Controversial role of neutrophilic granulocytes in the immunopathogenesis of COVID-19: correlation with imbalance of pro-inflammatory neutrophil-associated cytokines and interferon alpha deficiency.

Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Acute Coronary Syndrome during the Pandemic New Coronavirus Infection.

The experience of managing patients with COVID-19 around the world has shown that, although respiratory symptoms predominate during the manifestation of infection, then many patients can develop serious damage to the cardiovascular system. However, coronary artery disease (CHD) remains the leading cause of death worldwide. The purpose of the review is to clarify the possible pathogenetic links between COVID-19 and acute coronary syndrome (ACS), taking into account which will help to optimize the management of patients with comorbid pathology. Among the body's responses to SARS-CoV-2 infection, which increase the likelihood of developing ACS, the role of systemic inflammation, the quintessence of which is a "cytokine storm" that can destabilize an atherosclerotic plaque is discussed. Coagulopathy, typical for patients with Covid-19, is based on immunothrombosis, caused by a complex interaction between neutrophilic extracellular traps and von Willebrandt factor in conditions of systemic inflammation. The implementation of a modern strategy for managing patients with ACS, focused on the priority of percutaneous interventions (PCI), during a pandemic is experiencing great difficulties due to the formation of time delays before the start of invasive procedures due to the epidemiological situation. Despite this, the current European, American and Russian recommendations for the management of infected patients with ACS confirm the inviolability of the position of PCI as the first choice for treating patients with ACS and the undesirability of replacing invasive treatment with thrombolysis.Copyright © 2023 Stolichnaya Izdatelskaya Kompaniya. All rights reserved.

Controversial role of neutrophilic granulocytes in the immunopathogenesis of COVID-19: correlation with imbalance of pro-inflammatory neutrophil-associated cytokines and interferon alpha deficiency.

Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Acute Coronary Syndrome during the Pandemic New Coronavirus Infection.

The experience of managing patients with COVID-19 around the world has shown that, although respiratory symptoms predominate during the manifestation of infection, then many patients can develop serious damage to the cardiovascular system. However, coronary artery disease (CHD) remains the leading cause of death worldwide. The purpose of the review is to clarify the possible pathogenetic links between COVID-19 and acute coronary syndrome (ACS), taking into account which will help to optimize the management of patients with comorbid pathology. Among the body's responses to SARS-CoV-2 infection, which increase the likelihood of developing ACS, the role of systemic inflammation, the quintessence of which is a "cytokine storm" that can destabilize an atherosclerotic plaque is discussed. Coagulopathy, typical for patients with Covid-19, is based on immunothrombosis, caused by a complex interaction between neutrophilic extracellular traps and von Willebrandt factor in conditions of systemic inflammation. The implementation of a modern strategy for managing patients with ACS, focused on the priority of percutaneous interventions (PCI), during a pandemic is experiencing great difficulties due to the formation of time delays before the start of invasive procedures due to the epidemiological situation. Despite this, the current European, American and Russian recommendations for the management of infected patients with ACS confirm the inviolability of the position of PCI as the first choice for treating patients with ACS and the undesirability of replacing invasive treatment with thrombolysis.Copyright © 2023 Stolichnaya Izdatelskaya Kompaniya. All rights reserved.

The Impact of COVID-19 on Breast Cancer Recurrence: A Brief Review

COVID-19 has affected several aspects of health care systems worldwide. While our understanding of the impact of cancer and its treatment on COVID-19 mortality is improving, there is still little known regarding the possible mechanisms by which COVID-19 might affect cancer cells, especially breast cancer. Several factors activated during COVID-19 have been implicated in tumorigenesis and the development of metastasis. Inflammation, hypoxia, reduced levels of angiotensin-converting enzyme 2, and elevated levels of interleukin 6 and some other cytokines that are hallmarks of COVID-19 are capable of inducing tumor relapse and metastasis. Understanding the interaction between COVID-19 and breast cancer cells is essential for evaluating the potential long-term risks of COVID-19 in patients and for scheduling necessary preventive, screening, and therapeutic interventions.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Abnormal thrombosis and neutrophil activation increase hospital-acquired sacral pressure injuries and morbidity in COVID-19 patients.

