Immune Markers Predict Long-Term COVID-19 Sequelae

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The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has left an indelible mark on the world, with over three-quarters of a billion cases reported to the World Health Organization (WHO). Beyond the acute phase of infection, a significant proportion of survivors are grappling with a troubling phenomenon known as “long COVID.”

This condition, characterized by the persistence of symptoms for at least three months after the initial infection, affects approximately 10% of individuals who contract the virus. Long COVID encompasses a wide range of debilitating symptoms, including asthenia, shortness of breath, neurocognitive disorders, insomnia, anxiety, cardiovascular dysfunction, muscular weakness, and depression. As the global medical community grapples with the ongoing pandemic, understanding the pathophysiology of long COVID and identifying predictive markers has become paramount (1, 2, 3).

Emerging data suggests that the severity of the acute SARS-CoV-2 infection plays a crucial role in the development of long COVID. A staggering 70% of patients hospitalized for COVID-19 go on to experience sequelae, especially those who require extended hospital stays or admission to the intensive care unit (ICU) (4, 5, 6). Several biomarkers have been associated with the risk of developing long COVID.

Lactate dehydrogenase (LDH), which reflects tissue damage, has shown a significant correlation with long COVID development (7). In addition, markers of peripheral inflammation, such as C-reactive protein (CRP), Tumor Necrosis Factor-α (TNF-α), interleukin-6 (IL-6), IL-8, and CXCL10, have been identified as predictors of long COVID (8, 9, 10, 11, 12, 13).

Type I and Type III interferons (IFN) also appear to play a role in determining the likelihood of sequelae (14). When it comes to lymphocytes, low levels of naïve T cells and an abundance of exhausted T cells have been linked to long COVID (15). Furthermore, an increase in inflammatory monocytes and the frequency of CD57-expressing mature/senescent natural killer (NK) cells have been associated with the development of pulmonary sequelae (16, 17).

To gain a deeper understanding of the immune markers predictive of long COVID, a comprehensive study was conducted, focusing on 29 patients who had recently been hospitalized for COVID-19 and were monitored for one year. The study aimed to compare the immune profiles of those who later developed long COVID with those who did not.

The immune profiling encompassed 19 soluble markers, quantified in both plasma and the supernatant of non-stimulated peripheral blood mononuclear cells (PBMCs). Additionally, a panel of cell surface markers was utilized to analyze T and NK cell differentiation, activation, exhaustion, and senescence, as well as monocyte subpopulations and T cell apoptosis. This last aspect is particularly noteworthy, as previous research has shown that programmed T cell death is closely linked to disease severity in COVID-19 patients (18).

The results of this study provide valuable insights into the complex interplay between the immune system and long COVID. It was observed that programmed T cell death primarily occurred through apoptosis rather than pyroptosis, necroptosis, or PANoptosis. Several key indicators supported this finding, including the up-regulation of proapoptotic Bcl-2 family members Bax and Bak in T cells, over-expression of CD95 at the T cell surface, increased plasma levels of soluble Fas, and the enhanced efficacy of the pan-caspase inhibitor Q-VD in preventing T cell death compared to inhibitors of inflammasome/pyroptosis, necroptosis, and other pathways.

This groundbreaking research sheds light on the intricate mechanisms underlying long COVID and highlights the importance of immune profiling as a tool to predict and understand the condition. As the COVID-19 pandemic continues to evolve, these findings offer hope for the development of targeted interventions and treatments to mitigate the long-term effects of this devastating virus.


TABLE 1 – Simplified explanation

let’s delve into the details of immune markers linked to long COVID, focusing on Type I/III interferons, T cells, and the study presented:

Type I and Type III Interferons (IFN):

  • Functions: These interferons are key antiviral signals produced by various immune cells.
    • Type I IFN (IFN-α/β) activates immune cells, enhances antigen presentation, and inhibits viral replication.
    • Type III IFN (IFN-λ) has similar functions but primarily targets epithelial cells (lining tissues).
  • Long COVID Link:
    • Possible Mechanisms: Dysregulation of IFN responses might contribute to long COVID through:
      • Persistent inflammation: Uncontrolled IFN signaling can lead to chronic inflammation, damaging tissues and causing various symptoms.
      • Tissue damage: Direct or indirect effects of IFNs on tissues could contribute to pulmonary fibrosis or other organ damage.
      • Autoimmunity: In some cases, IFN responses might trigger mistaken attacks on healthy tissues.
    • Research: Studies are ongoing to understand the specific roles of Type I and III IFNs in predicting different long COVID sequelae.

T Cells and Long COVID:

  • T Cell Subsets:
    • Naïve T cells: These “unprimed” cells encounter new pathogens and initiate immune responses.
    • Exhausted T cells: These T cells become dysfunctional after prolonged exposure to antigens, potentially contributing to immunosuppression.
  • Long COVID Link:
    • Low naïve T cells: Reduced ability to mount new immune responses might increase susceptibility to secondary infections or worsen long COVID symptoms.
    • Exhausted T cells: Impaired T cell function could contribute to chronic inflammation and tissue damage.
    • Studies: Research suggests a link between T cell exhaustion and specific long COVID symptoms like fatigue and cognitive dysfunction.

