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Rationale for Evaluating PDE4 Inhibition for Mitigating against Severe Inflammation in COVID-19 Pneumonia and Beyond
Charlie Bridgewood1, Giovanni Damiani2,3, Kassem Sharif1,4
1Department of Musculoskeletal Disease, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
Background:
In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indications in inflammatory skin and joint diseases as well as chronic obstructive pulmonary disease (COPD). Furthermore, multiple animal models demonstrate strong anti-inflammatory effects of PDE4i in respiratory models of viral and bacterial infection and also after chemically mediated lung injury. The rationale for PDE4i use in COVID-19 patients comes from the multimodal mechanism of action with cytokine, chemokine, and other key pathway inhibition all achieved with an excellent safety profile. We highlight how PDE4i could be an overlooked treatment from the rheumatologic and respiratory armamentarium, which has potential beneficial immune-modulation for treating severe COVID-19 pneumonia associated with cytokine storms. The proposed use of PDE4i is also supported by age-related immune changes in inflammation severity in PDE4i modifiable pathways in primate coronavirus disease. In conclusion, over-exuberant anti-viral immune responses in older patients with COVID-19 may pose a substantial risk to patient survival and mitigation against such hyper-inflammation with PDE4i, especially with anti-viral agents, is a strategy that need to be pursed, especially in older patients.
Insights
Phosphodiesterase 4 inhibitors (PDE4i) may mitigate severe inflammation in COVID-19 pneumonia, particularly in older patients. This approach targets cytokine storms and enhances survival by modulating immune responses.
Area of Science:
- Immunology and Pharmacology
- Respiratory Medicine
Background:
- Severe inflammatory reactions, or cytokine storms, complicate COVID-19 pneumonia, impacting survival.
- Phosphodiesterase 4 inhibitors (PDE4i) possess anti-inflammatory properties and are approved for inflammatory conditions and COPD.
- Animal models show PDE4i efficacy in respiratory infections and lung injury.
Purpose of the Study:
- To explore the potential of PDE4 inhibitors as a treatment strategy for severe COVID-19 pneumonia.
- To highlight PDE4i's immune-modulatory effects in mitigating cytokine storms associated with COVID-19.
Main Methods:
- Review of existing literature on PDE4 inhibitor mechanisms and efficacy in inflammatory and respiratory diseases.
- Analysis of multimodal anti-inflammatory pathways targeted by PDE4 inhibitors.
- Consideration of age-related immune responses and their modulation by PDE4i in the context of coronavirus disease.
Main Results:
- PDE4 inhibitors demonstrate a multimodal mechanism of action, inhibiting key inflammatory pathways.
- PDE4i exhibit a favorable safety profile, making them a viable option for COVID-19 treatment.
- Age-related hyper-inflammation in COVID-19 patients may be effectively managed by PDE4i.
Conclusions:
- PDE4 inhibitors represent a potentially overlooked therapeutic strategy for severe COVID-19 pneumonia.
- Mitigating hyper-inflammation with PDE4 inhibitors, especially in older adults, could improve patient survival.
- Combining PDE4 inhibitors with anti-viral agents warrants further investigation for COVID-19 management.
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