Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid, 2024, Krishna et al

Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid

Abstract
After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid. Understanding the mechanisms that cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic, and monitoring purposes are urgently required.

We detected persistently high levels of interferon-γ (IFN-γ) from peripheral blood mononuclear cells of patients with Long Covid using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in patients with Long Covid, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. The IFN-γ release was CD8+ T cell–mediated and dependent on antigen presentation by CD14+ cells.

Longitudinal follow-up of our study cohort showed that symptom improvement and resolution correlated with a decrease in IFN-γ production to baseline levels. Our study highlights a potential mechanism underlying Long Covid, enabling the search for biomarkers and therapeutics in patients with Long Covid.

https://www.science.org/doi/full/10.1126/sciadv.adi9379

 

Cohort selection

3 groups:

• n=54 Unexposed pre-pandemic controls
  
• n=? Covid positive controls*
• n=55 Long-Covid patients (infection confirmed via RT-qPCR result, antibody seropositity to N, or a positive IL-2 response to M and N peptides)

*This is a cohort I haven't understood. In the supplementary material S1 there seems to be n=81 Covid positive controls of which n=24 were hospitalised and n=57 had a mild illness. In the text of the study they however write that there were far more hospilatized patients "The COVID-confirmed hospitalized patients [day 28 (n = 51), day 90 (n = 20), and day 180 (n = 40)]" and some of these were also PCR-negative according to S1, which appears to be in contrast with what is written in the text.

Cohort characteristics:

The LC patients were recruited on the basis of symptoms that had persisted for at least 5 months after acute COVID-19 that could not be explained by an alternative diagnosis, patients reinfected during the study were excluded to not introduce additional problems. The largest caviat would be that at study start the LC patients had only been sick for an average duration of 7 months (this study was conducted in the early days of the pandemic, so this would be excusable).

The average age of LC patients was 46 years and 43.6% were males (so perhaps slightly too old and a bit too many males, but certainly not too bad). 7/55 Long-Covid patients were hospitalised with acute Covid the rest had a mild acute illness. By first looks the matching between the different cohorts seems decent and this is finally a LC cohort with slightly less comorbidities (the only significant thing would be that 14/55 patients in the LC group had COPD/Asthma, which wasn't additionally wasn't well matched) on the positive side of things only one LC patient was considered to be obese.

Reading over the study for the first time there doesn't seem to be any raw data on the symptomology of the patients when they where recruited, neither how many symptoms these had, which symptoms these were and how much these impacted their daily life etc. There is however some data on symptom distribution post vaccination in S2 and figures 5A&B provide an extremely rough overview on the symptomology of the patients.

Overall most patients recovered to a very large degree by the end of the study at the 31 month mark (it seems like roughly 15 fully recovered "spontaneously" whilst the full recovery of additionally roughly 10 patients was attributed to vaccination). As one would expect symptoms such as shortness of breath, anosmia, cough, pneumonia resolved in all those patients that experienced this. Fatigue, the most dominant symptom, seemed to resolve roughly half of the time, whilst something like "brain fog" seemed to be one of the more persistent symptoms (something like PEM or sleep problems was either not present or wasn't assessed). Based on what is visible it appears to be a rather mild cohort, but the authors state patients "tended to have more severe symptoms, having been recruited from a specialist Long Covid clinic".

Unfortunately, overall the symptomology description is far too vague to be able to say anything meaningful about these cohorts and going by the graph it seems most patients would have on average something like 2 symptoms, but it's hard to say what is going on. The whole graphical presentation without additional data is horrible. You can't tell how many people had how many symptoms, if those that recovered had less symptoms and which those were etc.

 

If the findings were to hold any water there would have to be an explanation as to why other groups haven't found the same thing.

The argument may be that the authors propose that the highly sensitive FluoroSpot assays are more sensitive than what others have done. This is the same argument one of the authors of the serotonin study proposed to me when it came to measuring IFN (see my comment here). Whether that actually holds any water remains to be seen (it should also be possible to do a comparison between different assays)...

 

Just to note that this study is covered in an article on the landing page of the Financial Times today:

Anti-viral protein found to be important long Covid indicator (ft.com)

 

We should always question whether data from using "a new highly-sensitive technique" is just a flaw in the technique, or at least a flaw in interpreting the data. It takes time to figure out how to use a new tool properly.

 

The company producing this precise assay is a small Swedish company. It does however seem like a somewhat common technique, or at least it has over 100 hits on Pubmed alone with the majority of studies coming from 2010 onwards (on the other hand the time frame when publications started is similar to that of the SIMOA assay, which however has over 700 hits on Pubmed and has been hyped up as "new technology" in the LC field). Given the recent LC study finding vastly different results in the different antigen assays (including SIMOA), explaining why this study gets vastly different results to other studies, by running a simultaneous comparison with the assays other studies used, seems well-worth the effort.

 

What comes to my mind when I read about amazing findings from a "new technique" is the Bre-X scandal. The prospecting company showed amazing quantities of gold at their claim ... based on a new technique for measuring gold content. If people had requested the samples be processed by the traditional technique, there wouldn't have been much interest, since there actually wasn't much gold.

 

Press release:
Long COVID linked to persistently high levels of inflammatory protein: a potential biomarker and target for treatments
Peer-Reviewed Publication
https://www.eurekalert.org/news-releases/1034636
UNIVERSITY OF CAMBRIDGE