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2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316601

ABSTRACT

Background: Increased inflammation is a hallmark of COVID-19, with pulmonary and systemic inflammation identified in multiple cohorts of patients. Definitive cellular and molecular pathways driving severe forms of this disease remain uncertain. Neutrophils, the most numerous leukocytes in blood circulation, can contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Neutrophilia, elevated neutrophil:lymphocyte ratios, and elevated neutrophil-associated cytokines are present in COVID-19, but changes in neutrophil functions have not been characterized. Here we analyzed the functional state of circulating neutrophils in COVID-19.Methods: Blood was obtained from critically ill COVID-19 patients over two weeks and healthy controls across multiple timepoints. Plasma cytokine profiles were assessed by bead array. Neutrophils were isolated and tested ex vivo for oxidative burst, neutrophil extracellular trap formation (NETosis) and phagocytosis. Lung tissue was obtained immediately post-mortem from COVID-19 patients for immunostaining.Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6 were identified in COVID-19 plasma both at the first measurement and across their hospitalization (p < 0.0001). Elevations in cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF were also present at the first measurement and across hospital stays. Functionally, circulating neutrophils from COVID-19 patients had exaggerated oxidative burst (p < 0.0001), NETosis (p < 0.0001) and phagocytosis (p < 0.0001) relative to controls. Increased NETosis was found to be correlated with both leukocytosis and neutrophilia in COVID-19 patients. Neutrophils and NETs were identified within airways and alveoli in lung parenchyma. While elevations in IL-8 and ANC correlated to COVID-19 disease severity, plasma IL-8 levels alone correlated with death.Conclusions: Circulating neutrophils in COVID-19 exhibit an activated phenotype with increased oxidative burst, NETosis and phagocytosis. Readily accessible and dynamic, plasma IL-8 and circulating neutrophil function can be explored as potential COVID-19 disease biomarkers.Funding Statement: This work was supported by the Department of Veterans Affairs (salary support and VA Merit Award, PI Crotty Alexander) and NIH NHLBI (PI Crotty Alexander).Declaration of Interests: The authors report no conflicts of interest.Ethics Approval Statement: The research protocol was approved by the UCSD, VASDHS and Rady Children’s Hospital institutional review boards (IRBs) and all participants or designated family member gave written informed consent.

3.
Clin Infect Dis ; 74(3): 479-489, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1684541

ABSTRACT

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.


Subject(s)
COVID-19 , Extracellular Traps , Critical Illness , Humans , Neutrophil Activation , Neutrophils , Phenotype , SARS-CoV-2
4.
Front Physiol ; 12: 649604, 2021.
Article in English | MEDLINE | ID: covidwho-1268279

ABSTRACT

Conventional smoking is known to both increase susceptibility to infection and drive inflammation within the lungs. Recently, smokers have been found to be at higher risk of developing severe forms of coronavirus disease 2019 (COVID-19). E-cigarette aerosol inhalation (vaping) has been associated with several inflammatory lung disorders, including the recent e-cigarette or vaping product use-associated lung injury (EVALI) epidemic, and recent studies have suggested that vaping alters host susceptibility to pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the impact of vaping on lung inflammatory pathways, including the angiotensin-converting enzyme 2 (ACE2) receptor known to be involved in SARS-CoV-2 infection, mice were exposed to e-cigarette aerosols for 60 min daily for 1-6 months and underwent gene expression analysis. Hierarchical clustering revealed extensive gene expression changes occurred in the lungs of both inbred C57BL/6 mice and outbred CD1 mice, with 2,933 gene expression changes in C57BL/6 mice, and 2,818 gene expression changes in CD1 mice (>abs 1.25-fold change). Particularly, large reductions in IgA and CD4 were identified, indicating impairment of host responses to pathogens via reductions in immunoglobulins and CD4 T cells. CD177, facmr, tlr9, fcgr1, and ccr2 were also reduced, consistent with diminished host defenses via decreased neutrophils and/or monocytes in the lungs. Gene set enrichment (GSE) plots demonstrated upregulation of gene expression related to cell activation specifically in neutrophils. As neutrophils are a potential driver of acute lung injury in COVID-19, increased neutrophil activation in the lungs suggests that vapers are at higher risk of developing more severe forms of COVID-19. The receptor through which SARS-CoV-2 infects host cells, ACE2, was found to have moderate upregulation in mice exposed to unflavored vape pens, and further upregulation (six-fold) with JUUL mint aerosol exposure. No changes were found in mice exposed to unflavored Mod device-generated aerosols. These findings suggest that specific vaping devices and components of e-liquids have an effect on ACE2 expression, thus potentially increasing susceptibility to SARS-CoV-2. In addition, exposure to e-cigarette aerosols both with and without nicotine led to alterations in eicosanoid lipid profiles within the BAL. These data demonstrate that chronic, daily inhalation of e-cigarette aerosols fundamentally alters the inflammatory and immune state of the lungs. Thus, e-cigarette vapers may be at higher risk of developing infections and inflammatory disorders of the lungs.

