THE ROLE OF NEUTROPHIL EXTRACELLULAR TRAPS (NETs) IN THE IMMUNOPATHOGENESIS OF SEVERE COVID-19: POTENTIAL IMMUNOTHERAPEUTIC STRATEGIES REGULATING NET FORMATION AND ACTIVITY.

The role of neutrophil granulocytes (NG) in the pathogenesis of COVID-19 is associated with the NG recruitment into inflammatory foci, activation of their functions and enhanced formation of neutrophil extracellular networks (NETs). In this review, we analyzed a large body of scientific literature devoted to the features of developing NETs, their role in the COVID-19 pathogenesis, a role in emerging immunothrombosis, vasculitis, acute respiratory distress syndrome, cytokine storm syndrome, and multi-organ lesions. Convincing data are presented clearly indicating about a profound role of NETs in the COVID-19 immunopathogenesis and associated severe complications resulting from intensified inflammation process, which is a key for the course of SARS-CoV-2 virus infection. The presented role of NGs and NETs, along with that of other immune system cells and pro-inflammatory cytokines, is extremely important in understanding development of overactive immune response in severe COVID-19. The scientific results obtained available now allow to identify an opportunity of regulatory effects on hyperactivated NGs, NETosis at various stages and on limiting a negative impact of pre-formed NETs on various tissues and organs. All the aforementioned data should help in creating new, specialized immunotherapy strategies designed to increase the odds of survival, reduce severity of clinical manifestations in COVID-19 patients as well as markedly reduce mortality rates. Currently, it is possible to use existing drugs, while a number of new drugs are being developed, the action of which can regulate NG quantity, positively affect NG functions and limit intensity of NETosis. Continuing research on the role of hyperactive NG and NETosis as well as understanding the mechanisms of regulating NET formation and restriction in severe COVID-19, apparently, are of high priority, because in the future the new data obtained could pave the basis for development of targeted approaches not only for immunotherapy aimed at limiting education and blocking negative effects already formed NETs in severe COVID-19, but also for immunotherapy, which could be used in combination treatment of other netopathies, primarily autoimmune diseases, auto-inflammatory syndromes, severe purulent-inflammatory processes, including bacterial sepsis and hematogenous osteomyelitis.Copyright © 2023 Saint Petersburg Pasteur Institute. All rights reserved.

DNase analysed by a novel competitive assay in patients with complications after ChAdOx1 nCoV-19 vaccination and in normal unvaccinated blood donors

Increased levels of neutrophil extracellular traps (NETs) have been detected in individuals with vaccine complications after the ChAdOx1 nCov vaccine with a correlation between the severity of vaccine side effects and the level of NETosis. DNases may disrupt NETs by degrading their content of DNA, and a balance has been reported between NETs and DNases. Because of this and since the inflammatory marker NETs may be used as a confirmatory test in diagnosing VITT, it is of interest to monitor levels of DNase in patients with increased NETs levels. The current novel rapid DNase ELISA was tested in blood samples of patients with known increased levels of NETs with or without VITT after ChAdOx1 nCoV-19 vaccination. DNase levels in VITT patients were significantly increased compared with normal unvaccinated blood donors and compared with patients with post-vaccination symptoms but not VITT. However, since EDTA was found to inhibit DNase, serum and not EDTA-plasma samples should be applied for DNase testing. The novel DNase assay may serve as a supplementary test to the NETs test when analysing samples from patients with suspected increased NETs levels.Copyright © 2023 The Scandinavian Foundation for Immunology.

COVID-19 and Beyond: Taming the Virtual Healthcare Tiger with Colored Petri Nets based Modeling and Simulation

The Coronavirus crisis has forced hospitals globally to develop new virtual service portals and systems to: 1) triage, diagnose, and manage new patients virtually for every clinical specialty at home as their symptoms emerge, avoiding COVID-19 exposure to patient or physicians, and hospitalization, as much as possible, and 2) discharge, track, and support recovered patients via homecare and virtual visits to free as many critical care beds as possible. This paper focuses on simulating and modeling an episode of care with innovative initial patient contact and triage processes using the Colored Petri Net (CPN) formalism to help optimize workflow, patient throughput, and overall system efficacy. The two patient triage programs under consideration are a health system in Australia and an orthopedic surgical program in the US. We describe our model for the US program. Our presented results establish a desired stratification of patients through a virtual musculoskeletal triage. © 2022 IEEE Computer Society. All rights reserved.

