The pathogenesis of COVID-19

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Based on our lab's work over the past few years on the role of the tyrosine kinase BTK (Bruton's tyrosine kinase) in host defense against invasive fungal infections, we hypothesized that inhibition of BTK in patients with severe COVID-19 might ameliorate the hyper-inflammatory responses that appear to drive morbidity and mortality in hospitalized patients. For that, in collaboration with Dr. Wilson, Staudt and Roschewski from the NCI/NIH, we treated patients with severe COVID-19 and evidence of hyper-inflammation off-label with the BTK inhibitor Acalabrutinib and observed improvement in clinical and inflammatory endpoints in treated patients. This led to deployment of a randomized clinical trial, which is now finalized, to evaluate the safety and efficacy of BTK inhibition in hypoxemic hospitalized patients with severe COVID-19. In parallel, correlative research is planned using human samples from these patients to evaluate the mechanisms by which BTK inhibition might ameliorate hyper-inflammation in these patients. In addition, APECED patients were recognized to be at high risk for COVID-19 pneumonia associated with the presence of type I interferon autoantibodies and autoimmune pneumonitis. Our lab has become interested in the clinical and immunological readouts and vaccination responses to COVID-19 in APECED. Moreover, in the setting of the NIAID consortium for COVID-19, we have developed an interest in identifying immune-based biomarkers that could predict poor outcomes after COVID-19 infection.