‘Common and unique immune features’ in long COVID may lead researchers to treatments
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Patients with long COVID symptoms demonstrate elevated levels of several inflammatory molecules — findings that could have important implications in both rheumatology and the search for a potential treatment for long COVID.
“Long COVID is a heterogenous disease, and patients report a wide diversity of symptoms and experiences,” Ryan Thwaites, PhD, of Imperial College London, told Healio. “Our work demonstrates that there are common and unique immune features of these different symptom types, relative to a cohort of patients that made a full recovery after hospitalization with COVID-19. A one-pill-fits-all approach to managing long COVID may be unlikely to succeed, but identifying common immune features between symptom groups may enable us to identify treatable traits for therapeutic targeting.”
The study, published recently by Thwaites and colleagues in Nature Immunology, saw the researchers profile 368 plasma proteins from 657 individuals who had been hospitalized with acute COVID-19 infection. The population was culled from the Post-hospitalization COVID-19 (PHOSP-COVID) study. The current analysis compared the outcomes of 426 patients with at least one long COVID symptom with those observed in the 233 patients who did not have symptoms.
According to the researchers, the results showed a correlation between long COVID and elevated markers of myeloid inflammation and complement activation. Patients with cardiorespiratory symptoms, fatigue and anxiety or depression reported higher levels of IL-1R2, MATN2 and COLEC12, while MATN2, CSF3 and C1QA were observed among patients experiencing gastrointestinal symptoms. C1QA was elevated in those who reported cognitive impairment.
Further analysis revealed associations suggesting a disturbance in the brain-gut axis. In addition, some patients with long COVID demonstrated persistent elevation of severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG).
The researchers suggested that these findings could help with long COVID phenotyping and, ultimately, aid future investigators in defining therapeutic targets.
Healio sat down with Thwaites to discuss the importance of categorizing long COVID symptoms, the need for therapies to treat this condition, and the implications of the findings in rheumatology.
Healio: Why did you decide to investigate these plasma proteins in the first place? What was the rationale and what were you looking for?
Thwaites: Plasma protein responses have proven to be useful research tools across a multitude of clinical syndromes and diseases. Modern approaches allow us to study the levels of hundreds of plasma proteins in parallel, enabling a holistic approach to studying the immunology underpinning disease.
We took similar approaches in studying acute COVID-19, and other groups have done similar work in long COVID. What made our study stand out was the scale we could achieve by working within the PHOSP-COVID study, and by seeking to understand the associations between an individual patient’s symptoms and the inflammation evident in their plasma.
Healio: Why did you only study patients who had been hospitalized?
Thwaites: In this study we recruited participants through the PHOSP-COVID study, which aimed to understand sequelae of SARS-CoV-2 after hospitalization. This was designed and initiated before we knew anything about long COVID, or the high rates of symptoms in people who suffered relatively milder acute COVID-19 and did not require hospitalization.
For our analysis we used the recovered group within our cohort as a control group to understand what immune mediators in the blood were associated with persistence of symptoms.
Healio: Are the inflammatory markers you observed from the innate or adaptive immune system, or both?
Thwaites: Our analysis found quite a strong signature for overlapping parts of the innate immune system, particularly myeloid inflammation and complement activation. We did also observe associations between some immune mediators associated with the adaptive immune system and some symptom types.
So, while the innate component is the strongest based on our data, it is likely that a dysregulated coordination between both innate and adaptive arms of immunity is associated with persistent symptoms after COVID-19.
Healio: There seems to be some uncertainty as to whether this ongoing inflammation is left over from acute COVID-19 infection or whether long COVID is something different, or independent of the infection. What you think is happening?
Thwaites: We specifically designed our analysis to try to understand whether any immune mediators elevated in the plasma were purely residual responses after infection. To do this, we included the acute COVID-19 disease severity within our analysis and found that heightened plasma proteins could not be explained as a consequence of having had more severe acute disease.
This implies that after equally severe acute infections, some people resolve inflammatory responses that are perpetuated in others. We think that by understanding the differences between these processes, including both immunopathogenesis and tissue repair, we can understand both what the immune system does wrong in long COVID, and what it does right in people who make full recoveries. In long COVID, there is evidently a persistent inflammatory immune response and a failure of tissue repair processes, but what drives this failure to resolve the immune response is still unclear.
Healio: The inflammatory markers you observed are associated with a number of clinical outcomes, from anxiety and depression to the brain-gut axis, to fatigue and cardiorespiratory symptoms. How are these symptoms potentially associated? Do you think it is important or worthy of further study to describe potential associations?
Thwaites: We found associations between different symptom types and groups of inflammatory markers. Many of these markers were similar between symptom groups, and crucially this relates to the experiences of patients with long COVID. Most participants in our cohort, and in other studies, report a variety of symptoms across different tissues. We believe that this implies a common immune mechanism between many different long COVID manifestations that disturbs different tissues, for example the gastrointestinal tract or the cardiorespiratory system.
The inflammation underpinning these symptoms could have knock-on effects on other tissues and account for the neurologic and cognitive symptoms we observe, or there could be independent mechanisms at play that affects these systems in parallel. In our analysis, we see a stronger association between some symptom types — such as fatigue and cardiorespiratory symptoms — and greater independence of others — for example, cognitive impairment or brain fog — which might imply different biological processes.
Healio: Can your findings help develop possible treatments for acute COVID-19 infection? If so, how?
Thwaites: Our work supports the determination that acute COVID-19 has a major element of immunopathogenesis, and it is possible that this immunopathogenesis has failed to resolve in patients with persistent symptoms. This immunopathogenesis has been successfully targeted with existing small-drug and monoclonal antibody treatments for severe COVID-19, but there is still much to learn about these processes that could result in new therapies.
Healio: What about treatments for long COVID?
Thwaites: Treatment of long COVID is an essential direction. Patients with long COVID are eagerly awaiting new trials and treatment options. Before we can make informed decisions about the best therapies that might be trialed, it is essential to have a biological rationale to inform drug candidate selection. This gives trials the best chance of success and exposes patients to the smallest degree of risk.
We think it will be essential for therapeutic trials to consider the symptom types of prospective participants, and to understand something about the underlying immune features of their disease. Our work suggests that a “one pill fits all” approach to treating long COVID may be unlikely to succeed.
Healio: Do you have another study planned to build on these results? If so, what direction will you take?
Thwaites: We are continuing to monitor the patients in our cohort and are collecting longitudinal blood samples through their post-COVID experience. Our immediate plans are to study the plasma proteins this study has identified in these new longitudinal samples, and determine whether the proteins change when symptoms diminish or resolve.
In addition, we are partnering with the REACT-Long COVID study consortium to collect samples from patients who experienced milder acute COVID-19, but did or did not develop long COVID. This will allow us to understand the plasma protein signature in patients with long COVID irrespective of their acute COVID-19 severity. This will be an important step in understanding the immunopathology in the majority of patients with long COVID that were not hospitalized with COVID-19. We hope that this work will lead to translations into clinic for designing trials to treat long COVID.
Reference:
Liew F, et al. Nat Immunol. 2024; doi:10.1038/s41590-024-01778-0.
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