Is long COVID forever? A new study has clues.

A new study shows that an abnormally active immune system, a characteristic of long COVID patients, largely subsides two years after the initial infection. The finding offers hope that gradual recovery is possible in some long COVID patients.

One in 10 COVID-19 patients, even those with a mild infection, suffer from a range of symptoms such as fatigue, brain fog, shortness of breath, heart palpitations, and depression. These lingering symptoms collectively called long COVID are now recognized as disability under the Americans with Disabilities Act and can continue for weeks, months, or even years.

While scientists don’t know what causes long COVID, a hyperactive immune system appears to play a major role in persistent symptoms. A new study, published in Nature Communications, now shows that this heightened immune response calms down in long COVID patients 24 months after initial infection.

"It looks like those people's immune systems have largely returned to what we would expect," says Gail Matthews, an infectious disease physician at St Vincent's Hospital, Sydney, who led the study. "And that's really good."

(Why does COVID-19 cause brain fog? Scientists may finally have an answer.)

The study doesn't explain why some long COVID patients did not get better, but this could be due to other underlying health conditions, says Matthews. However, there is evidence of significant improvements in both immunological disturbances and the self-reported health of many patients two years post-COVID.

"It's good news for those with long COVID that there seems to be resolution of not only immune perturbations but also symptoms over time," says Nadia Roan, an immunologist at The J. David Gladstone Institutes at the University of California San Francisco.

The blood markers of long COVID

Scientists at the Kirby Institute, UNSW Sydney, began collecting blood samples from some COVID-19 patients in April 2020 when the first wave of the pandemic hit Australia. These patients regularly self-report their health information and were not vaccinated when they got COVID-19 because the shots were not available in Australia until early 2021.

In 2022, scientists found that immune-system molecules related to inflammation remained abnormally high in the blood of patients who felt fatigue, shortness of breath, or chest pain, eight months after infection. The levels of these molecules, called cytokines, should return to normal levels within 30-90 days after recovering from the initial viral infection.

You May Also Like

SCIENCE

What causes long COVID? The answer might be in your gut

SCIENCE

How long does COVID-19 linger in your body? New report offers clues.

SCIENCE

Could viruses cause Alzheimer's? COVID-19 brain studies offer new clues.

"It was quite surprising for us to see that even after mild to moderate COVID-19, the inflammatory biomarkers were high up until eight months for long COVID patients," says Chansavath Phetsouphanh, an immunologist at the Kirby Institute, UNSW Sydney. Phetsouphanh led the study that first hinted at a prolonged abnormal immune response in people who had long COVID compared to those who had been infected with SARS-CoV-2 and fully recovered. The biomarkers included molecules that activate immune cells—called T cells—and trigger inflammation.

In their recent study, the scientists followed up on 62 of the long COVID patients for an additional one and a half years and found that biomarkers previously indicating abnormal immune function in their blood samples had largely fallen to normal levels. They found no difference in the blood inflammatory biomarkers between the recovered long COVID patients and those who had never reported any long COVID symptoms.

"It is a well-done study [that] does show that some people can improve immune function over time," says Timothy Henrich, a professor of medicine at the University of California San Francisco.

There are other causes of long COVID

While the Nature Communications study builds on previously identified biomarker signatures that predicted the persistence of long COVID symptoms at eight months, Wolfram Ruf, an immunologist at Johannes Gutenberg University Medical Center in Mainz, Germany, says other immune markers that have also been linked to long COVID were not taken into consideration in this recent study.

For example, the study team didn’t address the overactivation of the "complement" part of the immune system—which protects the body from infection and inflammation—and has been implicated in causing long COVID. Similarly, the team did not assess the abnormal blood clotting or coagulation system, which has also been shown to cause some long COVID symptoms.

(Long COVID can destroy your ability to exercise. Now we know why.)

While 62 percent of the patients in the Australian study also reported improved health during the follow-up period, the rest of the cohort claimed that long COVID was still curbing the quality of life despite an improved inflammation biomarker profile.

"We want to be really careful not to dismiss the fact that some people did not recover," says Matthews. This could be because there are other causes of long COVID; the persistence of SARS-CoV-2 virus; reactivation of other dormant viruses; the formation of autoantibodies that attack a person’s own organs and tissues; or disturbed gut microbes.

"The immunological basis for long COVID does not explain all the symptoms, and we know that long COVID is a basket of potential different diagnoses," says Matthews.

Other studies involving more patients, such as the National Institutes of Health's RECOVER Initiative, are expected to reveal why symptoms do not resolve years after initial infection in many people with long COVID.

"Immune perturbations are clearly associated with long COVID,” says Roan. "Whether they drive it is still an open question."