Hospitalized patients have an increased risk of developing hospital-acquired sacral pressure injury (HASPI). However, it is unknown whether SARS-CoV-2 infection affects HASPI development. To explore the role of SARS-CoV-2 infection in HASPI development, we conducted a single institution, multi-hospital, retrospective study of all patients hospitalized for ≥5 days from March 1, 2020 to December 31, 2020. Patient demographics, hospitalization information, ulcer characteristics, and 30-day-related morbidity were collected for all patients with HASPIs, and intact skin was collected from HASPI borders in a patient subset. We determined the incidence, disease course, and short-term morbidity of HASPIs in COVID-19(+) patients, and characterized the skin histopathology and tissue gene signatures associated with HASPIs in COVID-19 disease. COVID-19(+) patients had a 63% increased HASPI incidence rate, HASPIs of more severe ulcer stage (OR 2.0, p<0.001), and HASPIs more likely to require debridement (OR 3.1, p=0.04) compared to COVID-19(-) patients. Furthermore, COVID-19(+) patients with HASPIs had 2.2x increased odds of a more severe hospitalization course compared to COVID-19(+) patients without HASPIs. HASPI skin histology from COVID-19(+) patients predominantly showed thrombotic vasculopathy, with the number of thrombosed vessels being significantly greater than HASPIs from COVID-19(-) patients. Transcriptional signatures of a COVID-19(+) sample subset were enriched for innate immune responses, thrombosis, and neutrophil activation genes. Overall, our results suggest that immunologic dysregulation secondary to SARS-CoV-2 infection, including neutrophil dysfunction and abnormal thrombosis, may play a pathogenic role in development of HASPIs in patients with severe COVID-19.

COVID-19 and kidneys: A follow-up.

In coronavirus disease 2019 (COVID-19) patients, acute tubular injury is the most frequently documented kidney disease. According to the current knowledge, its cause is assumed to be multifactorial. Other kidney diseases observed in non-severely ill COVID-19 patients are thrombotic microangiopathy, necrotizing glomerulonephritis, primary podocytopathy and interstitial nephritis. Even after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, necrotizing glomerulonephritis and other kidney diseases were observed. It is recommended that a renal biopsy be performed in COVID-19 patients with elevated creatinine, proteinuria, and/or hematuria to rule out a variety of other renal disorders. Both diseases (during a SARS-CoV-2 infection and after vaccination) probably share common features that act as triggers when the patient is preconditioned for a renal disease. The activation of the complement system and the formation of neutrophil extracellular traps (NET) could play a role in the pathogenesis. As the first report on autopsies carried out on COVID-19 patients throughout Germany showed, the autopsy plays a central role for a better understanding of this (relatively) new disease.Copyright © 2022, The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.

Jing Si Herbal Drink as a prospective adjunctive therapy for COVID-19 treatment: Molecular evidence and mechanisms

Background: SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide;therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives: This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method(s): We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Result(s): We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion(s): Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment.Copyright © 2021

Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma.

