COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n=33) with age- and sex-matched controls (n=17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), Platelet Factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-Inhibitory Factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19 with intubation (P<0.0001) and death as outcome (P<0.0005). Illness severity correlated directly with plasma MPO-DNA complexes (P=0.0360), while PaO2/FiO2 correlated inversely(P=0.0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19 and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline and COVID-19 plasma triggered NET formation which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19 and NETs may represent targets for therapeutic intervention.

Neutrophils are highly specialized innate effector cells that have evolved for killing of pathogens. Human neonates have a common multifactorial syndrome of neutrophil dysfunction that is incompletely characterized and contributes to sepsis and other severe infectious complications. We identified a novel defect in the antibacterial defenses of neonates: inability to form neutrophil extracellular traps (NETs). NETs are lattices of extracellular DNA, chromatin, and antibacterial proteins that mediate extracellular killing of microorganisms and are thought to form via a unique death pathway signaled by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-generated reactive oxygen species (ROS). We found that neutrophils from term and preterm infants fail to form NETs when activated by inflammatory agonists-in contrast to leukocytes from healthy adults. IntroductionPolymorphonuclear leukocytes (PMNs, neutrophils) are highly specialized cellular effectors in host defense and immune surveillance. Mature human PMNs from healthy adults have a unique repertoire of activities, including phagocytosis, degranulation of antimicrobial enzymes and peptides, and generation of oxygen radicals with antimicrobial properties. 1-6 Synthesis of inflammatory and regulatory lipids and proteins complements these innate mechanisms. 1,4,5 PMNs have evolved for capture, containment, and destruction of bacteria and fungi and also have activity against intracellular pathogens and viruses. 2,3 PMNs have additional important roles in tissue repair and integration of innate and adaptive immune responses. 6 If, however, these specialized defensive mechanisms become dysregulated or unregulated, PMNs can paradoxically be mediators of inflammatory tissue injury. 1,6 Consistent with their requisite activities in host defense, defects in PMN functions cause immune deficiency syndromes. 2,7 Neutrophil defects can be hereditary, developmental, or acquired in nature. Specific genetic deficiencies in PMN function cause significant morbidity in subsets of children and adults and, in parallel, provide unique insights into molecular mechanisms that regulate leukocyte activities. 7,8 Nevertheless, these disorders are rare and arcane. In contrast, the developmental syndrome of neonatal neutrophil dysfunction, which is particularly important in premature infants, is common and contributes to infections in infants worldwide. As an example, neonatal PMN dysfunction is thought to be a pivotal feature of sepsis in the newborn. 9-11 The incidence of neonatal sepsis is estimated to be 1 to 5 cases per 1000 live births in the United States and to be even higher after very low birth weight premature deliveries (15-19/1000); in contrast, the incidence of sepsis is much lower in children older than 1 year of age and in young adults. 12-15 Furthermore, the incidence of neonatal sepsis is as high as 25% in some areas of the developing world. 16,17 Thus, neonatal PMN dysfunction is a contributor to a public health problem of significant proportions, and also may pr...

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In a Plenary Paper, Middleton and colleagues describe important transcriptional and translational changes in murine and human platelets during sepsis, elucidating the emerging role of platelets in the complications of systemic inflammatory illness.

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