Circulating neutrophil extracellular trap (NET)-forming 'rogue' neutrophil subset, immunotype [DEspR + CD11b +], mediate multi-organ failure in COVID-19-an observational study.

Background: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, there is no curative intent therapy able to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating NET-forming neutrophils [NET + Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. Methods: We conducted a prospective observational study of circulating levels of CD11b + [NET + N] immunotyped for dual endothelin-1/signal peptide receptor (DEspR ±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET + N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. Results: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r S = 0.80) and ICUFD (r S = -0.76); circulating DEspR + [NET + Ns] with t1-SOFA (r S = 0.71), t2-SOFA (r S = 0.62), and ICUFD (r S = -0.63), and ANC with t1-SOFA (r S = 0.71), and t2-SOFA (r S = 0.61).Causal mediation analysis identified DEspR + [NET + Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR + [NET + Ns] were theoretically reduced to zero. Concordantly, DEspR + [NET + Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR + [NET + Ns] were reduced to zero. In patients with t1-SOFA > 1, the indirect effect of a hypothetical treatment eliminating DEspR + [NET + Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR + [NET + Ns], and no significant mediation of SOFA-score through ANC. Conclusions: Despite equivalent correlations, DEspR + [NET + Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR + [NET + Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-023-00143-x.

COVID-19, Blood Lipid Changes, and Thrombosis.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

Face Mask Detection using Single Shot Multibox Detector and Mobile Net

During the pandemic time government took many safety measures to protect the public at common gathering places. People are insisted on wearing a face mask to protect themselves from COVID. Even then many people were roaming without a mask in public places. The proposed technique to detect the face mask is to identify the person's face with mask and person's face without mask and reporting to the safety officers about the persons without mask for further action. The proposed Face mask detection is developed using the ML technique which can be used to classify the people wearing masks and not wearing masks with the input given to the model. The proposed face mask detector is a one-stage detector that focuses on detecting the face mask alone. This work is implemented using the Tensor flow and Computer vision libraries. NumPy is used for image processing. The data set used in MAFA dataset. The model is trained using this data set to get the accurate results. To enable multiple detection here the single shot with multi box detector is used. The base model used for this process is Mobile Net V2. The proposed model is simple and it can be integrated with several other technologies to provide high accuracy percentage of output in the minimum possible time. © 2022 IEEE.

Maternal and fetal issues in COVID-19-mediated thromboinflammation

The COVID-19 pandemic has become the greatest challenge to humanity of this century and has raised many new questions in various fields, primarily in medicine—in the field of microbiology, pathological anatomy and pathophysiology, immunology, clinical hemostasis, and almost all clinical disciplines, including, of course, obstetrics and perinatology. Systemic effects of SARS-CoV-2 are largely associated with thromboinflammation. The cause of death from COVID-19 is mainly pulmonary insufficiency and/or thrombosis (macro- and microcirculation). Pregnancy, even under normal conditions, is accompanied by changes in hemostasis with a shift toward hypercoagulation and increased inflammation, mainly in the third trimester of pregnancy. This in itself creates conditions for unfavorable outcomes for the mother and fetus. At the same time, pregnancy is a unique condition when a semiallogeneic fetus is reliably protected by the placenta from pathogenic influences under normal conditions. Despite this, the issue of transplacental transmission of the SARS-CoV-2 virus from mother to fetus is still debatable—individual observations allow us to judge this possibility. The issue of vaccination in pregnant women and its effect on the fetus is also extremely relevant. The chapter discusses the pathogenesis of complications in COVID-19, epidemiology, as well as possible ways to predict and prevent SARS-CoV-2-mediated pregnancy complications. © 2023 Elsevier Inc. All rights reserved.

Leveraging Deep Learning for Designing Healthcare Analytics Heuristic for Diagnostics.

