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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.

Published onNov 28, 2023
Review 2: "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:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



This original research work discuss the double-edged role of complement proteins, so-called immune soldiers in our body, and also highlights the need to control the same in patients suffering from the long COVID.

This is an interesting piece of work on relatively less explored field of dysregulation of the complement system in long COVID. The main study claims are very well-justified by the data and analytic methods and the study’s main claims are conclusive and actionable without reservation. The authors have meticulously put their original scientific work, and discussed the shortcomings of their study. Summary of my review is outlined below:

  1. The manuscript adds value to the current understanding of inflammation and the role played by the complement system. The manuscript is well positioned and has cited own work and the work of the other research groups with clear actions and recommendations out of their own research work and the study was performed with due attention to the ethics, diversity, and inclusion and is thus in alignment with the journal’s publication goals. 

  2. Briefly, significant differences in the levels of complement proteins, including anaphylatoxins and terminal complement components between the control group (healthy convalescents) and the long COVID cases, are reported based on the P values well below 0.5 and / or other statistical means. 

  3. Despite elevation of the levels of the complement regulatory proteins, there are no complement regulatory agents being tried to treat long COVID cases. We have also discussed briefly about the need for the development of complement regulatory agents to control upregulation of the complement system in our recently published article on the cytokine storm in COVID-19 patients. Authors have aptly showed the need to develop complement regulatory agents in the long COVID patients. However, I feel that not just the alternate pathway, but the classical pathway regulators may also work. Further study is required in this direction. 

  4. Excellent data representation with the meticulous data analyses and inclusion of self-explanatory plots/figures 

However, there are some suggestions/recommendations:

  1. Include references for the assays performed. 

  2. Who was the biostatistician? Better to identify in the contributions.

  3. If the authors are proposing these markers as diagnostic markers, is there any possibility to generate the sensitivity, specificity, positive predictive value and negative predictive value of the key complement proteins that has a potential to be used as the diagnostic markers? This is a non-binding recommendation. 

  4. Properdin levels have been reported to be significantly reduced in severe COVID-19 patients as reported by the same group ( / Reference 10 of this article. This should have been discussed along with the reduced clusterin levels on page 15. Brief discussion would be appropriate on these interesting differences in the levels of these regulators between the long COVID and severe acute COVID.

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