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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.

Published onNov 28, 2023
Review 1: "Complement Dysregulation is a Predictive and Therapeutically Amenable Feature of Long COVID"
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key-enterThis Pub is a Review of
Complement dysregulation is a predictive and therapeutically amenable feature of long COVID
Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

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.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



This is an observational study highlighting that the complement system is active in the chronic symptomatic post-infectious phase of SARS-CoV2 when compared with convalescent asymptomatic post SARS-CoV-2 controls. Eligible patients are claimed to have no underlying co-morbidities that could have confounded the findings. 

The results of this manuscript highlight differences in the classical, alternative, and terminal pathways of complement activation and their regulators at least 12 weeks after the initial COVID-19 diagnosis, consistent with ongoing activity of inflammation. These differences are not explained by ethnicity. Nor were they explained by comorbidity except for obesity, which was more prevalent in the Long COVID-19 group. 

The study is limited by the lack of understanding of what was driving the complement cascade. Could it be part of a reparative process following more severe infection or a sign of lasting tissue pathology, and therefore inform whether the activity of the complement system is bystander or contributing? There are no obvious clues provided about where complement activation is taking place. That is, whether complement is being triggered at the seat of the primary lung infection or reflective or multisystem involvement.

Authors advocate an interventional study where choice of complement inhibitor is rationalized on the pathway-specific abnormalities defined by their analysis. This seems a reasonable proposition. A therapeutic probing study may help to solve the matter of causal relationship. The parameters so thoroughly investigated might also provide an early response signal to predict long-term benefit. 

The set of inflammatory markers identified in this study not only provide evidence of ongoing inflammation in long COVID19, but they also provide a druggable target with a view to improving recovery from the chronic condition. 

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