A novel definition and treatment of hyperinflammation in COVID-19based on purinergic signallin

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Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers definehyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated withanti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by seriousadverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergicreceptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drivesthe ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation.

Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolledATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results inimmune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. Thereadily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immunefunction. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than themaximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit theP2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently,these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) localhyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

Djo Hasan1&Atsuko Shono2&Coenraad K. van Kalken3&Peter J. van der Spek4&Eric P. Krenning5&Toru Kotani2Received: 20 January 2021 /Accepted: 18 July 2021#The Author(s) 2021Abstract