the NIH researchers find their new findings “encouraging.” As Epling wrote in a tweet on Tuesday, ” the findings suggest that “an appropriate immune response is developing, so rebound isn’t caused by people not developing an immune response to COVID while on Paxlovid.”

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Among thousands of the earliest survivors of COVID-19 in Wuhan, China, nearly half had at least one persistent symptom a full year after being released from the hospital, according to a new study published in JAMA Network Open.

The study followed up with 2,433 adult patients who had been hospitalized in one of two hospitals in Wuhan early on in the pandemic. Most had nonsevere cases, but a small number had severe COVID-19 and required intensive care. All of the patients were discharged between February 12 and April 10, 2020, and the study follow-up took place in March of 2021.

Overall, 45 percent of the patients reported at least one symptom in that one-year follow-up. The most common symptoms were fatigue, sweating, chest tightness, anxiety, and myalgia (muscle pain). Having a severe case of COVID-19 increased the likelihood of long-lingering symptoms; 54 percent of the 680 severe cases reported at least one symptom after a year. But persistent symptoms were also common among the nonsevere cases, with 41.5 percent of 1,752 nonsevere cases reporting at least one symptom a year later.

The data echo that of other studies, which have also found that it is not rare for people with milder cases of COVID-19 to experience persistent symptoms. A small Norwegian study published by Nature Medicine in June found 55 percent of 247 nonhospitalized patients with mild-to-moderate disease had persistent symptoms six months after testing positive. A UK study involving 273,618 COVID-19 patients noted that more than half of nonhospitalized patients reported features of long-COVID within a six-month follow-up period. That study was published earlier this week in PLOS Medicine.

Multisystem attack

Still, in the new study as well as the others, severe disease was a significant risk factor for having any persistent symptoms—and also more than three symptoms. Older age and being female also increased the risk of persistent symptoms.

Researchers and medical experts have yet to fully understand why COVID-19 causes long-term symptoms and why symptoms strike some patients and not others. The authors of the latest study highlight the multisystem nature of the infectious disease.

“COVID-19 can affect multiple organs, which leads to both acute organ damage and long-term sequelae, with the latter effects gaining increasing concerns,” they write. In particular, they note that fatigue was the most common persistent symptom identified—something backed up in other studies. Fatigue is common after acute lung injuries but could also be the consequence of multiple organ injuries. The researchers also highlighted that about 4 percent of patients still reported heart palpitations a year later, pointing to possible long-term damage to the cardiovascular system. Cardiovascular complications are a known risk of COVID-19, including inflammation of the heart muscle (myocarditis).

The study does have limitations, though. It does not have a control group, and the researchers were unable to contact everyone who was discharged from the hospital during the studied time period. This could create biases in the data based on those who were able or willing to participate in the follow-up. The study also only looked on early in the pandemic before the emergence of any variants, which could have different long-term effects.

Still, the findings are largely in line with other studies. The authors conclude that “taken together, our research suggests that the health consequences of COVID-19 extend far beyond acute infection.”

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A significant number of people infected with the pandemic coronavirus, SARS-CoV-2, are experiencing long-term symptoms and taking many weeks or months to fully recover, the World Health Organization emphasized in a press conference today.

“I have heard first hand from people who face mid- to long-term effects of COVID-19 infection,” WHO Director-General Dr. Tedros Adhanom Ghebreyesus said. “What’s really concerning is the vast spectrum of symptoms that fluctuate over time, often overlap, and can affect any system in the body.”

While there have long been reports of COVID-19 long-haulers, the WHO worked to raise awareness of the problem today. It’s still unclear what proportion of infected people go on to have mid- to long-term health problems, Tedros noted. But, it’s clear that “this is not just a virus that kills people.” And with more than 45 million cases globally—and counting—even a small percentage will mean a large number of people will have long-term disability.

It’s also clear that long-term symptoms and complications strike a wide range of COVID-19 patients. Long-term effects have shown up in people with mild disease as well as severe disease. Young adults, the elderly, women, men, even children have reported struggling with the disease for extended periods of time.

In today’s press conference, Tedros invited three guests to share their experiences with long-term COVID-19. He started with professor Paul Garner, an infectious disease epidemiologist at Liverpool School of Tropical Medicine. Garner became ill with COVID-19 in March. “I was fit and well and assumed that this COVID illness—I would be able to brush it off my shoulder,” he said. But that was not the case.

Garner said that for four months he suffered dreadful fatigue, sweats, headaches, and mood swings. He was also unable to move. That was followed by three months of being completely exhausted and backsliding in his recovery anytime he overdid it. He said things have only gotten better over the last two weeks.

“I never thought I would have seven months of my life wiped out by this virus. It’s just gone. Evaporated,” he said.

Huge scale

As an epidemiologist, he noted that long-term COVID seems to present with a huge array of symptoms. “I had one particular form,” he said. Other victims, data show, develop heart damage, persistent breathlessness, problems thinking, and other evidence of organ damage.

“Post viral syndromes are not new,” he added. “But what we have here is just a huge scale of people that are suddenly severely disabled.”

Tedros next welcomed Martha Sibanda, a nurse in Johannesburg, South Africa, who was infected in June. Her symptoms started with shortness of breath, cough, and fatigue, and things quickly escalated to the point that she needed oxygen. She was hospitalized at first but then moved to intensive care, where she spent eight days. Though she was able to move back to the hospital ward after that, she still had trouble weaning off oxygen. She stayed in the hospital for 26 more days, all on oxygen. Now, in her fourth month, she still struggles to breath and has not been able to return to work. Her aim is to be back to work by then end of the month, a full five months since falling ill.

Last, Tedros invited Lyth Hishmeh, a previously healthy 26-year-old software engineer from the United Kingdom. Lyth became infected in March and first presented with flu-like symptoms. After weeks of dealing with his illness at home, he collapsed while out trying to get groceries. Though the doctors at the hospital told him he was at the end stages of pneumonia, he has yet to recover and be able to go back to work.

“It’s been almost eight months now and I’m still suffering from fatigue, brain fog, chest pain, heart palpitations, digestive issues, short term memory loss,” he said. “There’s no system in my body which has not been affected. If you’d asked me eight months ago if I thought this would happen if I caught COVID, I’d say no, no, not at all.”

This threat “really reinforces what a dangerous virus COVID-19 is,” Tedros added. “It also reinforces to me just how morally unconscionable and unfeasible the so called ‘natural herd immunity’ strategy is. Not only would it lead to millions more unnecessary deaths, it would also lead to a significant number of people facing a long road to full recovery.”

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