Healthcare Informatics is a phenomenon being talked about from the early 21st century in the era in which we are living. With evolution of new computing technologies huge amount of data in healthcare is produced opening several research areas. Managing the massiveness of this data is required while extracting knowledge for decision making is the main concern of today. For this task researchers are doing explorations in big data analytics, deep learning (advanced form of machine learning known as deep neural nets), predictive analytics and various other algorithms to bring innovation in healthcare. Through all these innovations happening it is not wrong to establish that disease prediction with anticipation of its cure is no longer unrealistic. First, Dengue Fever (DF) and then Covid-19 likewise are new outbreak in infectious lethal diseases and diagnosing at all stages is crucial to decrease mortality rate. In case of Diabetes, clinicians and experts are finding challenging the timely diagnosis and analyzing the chances of developing underlying diseases. In this paper, Louvain Mani-Hierarchical Fold Learning healthcare analytics, a hybrid deep learning technique is proposed for medical diagnostics and is tested and validated using real-time dataset of 104 instances of patients with dengue fever made available by Holy Family Hospital, Pakistan and 810 instances found for infectious diseases including prognosis of; Covid-19, SARS, ARDS, Pneumocystis, Streptococcus, Chlamydophila, Klebsiella, Legionella, Lipoid, etc. on GitHub. Louvain Mani-Hierarchical Fold Learning healthcare analytics showed maximum 0.952 correlations between two clusters with Spearman when applied on 240 instances extracted from comorbidities diagnostic data model derived from 15696 endocrine records of multiple visits of 100 patients identified by a unique ID. Accuracy for induced rules is evaluated by Laplace (Fig. 8) as 0.727, 0.701 and 0.203 for 41, 18 and 24 rules, respectively. Endocrine diagnostic data is made available by Shifa International Hospital, Islamabad, Pakistan. Our results show that in future this algorithm may be tested for diagnostics on healthcare big data.

Chemokines and chemokine receptors during COVID-19 infection.

Chemokines are crucial inflammatory mediators needed during an immune response to clear pathogens. However, their excessive release is the main cause of hyperinflammation. In the recent COVID-19 outbreak, chemokines may be the direct cause of acute respiratory disease syndrome, a major complication leading to death in about 40% of severe cases. Several clinical investigations revealed that chemokines are directly involved in the different stages of SARS-CoV-2 infection. Here, we review the role of chemokines and their receptors in COVID-19 pathogenesis to better understand the disease immunopathology which may aid in developing possible therapeutic targets for the infection.

Xuanfei Baidu Decoction regulates NETs formation via CXCL2/CXCR2 signaling pathway that is involved in acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening symptoms in Coronavirus Disease 2019 (COVID-19) patients. Xuanfei Baidu Decoction (XFBD) is a recommend first-line traditional Chinese medicine (TCM) formula therapeutic strategy for COVID-19 patients. Prior studies demonstrated the pharmacological roles and mechanisms of XFBD and its derived effective components against inflammation and infections through multiple model systems, which provided the biological explanations for its clinical use. Our previous work revealed that XFBD inhibited macrophages and neutrophils infiltration via PD-1/IL17A signaling pathway. However, the subsequent biological processes are not well elucidated. Here, we proposed a hypothesis that XFBD can regulate the neutrophils-mediated immune responses, including neutrophil extracellular traps (NETs) formation and the generation of platelet-neutrophil aggregates (PNAs) after XFBD administration in lipopolysaccharide (LPS)-induced ALI mice. The mechanism behind it was also firstly explained, that is XFBD regulated NETs formation via CXCL2/CXCR2 axis. Altogether, our findings demonstrated the sequential immune responses of XFBD after inhibiting neutrophils infiltration, as well as shedding light on exploiting the therapy of XFBD targeting neutrophils to ameliorate ALI during the clinical course.

Coagulopathy in COVID-19 and anticoagulation clinical trials.

Severe acute respiratory disease coronavirus 2 (SARS-COV-2) first emerged in Wuhan, China, in December 2019 and has caused a global pandemic of a scale unprecedented in the modern era. People infected with SARS-CoV-2 can be asymptomatic, moderate symptomatic or develop severe COVID-19. Other than the typical acute respiratory distress syndrome (ARDS), patients with moderate or severe COVID-19 also develop a distinctive systemic coagulopathy, known as COVID-19-associated coagulopathy (CAC), which is different from sepsis-related forms of disseminated intravascular coagulation (DIC). Endotheliopathy or endotheliitis are other unique features of CAC. The endothelial cell perturbation can further increase the risk of thrombotic events in COVID-19 patients. In this review, we will summarize the current knowledge on COVID-19 coagulopathy and the possible mechanisms for the condition. We also discuss the results of clinical trials testing methods for mitigating thrombosis events in COVID-19 patients.

