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Anakinra: a silver lining in COVID-19?

Dear Editor,

In the recent review article Blocking IL-1 to prevent respiratory failure in COVID-19 by Dr. Veerdonk and Dr. Netea [1], 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 [2]. Also, high serum levels of receptor-interacting protein kinase 3 (RIPK-3) in severe patients corroborate necroptosis too [3].

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 [4]. IL-1α by further engagement to IL-1R lead to the production of an array of chemokines and cytokines [4]. 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 [1]. 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) [5]. 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 [1]. 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.

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References

  1. 1.

    van de Veerdonk FL, Netea MG. Blocking IL-1 to prevent respiratory failure in COVID-19. Crit Care. 2020. https://doi.org/10.1186/s13054-020-03166-0.

  2. 2.

    Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis. 2020. https://doi.org/10.1016/S1473-3099(20)30434-5.

  3. 3.

    Nakamura H, Kinjo T, Arakaki W, Miyagi K, Tateyama M, Fujita J. Serum levels of receptor-interacting protein kinase-3 in patients with COVID-19. Crit Care. 2020. https://doi.org/10.1186/s13054-020-03209-6.

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    Di Paulo NC, Shayakhmetov DM. Interleukin 1α and the inflammatory process. Nat Immunol. 2016;17:906–13.

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  5. 5.

    Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA, Pao CRR, et al. Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients. Blood. 2020. https://doi.org/10.1182/blood.2020007252.

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Acknowledgements

Rahul is very grateful to Dr. Kate Fitzgerald and Dr. Doug Golenbock (UMASSMED) for the initial insightful discussion.

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Rahul did the literature survey and wrote the manuscript. The author read and approved the final manuscript.

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Correspondence to Rahul Gupta.

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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

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