The largest study of hospitalized COVID patients carried out in the UK to date has revealed people with long COVID may have patterns of inflammation that can be picked up in a blood sample. The patterns seem to mirror the collection of symptoms that each individual experiences, and could help doctors devise more effective treatments.

Long COVID, sometimes referred to by other names like post-COVID conditions, is a term that covers a whole range of symptoms that linger after someone has recovered from an initial COVID-19 infection. There’s been some debate around how common the condition is, but many still go by the estimate that one in 10 COVID-19 cases leads to some degree of long COVID.

Given how many infections with SARS-CoV-2 have been recorded since the start of the pandemic, even with the development of vaccines, that’s a lot of people contending with often debilitating long-term illness. 

“With one in ten SARS-CoV-2 infections leading to long COVID and an estimated 65 million people around the world suffering from ongoing symptoms, we urgently need more research to understand this condition,” said one of the lead investigators, Professor Peter Openshaw, in a statement. “At the moment, it’s very hard to diagnose and treat.”

As such, the new study led by a team at Imperial College London assessed a group of patients who’d been hospitalized with severe COVID-19 infection at least six months prior. While any COVID infection can lead to long-term symptoms, those with the most severe initial disease are thought to be most at risk.

Of these patients, 426 were experiencing symptoms of long COVID, whereas 233 had fully recovered. The team analyzed samples of blood plasma, looking at 368 separate proteins known to be involved in immunity and inflammation.

Compared with the patients who had fully recovered, the long COVID patients had detectable patterns of blood markers consistent with ongoing immune system activation. These included markers of inflammation in the myeloid cells of the bone marrow, which give rise to white blood cells, as well as a cascade of interlinked proteins called the complement system. Complement is fired up whenever there is infection or tissue damage in the body, and it’s known to be associated with numerous autoimmune diseases.

“It is unusual to find evidence of ongoing complement activation several months after acute infection has resolved, suggesting that long COVID symptoms are a result of active inflammation,” explained first author Dr Felicity Liew. 

It was even possible to link certain patterns of these blood markers with different symptom groups. Long COVID has been associated with a huge range of effects on many different systems within the body, but this analysis revealed five distinct signatures: 

• fatigue
• cognitive impairment
• anxiety and depression
• cardiorespiratory
• gastrointestinal

While people can fall into more than one group, this information could still be helpful when it comes to designing trials for more targeted treatments. The team highlights a class of drugs called IL-1 antagonists, which are currently used to treat rheumatoid arthritis, but target components of the immune system that appear to be activated in some subtypes of long COVID.

There are some limitations that the team address. As Dr Liew points out, “we can’t be sure that this is applicable to all types of long COVID, especially if symptoms occur after non-hospitalized infection.” 

But a key takeaway, according to Professor Openshaw, is the clear need for an even greater understanding of the intricacies of long COVID: “This work provides strong evidence that long COVID is caused by post-viral inflammation but shows layers of complexity.”

“We hope that our work opens the way to the development of specific tests and treatments for the various types of long COVID and believe that a ‘one size fits all’ approach to treatment may not work.”

The study is published in the journal Nature Immunology.