scholarly journals Neutrophil Extracellular Traps in Fatal COVID-19-Associated Lung Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Astrid Obermayer ◽  
Lisa-Maria Jakob ◽  
Jasmin D. Haslbauer ◽  
Matthias S. Matter ◽  
Alexandar Tzankov ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Distress Syndrome ◽  
Clinical Presentation ◽  
Diffuse Alveolar Damage ◽  
Treatment Options ◽  
Neutrophil Extracellular Traps ◽  
Lung Damage ◽  
Morphological Evidence ◽  
Potential Treatment ◽  
Extracellular Traps

An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.

scholarly journals Countermeasures to Coronavirus Disease 2019: Are Immunomodulators Rational Treatment Options—A Critical Review of the Evidence

2020 ◽  
Vol 7 (7) ◽  
Author(s):  
Daniel B Chastain ◽  
Tia M Stitt ◽  
Phong T Ly ◽  
Andrés F Henao-Martínez ◽  
Carlos Franco-Paredes ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Failure ◽  
Distress Syndrome ◽  
Treatment Options ◽  
Immune Dysregulation ◽  
Lung Damage ◽  
Safety And Efficacy ◽  
Rational Treatment ◽  
Immunomodulatory Therapies

Abstract Severe acute respiratory syndrome coronavirus 2 is associated with higher concentrations of proinflammatory cytokines that lead to lung damage, respiratory failure, and resultant increased mortality. Immunomodulatory therapy has the potential to inhibit cytokines and quell the immune dysregulation. Controversial data found improved oxygenation after treatment with tocilizumab, an interleukin-6 inhibitor, sparking a wave of interest and resultant clinical trials evaluating immunomodulatory therapies. The purpose of this article is to assess potential proinflammatory targets and review the safety and efficacy of immunomodulatory therapies in managing patients with acute respiratory distress syndrome associated with coronavirus disease 2019.

scholarly journals Presence of hyaluronan in lung alveoli in severe Covid-19: An opening for new treatment options?

2020 ◽  
Vol 295 (45) ◽  
pp. 15418-15422 ◽  
Author(s):  
Urban Hellman ◽  
Mats G. Karlsson ◽  
Anna Engström-Laurent ◽  
Sara Cajander ◽  
Luiza Dorofte ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Distress Syndrome ◽  
Staining Method ◽  
Present Finding ◽  
Treatment Options ◽  
Normal Lung ◽  
Clear Liquid ◽  
Respiratory Impairment ◽  
New Treatment ◽  
Inflammation Of The Lungs

Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation of the lungs with increasing respiratory impairment. In fatal Covid-19, lungs at autopsy have been filled with a clear liquid jelly. However, the nature of this finding has not yet been determined. The aim of the study was to demonstrate whether the lungs of fatal Covid-19 contain hyaluronan, as it is associated with inflammation and acute respiratory distress syndrome (ARDS) and may have the appearance of liquid jelly. Lung tissue obtained at autopsy from three deceased Covid-19 patients was processed for hyaluronan histochemistry using a direct staining method and compared with staining in normal lung tissue. Stainings confirmed that hyaluronan is obstructing alveoli with presence in exudate and plugs, as well as in thickened perialveolar interstitium. In contrast, normal lungs only showed hyaluronan in intact alveolar walls and perivascular tissue. This is the first study to confirm prominent hyaluronan exudates in the alveolar spaces of Covid-19 lungs, supporting the notion that the macromolecule is involved in ARDS caused by SARS-CoV-2. The present finding may open up new treatment options in severe Covid-19, aiming at reducing the presence and production of hyaluronan in the lungs.

scholarly journals Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Blood ◽  
2020 ◽  
Vol 136 (10) ◽  
pp. 1169-1179 ◽  
Author(s):  
Elizabeth A. Middleton ◽  
Xue-Yan He ◽  
Frederik Denorme ◽  
Robert A. Campbell ◽  
David Ng ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Ex Vivo ◽  
Neutrophil Extracellular Traps ◽  
Dna Complexes ◽  
Platelet Factor ◽  
Extracellular Traps ◽  
Fraction Of Inspired Oxygen

Abstract 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 they 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) and 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 < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .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.

