By Dean L. Winslow, MD, FACP, FIDSA, FPIDS
Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine
SYNOPSIS: Neutrophil extracellular traps (NETs) contribute to immune-mediated inflammation and thrombosis. Donor neutrophils were stimulated with plasma from patients hospitalized with COVID-19. R406 (metabolically active component of fostamatinib) abrogated release of NETs in vitro.
SOURCE: Strich JR, Ramos-Benitez MJ, Randazzo D, et al. Fostamatinib inhibits neutrophils extracellular traps induced by COVID-19 patient plasma: A potential therapeutic. J Infec Dis 2021;223:981-984.
Plasma was obtained from seven healthy donors and seven COVID-19 patients (six hospitalized at the National Institues of Health Clinical Center and from one patient hospitalized at University of Maryland Hospital who was receiving extracorporeal membrane oxygenation [ECMO] support). Neutrophils were isolated from one healthy donor. Cells were plated in microtiter plates at 20,000 cells/mL, incubated at 37°C, and then stimulated with either normal plasma or plasma from the COVID-19 patients. Neutrophil extracellular trap (NET) formation was measured by labeling of released extracellular deoxyribonucleic acid (DNA), which was visualized by fluorescent microscopy and quantitated by relative fluorescent units (RFU). For inhibition experiments, R406 was preincubated with the healthy neutrophils at either 1 µM or 4 µM for 30 minutes prior to stimulation with plasma.
Kinetics of NETs formation showed a gradual increase over six hours when stimulated by serum from COVID-19 patients, which was approximately 10 times greater than that seen with normal serum. Preincubation of neutrophils with R406 dramatically reduced NETs release triggered by COVID-19 patient plasma at all time points, but did not alter NETosis induced by phorbol myristate ester (PMA).
Those of us who, since last February, have been caring for patients with COVID-19 who are ill enough to require hospitalization have been quite impressed with the degree of inflammation and activation of coagulation in these patients, as evidenced by dramatically elevated levels of C-reactive protein (CRP) and D-dimer levels. We learned early on that these patients all require at least prophylactic doses of anticoagulants, and to have a high index of suspicion for clinical deep venous thrombosis and pulmonary thromboembolism requiring therapeutic anticoagulation.
At our institution, most patients ill enough to be hospitalized are treated with remdesivir (which shortens recovery time but has a modest effect on mortality), and those with significant supplemental oxygen requirement are treated with dexamethasone (which has been shown to reduce mortality in moderately to severely ill patients).1 Other modalities to target inflammation more selectively, such as blocking interleukin-6 (IL-6) with tocalizumab or Janus kinase 1 and 2 with baricitinib, appear to have a more modest effect than dexamethasone but may have additive benefit.2,3 The demonstration of the likely contribution of NETs to inflammation and coagulation and the demonstration that R406, an inhibitor of spleen tyrosine kinase and NETs activation, works in cell culture, suggests that inhibition of this pathway may be worthy of study in patients.
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- Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021;384:795-807.