BACKGROUND: Neutrophil extracellular traps (NETs) are considered significant contributors to cancer progression, especially metastasis. However, it is still unclear whether NETs are involved in hepatitis B virus (HBV)-related hepatocarcinogenesis and have potential clinical significance during evaluation and management for hepatocellular carcinoma (HCC). In this study, we aimed to investigate the functional mechanism of NETs in HBV-related hepatocarcinogenesis and their clinical significance. METHODS: A total of 175 HCC patients with and without HBV infection and 58 healthy controls were enrolled in this study. NETs were measured in tissue specimens, freshly isolated neutrophils and blood serum from these patients, and the correlation of circulating serum NETs levels with malignancy was evaluated. The mechanism by which HBV modulates NETs formation was explored using cell-based studies. In addition, in vitro and in vivo experiments were further performed to clarify the functional mechanism of NETs on the growth and metastasis of HCC. RESULTS: We observed an elevated level of NETs in blood serum and tissue specimens from HCC patients, especially those infected with HBV. NETs facilitated the growth and metastasis of HCC both in vitro and in vivo, which were mainly dominated by increased angiogenesis, epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinases (MMPs)-induced extracellular matrix (ECM) degradation and NETs-mediated cell trapping. Inhibition of NETs generation by DNase 1 effectively abrogated the NETs-aroused HCC growth and metastasis. In addition, HBV-induced S100A9 accelerated the generation of NETs, which was mediated by activation of toll-like receptor (TLR4)/receptor for advanced glycation end products (RAGE)-reactive oxygen species (ROS) signaling. Further, circulatory NETs were found to correlate with viral load, TNM stage and metastasis status in HBV-related HCC, and the identified NETs could predict extrahepatic metastasis, with an area under the ROC curve (AUC) of 0.83 and 90.3% sensitivity and 62.8% specificity at a cutoff value of 0.32. CONCLUSIONS: Our findings indicated that activation of RAGE/TLR4-ROS signaling by HBV-induced S100A9 resulted in abundant NETs formation, which subsequently facilitated the growth and metastasis of HCC cells. More importantly, the identified circulatory NETs exhibited potential as an alternative biomarker for predicting extrahepatic metastasis in HBV-related HCC.

NEUTROPHIL AND MONOCYTE EXTRACELLULAR TRAPS IN THE DIAGNOSIS OF POST-COVID SYNDROME

Post-COVID syndrome (long covid, post COVID-19 condition) is characterized by cognitive and mental disorders, chest and joint pain, impaired sense of smell and taste, as well as by gastrointestinal and cardiac disorders. The diagnosis of post-COVID syndrome is based mainly on the patients' complaints. To date, no optimal diagnostic method has been proposed. The study was aimed to compare the informative value of the indicators obtained during conventional assessment of patients with post-COVID syndrome and the blood levels of neutrophil (NETs) and monocyte (METs) extracellular traps. The study involved neutropils and monocytes collected from 21 patients with post-COVID syndrome aged 18-59. Fluorescence microscopy and the SYBR Green (Evrogen) fluorescent dye for double-stranded DNA were used for enumeration and imaging of extracellular traps. Clinical and laboratory indicators make it impossible to identify the changes specific for post-COVID syndrome. At the same time, post-COVID syndrome is characterized by inflammation in the vascular endothelium. The filamentous forms of NETs found in blood are a laboratory feature of such aseptic inflammation. The filamentous forms of NETs have been detected only in those patients who have a history of mild to severe СOVID-19, while the filamentous forms of METs have been found in patients having a history of severe infection. The findings show that the detection of the filamentous forms of NETs and METs in blood is the most informative diagnostic feature of post-COVID syndrome.

Melastoma malabathricum L. Suppresses Neutrophil Extracellular Trap Formation Induced by Synthetic Analog of Viral Double-Stranded RNA Associated with SARS-CoV-2 Infection.

Platelet hyper-reactivity and neutrophil extracellular trap (NET) formation contribute to the development of thromboembolic diseases for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study investigated the pathophysiological effects of SARS-CoV-2 surface protein components and the viral double-stranded RNA (dsRNA) on platelet aggregation and NET formation. Traditional Chinese medicine (TCM) with anti-viral effects was also delineated. The treatment of human washed platelets with SARS-CoV-2 spike protein S1 or the ectodomain S1 + S2 regions neither caused platelet aggregation nor enhanced agonists-stimulated platelet aggregation. Moreover, NET formation can be induced by polyinosinic-polycytidylic acid (poly(I:C)), a synthetic analog of viral dsRNA, but not by the pseudovirus composed of SARS-CoV-2 spike, envelope, and membrane proteins. To search for TCM with anti-NET activity, the plant Melastoma malabathricum L. which has anticoagulant activity was partially purified by fractionation. One of the fractions inhibited poly(I:C)-induced NET formation in a dose-dependent manner. This study implicates that SARS-CoV-2 structural proteins alone are not sufficient to promote NET and platelet activation. Instead, dsRNA formed during viral replication stimulates NET formation. This study also sheds new insight into using the active components of Melastoma malabathricum L. with anti-NET activity in the battle of thromboembolic diseases associated with SARS-CoV-2 infection.

