Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

The mucous secretions found in the airways of COVID-19 patients ( Mao et al., 2020 ,Preprint) are reminiscent of those seen in CF patients ( Martínez-Alemán et al., 2017 ). The cause and origin of these secretions are unclear. However, in CF, mucous secretions impair gas exchange and have been shown to contain extracellular DNA, in part originating from NETs released in response to persistent lung infections. Furthermore, the excessive formation of NETs with increased NE makes the mucus thick and viscous ( Manzenreiter et al., 2012 ), not only impairing ventilation but also facilitating the colonization of bacteria. Such colonization further promotes neutrophil recruitment and NET formation, increasing mucus viscosity and consequently lowering the patient’s respiratory function. If the mucous secretions in COVID-19 contain NETs, they may play similar roles as they do in CF: impairing gas exchange and facilitating secondary infections.

Due to the clear similarities between the clinical presentation of severe COVID-19 and known NETopathies—ARDS and microthrombosis—we propose that excess NETs may play a major role in the disease. Our understanding of NET formation and function is incomplete, but drugs that target NETs exist or are in development (Fig. 4). These drugs include inhibitors of the molecules required for NET formation: NE, PAD4, and gasdermin D. For example, endogenous inhibitors of NET formation, which may function by inhibiting PAD4, have been isolated from umbilical cord plasma (Yost et al., 2016), and these are in development for the treatment of inflammatory syndromes such as COVID-19. Clinical development of inhibitors against NE is the most advanced, and importantly, they could inhibit both the formation of NETs, where NE activity is part of the signaling mechanism, and the toxic activities of NE on the NETs. The NE inhibitor sivelestat was approved to treat ARDS in Japan and South Korea, but it did not increase survival after ARDS in a meta-analysis of clinical trials (Tagami et al., 2014). However, a new generation of potent NE inhibitors, including lonodelestat (POL6014), alvelestat, CHF6333, and elafin, have undergone Phase I testing. As a result, it may be possible to expedite their development as treatments for COVID-19. Gasdermin D inhibitors remain in preclinical development, but an existing drug—disulfiram, used to treat alcoholism—has been reported to inhibit gasdermin D and limit lung injury in animal models (Hu et al., 2018 Preprint). Finally, colchicine is another existing drug that could inhibit both neutrophil recruitment to sites of inflammation and the secretion of IL1β, and trials using colchicine in COVID-19 are underway (ClinicalTrials.gov identifiers: NCT04326790, NCT04328480, NCT04322565, NCT04322682).

A recombinant DNase I (dornase alfa), delivered by inhalation, is approved to dissolve NETs in the airways of patients with CF to clear mucus and improve symptoms (Papayannopoulos et al., 2011). Additionally, an actin-resistant DNase (PRX-110/alidornase alfa) has been tested in CF patients in Phase I and II trials with encouraging results (ClinicalTrials.gov identifiers: NCT02605590, NCT02722122) and could potentially be more potent than dornase alfa. Other engineered DNase proteins, such as DNase 1–like 3, which is being developed to dissolve NETs (Fuchs et al., 2019), could enter clinical development soon. We propose that DNases may help dissolve the mucous secretions of COVID-19 patients as they do in CF patients, improving ventilation and reducing the risk of secondary infections. Dornase alfa is normally administered through nebulizers, but in many medical centers, these are avoided in COVID-19 due to the risk of aerosolizing SARS-CoV-2 and endangering healthcare workers. However, approaches exist that deliver aerosols in closed circuits for mechanically ventilated patients (Dhand, 2017). For nonintubated patients, therapies can be safely nebulized in negative pressure rooms. In addition to their possible effects on mucous secretions, DNase treatments may also prevent the further progression to ARDS, as DNase I delivered through the airways increases survival in relevant animal models (Lefrançais et al., 2018; Thomas et al., 2012; Zou et al., 2018).