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Anakinra: a silver lining in COVID-19?
Critical Care volume 24, Article number: 598 (2020)
In the recent review article Blocking IL-1 to prevent respiratory failure in COVID-19 by Dr. Veerdonk and Dr. Netea , they have implicated the importance IL-1 signaling in severe COVID-19 pathogenesis and proposed anakinra as a therapeutic intervention. I would like to humbly add some views to it; in severe COVID-19 pathology, higher amounts of microthrombi deposition can lead to the blockage in the capillaries and arteries culminating in hypoxic condition and ensuing necrosis-like events. In fact, autopsy studies have reported necrotic events of lung pneumocytes in severe COVID-19 patients . Also, high serum levels of receptor-interacting protein kinase 3 (RIPK-3) in severe patients corroborate necroptosis too .
The damage-associated molecular pattern IL-1α (alarmin) liberated by necrotizing lung epithelial cells could be one of the initial cytokine produced during COVID-19 pathogenesis . IL-1α by further engagement to IL-1R lead to the production of an array of chemokines and cytokines . IL-1β, IL-6, TNF-α, GM-CSF, IL-17, CXC chemokines, CCL chemokines, etc. are some of the few upregulated cytokines/chemokines in severe COVID-19 responsible for exacerbating the lung pathophysiology by fueling up infiltration of macrophages/neutrophils, hypercoagulability, and fibrosis phenomena . Interestingly, IL-17, IL-6, GM-CSF, HIF-α, and CXC chemokines are regulated by IL-1β. The hypercoagulability with thromboembolic indications in severe patients is attributed to platelet activation and platelet monocyte aggregation, leading to the induction of tissue factor (TF) . Also, IL-1β is known to positively regulate TF expression. Taming the cytokine storm can be an effective management strategy and IL-1 signaling might play a crucial role in the pathogenesis of the disease. It could be initial necrosis liberating IL-1α, which drives amplifying inflammation loop eventually leading to inflammasome-dependent pyroptosis determining the severity of the disease. Anakinra (IL-1α and IL-1β blocker) has shown greatly reduced mortality, need for invasive mechanical ventilation, and bettering oxygenation status in severe COVID-19 patients in smaller clinical studies . Hence, anakinra might be effective in managing the severe pandemic state; more so, it is a well-tolerated molecule with no adverse effects. Larger controlled clinical trials with anakinra are much warranted to test the efficacy unequivocally.
Availability of data and materials
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Rahul is very grateful to Dr. Kate Fitzgerald and Dr. Doug Golenbock (UMASSMED) for the initial insightful discussion.
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Gupta, R. Anakinra: a silver lining in COVID-19?. Crit Care 24, 598 (2020). https://doi.org/10.1186/s13054-020-03312-8