scholarly journals Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Coraline Radermecker ◽  
Nancy Detrembleur ◽  
Julien Guiot ◽  
Etienne Cavalier ◽  
Monique Henket ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Neutrophil Extracellular Traps ◽  
Pulmonary Complications ◽  
Lung Damage ◽  
Extracellular Traps

Infection with SARS-CoV-2 is causing a deadly and pandemic disease called coronavirus disease–19 (COVID-19). While SARS-CoV-2–triggered hyperinflammatory tissue-damaging and immunothrombotic responses are thought to be major causes of respiratory failure and death, how they relate to lung immunopathological changes remains unclear. Neutrophil extracellular traps (NETs) can contribute to inflammation-associated lung damage, thrombosis, and fibrosis. However, whether NETs infiltrate particular compartments in severe COVID-19 lungs remains to be clarified. Here we analyzed postmortem lung specimens from four patients who succumbed to COVID-19 and four patients who died from a COVID-19–unrelated cause. We report the presence of NETs in the lungs of each COVID-19 patient. NETs were found in the airway compartment and neutrophil-rich inflammatory areas of the interstitium, while NET-prone primed neutrophils were present in arteriolar microthrombi. Our results support the hypothesis that NETs may represent drivers of severe pulmonary complications of COVID-19 and suggest that NET-targeting approaches could be considered for the treatment of uncontrolled tissue-damaging and thrombotic responses in COVID-19.

scholarly journals Targeting potential drivers of COVID-19: Neutrophil extracellular traps

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Betsy J. Barnes ◽  
Jose M. Adrover ◽  
Amelia Baxter-Stoltzfus ◽  
Alain Borczuk ◽  
Jonathan Cools-Lartigue ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Cytokine Production ◽  
Neutrophil Extracellular Traps ◽  
Organ Damage ◽  
Clinical Severity ◽  
Pulmonary Diseases ◽  
Cytokine Storm ◽  
Extracellular Traps ◽  
Autopsy Specimen

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 Pathologist's Approach to Acute Lung Injury

2010 ◽  
Vol 134 (5) ◽  
pp. 719-727 ◽  
Author(s):  
Mary Beth Beasley
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Personal Experience ◽  
Distress Syndrome ◽  
Clinical Presentation ◽  
Diffuse Alveolar Damage ◽  
Eosinophilic Pneumonia ◽  
Patient Treatment ◽  
Acute Eosinophilic Pneumonia ◽  
Etiologic Agents

Abstract Context.—Acute lung injury and acute respiratory distress syndrome are significant causes of pulmonary morbidity and are frequently fatal. These 2 entities have precise definitions from a clinical standpoint. Histologically, cases from patients with clinical acute lung injury typically exhibit diffuse alveolar damage, but other histologic patterns may occasionally be encountered such as acute fibrinous and organizing pneumonia, acute eosinophilic pneumonia, and diffuse hemorrhage with capillaritis. Objective.—To review the diagnostic criteria for various histologic patterns associated with a clinical presentation of acute lung injury and to provide diagnostic aids and discuss the differential diagnosis. Data sources.—The review is drawn from pertinent peer-reviewed literature and the author's personal experience. Conclusions.—Acute lung injury remains a significant cause of morbidity and mortality. The pathologist should be aware of histologic patterns of lung disease other than diffuse alveolar damage, which are associated with a clinical presentation of acute lung injury. Identification of these alternative histologic findings, as well as identification of potential etiologic agents, especially infection, may impact patient treatment and disease outcome.

scholarly journals Neutrophil extracellular traps persist at high levels in the lower respiratory tract of critically ill COVID-19 patients

2021 ◽  
Author(s):  
Werner J D Ouwendijk ◽  
Matthijs P Raadsen ◽  
Jeroen J A van Kampen ◽  
Robert M Verdijk ◽  
Jan H von der Thusen ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Tract ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Critically Ill ◽  
Inflammatory Markers ◽  
Lower Respiratory Tract ◽  
Distress Syndrome ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps

Abstract SARS-CoV-2 induced lower respiratory tract (LRT) disease can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill COVID-19 patients. Plasma NET levels peaked early after ICU admission and correlated with SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma. Baseline plasma NET quantity correlated with disease severity, but was not associated with soluble markers of thrombosis nor with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from fatal COVID-19 patients. Thus, NETs are produced and retained in the LRT of critical COVID-19 patients and could contribute to SARS-CoV-2-induced ARDS pathology.  

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