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

Baillie, Kirsten, Davies, Helen E., Keat, Samuel B. K., Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Miners, Kelly L., Jones, Samantha A., Mellou, Ermioni, Toonen, Erik J. M., Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676 and Zelek, Wioleta M. 2024. Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID. Med 5 (3) , pp. 239-253. 10.1016/j.medj.2024.01.011

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Abstract

Background Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with 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/sex/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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	2666-6340
Funders:	UK DRI
Date of First Compliant Deposit:	19 February 2024
Date of Acceptance:	22 January 2024
Last Modified:	08 Apr 2024 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/166328

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