Nearly three years into the coronavirus pandemic, the long-lasting consequences of COVID-19 are becoming more evident. What we don’t know: the exact causes of long COVID. What we don’t have: a test to diagnose the condition.

Most people who develop COVID recover quickly, but a subset suffer new or ongoing health problems that are first identified at least four weeks after infection, according to the Centers for Disease Control and Prevention.

Researchers – including from the National Institutes of Health, which was awarded more than $1 billion over four years to support research, and groups of patient-researchers – are working to develop a better understanding of the prolonged health consequences of infection with the virus.

“So many of the questions don’t yet have good answers,” said Harlan Krumholz, a professor of medicine at the Yale University School of Medicine, who has been studying long COVID.

How big a problem is long COVID?

U.S. government estimates suggest that between 7 million and 23 million Americans – including 1 million who can no longer work – are suffering from the long-term effects of infection with the virus that causes COVID. Those numbers are expected to rise as COVID becomes an endemic disease.

A large Scottish study published this week in Nature Communications found that between six and 18 months after infection, 1 in 20 people had not recovered and 42 percent reported partial recovery. That study found that the risk of long COVID was greater among women, older people and those who live in economically disadvantaged communities.

The results of that study are compelling because it is so large. It included more than 33,000 people with laboratory-confirmed infections, along with 62,957 never-infected individuals.

Even people with mild infections can develop long covid, but experts say it is more common among people who are the sickest during the period of acute infection. People who have preexisting physical and mental health problems, such as respiratory disease and depression, are also more prone to long COVID.

Many experts see long COVID as a growing public health crisis.

What are the symptoms?

Long-hauler symptoms range widely from person to person. In the Scottish study, the most commonly reported symptoms were cardiovascular, including palpitations and chest pain; breathlessness; and “brain fog,” or reduced mental acuity.

Some people report lingering fatigue, tinnitus or ringing in their ears, and tremors that can be debilitating. Others, including Sen. Tim Kaine, D-Va., report recurrent pins-and-needles feelings.

Since July 2021, long COVID can be considered a disability under the Americans With Disabilities Act.

Long COVID can also strip away the equivalent of a decades’ worth of aerobic fitness, according to a large-scale new scientific review of long covid patients and exercise.

What are the big unanswered questions about long COVID?

There are many unanswered questions, including understanding the mechanism that causes these debilitating conditions. That is key to diagnosis and treatments.

Researchers do not know why only some people are affected – and whether there is a chance to reduce the risk of developing long-term problems.

Because the coronavirus has been with us for less than three years, researchers can’t yet tell how long the symptoms of long COVID will persist. Researchers in the Scottish study were able to follow up with participants six, 12 and 18 months after infection. Among them, 13 percent of people with long covid showed improvement between six and 18 months after infection, and investigators are trying to figure out the factors associated with that change

Another big outstanding question is how much protection vaccination offers. The Scottish study offers some optimistic data. But David Putrino, director of rehabilitation innovation for the Mount Sinai Health System in New York, said recent studies show that even though vaccination reduces the chance of developing long COVID, the protective effect was not as much as previously believed.

“That is one of the most important things we need to understand next,” Putrino said.

Are there promising treatments?

Researchers are considering many potential drugs and other strategies for treating long covid. But developing effective therapies depends on understanding the mechanism that causes it.

Some of these treatments seek to eradicate any persistence of the virus, others seek to modulate the immune system, others are designed to mitigate certain symptoms.

“The key is to start testing these approaches with rigorous methods so that we can determine if there are benefits and to define any risks,” Krumholz said. “Trials will be starting soon.”

Those trials will test whether specific interventions can improve people’s health and even restore their function and feeling to pre-infection days.

“They need to be done well,” Krumholz said, “because right now, so many people are trying novel therapies with very little evidence.”