A recent study published in eLife determines whether immune activation is related to long coronavirus disease 2019 (COVID-19). Herein, patients with severe COVID-19 exhibited persistent activation of clusters of differentiation 8 (CD8+) and CD4+ T-cells as in comparison with patients with mild or moderate COVID-19.

Study: Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months. Image Credit: iunewind / Shutterstock.com

Background

Long COVID, which can be known as post-acute sequelae of COVID-19 (PASC), is characterised by chronic symptoms that affect multiple organs following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While long COVID is reported in 8-21% of mild to severe COVID-19 patients, the next prevalence of long COVID symptoms is reported in COVID-19 patients who required admission to the intensive care unit (ICU) and/or mechanical ventilation.

Despite extensive research, it stays unclear whether current COVID-19 vaccines are effective in stopping long COVID and what treatment modalities could be used to treat the condition.

While pervious research has attributed long COVID to incomplete recovery of damaged lung tissue, auto-immune disorders, or reactivation of other latent viruses like cytomegalovirus (CMV), the connection between long COVID and the patient’s cellular immune response has not been determined. Given the increasing burden of long COVID on healthcare systems worldwide, a greater understanding of the underlying mechanisms which can be answerable for this condition is urgently needed.

In regards to the study

The researchers of the current study assessed immune activation in COVID-19 patients three months after hospitalization. Moreover, the researchers investigated whether there was an association between these patients’ immunological profile, severity of COVID-19, and long COVID symptoms.

A complete of 187 samples were collected from 63 patients who had been hospitalized and were recovering from mild, moderate, or severe COVID-19. Immunological profile testing was performed for all patients.

Flow cytometry was used to find out the expression of CD38, HLA-DR, Ki67, and granzyme B on CD8+ and CD4+ T-cells. Enzyme-linked immunosorbent assay (ELISA) was also used to find out the degrees of interleukin 4 (IL-4), IL-7, IL-17, and tumor necrosis factor-alpha (TNF-α) in plasma.

T-cell response during infection doesn’t cause long COVID

Three months following SARS-CoV-2 infection, activated CD-4+ and CD-8+ T-cell levels, in addition to other cytokines including TNF-α, IL-4, IL-7, and IL-17, were higher in patients with severe COVID-19 as in comparison with those with mild or moderate disease. Presently point, patients with severe COVID-19 also experienced a greater variety of symptoms related to long COVID as in comparison with those with mild or moderate disease.

When these observations were correlated to the immunological analyses of those patients, the associations weren’t statistically significant. This means that there isn’t a direct correlation between long COVID and the immunological findings.

Inflammatory events proceed to occur within the patient’s immune system after hospitalization with COVID-19. Similar results were observed within the immunological evaluation at each three and 12 months following recovery from COVID-19.

Cytokine and T-cell levels rose three months following infection but ultimately decreased by 12 months. This could be attributed to a high viral load through the initial stage of the disease, which increases cytokine levels and, in consequence, further stimulates the discharge of T-cells. This remark validates similar results reported in previous studies.

Likewise, 80% of patients with mild, moderate, and severe COVID-19 reported long COVID symptoms, which aligns with previous research.

The prevalence of long COVID is higher in patients who were hospitalized and/or admitted to the ICU. Nonetheless, patients who developed long COVID didn’t appear to have similar risk aspects to those that developed acute viral infections, thus indicating that these processes could have different pathophysiologies.

Conclusions

Prolonged activation of T-cells and long COVID symptoms may associate independently with severe COVID-19 three months after recovery. Thus, the evolution of long COVID from COVID-19 could also be an independent process, as no correlation within the immunochemistry of each conditions was observed.

Although severe COVID-19 patients exhibited persistent T-cell activation as in comparison with mild/moderate COVID-19 patients, the variety of long COVID symptoms didn’t correlate with immune activation after adjusting for sex, age, and COVID severity.

Some limitations of this study include inadequate tissue samples, which led to an inability to investigate T-cells, which have essential anti-inflammatory and regulatory roles. One other limitation was the small sample size and racial background of the participants, who were predominantly White Caucasians.

Additional studies are needed for a more comprehensive understanding of the pathophysiology and evolution of long COVID, considering its enormous impact on public health and the worldwide economy.