Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

  1. Kirsten Baillie
  2. Helen E Davies
  3. Samuel B K Keat
  4. Kristin Ladell
  5. Kelly L Miners
  6. Samantha A Jones
  7. Ermioni Mellou
  8. Erik J M Toonen
  9. David A Price
  10. B Paul Morgan
  11. Wioleta M Zelek

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Abstract

Background

Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.

Methods

We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID.

Findings

Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.

Conclusions

These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.

Funding

This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10258923.

    Does the introduction explain the objective of the research presented in the preprint? Yes The introduction emphasizes the idea that complement dysregulation is important in the pathogenesis of long COVID. The researchers state that the SARS-CoV-2 pandemic left many people struggling with long COVID and symptoms that included cognitive blunting, chest pain, fatigue, etc. The researchers also mention there is a socioeconomic consequence because of long COVID but do not add specific details on why this is or why this is important. Despite this, the researchers still manage to explain the objective of analyzing the complement system in plasma samples of a wide range of individuals.
    Are the methods well-suited for this research? Highly appropriate -The methods are well-suited for this research because they use a control group that does not have long COVID and compare it to an experimental group with long COVID. -To see whether or not complement system dysregulation was an indication of what causes long COVID blood samples were taken from the groups with the plasma being immediately removed. -When analyzing the data, various factors were taken into consideration, including immunoassays, the anti-RBD IgG assay, and haemolytic assays. Three confounding variables were considered: age, gender, and BMI, which may help eliminate confounding variables but raise the question of whether or not other confounders may have played a role in the data.
    Are the conclusions supported by the data? Highly supported -The conclusion that complement system dysregulation may cause long COVID is supported by the data as C1s-C1INH was elevated compared to the control. The data also shows that complement components and regulators are altered in patients with long COVID, strengthening the argument that complement system dysregulation impacts long COVID.
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear -The data presentations and visualizations are well-suited to represent the data because they accurately display the data in a visual setting. Each figure or data table has a brief description accurately explaining the visual included below. -However certain figures, particularly figure 4, show a high volume of dots that are hard to interpret even when zoomed in on the full image. This takes away from the data the researchers are attempting to convey becuase of a lack of clarity in what the data is representing.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly -The authors clearly state the findings of their research stating that complement dysregulation and inflammatory response is a cause of long COVID. -The researchers also clearly explain that going forward, it is important to test drugs such as pegcetacoplan, iptacopan, and vemircopan to target the alternative pathway. This is clearly communicated and shows a direct plan of action to continue the research they have done on long COVID.
    Is the preprint likely to advance academic knowledge? Highly likely This preprint is likely to advance scientific knowledge because as of today, very little is known about what is the cause of long COVID. This paper shines light onto the possible correlation between complement dysregulation and long COVID. The paper also gives possible solutions, all of which will work to advance healthcare and academic knowledge as a whole.
    Would it benefit from language editing? No The language used in this paper is clear and concise and provides direct evidence for their findings.
    Would you recommend this preprint to others? Yes, it's of high quality I would recommend this prepirnt to others. The language, though technical at times, is clear and gives valuable insight into the actual cause of long COVID.
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is This preprint is ready for attention from an editor, publisher, or broader audience. The preprint cohesively brings together data to support its claim that complement dysregulation is a major contributing factor for long COVID. The researchers provide valuable insight into a relevant topic in modern day healthcare.

    Competing interests

    The author declares that they have no competing interests.

  2. Rapid Reviews Infectious Diseases

    Amod Kulkarni

    Review 2: "Complement Dysregulation is a Predictive and Therapeutically Amenable Feature of Long COVID"

    Reviewers found this preprint to be reliable or strong, and investigating an under-studied area of COVID-19 research. According to reviewers, the methods were overall thorough and the paper well-developed.

  3. Rapid Reviews Infectious Diseases

    Steven Sacks

    Review 1: "Complement Dysregulation is a Predictive and Therapeutically Amenable Feature of Long COVID"

    Reviewers found this preprint to be reliable or strong, and investigating an under-studied area of COVID-19 research. According to reviewers, the methods were overall thorough and the paper well-developed.

  5. Version published to 10.1101/2023.10.26.23297597v1 on medRxiv