Antioxidant Strategies to Modulate NETosis and the Release of Neutrophil Extracellular Traps during Chronic Inflammation.

Extracellular traps are released by neutrophils and other immune cells as part of the innate immune response to combat pathogens. Neutrophil extracellular traps (NETs) consist of a mesh of DNA and histone proteins decorated with various anti-microbial granule proteins, such as elastase and myeloperoxidase (MPO). In addition to their role in innate immunity, NETs are also strongly linked with numerous pathological conditions, including atherosclerosis, sepsis and COVID-19. This has led to significant interest in developing strategies to inhibit NET release. In this study, we have examined the efficacy of different antioxidant approaches to selectively modulate the inflammatory release of NETs. PLB-985 neutrophil-like cells were shown to release NETs on exposure to phorbol myristate acetate (PMA), hypochlorous acid or nigericin, a bacterial peptide derived from Streptomyces hygroscopicus. Studies with the probe R19-S indicated that treatment of the PLB-985 cells with PMA, but not nigericin, resulted in the production of HOCl. Therefore, studies were extended to examine the efficacy of a range of antioxidant compounds that modulate HOCl production by MPO to prevent NETosis. It was shown that thiocyanate, selenocyanate and various nitroxides could prevent NETosis in PLB-985 neutrophils exposed to PMA and HOCl, but not nigericin. These results were confirmed in analogous experiments with freshly isolated primary human neutrophils. Taken together, these data provide new information regarding the utility of supplementation with MPO inhibitors and/or HOCl scavengers to prevent NET release, which could be important to more specifically target pathological NETosis in vivo.

Safety of ANCA-associated vasculitis patients receiving covid-19 vaccination

Background: The Covid-19 vaccines administration programs implemented in most countries, WHO showed 5.22 billion persons vaccinated at least one dose up to June 29th 2022. EULAR and ACR guidelines suggested autoimmune and inflammatory rheumatic diseases (AIIRDs) patients with stable or low disease activity should receive Covid-19 vaccination. ANCA-associated vasculitis (AAV) patients are AIIRDs subgroup during pandemic, the safety of Covid-19 vaccination has not been reported in large scale study. We analyzed publications of patients with AAV who had relapse post-vaccination and further discussed the challenges for AAV patients under B-depleting therapy with appropriate vaccination recommendations. Method(s): We used descriptive thematic analysis to find out the flare features including severity, organ involvement, therapy strategy in AAV patients after Covid-19 vaccination. This article conforms with the Scale for Assessment of Narrative Review Articles (SANRA) guidelines. After eligibility criteria and selection process, there were 6 matched articles which had 10 individual cases. Result(s): AAV could involve several organs throughout the body, most cases involved kidney and lung injury. Among the 10 cases, there were 2 cases of EGPA, 3 of MPA and 1 RLV patient with clearly written diagnosis and all patients were assessed as being in disease remission prior to vaccination. The cases were special in age characteristic with 71-85 years old. Seven patients had anti-ANCA type test in 3 cases were anti-PR3 type and another 4 cases were anti-MPO type both with higher titers than during remission. Four had new onset organ involvements rather than the recurrence of the original organ relapse after vaccination. Among them, the 74-year- old male suspended rituximab for 6 months interval before vaccination, he developed diffuse alveolar hemorrhage and infection followed under restart rituximab treatment and eventually died of respiratory failure. Another same age male was diagnosed with new crescentic pauci-immune glomerulonephritis and discharged with creatine level as 307umol/L. Conclusion(s): Patients with AAV in remission rarely experienced severe relapse after vaccination, and some involved new-onset organ while others are worsened of the original involvement. Pulmonary new onset involvement might be triggered by neutrophil extracellular traps promotion. The elderly receiving B-cell depleting therapy who are at infection risk with low humoral response should be under careful evaluation between last dose of rituximab and next dose of vaccination. Kidney injury presented mostly with good clinical treatment response. However, longer observation should be considered whether those patients received kidney replacement therapy earlier than expected. (Figure Presented).

Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

Several studies shed light on the interplay among inflammation, thrombosis, multi-organ failures and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Increasing levels of both free and/or circulating histones have been associated to coronavirus disease 2019 (COVID-19), enhancing the risk of heart attack and stroke with coagulopathy and systemic hyperinflammation. In this view, by considering both the biological and clinical rationale, circulating histones may be relevant as diagnostic biomarkers for stratifying COVID-19 patients at higher risk for viral sepsis, and as predictive laboratory medicine tool for targeted therapies.

SARS-CoV-2-Associated ssRNAs Activate Human Neutrophils in a TLR8-Dependent Fashion.

COVID-19 disease is characterized by a dysregulation of the innate arm of the immune system. However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that GU-rich RNA sequences from the SARS-CoV-2 genome (i.e., SCV2-RNA1 and SCV2-RNA2) activate dendritic cells. To clarify whether human neutrophils may also represent targets of SCV2-RNAs, neutrophils were treated with either SCV2-RNAs or, as a control, R848 (a TLR7/8 ligand), and were then analyzed for several functional assays and also subjected to RNA-seq experiments. Results highlight a remarkable response of neutrophils to SCV2-RNAs in terms of TNFα, IL-1ra, CXCL8 production, apoptosis delay, modulation of CD11b and CD62L expression, and release of neutrophil extracellular traps. By RNA-seq experiments, we observed that SCV2-RNA2 promotes a transcriptional reprogramming of neutrophils, characterized by the induction of thousands of proinflammatory genes, similar to that promoted by R848. Furthermore, by using CU-CPT9a, a TLR8-specific inhibitor, we found that SCV2-RNA2 stimulates neutrophils exclusively via TLR8-dependent pathways. In sum, our study proves that single-strand RNAs from the SARS-CoV-2 genome potently activate human neutrophils via TLR8, thus uncovering a potential mechanism whereby neutrophils may contribute to the pathogenesis of severe COVID-19 disease.

A CASE OF MICROSCOPIC POLYANGIITIS (MPA) FOLLOWING SARS-COV-2 INFECTION

SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: ANCA-associated vasculitis (AAV) is a systemic disease that causes inflammation of small vessels in various organs, such as the lungs, kidneys, and nervous system. We report a case of AAV following SARS-CoV-2 infection. CASE PRESENTATION: A 64-year-old female from Albania with no known medical history, presented with intermittent low-grade hemoptysis and fever for 1 week prior to admission. She had chills, myalgias, fatigue, and poor appetite 6 weeks prior. On arrival, she was febrile (101F), and hypoxic (Spo2 92% on 3L O2). Labs were significant for anemia [Hb 6.8 g/dl], acute kidney injury (AKI) [Cr 2.5 mg/dl]. She was found to be Positive for Sars-CoV-2 by PCR. Chest X-Ray showed patchy bilateral airspace opacities with peripheral and lower lobe predominance, concerning for atypical pneumonia (Fig 1). Urinalysis was significant for proteinuria (2+) and hematuria (2+). CT (Computed Tomography) thorax showed extensive bilateral airspace disease (dense consolidations and ground-glass opacities) favoring multifocal infection and mediastinal lymphadenopathy(Fig 2). Due to the chronicity of her symptoms and atypical imaging for viral pneumonia, other diagnoses were explored including bacterial superinfection, Tuberculosis, and autoimmune disease. Sputum studies were negative for infections including Acid Fast Bacilli. Workup revealed elevated Antimyeloperoxidase antibodies (MPO) and positive COVID-19 Ig G. She was started on methylprednisolone 1g for AAV. Renal biopsy revealed pauci-immune glomerulonephritis with features of cellular crescent consistent with microscopic polyangiitis (Fig 3). Follow-up CT chest showed improved airspace abnormalities and mediastinal lymphadenopathy. After induction therapy with Rituximab was initiated, she continued to recover and was discharged home. DISCUSSION: The pathogenesis of AAV is believed to be an aberrant pathogenic autoimmune response that follows an initial insult which can include infections. SARS-CoV-2 has been associated with the emergence of autoimmune diseases in susceptible patients(1). The proposed mechanism is linked to elevated levels of circulating neutrophil extracellular traps (NETs) observed in covid infection. These NETS are covered with proteins including neutrophilic enzymes which can activate complement pathways causing tissue destruction and vasculitis. The diagnosis of new-onset AAV can be challenging in COVID-19 patients as symptoms and clinical manifestations of both diseases can overlap. AAV should be considered strongly in patients who are currently infected or have been infected with SARS-CoV-2 and present with atypical or non-resolving pneumonia and other organ involvement such as AKI to avoid permanent organ damage. CONCLUSIONS: The presence of non-resolving or atypical pneumonia and AKI in a patient with SARS-CoV-2 should prompt evaluation of immunological markers to assess or rule out AAV for early diagnosis and treatment. Reference #1: Caso F, Costa L, Ruscitti P, Navarini L, Del Puente A, Giacomelli R, Scarpa R. Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects? Autoimmun Rev. 2020;19(5):102524. doi: 10.1016/j.autrev.2020.102524 DISCLOSURES: No relevant relationships by Tarik Al-Bermani No relevant relationships by Anant Jain No relevant relationships by Ian Kaplan No relevant relationships by Alina Kifayat No relevant relationships by Lisa Paul

