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Long COVID Subtypes Linked to Overlapping Inflammation-Related Blood Protein Shifts

NEW YORK – A large international team led by investigators in the UK has uncovered blood-based inflammation patterns that overlap between, and distinguish, different forms of long COVID involving fatigue, cognitive, anxiety/depression, cardiorespiratory, and/or gastrointestinal features.

For a paper published in Nature Immunology on Monday, investigators profiled 368 inflammation- and immune system-related proteins in blood plasma samples from 657 individuals previously hospitalized due to SARS-CoV-2 infections, comparing patterns in 233 individuals who fully recovered within three months of acute COVID-19 with 426 individuals who had one or more symptoms of long COVID three or more months after the acute infection.

The participants were enrolled through a UK multicenter study known as PHOSP-COVID, and clinically assessed with the help of symptom questionnaires at sites across the UK roughly six months after being discharged from the hospital, co-senior and co-corresponding author Ryan Thwaites, a respiratory immunology lecturer at ICL, told reporters during an online press briefing today. Clinicians also collected blood samples from the patients, which were subsequently assessed using Olink proteomic assays.

"We reasoned that by connecting these clinical data, which were all about these patients' symptoms, and this immune signaling data, we could start to understand whether there was a biological basis for long COVID," Thwaites explained, "and particularly whether there were differences apparent between different symptom manifestations of long COVID."

Although the analyses focused on individuals who had been hospitalized with COVID-19, the study's authors noted that long COVID can occur in individuals who've had relatively mild infection with SARS-CoV-2 variants circulating recently.

And because long COVID has been estimated to impact some 65 million individuals globally, they suggested that such persistent symptoms are likely to contribute to "substantial long-term ill health, requiring targeted management based on an understanding of how disease phenotypes relate to underlying mechanisms."

"There's been so much interest in the delayed effects of viral infections in the aftermath of COVID, and it's really brought to the fore questions about why some people get delayed effects and others don't, and what are these delayed effects caused by," co-senior and co-corresponding author Peter Openshaw, an experimental medicine researcher with the Imperial College London's National Heart and Lung Institute, told reporters, noting that there is a need for treatments to mitigate such long-term symptoms, which are severe in some individuals and relatively transient in others.

Similarly, the team explained that long COVID has been linked to ongoing inflammation in prior studies, though the full suite of long COVID features and underlying disease mechanisms remain incompletely characterized.

Broadly speaking, the researchers saw signs that long COVID cases involved inflammation of white blood cell-forming myeloid cells in the bone marrow, along with higher-than-usual activity by complement immune proteins that typically respond to infection or cell damage. In contrast, long COVID-free individuals carried blood protein markers for tissue repair and immune regulation.

"Taking this together, we see that there may be evidence of abnormal, ongoing inflammation in people with persistent symptoms, and if there is adequate tissue repair and regulation of that inflammation, then that's associated with feeling recovered," co-author Felicity Liew, a clinical research fellow and respiratory registrar at ICL's National Heart and Lung Institute, told reporters.

When the team delved into blood protein profiles that coincided with specific sets of long COVID symptoms, meanwhile, it highlighted five, overlapping subtypes marked by fatigue, cognitive impairment, anxiety/depression, cardiorespiratory symptoms, or gastrointestinal features.

Fatigue was among the most common symptoms, Liew explained, noting that fatigue "commonly coexisted with symptoms of breathlessness and palpitations, [as in the] cardiorespiratory group, as well as people who have mental health presentations like anxiety and depression."

Among the blood protein shifts found in the long COVID cases enriched for fatigue features, for example, the team saw changes linked to elevated mucosal tissue inflammation and other immune responses more often associated with acute stages of disease.

Long COVID cases marked by gastrointestinal features tended to turn up in individuals with altered blood levels of a network of proteins that included MATN2, ISM1, and the irritable bowel syndrome-related protein SCG3, while investigators uncovered elevated levels of proteins such as the complement system player C1QA in the network associated with cognitive impairment symptoms.

In addition, their analyses highlighted still other protein shifts in individuals with long COVID who experienced a combination of cognitive impairment and gut-related symptoms, potentially reflecting changes to the brain-gut axis.

Although the authors noted that the current work "was not designed for biomarker discovery," they suggested that the tissue damage-related inflammatory signals identified may ultimately help in identifying, developing, and testing targeted treatment options.

"There is a lot of hope in the findings of the paper," Liew suggested, "because some of the pathways that we've highlighted already have treatments available that target those aspects of the immune system, and they're treatments that are licensed and shown to be safe in other conditions such as rheumatoid arthritis."

Members of the team are reportedly planning a proof-of-concept precision medicine study to test anti-IL-6 cytokine treatment in long COVID cases marked by demonstratively higher levels of inflammation, established by C-reactive protein testing.

"We're using many of the tools described here … to then try to understand the mechanisms further [and] hopefully find a treatment that might be valuable in some patients," Christopher Brightling, a University of Leicester respiratory medicine researcher involved in that study, explained during the briefing.