The Study:

  • Aim: Compare immune profiles of hospitalized COVID-19 patients who develop long COVID vs. those who don’t.
  • Methods:
    • Analyzed 19 soluble markers in plasma and PBMC supernatants (representing immune system activity).
    • Analyzed cell surface markers on T and NK cells (assessing differentiation, activation, exhaustion, and senescence).
    • Monitored T cell apoptosis (programmed cell death).
  • Key Findings:
    • T cell death primarily occurred through apoptosis, not other programmed cell death pathways.
    • Pro-apoptotic markers (Bax, Bak) increased in T cells.
    • Increased CD95 (Fas receptor) expression on T cells and soluble Fas in plasma.
    • Pan-caspase inhibitor prevented T cell death, suggesting caspase involvement in apoptosis.

Implications and Future Directions:

  • Understanding mechanisms: This study sheds light on T cell death pathways in long COVID, potentially leading to targeted interventions.
  • Predictive markers: Identifying specific immune markers associated with long-COVID development could aid in early diagnosis and risk stratification.
  • Treatment strategies: Targeting T cell death pathways or boosting T cell function might offer therapeutic avenues for long COVID.

Discussion

In this comprehensive study involving 29 individuals hospitalized for acute SARS-CoV-2 infection, the aim was to identify predictive biomarkers for the subsequent development of long COVID. Several interesting findings emerged from the research, shedding light on the intricate interplay between immune responses, viral infection severity, and the pathogenesis of long COVID.

One notable outcome was the identification of peripheral blood soluble P-selectin as a non-significant predictor of long COVID. This marker, indicative of endothelium and platelet activation, had previously been associated with severe COVID-19, highlighting the connection between vascular health and the disease’s progression (20). However, it did not emerge as a strong predictor of long COVID in this study, possibly due to the limited number of patients in the cohort.

Surprisingly, the study did not find inflammation markers such as TNF-α, IL-6, or IFNI, which had been previously linked to the onset of long COVID, to be significant predictors in this context. This discrepancy may again be attributed to the relatively small sample size of the study, which may have masked subtle differences among patients.

On the other hand, the research did reveal important insights into the immune responses of patients with severe COVID-19. These individuals exhibited significant increases in T cell differentiation, activation, and exhaustion, as well as perturbations in NK cell and monocyte subpopulations, consistent with findings from other studies (21–25). However, these markers of COVID-19 severity did not differentiate between patients who progressed to long COVID and those who did not, once again emphasizing the need for larger sample sizes to draw more definitive conclusions.

In contrast, a significant correlation was observed between the intensity of programmed T4 cell death in the acute phase of infection and the subsequent development of long COVID. This finding underscores the pivotal role of T cell apoptosis in the pathogenesis of severe COVID-19 and potentially in the development of long-lasting sequelae. It should be noted that this association held despite the limited number of participants in the study, further highlighting the robustness of this link between initial T4 cell death and subsequent sequelae.

T cell apoptosis, a major feature of severe COVID-19, can have profound implications for immune responses. It can lead to poor quality anti-spike humoral responses, which is critical in the context of vaccination and natural immunity (26). Additionally, the apoptosis of T8 cells may favor a cytokine storm by impairing the immune system’s ability to regulate the inflammatory response (27).

The study also provided insights into the potential pathophysiological mechanisms underlying long COVID. Various hypotheses have been proposed, including initial tissue lesions, viral persistence or reactivation (such as Epstein-Barr virus), immunological dysfunction (including autoimmunity and ongoing immune activation), endothelial activation, coagulopathy, dysbiosis, and metabolic and hormonal dysregulation. Many of these mechanisms could be exacerbated or triggered by T4 cell apoptosis. For example, programmed T4 cell death could hinder specific immune responses, favor tissue lesions, facilitate viral reactivation, provoke immune activation and autoimmunity, and contribute to endothelial cell activation and coagulation. Moreover, it may have downstream effects on microbiota, metabolism, and hormonal regulation, leading to dysbiosis and metabolic perturbations (30, 31, 32, 33, 34).

These findings are consistent with previous research demonstrating a low frequency of perforin-positive T8 cells during the acute phase of SARS-CoV-2 infection in patients who later developed long COVID. This supports the hypothesis that T cell deficiency plays a significant role in the development of long COVID.

The implications of this study are far-reaching. It suggests that preventing T cell apoptosis during SARS-CoV-2 infection may be a crucial strategy in mitigating the development of long COVID. Previous research has shown that the pan-caspase inhibitor Q-VD can inhibit programmed death of COVID-19 T cells ex vivo (18). Additionally, other interventions, such as angiotensin-II-receptor antagonists (sartans) and the antioxidant N-acetylcysteine, have shown promise in blocking the cascade of monocytic reactive oxygen species production, DNA damage, and T cell apoptosis in hospitalized COVID-19 patients (19). These findings open the door to potential therapeutic avenues for preventing T cell apoptosis and, subsequently, the development of long COVID.

In conclusion, this comprehensive study provides valuable insights into the intricate relationship between immune responses, T cell apoptosis, and the pathogenesis of long COVID. While the study’s sample size is limited, its findings highlight the need for further research and the potential for targeted interventions to alleviate the long-term effects of COVID-19 on survivors. As the pandemic continues to evolve, understanding the immunological mechanisms behind long COVID becomes increasingly crucial in shaping effective treatments and public health strategies


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