Post-COVID-19 sequelae are associated with sustained SARS-CoV-2-specific CD4+ immune responses, 2025, Venegoni et al.

[SNT Gatchaman]

Post-COVID-19 sequelae are associated with sustained SARS-CoV-2-specific CD4+ immune responses
Venegoni; Raineri; Mazzucca; Ghazanfar; Cappellano; Baricich; Patrucco; Zeppegno; Gramaglia; Balbo; Cantaluppi; Patti; Giordano; Manfredi; Rolla; Sainaghi; Pirisi; Bellan; Chiocchetti

BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to widespread post-acute sequelae of COVID-19 (PASC), affecting multiple body systems. Despite its prevalence, PASC’s pathogenesis remains unclear, with hypotheses suggesting viral persistence, immune activation, and autoimmune responses among the pathogenetic mechanism. This study aimed to evaluate T cell memory response in PASC patients, one year post-hospital discharge and correlate it with clinical parameters to identify a potential PASC-associated fingerprint.

METHODS
Peripheral blood mononuclear cells (PBMCs) from PASC patients and healthy controls (HC) were stimulated with a pool of spike peptides. CD4 + and CD8 + T cell responses were evaluated by flow cytometry using the activation-induced markers assay (AIM).

RESULTS
Findings showed significant activation of the CD4 + T cell compartment, with a higher proportion of responders among PASC patients. Central memory (CM) T cells expressing pro-inflammatory cytokines were more prevalent in responders. Clinical correlations revealed higher SARS-CoV-2-specific T cell responses in patients with reduced diffuse lung capacity for carbon monoxide (DLCO) and residual symptoms.

CONCLUSION
These immune changes, especially in CM T cells, could play a pivotal role in PASC’s development and persistence, impacting patients’ daily lives.

Link (International Immunopharmacology)

 

[forestglip]

Clinical correlations revealed higher SARS-CoV-2-specific T cell responses in patients with reduced diffuse lung capacity for carbon monoxide (DLCO) and residual symptoms.

Didn't know what this was. From StatPearls:

The diffusing capacity of the lungs for carbon monoxide (DLCO), also known as the transfer factor for carbon monoxide (TLCO), measures the amount of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (RBCs). This test provides critical insights into the lungs' ability to transfer oxygen from inhaled air to the bloodstream, making it essential for diagnosing and monitoring various pulmonary conditions.

 

[forestglip]

Can't see the paper, just snippets, but alopecia as a symptom in PASC in this graphic is interesting:

In a study by Hou et al., the authors performed an ELISPOT assay in PASC patients’ serum collected one year after the primary infection. They demonstrated that specific T-cell response can last several months after the infection [12]. In their work, Opsteen et al. evaluated SARS-CoV-2 specific T-cell response through the activation induced marker (AIM) assay, 6 months post-infection. They found that PASC patients had an increased and sustained SARS-CoV-2-specific CD4+ T-cell response overtime, with respect to those who recover from the infection without any symptoms [13]. These findings, taken together with other data, point to the persistence of viral antigen stimulation, that continuously triggers the adaptive immune system.

So they replicated the high SARS-CoV-2 specific CD4 response in long COVID from Opsteen 2023.

The role of immune activation and antigen persistence in acute and long COVID, 2023, Opsteen et al (Journal of Investigative Medicine)

 

[Yann04]

We enrolled 92 patients who have been hospitalized due to COVID-19 between March 1st, 2020, and June 29th, 2020. The follow-up occurred with an average of 366 days after recovery and hospital discharge.

Results might just be noise from more severe infections -> post-ICU syndrome

 

[SNT Gatchaman]

Results might just be noise from more severe infections -> post-ICU syndrome

Except the HCs were also hospitalised (not specified in abstract). Sex ratio biased to male and older.

Briefly, out of the 92 participants, 71% were males and 29% females, with an average age of 60 years. In this cohort, average half of the subjects displayed a reduced DLCO (47.8%) and more than 60%, residual symptoms (which include fever, cough, dyspnea, asthenia, diarrhea, dysgeusia, anosmia, arthralgia and myalgia) with 70% alteration of the 2MWT. In contrast, the HC group included in this study, although they had also been hospitalized during the first wave of COVID-19, showed no signs of PASC 12 months post-infection. Specifically, they did not exhibit any residual symptoms, DLCO impairment, or abnormalities in the 2MWT. Overall, the cohort consisted of 70% (n = 64) PASC patients and 30% (n = 28) HC.

 

[SNT Gatchaman]

From discussion —

Based on the immunological T-cell response against the SARSCoV-2 peptides, we were able to discriminate, among enrolled subjects those who showed an activation, either in CD4+ or CD8+ compartment. Our data highlighted a defective CD8+ response compared to the CD4+ subset, one after year the primary infection. Given their ability to eliminate virus-infected cells and produce effector cytokines, CD8+ T cells are crucial in the regulation of viral infection; in the contraction phase that follows antigen clearance, a small proportion of effector CD8+ T cells differentiate into memory CD8+ T cells. However, previous studies indicated that, in cases of viral persistence or cancer, the formation of memory CD8+ T cells is compromised. This may explain the huge impairment of CD8+ activation observed in our cohort.

Longitudinal studies have revealed sustained dysregulation of immune responses in subjects with PASC; accordingly, the stratification of our cohort in PASC and non-PASC subjects, revealed an increased proportion of subjects with a persistent memory response in the CD4+ subset in the symptomatic group, while no significant differences emerged in the CD8+ compartment, even though the number of responders among symptomatic subjects outnumbered those of asymptomatic ones. This result may provide a deeper insight in the immune regulation in recovered patients, since CD8+ response seems to be generally more hampered, and it does not discriminate subjects according to post-infection repercussions.

On the other hand, a more efficient response against spike peptides, in terms of magnitude, emerged to be restricted to CD4+ compartment in PASC subjects. Significant differences came out in CM CD4+ AIM+ cells, producing at least one of the evaluated cytokines. Our data are in line with a previous study that found a higher proportion of CD4+ CM cells in PASC compared to recovered individuals, potentially supporting a persistent reservoir. Indeed, CD4+ CM cells are essential for the establishment of immunological memory and to provide long-lasting protection against pathogens, by activating and orchestrating the functions of other immune cells through the secretion of cytokines (IL-2, TNF-α, IFN-γ). Our results support previous evidence, suggesting a persistent activation of CD4+ T cells after severe SARS-CoV-2 infection.