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.
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In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have potential to propagate inflammation and microvascular thrombosis, including in the lungs of patients with acute respiratory distress syndrome. While elevated levels of blood neutrophils predict worse outcomes in COVID-19, the role of NETs has not been investigated. We now report that sera from patients with COVID-19 (n=50 patients, n=84 samples) have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute phase reactants including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. In summary, these data reveal high levels of NETs in many patients with COVID-19, where they may contribute to cytokine release and respiratory failure. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts, and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.
Background Cytokine storm is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. Research Question To identify if immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm. Study Design and Methods We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020 and April 24, 2020 were included. Cytokine storm was defined by inflammatory markers: ferritin >700ng/mL, C-reactive protein >30mg/dL or lactate dehydrogenase >300U/L. Patients were subdivided into six groups—no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-interleukin 6 antibody (tocilizumab) or anti-interleukin-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. Results 5,776 patients met the inclusion criteria. The most common comorbidities were hypertension (44-59%), diabetes (32-46%) and cardiovascular disease (5-14%). Patients most frequently met criteria with high lactate dehydrogenase (76.2%) alone or in combination, followed by ferritin (63.2%) and C-reactive protein (8.4%). More than 80% of patients had an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination had lower mortality compared to standard of care (Hazard Ratio (HR):0.44, 95% confidence interval (CI): 0.35-0.55; p <0.0001) and when compared to corticosteroids alone (HR:0.66, 95%CI: 0.53-0.83; p-value=0.004), or in combination with anakinra (HR:0.64, 95%CI:0.50-0.81; p-value=0.003) . Corticosteroids when administered alone (HR:0.66, 95%CI:0.57-0.76; p<0.0001) or in combination with tocilizumab (HR:0.43, 95%CI:0.35-0.55; p<0.0001) or anakinra (HR:0.68, 95%CI:0.57-0.81; p<0.0001) improved hospital survival compared to standard of care. Interpretation The combination of corticosteroids with tocilizumab had superior survival outcome when compared to standard of care and corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with COVID-19 cytokine storm compared to standard of care.
Background Mechanically ventilated patients with COVID-19 have a mortality of 24–53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. Methods Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19—including three requiring veno-venous extracorporeal membrane oxygenation—treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. Results The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. Conclusions Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.
The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated levels of inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and suggest potential therapeutic targets.
The use of e-cigarettes to deliver aerosolized nicotine has gained popularity in recent years.Numerous reports have cited the development of acute pulmonary disease linked to vaping nicotine as well as marijuana-based products. As cultural attitudes evolve and policies shift toward the legalization of marijuana, its use has become more prevalent. Given the increased prevalence of marijuana consumption and e-cigarette usage, better insight into its potential to cause lung toxicity is warranted. The clinical, radiographic, and histopathologic characteristics of lung injury associated with vaping, particularly with marijuana-based products, have yet to be well described in the literature. We present eight patients, most of whom were admitted recently to our institution with acute respiratory failure following vaping. The majority of patients were young, with a median age of 31.5 years (range, 24-62 years) and with no known underlying lung disease. This case series highlights common clinical findings as well as the varied radiographic and histopathologic features of acute respiratory failure associated with vaping predominantly marijuana-based products. As more cases of vaping-associated pulmonary injury unfold, data will be available to further characterize this emerging disease entity.Improved understanding of disease pathogenesis and its clinical course will help clinicians determine optimal management and follow-up strategies for this patient population. CHEST 2020; 157(3):e63-e68
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