Immunological and clinical markers of PASC: Insights from mild and severe cases six months post-infection, 2025, William Mouton et al

[Mij]

Abstract
Post-acute sequelae of COVID-19 (PASC) is a complex and multifaceted clinical challenge requiring to emphasize its underlying pathophysiological mechanisms.

This study assessed hundreds of virological, serological, immunological, and tissue damage biomarkers in two patient cohorts who experienced mild (n=270) or severe (n=188) COVID-19, 6 to 9 months post-initial infection, and in which 40% and 57.4% of patients, respectively, developed PASC. Blood analysis showed that mains differences observed in humoral, viral, and biological biomarkers were associated with the initial COVID-19 severity, rather than being specifically linked to PASC.

However, patients with PASC displayed altered CD4+ and CD8+ memory T-cell subsets, with higher cytokine-secreting cells and increased terminally differentiated CD45RA+ effector memory T cells (TEMRA). Elevated SARS-CoV-2-specific T cells responsive to nucleocapsid/membrane proteins with a TEMRA phenotype were also observed.

A random forest model identified these features and initial symptom duration as top variables discriminating PASC, achieving over 80% classification accuracy.
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[SNT Gatchaman]

cortisol was quantified in 160 of the available 175 samples (with enough volume), and significantly higher levels were observed in severe patients, as compared to mild patients (90.9 [73.9-124.4] vs. 74.9 [60.9-101.4] pg/mL, p=0.0045; Figure S2A). However, no significant difference in cortisol levels was found between patients with and without PASC, neither in the mild (93.6 [63.4-109.2] vs. 71.2 [55.3-93.4] pg/mL, p=0.070; Figure S2B) nor in the severe cohort (90.4 [67.6-125.3] vs. 100.3 [80.4-118.3] pg/mL, p=0.38; Figure S2C).

(Supplementary figures not currently downloadable)

 

[SNT Gatchaman]

Our analysis found that patients with severe COVID-19 had significantly higher levels of SARS-CoV-2 anti-RBD IgG compared to those with mild COVID-19. However, in both cohorts no significant difference in anti-RBD IgG levels was found according to the PASC status. This highlights that the humoral response fluctuation is predominantly influenced by the initial COVID-19 form but may not correlate with the presence of persistent symptoms, as already suggested.

We also considered the presence of anti-IFN-α 2 autoantibodies, which has been associated with severe forms of the disease, as a driver of PASC. However, no link to PASC status could be established herein, as only two of the six positive patients were PASC. These results are in agreement with studies that found limited contribution of such autoantibodies to PASC

We found no link between CMV or EBV reactivation, and disease severity or PASC status.

The persistence of SARS-CoV-2 in patients with PASC has been suggested by the detection of SARS-CoV-2 antigens in the blood or non-classical monocytes of patients with PASC. In addition, the presence of RNA encoding viral proteins was found in multiple tissue-biopsies obtained from these patients. However, in the present study, we have been unable to detect circulating SARS-CoV-2 nucleocapsid antigens in the plasma samples of the 458 included patients, regardless of the PASC status.

The present study highlighted that the immune alterations observed in patients with PASC cannot be considered a universal feature, since they are significantly influenced by the severity of the initial COVID-19 episode and PASC heterogeneity, which encompasses a wide range of symptoms and mechanisms.

 

[Utsikt]

We found no link between CMV or EBV reactivation, and disease severity or PASC status.

Completely anecdotal, but I have severe PASC (ME/CFS) and I don’t have EBV antibodies.

 

[Midnattsol]

Completely anecdotal, but I have severe PASC (ME/CFS) and I don’t have EBV antibodies.

I didn't either when I first got sick. I did have CMV antibodies though.

 

[Utsikt]

I didn't either when I first got sick. I did have CMV antibodies though.

I also have CMV IgG, but not IgM.

 

[EndME]

Completely anecdotal, but I have severe PASC (ME/CFS) and I don’t have EBV antibodies.

So IgG,IgM (EBNA, VCA etc) are all negative, or you've had a past infection but no indication of anything more recent (as in most people with ME/CFS)?

 

[Midnattsol]

I also have CMV IgG, but not IgM.

Mine was also IgG. Apparently there was an outbreak at the hospital when I was born, but I had seemingly not been one if the babies infected. My mother was very surprised I had antibodies and could think of no other place I could have been exposed than that hospital outbreak.

 

[Utsikt]

So IgG,IgM (EBNA, VCA) are all negative

Yes. I got ME/CFS from PCR-confirmed Covid three years ago.

• Negative EBV EBNA (IgG and IgM) and VCA (IgG)
• Negative Paravirus B19 IgG and IgM
• Positive CMV IgG, negative IgM
• Positive Varicella-zoster virus IgG

 

[Utsikt]

Mine was also IgG. Apparently there was an outbreak at the hospital when I was born, but I had seemingly not been one if the babies infected. My mother was very surprised I had antibodies and could think of no other place I could have been exposed than that hospital outbreak.

I have no idea how I got it. Idk if my sisters had it. One had mono as a child, all three of us had Varielle Zoster (vannkopper/chicken pox) before school age.