Treating exuberant, non-resolving inflammation in the lung; Implications for acute respiratory distress syndrome and COVID-19

Abstract

While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.

Keywords: ARDS; COVID-19; Inflammation; SARS-CoV-2; p38 MAP kinase.

Fig. 1

Time course of immune activation following SARS-CoV-2 viral infection in the context of p38 MAP kinase activation. In essence, many of the pathological events underpinning mortality following SARS-CoV-2 infection including neutrophilic and monocytic infiltrates, cytokine storm, oedema formation and clotting as well as risk factors are driven by elevated p38 MAP kinase activity.