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

• Published in: Med (New York, N.Y. : Online) Vol. 5; no. 3; pp. 239 - 253.e5
• Main Authors: Baillie, Kirsten, Davies, Helen E., Keat, Samuel B.K., Ladell, Kristin, Miners, Kelly L., Jones, Samantha A., Mellou, Ermioni, Toonen, Erik J.M., Price, David A., Morgan, B. Paul, Zelek, Wioleta M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2024
• Subjects: biomarkers of disease; Complement C3b; complement system; Complement System Proteins - metabolism; COVID-19 - epidemiology; Humans; long COVID; Post-Acute COVID-19 Syndrome; SARS-CoV-2; biomarkers of disease; long COVID; Translation to patients; complement system
• ISSN: 2666-6340; 2666-6340
• DOI: 10.1016/j.medj.2024.01.011

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. 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. 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. 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. This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute. [Display omitted] •Complement dysregulation is a hallmark of long COVID•Complement biomarkers associate with the diagnosis of long COVID•Complement inhibition is a potential therapy for long COVID SARS-CoV-2 has left a global legacy of ill health, commonly known as long COVID. Although the causes of this new disease remain largely unknown, emerging evidence suggests an important role for chronic inflammation. In this study, researchers at Cardiff University show that overactivation of the complement system, a series of proinflammatory proteins circulating throughout the body, frequently associates with the clinical diagnosis of long COVID. The authors speculate that currently licensed inhibitors of complement activation could be repurposed to reduce systemic inflammation and counteract the associated illness in selected patients with long COVID. Long COVID is a heterogeneous and poorly understood illness triggered by infection with SARS-CoV-2. In this study, Baillie et al. show that complement dysregulation, a known driver of systemic inflammation, is a common and highly indicative feature of long COVID.