Since the declaration of the COVID-19 pandemic by the World Health Organization in 2020, understanding the pathophysiology of the disease has been crucial in developing effective treatment strategies. Recent advancements have shed light on the role of cytokine release syndrome (CRS) in severe cases of COVID-19, indicating elevated levels of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α). Managing CRS has emerged as a potential therapeutic approach to rescue severe COVID-19 patients.
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The Immune Response and CRS in COVID-19
Recent advancements in understanding COVID-19 pathophysiology reveal a strong correlation between cytokine release syndrome (CRS) and disease severity. Elevated levels of TNF-α, G-CSF, IP-10, MCP-1, and MIP1A are associated with severe cases. Studies show heightened levels of IL-6, TNF-α, IL-10, and IL-1b in severe patients, along with increased IL-6, IL-8, IL-10, IL-2R, and TNF-α in severe cases compared to non-severe ones. Higher expressions of various cytokines predict disease severity and prognosis, positively correlating with SARS-CoV-2 viral load. CRS manifests as interstitial mononuclear inflammatory infiltrates in the lungs, dominated by lymphocytes, contributing to tissue damage. Multisystem inflammatory syndrome in children (MIS-C) shares similarities with Kawasaki disease but presents with distinct features, suggesting a predisposition to an exaggerated immune response and CRS induction by SARS-CoV-2. Overall, dysregulated cytokine production and lymphocyte alterations play a pivotal role in CRS and subsequent tissue damage in COVID-19.
TNF-α Signaling Pathway in CRS
The TNF-α signaling pathway is crucial in cytokine release syndrome (CRS), orchestrating acute and chronic systemic inflammatory responses. TNF-α regulates apoptosis, proliferation, and the production of other cytokines and chemokines, impacting anti-tumor responses, inflammation control, and immune system balance. Dysregulated TNF-α signaling can trigger CRS, as observed in COVID-19 patients, where sustained TNF-α and IL-6 production by monocytes is linked to hyper-inflammatory responses and lymphocyte dysregulation. Elevated TNF-α levels facilitate viral infection and organ damage, but anti-TNF therapy has shown promise in reducing inflammation and disease severity. While TNF-α inhibition is beneficial in autoimmune and chronic inflammatory diseases, excessive suppression may compromise immune function. In COVID-19, TNF inhibitors can mitigate the inflammatory cascade by reducing IL-6, IL-1, adhesion molecules, and vascular endothelial growth factor levels, thereby alleviating macrophage activation syndrome and pulmonary capillary leak. Additionally, TNF-targeting treatments have shown efficacy in attenuating lung injury and improving outcomes in acute respiratory distress syndrome models. TNF-α synergizing with IFN-γ triggers robust cell death, highlighting its pivotal role in CRS pathogenesis. Targeting TNF-α-mediated inflammatory cell death signaling may mitigate tissue damage in COVID-19 and other infectious diseases, underscoring the therapeutic potential of modulating the TNF-α pathway to manage CRS.
Implications on Antibacterial and Antiviral Immunity
TNF-α plays a significant role in the interaction between SARS-CoV and ACE2 receptors, facilitating viral entry into cells. While SARS-CoV-2 may upregulate ACE2 expression through cytokine storms involving TNF-α, physiologically, ACE2 exhibits anti-inflammatory properties. SARS-CoV-2 infection downregulates ACE2, leading to increased angiotensin II levels, pulmonary vascular permeability, and lung damage. TNF-α also contributes to ACE2 shedding, crucial for viral entry. Modulating TNF-α may thus be key in combating SARS-CoV-2. NF-κB, pivotal in COVID-19 progression, regulates pro-inflammatory cytokines and immune responses. Enhanced NF-κB activation correlates with severe COVID-19 and lung pathology. Blocking NF-κB may mitigate disease progression but poses risks of immune suppression. TNF-α, through TRAF 2, activates NF-κB, suggesting TNF-α inhibition as a potentially more effective strategy with fewer adverse effects.
Fig. 1 TNF-α plays a significant role in activation of NF-κB and ACE2 shedding in SARS-CoV-2 infection (Guo Y., et al. 2022).
Potential of TNF-α Inhibitors in COVID-19
Inhibiting TNF-α production emerges as a promising strategy against SARS-CoV2 infection and ensuing organ damage. Early anti-TNF therapy upon hospital admission may prevent COVID-19 progression, as suggested by Feldmann et al. Existing therapies like Humira, Remicade, and others show potential. Clinical trials evaluating adalimumab and infliximab demonstrate promising results, with successful outcomes reported in COVID-19 patients treated with etanercept. Studies suggest TNF antagonists like infliximab could play a crucial role in managing CRS in COVID-19. Additionally, research from the SECURE-IBD database indicates that TNF antagonist therapy isn't an independent risk factor for severe COVID-19 and may even offer protective effects, especially when compared to other medications like thiopurines. Case reports and studies on patients with IBD and rheumatic diseases further support the safety and efficacy of TNF inhibitors in mitigating COVID-19 outcomes.
Controversy on the Safety of Anti-TNF Therapy in Patients With COVID-19
While TNF-α inhibitors offer therapeutic benefits, they may exacerbate disease progression and raise infection risks. Studies highlight increased rates of bacterial, mycobacterial, and latent viral infections, including tuberculosis and hepatitis B, among patients on TNF inhibitors. Immunosuppressive effects also elevate susceptibility to COVID-19 and its complications. Paradoxical effects like sarcoidosis and granulomatous disorders further complicate treatment. Nonetheless, discontinuation or switching of anti-TNF therapy can often resolve these adverse effects. Careful patient selection and proactive screening for latent tuberculosis and venous thromboembolism are crucial before initiating TNF inhibitor therapy. Despite potential risks, IFX demonstrates promise in pediatric patients with low risk of MAS occurrence, making it a viable option among TNF inhibitors. However, caution is warranted, as IFX use in COVID-19-related CRS with organ failure may temporarily reduce pro-inflammatory cytokines but could heighten infection risk.
Conclusions and Future Perspectives
The targeting of TNF-α pathway presents a promising approach in COVID-19 treatment, offering potential benefits in attenuating inflammatory responses and improving clinical outcomes. However, challenges regarding safety, patient selection, and timing of therapy necessitate further research and clinical trials. The role of TNF-α inhibitors in COVID-19 treatment warrants continued investigation to elucidate their efficacy and safety profile, providing valuable insights for future therapeutic strategies.
Overall, targeting TNF-α pathway in COVID-19 treatment holds significant promise, but careful consideration of its implications and challenges is essential for successful implementation in clinical practice. Further research and clinical trials are needed to validate the efficacy and safety of TNF-α inhibitors, paving the way for improved management of severe COVID-19 cases.
Reference
- Guo Y., et al. Targeting TNF-α for COVID-19: recent advanced and controversies. Frontiers in Public Health. 2022, 10: 833967.
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