A RARE CASE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA)-ASSOCIATED VASCULITIS IN THE SETTING OF COVID-19 INFECTION

SESSION TITLE: Management of COVID-19-Induced Complications SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-AV) is an autoimmune mediated inflammation of small and medium sized vessel walls. The occurrence of this autoimmune vasculitis is typically associated with underlying infection, medications, and genetic predisposition.(1) The objective of this case report is to describe a rare presentation of ANCA-AV in the setting of COVID-19 infection. CASE PRESENTATION: A 67-year-old male presented to the hospital with a three-week history of cough productive of brown sputum, epistaxis, fatigue, decreased appetite, and unintentional weight loss. During the previous week, he experienced worsening dyspnea and bilateral lower extremity swelling. On physical examination, he was hypoxic requiring 4L of supplemental oxygen to maintain saturations greater than 90%. Diffuse and bilateral wheezes were heard on auscultation of his lungs. A tender petechial rash was dispersed over his limbs, trunk, oropharynx, and nasopharynx. A basic metabolic panel revealed a mild, acute renal impairment. Urinalysis showed new onset proteinuria and hemoglobinuria. Nasopharyngeal swab was positive for SARS-COV-2. Contrast-enhanced computed tomography of the chest revealed diffuse, bilateral ground glass opacities and interstitial changes. Therapy with piperacillin-tazobactam was started for presumed superimposed bacterial community acquired pneumonia in the setting of COVID-19 infection. On day three of hospitalization, the petechial rash progressed to hemorrhagic blisters. His oral petechiae were now ulcerated. A punch biopsy of the affected skin showed leukocytoclastic vasculitis. Anti-Proteinase 3 (PR3) antibodies were positive. Subsequent renal biopsy showed pauci-immune focal necrotizing crescentic glomerulonephritis consistent with ANCA-AV. Therapy with intravenous pulse dose corticosteroids led to improvement in his rash and body aches, and he was discharged home on oral steroids ten days after admission. DISCUSSION: This report describes a rare case of ANCA-AV in the setting of recent COVID-19 infection. Differentiation of ANCA-AV, bacterial and COVID-19 pneumonia can be challenging on chest imaging alone.(1) New onset renal impairment, hematuria, proteinuria and the presence of the petechial rash were suspicious for co-existing ANCA-AV in this patient. COVID-19- associated cytokine storm and formation of neutrophil extracellular traps (NETs) is postulated to be the underlying cause.(1-3) NETs present myeloperoxidase (MPO) and PR3 antigens to the immune system. Formation of auto-antibodies to MPO and PR3 lead to the development of ANCA-AV. The findings of NETs on kidney biopsy specimens in patients with ANCA-AV supports this hypothesis.(1,2) CONCLUSIONS: To avoid the misdiagnosis of COVID-19-induced vasculitis, a low threshold to investigate co-existing vasculitis in patients with COVID-19 and associated clinical findings is highly recommended. Reference #1: Izci Duran T, Turkmen E, Dilek M, Sayarlioglu H, Arik N. ANCA-associated vasculitis after COVID-19. Rheumatol Int. 2021;41(8):1523-1529. Reference #2: Uppal NN, Kello N, Shah HH, et al. De Novo ANCA-Associated Vasculitis With Glomerulonephritis in COVID-19. Kidney Int Rep. 2020;5(11):2079-2083. Reference #3: Cobilinschi C, Cobilinschi C, Constantinescu A, Draniceanu I, Ionescu R. New-Onset ANCA-Associated Vasculitis in a Patient with SARS-COV2. Balkan Med J. 2021;38(5):318-320. DISCLOSURES: No relevant relationships by Andrei Hastings No relevant relationships by Jason Lane No relevant relationships by Tanya Marshall No relevant relationships by Palak Rath No relevant relationships by Sterling Shriber No relevant relationships by inderprit Singh No relevant relationships by Samuel Wiles

