An infection from the omicron variant is significantly less likely to lead to long Covid than an infection from the delta variant, according to a new study published in The Lancet—new findings that add to the growing body of research looking into the potential causes of the chronic condition.

Case study: Recovery clinics for Covid-19 long-haulers

Omicron less likely to lead to long Covid, research suggests

For the study, researchers used self-reported data from the U.K. ZOE Health Study COVID symptom app to compare adults who had tested positive for either the omicron or delta variants and their symptoms.

In total, the researchers identified 56,003 people who were infected by the omicron variant between Dec. 20, 2021, and March 9, 2022, and 41,361 people who were infected by the delta variant between June 1, 2021, and Nov. 27, 2021. All patients had been vaccinated prior to infection.

Among the omicron group, 2,501 people, or around 4.5%, reported new or ongoing symptoms four weeks after their initial infection. In comparison, 4,469 people, or 10.8%, in the delta group reported new or ongoing symptoms four weeks post-infection.

Overall, the researchers found that risk of long Covid among those who were infected with omicron was roughly 20% to 50% lower than those who were infected with delta. Although the study did not address why omicron may be less likely to lead to long Covid, the researchers suggested that omicron's reduced severity compared to delta may be factor.

However, despite a reduced risk of long Covid from omicron, the researchers said the overall potential burden of the chronic condition remains high.

"The caveat is that the omicron variant has spread very rapidly through our populations, and therefore a very much larger number of people have been affected. So the overall absolute number of people who are set to go on to get long COVID, sadly, is set to rise," said Claire Steves, a researcher at King's College London and the study's lead author. "So it's certainly not a time for us to reduce services for long COVID."

"Ultimately, we need a vaccine that can prevent infection or at least reduce the amount of replicating virus upon infection to prevent long COVID," said Akiko Iwasaki, an immunobiologist at Yale School of Medicine. "This would require mucosal immunity induced by nasal vaccines."

3 potential theories behind long Covid

Although a definitive cause of long Covid has not yet been determined, researchers from around the world have offered three potential theories regarding what might cause the chronic condition.

1. Damage to blood vessels and clots

According to Danilo Buonsenso, a pediatric infectious disease physician in Italy, some long Covid patients may have damage to the cells and tissues that control blood flow, which increases the risk of blood clots.

Using a sophisticated medical imaging technique called a SPECT-CT scan, Buonsenso scanned the lungs of 11 children who had severe long Covid to examine the structure of their lungs. In five of the children, the scans showed large areas of the lungs with little to no blood flow, which Buonsenso believes may be due to tiny blood clots or damage to blood vessel linings.

So far, Buonsenso and his colleagues have published their research in The Lancet Child & Adolescent Health, and other research is ongoing to determine whether healthy Covid-19 survivors also have blood vessel damage or if apheresis, a technique that filters blood and reinfuses it, may improve symptoms for long Covid patients with microclots in their blood plasma.

2. Lingering viral particles

Another potential hypothesis is that lingering coronavirus particles may be driving symptoms for some long Covid patients.

According to Amy Proal, a microbiologist at the PolyBio Research Foundation in Washington state, several studies have shown "the virus is capable of persistence in a wide range of body sites," including the nerves and other tissues.

For example, a study published in Gastroenterology examined 46 patients who previously had Covid-19, 21 of whom reported at least one symptom of long Covid. Of the patients, all 21 who had long Covid had either viral RNA or viral proteins. In addition, 11 other patients who had recovered from Covid-19 without lingering symptoms also had traces of the coronavirus in their bodies.

Currently, Proal and her colleagues are working to definitively connect lingering viral particles to long Covid symptoms. One of the team's planned studies will use colonoscopies to look for the coronavirus in patient's intestinal cells. They also want to examine immune cells in the region to see if they are being set off by viral particles.

3. An overactive immune response

Finally, some researchers posit that coronavirus infection can destabilize some patients' immune systems, leading to overactive immune responses that linger months later.

In a study published in Nature Immunology, researchers examined blood samples from 31 long Covid patients who were experiencing symptoms at least three months after their initial infection. Overall, the researchers found that the patients' levels of interferons, or proteins made to fight off infections, remained high even eight months after infection, and many of their T cells and b cells were still activated—all of which likely led to chronic inflammation and other health problems.

"It was a surprise that these cells did not recover," said Chansavath Phetsouphanh, an immunologist from the University of New South Wales, Sydney and one of the study's authors.

Although research on long Covid is still evolving, most researchers agree that "solo operators," or a single cause, of the condition is unlikely.

"I see this [the causes of long Covid] as a triangle," Buonsenso said, with each potential cause potentially explaining or amplifying the others. (Stein, "Shots," NPR, 6/16; Sullivan, The Hill, 6/17; George, MedPage Today, 6/17; Edwards, NBC News, 6/16; Carbajal/Gleeson, Becker's Hospital Review, 6/17; Couzin-Frankel, Science, 6/16)