Complement dysregulation is a predictive and therapeutically amenable feature of long COVID, 2023, Morgan et al

Published abstract and link here



Preprint
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.

https://www.medrxiv.org/content/10.1101/2023.10.26.23297597v1.full.pdf

 

Well age matched and not too focused on older age groups. However almost 1/2 of LC patients in this study are overweight so possibly a lot of noise here.

The largest chunk of data (including basic data such as Cohort demographics, symptomatology, and other key features) is in the supplementary tables, which however aren't part of the preprint (or I can't find them) so it currently isn't possible for me to assess this work (at least they do state that the long-Covid patients weren't hospitalised).

Edit: As pointed out below the supplementary material is available, I was just too stupid to find it.

 

Paul Morgan is a world class immunologist with a special interest in complement.
There might be recruitment problems for a study of this sort but otherwise I would expect the science to be of high quality.

 

Supplementary material here.

 

Yea, wonder if anyone has looked at this in ME/CFS, Lyme --- anything else that looks like ME/CFS?
My usual reply - I'm guessing that a GWAS study, which had a large cohort with this problem*, would have a strong (related) signal? Even if ME/CFS doesn't have such a high proportion of people with this pathology* it might be interesting to examine the DecodeME data i.e. to see it there's a related signal?

*"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."

 

Thank you! Then it is indeed my fault as I was too stupid to find it.

 

A Tweet by Polybio with regards to this study “They are expanding on the findings in this study, where measurement of complement proteins in blood will be combined with analysis of potential #SARS-CoV-2 reservoir in lung tissue, and measurement of endothelial dysfunction at that site: https://polybio.org/projects/elucid...-using-molecular-virology-advanced-sequencing/“

www.twitter.com/polybioRF/status/1720103521704382777

 

https://meassociation.org.uk/2023/12/medscape-new-tests-may-finally-diagnose-long-covid/


By Sara Novak

Extracts
Researchers at Cardiff University School of Medicine in Cardiff, Wales, United Kingdom, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.

In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular — Ba, iC3b, C5a, and TCC — predicted the presence of long COVID with 78.5% accuracy.

The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2.

The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID

 

It says that in the text, but Table 2 shows higher values for controls for both these proteins. Table 2 also doesn't match the scatter plots in Figure 2, at least for C4. The table says mean of 511.8 for controls but the mean line in the plot is below 500. Table S2 in the supplementary file uses medians instead, but this agrees with the text that these proteins are elevated in long COVID. I think the data for these two might be wrong in Table 2.

Also, the text says FH was significantly elevated, but Table 2 shows it is not significant. It isn't significant in Table S2 either, which used a different statistical test.