Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome (Cervia et al, 2022)

Consul

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Abstract

Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.

Discussion
[...]
In reflecting on the association of the identified Ig signature correlating with increased risk of PACS, the following aspects are worth considering. IgM and, particularly, IgG3 secretion by B cells is induced by interferons and antagonized by IL-4 signals19,20,21. Thus, reduced production of type I interferons, as proposed to occur in poorly controlled SARS-CoV-2 infection22,23, or a predisposition to secreting increased IL-4 concentrations, as present in asthma bronchiale24, may contribute to a failure to efficiently induce Ig isotype switching to IgG3. This hypothesis is consistent with our finding of low IgG3 in asthma bronchiale patients. Conversely, immune responses dominated by IgG3 can occur with similar temporal dynamics as IgM responses and have been associated with viral infections at mucosal tissues25,26. Thus, the reduced IgG3 concentrations in patients with PACS might support a role for IgG3 in Fc receptor-dependent viral control. Low IgG3 levels have also been linked to chronic fatigue syndrome, a debilitating condition resembling certain symptoms of PACS, as well as an increased rate of respiratory infections18,27.

PACS has been proposed to result from tissue damage due to direct effects of the virus, excessive inflammation, or thrombotic events; alternatively, PACS could be the consequence of bystander or virus-mediated activation of autoreactive T and B cells28. Recent observations of PACS resolution after SARS-CoV-2 vaccination might hint at the depletion of persisting viral reservoirs29. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which in turn is crucial for understanding the pathomechanisms of PACS and identification of preventive measures for treatment and care.


The study: https://www.nature.com/articles/s41467-021-27797-1

The central findings here are that people that on beforehand have low IgM and IgG3 are at higher risk of LC. When you get infected IgM is supposed to increase rapidly while IgG3 will increase later to provide longer term protection.
 

Consul

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I think many recent findings are hinting at persistent infection now for CFS. A few of those are the low antibodies here in this study increasing LC risk, the recent LC autopsy findings, Bruce Pattersons recent study and an interresting quote i noticed in the discussion part in the first post here: "Recent observations of PACS resolution after SARS-CoV-2 vaccination might hint at the depletion of persisting viral reservoirs29." Is the net closing in?
 
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Pyrrhus

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The central findings here are that people that on beforehand have low IgM and IgG3 are at higher risk of LC.
Wow, this seems significant.
(IgM = Immunoglobulin M, IgG3 = Immunoglobulin G subset 3)

From the article:
In individuals developing [Long Covid (PACS)], we detected decreased IgM, both at primary infection and 6-month follow-up (Fig. 2d). Whereas IgG1 was unaltered, IgG3 tended to be lower in patients with PACS (Fig. 2d), which was contrary to the increased IgG3 concentrations in both mild and severe COVID-19 cases.
[...]
This discrepancy in IgG3 was also evident when analyzing the proportion of IgG3 within total IgG during primary infection, with severe COVID-19 patients without PACS demonstrating increased IgG3, whereas severe COVID-19 patients developing PACS failed to show such increase in IgG3.
[...]
Notably, individuals with either low IgM or low IgG3 had an increased risk of developing PACS, whereas patients with both high IgM and high IgG3 were less likely to develop PACS (Fig. 2h). In line with this finding, we observed in healthy controls that contracted COVID-19 during the course of this study (Supplementary Table 1), those developing PACS had low IgM prior to SARS-CoV-2 infection, which remained low during the observation period.

We already know that many people with ME have low total IgG3 or low total IgM (I have both), but now it looks like:
  1. People with Long Covid may also have low total IgM or low total IgG3.
  2. People with Long Covid may have had low total IgM or low total IgG3 before they were infected.
Does this mean that people with ME may have had low total IgM or low total IgG3 before they fell ill with ME?

Is it possible that these immune abnormalities predispose someone to ME or Long Covid?
 
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Pyrrhus

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Related discussions:

Frequent IgG subclass and mannose binding lectin deficiency in patients with CFS (Guenther et al., 2015)
https://forums.phoenixrising.me/thr...lectin-deficiency-in-patients-with-cfs.40289/

Evaluation of immune dysregulation in an Austrian patient cohort suffering from ME/CFS (Lutz et al., 2021)
https://forums.phoenixrising.me/thr...n-patient-cohort-suffering-from-me-cfs.85541/

Selective IgM Deficiency (2013)
https://forums.phoenixrising.me/threads/holy-crap-igm-deficiency.25764/

Do low IgM levels affect our ability to make antibodies against infections? (2021)
https://forums.phoenixrising.me/thr...-to-make-antibodies-against-infections.84390/
 
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Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

https://www.cell.com/cell/fulltext/S0092-8674(22)00072-1#relatedArticles

Highlights
* Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
* Reactivation of latent viruses during initial infection may contribute to PASC
* Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
* Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
 

Pyrrhus

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Thanks @marcjf for mentioning this other paper that also looked for factors that could predict whether someone is likely to develop Long Covid!

We now have a third paper about predicting which COVID patients might develop Long Covid:

Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19 (Ram-Mohan et al., 2022)
https://doi.org/10.1093/ofid/ofab646
Determinants of [Long Covid] are not known. Here we show that 83.3% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. [Viral RNA in the blood during acute COVID] successfully predicted [Long Covid], independent of patient demographics, worst disease severity, and length of symptoms.