Summary: Researchers have advanced our understanding of long COVID by identifying distinct inflammatory signatures in the blood of people who were hospitalised with severe SARS-CoV-2 infection. In the largest UK study of its kind, involving more than 650 participants, investigators found persistent immune activation months after acute illness and identified patterns of inflammation that correlate with different symptom clusters, pointing toward more precise diagnostic and treatment approaches.
These findings open the possibility of repurposing existing immune-modulating drugs to treat long COVID and support the design of targeted clinical trials. The study highlights the complexity of the condition and the need for tailored therapies to address diverse biological pathways underlying long COVID symptoms.
Key Facts:
- Long COVID is associated with detectable, ongoing inflammation in the blood; inflammatory patterns differ by primary symptom cluster, indicating the need for personalized treatment strategies.
- Existing immune-modulating drugs, including IL‑1 antagonists (for example, anakinra) and JAK inhibitors, target pathways suggested by the study and could be evaluated in clinical trials.
- The study focused on people hospitalised with severe COVID-19, so its findings may not fully represent long COVID after mild or non-hospitalised infections.
Source: Imperial College London
People with long COVID show distinct inflammatory patterns in blood that may be amenable to immune-targeted therapies.
An analysis of more than 650 people hospitalised with COVID-19 found that individuals reporting ongoing symptoms months after discharge exhibited clear signs of immune activation in blood plasma. The pattern of inflammatory proteins differed by the dominant symptom group—such as fatigue, cognitive problems, cardiorespiratory complaints, gastrointestinal issues, or mood disturbances—revealing biological differences between symptom clusters.
Led by Imperial College London and published in Nature Immunology, the research was carried out by two UK-wide consortia, PHOSP-COVID and ISARIC-4C, with collaborators across multiple institutions and funding from UK Research and Innovation (UKRI) and the National Institute for Health and Care Research (NIHR).
Professor Peter Openshaw of Imperial’s National Heart & Lung Institute, an ISARIC-4C lead investigator, stressed the urgency of better diagnostics and treatments, noting that around one in ten SARS-CoV-2 infections lead to long COVID and that millions worldwide continue to suffer persistent symptoms. The team combined detailed clinical symptom data with broad plasma protein profiling to reveal biological signals associated with prolonged illness.
Inflammation months after acute infection
The study compared 426 participants who reported at least one long COVID symptom with 233 individuals who had recovered fully following hospitalisation. Researchers measured 368 plasma proteins known to relate to inflammation and immune regulation. Compared with recovered individuals, those with long COVID showed elevated markers indicating myeloid-cell inflammation and activation of the complement system—an immune cascade that, when overactivated, can contribute to autoimmune and inflammatory disease.
Myeloid cells, derived from bone marrow, include several types of white blood cells that respond to infection or tissue damage. The sustained complement activation observed months after recovery is unusual and suggests active inflammatory processes may underlie persistent symptoms rather than purely post-infectious fatigue without ongoing immune engagement.
Dr Felicity Liew from Imperial’s National Heart & Lung Institute commented that complement activation and myeloid inflammation appeared to be common features of long COVID after hospitalisation, while cautioning that these findings may not apply to people whose long COVID followed milder infections.
Distinct biological subtypes
By linking detailed symptom profiles to plasma protein levels, the researchers identified five overlapping mechanistic subtypes of long COVID: fatigue, cognitive impairment, anxiety and depression, cardiorespiratory, and gastrointestinal. These groups are not mutually exclusive—many people experience symptoms that span subtypes—but each subtype displayed characteristic protein signatures. For instance, the gastrointestinal group had higher levels of SCG3, a marker previously implicated in gut–brain communication.
Markers associated with nerve tissue repair (such as SPON‑1 and NFASC) were elevated in participants with cognitive impairment, while other proteins (for example IL‑1R2, MATN2, COLEC12, CSF3, and C1QA) linked to tissue damage and immune activation showed associations with specific symptom clusters, including cardiorespiratory complaints, fatigue and mood symptoms.
Some individuals with long COVID also retained elevated levels of SARS‑CoV‑2–specific IgG antibodies, though viral RNA was not detected in sputum samples. Analysis of inflammatory markers in nasal fluid did not show clear links to symptom profiles in this cohort.
These distinct biological signatures suggest that different inflammatory pathways and tissue-damage responses drive specific long COVID phenotypes, supporting a move away from a one-size-fits-all approach toward targeted trials of immune-directed therapies.
Therapeutic implications and limitations
Because the study points to complement and myeloid-driven inflammation, the authors propose that drugs already used to modulate the immune system—such as IL‑1 antagonists (for example anakinra) and JAK inhibitors—merit investigation in clinical trials for long COVID. These agents target components of the immune response implicated by the plasma protein profiles.
A key limitation is that the cohort consisted of people hospitalised with severe COVID-19; many individuals with long COVID in the wider population had mild initial illness, so further research will be needed to determine whether the same immune mechanisms apply more broadly.
Professor Openshaw concluded that the work provides strong evidence for a role of post‑viral inflammation in long COVID while revealing multiple layers of complexity. He emphasized the importance of developing specific tests and treatments tailored to the various mechanistic subtypes rather than relying on a single universal therapy.
The PHOSP‑COVD and ISARIC4C consortia are funded by UK Research and Innovation (UKRI) and the National Institute for Health and Care Research (NIHR) and include partner institutions across the UK.
About this long-COVID research news
Author: Ryan O’Hare
Source: Imperial College London
Contact: Ryan O’Hare – Imperial College London
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation” by Peter Openshaw et al. Nature Immunology
Abstract
Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation
One in ten SARS‑CoV‑2 infections results in prolonged symptoms known as long COVID, yet disease phenotypes and mechanisms remain poorly understood. The authors profiled 368 plasma proteins in 657 participants at least three months after hospitalisation; 426 reported at least one long COVID symptom and 233 had fully recovered.
Elevated markers of myeloid inflammation and complement activation were linked to long COVID. Specific proteins—IL‑1R2, MATN2 and COLEC12—were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms; and C1QA was elevated in cognitive impairment.
Markers of nerve tissue repair (SPON‑1 and NFASC) were increased in those with cognitive impairment, while SCG3, suggestive of disturbances in the brain–gut axis, was elevated in gastrointestinal symptoms. Some people with long COVID had persistently raised SARS‑CoV‑2–specific IgG, though virus was not detected in sputum. Nasal inflammatory markers showed no clear association with symptoms.
The study focused on inflammatory processes underlying long COVID and was not designed as a biomarker discovery project. Findings indicate that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID and could be targeted in future therapeutic trials.