What predicts long-COVID? Study led by Seattle researchers provides some answers

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ISB president James Heath. (ISB Photo)

What makes some people with COVID-19 develop the often-debilitating symptoms of long-COVID, with its varying symptoms like brain fog, weakness and fatigue? A new study led by researchers at Seattle’s Institute for Systems Biology provides some answers, identifying factors that may predict which patients go on to suffer from longer-term disease.

The researchers closely followed a group of 209 COVID-19 patients, seen at Swedish Medical Center or affiliated clinics. Their symptoms were tracked until two to three months after diagnosis and their blood analyzed for everything from immune cell composition to antibody types.

The researchers also performed some of their analyses on a separate group of 100 COVID-19 patients. The study is an “in depth assessment,” said Eric Topol, a professor of molecular medicine at Scripps Research, in a tweet. The data was compared to results from healthy people.

The researchers report that four factors present at initial diagnosis anticipated the development of long-COVID. Pre-existing Type 2 diabetes predicted the condition, as did the presence of certain “autoantibodies” that attack the body, commonly found in auto-immune diseases like lupus. Some of those antibodies may affect the immune system and interfere with the ability to combat COVID-19, said lead author and ISB president James Heath in an interview with GeekWire.

A third factor was the presence of COVID-19 RNA in the blood, instead of just the saliva, which occurred in 25% of patients.

A fourth factor involved another virus, Epstein Barr virus, which is present in about 90% of people, but generally lies in a quiet state inside cells. Fourteen percent of patients had evidence of active Epstein Barr virus in their blood, as detected by DNA, and those patients were more prone to develop long-COVID. “It appears that the COVID infection in some patients can wake up that virus,” said Heath.

Epstein Barr virus, which is the cause of mononucleosis, “mono,” is associated with fatigue. Long-COVID has a patchwork of symptoms, from gastrointestinal problems to loss of smell, but fatigue is the most common, said Heath. The link with Epstein Barr virus is consistent with another study suggesting it “wakes up” in people who go on to develop long-COVID.  

Overall, people with long-COVID showed signs “in general” of highly active immune system activity, said Heath, consistent with other studies. The researchers were also able to place people with long-COVID into different categories based on their mix of immune cells and other measurements.

The new study suggests avenues for future research on ways to prevent or combat long-COVID.

Antivirals might help ward off long-COVID, given the signs of COVID-19 or Epstein Barr virus in patients’ blood, noted the researchers. Some patients with long-COVID had low levels of the hormone cortisol, suggesting that cortisol replacement therapy could be explored.

“Lupus treatments may likely have high relevance,” added Heath. “That is an excellent area for further exploration.” Biotech company Resolve Therapeutics is testing that question with an experimental drug against Lupus in a clinical trial for long-COVID, administered through Fred Hutchinson Cancer Research Center.

James Heath and his colleagues discuss their new findings on long-COVID.

Estimates vary of the prevalence of long-COVID. One recent analysis of 57 studies found that more than half of the COVID-19 survivors, on average, had at least one symptom at 2-to-5 months. The analysis of prevalence, however, involved mainly hospitalized, unvaccinated individuals earlier in the pandemic.

Ultimately most people’s symptoms resolve, said Heath. But he estimates that about 10% have longer-term problems persisting from six months out to a year, and others struggle longer.

Studies assessing the effectiveness of vaccines at preventing long-COVID are only recently emerging. One recent study analyzed COVID-19 in healthcare workers who received two doses of the Pfizer/BioNTech vaccine; 19% of those with a “breakthrough” infection showed persistent symptoms at six weeks.

Larger studies are needed to back up the new study and to explore options for treatments.

The study was published Tuesday in the journal Cell and involved researchers at other institutions, including Swedish Medical Center, Fred Hutchinson Cancer Research Center, and the University of Washington. Researchers at Seattle biotech company Adaptive Biotechnologies also contributed.

Other recent studies from Seattle researchers have investigated questions such as the response to vaccines and how the virus evades immunity. Some of those studies are listed below.

  • Researchers in the lab of David Veesler at the University of Washington have been particularly busy lately. In Science, he and his colleagues looked at how the Delta and Kappa variants appear to have evolved to evade recognition by antibodies.
  • Veesler and colleagues also took a close look at how an antibody that is the basis sotrovimab, a COVID-19 treatment, binds to its target in the body.The findings, published this week in Science, help explain why other antibody treatments work poorly against Omicron.
  • The Veesler lab also led a project to identify a human antibody that has the potential to be developed into a therapy that could thwart a wide range of COVID-19-causing and other coronaviruses.
  • The UW researchers also recently explored the antibody response in people with breakthrough infections with the Omicron and other variants. They examined responses after vaccination, infection, or a mixture of the two in a study in Cell.
  • At Fred Hutch, researchers led by Leu Ping Zhao identified mutations in COVID-19 viruses from early in the pandemic that appear to have increased the chance of severe disease.
  • James Heath and his colleagues also recently showed that COVID-19 infection increases the risk of preterm birth, low birth weight and stillbirth in pregnant women.





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