In May 2023, the World Health Organization (WHO) declared the COVID-19 global health emergency over. 

Yet millions of people still experience fatigue, breathlessness and pain, years after having a COVID-19 infection. By some estimates, 400 million people had or still have post-COVID-19 syndrome, a condition better known as long COVID.

Scientists have struggled to find the causes of long COVID since the first cases of chronic symptoms emerged in late 2020. Clinicians still lack the tools to treat the disease.

Now, a new study published in the journal Science has discovered lung inflammation is a major cause. Data in mice and humans found infection with the SARS-CoV-2 virus, which causes COVID-19, impairs the ability of immune cells to repair lung damage. 

The study gives hope in treating long COVID, although further testing is required for the treatment to reach clinics.

"We demonstrated that an FDA-approved drug can enhance lung recovery and reduce long COVID-related tissue damage," said study lead author Jie Sun, an immunologist at the University of Virginia in the US.

COVID-19 impairs lung regeneration

"Long COVID presents a wide range of symptoms, and its underlying cellular and molecular mechanisms are highly complex," said Sun.

"One of the most significant gaps is identifying the specific mechanisms driving different types of long COVID. Understanding these drivers is crucial for developing targeted therapeutic strategies."

In searching for a true driver of long COVID, Sun and his collaborators analyzed lung samples from people with long COVID and mice given the disease. 

"We discovered that lung tissue from individuals who succumbed to acute COVID or suffered from severe respiratory long COVID exhibited decreased levels of peroxisomes in a type of immune cell responsible for tissue healing," said Sun.

Peroxisomes are tiny organelles inside immune cells. They are detox centers that remove toxic molecules and help tissues to heal after being damaged.

The study found peroxisomes play a crucial role in the rapid regeneration of damaged lung tissue.

"This research suggests that SARS-CoV-2 leads to dysfunctional peroxisomes. This, in turn, leads to impaired healing and scarring after infection —leading to long-term symptoms," said Ziyad Al-Aly, a senior clinical epidemiologist and long COVID researcher at Washington University in St. Louis, US.

Potential long COVID treatment needs further testing

The researchers looked for existing drugs that could reverse the lung damage caused by a COVID-19 infection and focused on drugs that boost the function of peroxisomes — which they hoped would improve lung repair.

Treating COVID-19 infected with a drug called sodium 4-phenylbutyrate (4-PBA) led to increased peroxisomes and reduced lung scarring. The researchers said this provides evidence the drug could help treat people with prolonged lung damage due to long COVID. 

"Given the significant number of affected individuals, this represents a promising therapeutic avenue," said Sun.

The benefit of 4-PBA is it is already approved by drug regulators like the US Food and Drug Administration (FDA) to treat urea cycle disorders. This means it has already been deemed safe to use as a treatment in humans, which could accelerate clinical trials testing it for long COVID.

However, Al-Aly, who was not involved in the study, warned findings in mice do not always translate to humans.

"Whether this works in mild COVID and whether it works in humans is not known. There is a clear need to evaluate this in humans," he said.

Long COVID has many causes

Sun said their discovery of lung inflammation as a driver of long COVID is important, but acknowledged there are other changes in the body after a COVID-19 infection that can cause long COVID. 

 "Long COVID is a highly heterogeneous condition, and different subtypes may involve distinct underlying mechanisms," Sun said.

Some of those drivers include viral reservoirs that continuously stimulate the immune system, microbiome imbalances, reactivation of latent viruses and blood clotting abnormalities. 

These mechanisms might all be interacting to cause long COVID symptoms. If one of the drivers is treated, it might be able to stop long COVID. 

Al-Aly said the study is part of a mobilization of scientists making significant progress on long COVID since 2020. 

"While we have not completely solved the puzzle of long COVID, we have made significant progress in just five years. The amount of progress made is huge in a relatively short amount of time," he said.

This research is critical, he said, as millions of people with long COVID are not fully recovered and are still struggling with symptoms.

Edited by: Matthew Ward Agius

Source:

Long COVID science, research and policy