Preprint Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID., 2024, Rodriguez et al

Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID.
Lucie Rodriguez; Ziyang Tan; Lakshmi Kanth Tadepally; Jun Wang; Hugo Barcenilla; Zoe Swank; Fanglei Zuo; Hassan Abolhassani; Ana Jimena Pavlovitch-Bedzyk; Chunlin Wang; Laura Gonzalez; Constantin Habimana Mugabo; Anette Johnsson; Yang Chen; Anna James; Jaromir Mikes; Linn Kleberg; Christopher Sundling; Mikael Bjornson; Malin Nygren-Bonnier; Marcus Stahlberg; MIchael Runold; Sofia Bjorkander; Erik Melen; Isabelle Meyts; Johan Van Weyenbergh; Qiang Pan Hammarstrom; Mark M Davis; David R. Walt; Nils Landegren; COVID Human Genetic Effort; Alessandro Aiuti; Giorgio Casari; Jean-Laurent Casanova; MARC JAMOULLE; Judith Bruchfeld; Petter Brodin

During the COVID-19 pandemic it was widely described that certain individuals infected by SARS-CoV-2 experience persistent disease signs and symptoms, Long COVID, which in some cases is very severe with life changing consequences.

To maximize our chances of identifying the underpinnings of this illness, we have focused on 121 of the most severe cases from >1000 patients screened in specialized clinics in Sweden and Belgium. We restricted this study to subjects with objective measures of organ damage or dysfunction, >3 months following a verified, but mild- to-moderate SARS-CoV-2 infection. By performing systems-level immunological testing and comparisons to controls fully convalescent following a similar mild/moderate COVID-19 episode, we identify elevated serological responses to SARS-CoV-2 in severe Long COVID suggestive of chronic antigen stimulation.

Persistent viral reservoirs have been proposed in Long COVID and using multiple orthogonal methods for detection of SARS-CoV-2 RNA and protein in plasma we identify a subset of patients with detectable antigens, but with minimal overlap across assays, and no correlation to symptoms or immune measurements. Elevated serologic responses to SARS-CoV-2 on the other hand were inversely correlated with clonally expanded memory CD8+ T cells, indicating that restrained clonal expansion enables viral persistence, chronic antigen exposure and elevated IgG responses, even if antigen-detection in blood is not universally possible.


Link | PDF (Preprint: MedRxiv)

 

Cohort selection

• 121 LC patients (selected out of >1,000 subjects at at Long COVID clinics in Leuven, Belgium & Karolinska University Hospital in Stockholm, Sweden)
• mild to moderate acute infection (non-hospitalised and verified in some way) at least 3 months ago, average age=48 (min-max, 14-72), 87% females
• The average sickness duration is given in Fig. 1f and appears to have a cluster around 750 days. It's hard to infer too much directly from the graph, but all the swedish LC patients (74%) have already passed the 500 day mark.
• Different to almost all other studies they focused on patients that had "objective measures" of Long-Covid. That means at least one of the following results yielded differences to the average population microvascular dysfunction shown by magnetic resonance imaging (MRI) of the heart, endothelial dysfunction by pulsatile arterial tonometry (EndoPAT), autonomic dysfunction and postural orthostatic tachycardia syndrome (POTS), hyperventilation, pulmonary air trapping or reduced carbon monoxide diffusion capacity and other respiratory abnormalities which can be objectively measured by computer tomography (their graphs also include things such as Neuro symptoms and cognitive impairment).
  • It's unclear how objective these differences are (EndoPAT doesn't seem very objective for instance), how many differences there were on average, how these deviated from the average population etc. Going by the available graphs there seem to be patients without differences in the things they listed. However, I very much appreciate the effort they took here and would like to know how some of these things were assessed (for example cognitive impairment) and the values that were obtained. One might wander whether this will not yield a very heterogeneous study population (even though they "do not cluster in relation to organs affected or immunological states").
• Other symptoms apart from the "objective measures" are not part of this pre-print (for example PEM). They focused on the "most severe cases" in their screening, but it is unclear to me what that means. Is there an association to QoL, disability, working hours etc?

I would think some of the questions above will be addressed in follow-up research, especially given the long author list. I'd be surprised if Johan van Weyenbergh wouldn't use trancriptomics on this cohort as well (as done here).

Overall a very long paper, that seems to produce a lot of negative results for many things related to different viral persistence hypotheses.

 

Though they offer indirect evidence for viral persistence, with direct evidence in plasma in only 10%, suggesting possibly viral persistence elsewhere such as marrow or gut.

In summary they say —

 

I have no biology background so this may be non sensical / irrelevant. Apologies in advance

How does this compare to HIV?

 

10 min talk by Petter Brodin on this preprint at the Polybio Spring 2024 Symposium.