Progressive Observation of Covid-19 Vaccination Effects on Skin-Cellular Structures by Use of Intelligent Laser Speckle Classification (ILSC) Technique.

The recent pandemic showed that the current global research strategies on vaccine development in an emergency period necessitates more optimized supplementary techniques to observe instant progressive vaccines' subtle effects on human metabolisms to make better and speedy evolutionary health assessments. To fill this gap, we have followed a multi-disciplinary approach exploiting AI, laser-optics, and specific imaging methods. The proposed technique can make progressive observations on Covid-19 Astra Zeneca vaccination effects on skin cellular network by use of the well-established technique-Intelligent Laser Speckle Classification (ILSC), as Covid-19 is a skin-affecting systemic disease. The method also managed to distinguish between three different subject groups via their laser speckle skin image samplings, grouped as early-vaccinated, late-vaccinated and non-vaccinated participants. The results have proven that the ILSC technique, in association with the parametrically optimised Bayesian network, can classify hidden skin changes of vaccinated and non-vaccinated individuals up to 90% accuracy and is also capable of detecting instant progressive developments pertaining to skin cellular properties. The proposed method has also proven that the continuous Covid-19 vaccine effect on the sub-skin layers can be observable by high frequency and speedy non-invasive data collection in real-time with high reliability.

Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections.

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics and correlative analysis of an immunologically naïve SARS-CoV-2 clinical cohort from blood plasma of uninfected controls, mild, and severe infections. Consistent with previous observations, severe patient populations showed an elevation of pulmonary surfactant levels. Intriguingly, mild patients showed a statistically significant elevation in the carnosine dipeptidase modifying enzyme (CNDP1). Mild and severe patient populations showed a strong elevation in the metabolite L-cystine (oxidized form of the amino acid cysteine) and enzymes with roles in glutathione metabolism. Neutrophil extracellular traps (NETs) were observed in both mild and severe populations, and NET formation was higher in severe vs. mild samples. Our correlative analysis suggests a potential protective role for CNDP1 in suppressing PSPB release from the pulmonary space whereas NET formation correlates with increased PSPB levels and disease severity. In our discussion we put forward a possible model where NET formation drives pulmonary occlusions and CNDP1 promotes antioxidation, pleiotropic immune responses, and vasodilation by accelerating histamine synthesis.

Can plant-derived anti-HIV compounds be used in COVID-19 cases?

People living with HIV are more exposed to the adverse health effects of the worldwide COVID-19 pandemic. The pandemic's health and social repercussions may promote drug abuse and inadequate HIV management among this demographic. The coronavirus pandemic of 2019 (COVID-19) has caused unprecedented disruption worldwide in people's lives and health care. When the COVID-19 epidemic was identified, people with HIV faced significant obstacles and hurdles to achieving optimal care results. The viral spike protein (S-Protein) and the cognate host cell receptor angiotensin-converting enzyme 2 (ACE2) are both realistic and appropriate intervention targets. Calanolides A, Holy Basil, Kuwanon-L, and Patentiflorin have anti-HIV effects. Our computational biology study investigated that these compounds all had interaction binding scores related to S protein of coronavirus of -9.0 kcal /mol, -7.1 kcal /mol, -9.1 kcal /mol, and -10.3 kcal/mol/mol, respectively. A combination of plant-derived anti-HIV compounds like protease inhibitors and nucleoside analogs, which are commonly used to treat HIV infection, might be explored in clinical trials for the treatment of COVID-19.

Anti-DNA-IgM Favors the Detection of NET-Associated Extracellular DNA.