The central role of neutrophil extracellular traps in SARS-CoV-2-induced thrombogenesis and vasculitis

Objective: Severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) seen in SARs-CoV-2 infection has been attributed to the disruption of the immune response in COVID-19 patients. Neutrophilia and marked lymphocyte reductions are associated with disease severity and seem predictive of disease outcome in moderate and severe COVID-19 patients. Herein, we aim to decipher possible mechanisms involved in extensive tissue injury observed in COVID-19 patients, accompanied by vasculopathy, coagulopathy, and a high incidence of thrombotic complications in severe patients. Method(s): We searched PubMED for keywords including COVID-19 pathogenesis, thrombosis, and vasculities. Result(s): Neutrophils can undergo a specialized form of apoptosis to yield thread-like extracellular structures termed neutrophil extracellular traps (NETs), termed NETosis, which form web-like scaffolds of DNA, histones, and toxic protein granules and enzymes, whose primary function is to trap and eliminate microbes. However, uncontrolled NET production can lead to ALI and ARDS, coagulopathy, multiple organ failure, and autoimmune disease. Dysregulation of NETs promotes production of anti-neutrophil cytoplasmic antibodies (ANCA) which affects small vessels through ANCA-associated vasculitis (AAV). Furthermore, NETs can also induce thrombosis via formation of scaffolds that trap platelets, RBCs, fibronectin, and other proteins, which can also induce coagulation. Conclusion(s): We suggest that NET production is central during SARS-CoV-2 infection and COVID-19 pathogenesis, associated with alveolar damage accumulation of edema, endothelial injury and coagulopathy, elevated platelet activation and thrombogenesis forming a NET production feed-forward loop, causing diffuse small vessel vasculitis in the lungs and other organs. Copyright © 2020 FSG Communications Ltd. All rights reserved.

Molecular mechanisms and therapeutic target of NETosis in diseases.

Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web-like structures composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: "suicidal" NETosis and "vital" NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell-free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small-vessel vasculitis, inflammatory bowel disease, cancer, COVID-19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll-like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis-induced diseases, and NETosis-targeted therapy.

The emerging role of neutrophil extracellular traps in fungal infection.

Fungal infections are global public health problems and can lead to substantial human morbidity and mortality. Current antifungal therapy is not satisfactory, especially for invasive, life-threatening fungal infections. Modulating the antifungal capacity of the host immune system is a feasible way to combat fungal infections. Neutrophils are key components of the innate immune system that resist fungal pathogens by releasing reticular extracellular structures called neutrophil extracellular traps (NETs). When compared with phagocytosis and oxidative burst, NETs show better capability in terms of trapping large pathogens, such as fungi. This review will summarize interactions between fungal pathogens and NETs. Molecular mechanisms of fungi-induced NETs formation and defensive strategies used by fungi are also discussed.