During inflammatory responses, neutrophils enter the sites of attack where they execute various defense mechanisms. They (I) phagocytose microorganisms, (II) degranulate to release cytokines, (III) recruit various immune cells by cell-type specific chemokines, (IV) secrete anti-microbials including lactoferrin, lysozyme, defensins and reactive oxygen species, and (V) release DNA as neutrophil extracellular traps (NETs). The latter originates from mitochondria as well as from decondensed nuclei. This is easily detected in cultured cells by staining of DNA with specific dyes. However, in tissues sections the very high fluorescence signals emitted from the condensed nuclear DNA hamper the detection of the widespread, extranuclear DNA of the NETs. In contrast, when we employ anti-DNA-IgM antibodies, they are unable to penetrate deep into the tightly packed DNA of the nucleus, and we observe a robust signal for the extended DNA patches of the NETs. To validate anti-DNA-IgM, we additionally stained the sections for the NET-markers histone H2B, myeloperoxidase, citrullinated histone H3, and neutrophil elastase. Altogether, we have described a fast one-step procedure for the detection of NETs in tissue sections, which provides new perspectives to characterize neutrophil-associated immune reactions in disease.

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic.

COVID-19 and Religion: Pandemic Lessons and Legacies

The essay draws on a multiyear project to assess how religious communities worldwide experienced the COVID-19 pandemic and how they have in turn shaped responses to the pandemic. It focuses on religious public health responses, religious gatherings, and practices such as funerals, and the remarkable responses, especially at community level, offering social safety nets to people devastated by lockdowns and economic crises. Stigma, violence against specific groups, effects on women and children, and mental health are central challenges. The pandemic casts new light on contemporary forms of religious practice, community, mobilization, and engagement. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Struggling, helping and adapting: Crowdfunding motivations and outcomes during the early US COVID-19 pandemic.

During the early months of COVID-19, many people in the US turned to charitable crowdfunding to seek and provide assistance. Little is known about the needs, hopes or experiences that motivated US pandemic crowdfunding and how these were correlated with campaign success. This study uses a mixed-methods data analysis of a randomised cluster sample of 919 US GoFundMe campaigns during the first 7 months of the pandemic. Overall, most campaigns performed poorly, and 38% got no donations at all. The largest proportion of campaigns aimed to address individual, acute financial struggles, often arising from considerable challenges accessing or qualifying for government assistance. These campaigns, as well as those involving campaigners and beneficiaries of colour, tended to be least successful. Qualitative thematic analysis revealed three key crowdfunding motivations that reflect individualistic, agentive responses to the pandemic: struggling, helping and adapting. These motivations reveal a shift away from social suffering and collective mobilisation and towards largely individualised efforts of survival as digital crowdfunding becomes a key domain of crisis response. Crowdfunding platforms are playing an increasingly important role in mediating and influencing individual and collective responses to crisis, which has important political ramifications for how societies perceive and address health emergencies.

The role of extracellular histones in COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread from China within 2 months to become a global pandemic. Infection can cause a diversity of symptoms ranging from asymptomatic to severe acute respiratory distress syndrome (ARDS) with an increased risk of vascular hyperpermeability, pulmonary inflammation, extensive lung damage and thrombosis. One of the host defense systems in coronavirus disease 2019 (COVID-19) is the formation of neutrophil extracellular traps (NETs). Numerous studies have revealed elevated levels of NET components, such as cell-free DNA (cfDNA), extracellular histones, neutrophil elastase (NE) and myeloperoxidase (MPO), in plasma, serum and tracheal aspirates of severe COVID-19 patients. Extracellular histones, a major component of NETs, are clinically very relevant since they represent promising biomarkers and drug targets given that several studies have identified histones as key mediators in the onset and progression of various diseases, including COVID-19. However, the role of extracellular histones in COVID-19 per se remains relatively under-explored. Histones are nuclear proteins that can be released into the extracellular space via apoptosis, necrosis or NET formation and are then regarded as cytotoxic damage-associated molecular patterns (DAMPs) that have the potential to damage tissues and impair organ function. This review will highlight the mechanisms of extracellular histone-mediated cytotoxicity and focus on the role that histones play in COVID-19. Thereby this paper facilitates a bench-to-bedside view of extracellular histone-mediated cytotoxicity, its role in COVID-19, and histones as potential drug targets and biomarkers for future theranostics in the clinical treatment of COVID-19 patients. This article is protected by copyright. All rights reserved.