5.
Clin Infect Dis ; 74(3): 479-489, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1228461

ABSTRACT

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.


Subject(s)
COVID-19 , Extracellular Traps , Critical Illness , Humans , Neutrophil Activation , Neutrophils , Phenotype , SARS-CoV-2
6.
Endocrinol Diabetes Metab J ; 4(4): 1-5, 2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-892729

ABSTRACT

Advanced age and medical co-morbidity are strong predictors of mortality in COVID-19 infection. Yet few studies (to date) have specifically addressed risk factors associated with COVID-19 mortality in a high-risk subgroup of older US adults having one or more chronic diseases. Our hypothesis is that medications having 'off-target' anti-inflammatory effects may play a role in modulating the immune response in COVID-19 infection. We analyzed baseline risk factors associated with respiratory failure or death in 55 older adult US military veterans hospitalized for COVID-19 infection during (March-June 2020) the peak of the pandemic in New Jersey. Fifty-three percent (29/55) of patients experienced respiratory failure and thirty-one percent (17/55) died. In adjusted logistic regression analysis, baseline neutrophil to lymphocyte ratio (NLR) (P=0.0035) and body mass index (P=0.03) were significant predictors of the risk for respiratory failure. Age (P=0.05) and non-use (vs. use) of psychotropic medications having serotonin 2A receptor antagonist properties (odds ratio 5.06; 95% confidence intervals 1.18-21.7; P= 0.029) was each a significant predictor of an increased risk of death. There was a significant interaction effect of age and non-use (vs.. use) of psychotropic serotonin 2A receptor antagonist medications on the odds ratio (OR) for death (P=0.011). In selected, ventilator-dependent COVID-19 pneumonia patients treated with psychotropic serotonin 2A receptor antagonist medications to control agitation and ICU delirium, there was an apparent positive association between medication use and significant rise in the absolute lymphocyte count and decrease in the neutrophil: lymphocyte ratio. Taken together, these data are the first to suggest that certain psychotropic medications used in the treatment of chronic psychiatric illness and/or for acute delirium are inversely associated with mortality in severe COVID-19 infection by unknown mechanism which may involve (in part) immunomodulatory effects.

7.
World Neurosurg ; 140: e373-e380, 2020 08.
Article in English | MEDLINE | ID: covidwho-593961

ABSTRACT

BACKGROUND: As of May 4, 2020, the coronavirus disease 2019 (COVID-19) pandemic has affected >3.5 million people and touched every inhabited continent. Accordingly, it has stressed health systems worldwide, leading to the cancellation of elective surgical cases and discussions regarding health care resource rationing. It is expected that rationing of surgical resources will continue even after the pandemic peak and may recur with future pandemics, creating a need for a means of triaging patients for emergent and elective spine surgery. METHODS: Using a modified Delphi technique, a cohort of 16 fellowship-trained spine surgeons from 10 academic medical centers constructed a scoring system for the triage and prioritization of emergent and elective spine surgeries. Three separate rounds of videoconferencing and written correspondence were used to reach a final scoring system. Sixteen test cases were used to optimize the scoring system so that it could categorize cases as requiring emergent, urgent, high-priority elective, or low-priority elective scheduling. RESULTS: The devised scoring system included 8 independent components: neurologic status, underlying spine stability, presentation of a high-risk postoperative complication, patient medical comorbidities, expected hospital course, expected discharge disposition, facility resource limitations, and local disease burden. The resultant calculator was deployed as a freely available Web-based calculator (https://jhuspine3.shinyapps.io/SpineUrgencyCalculator/). CONCLUSIONS: We present the first quantitative urgency scoring system for the triage and prioritizing of spine surgery cases in resource-limited settings. We believe that our scoring system, although not all encompassing, has potential value as a guide for triaging spine surgical cases during the COVID pandemic and post-COVID period.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections , Elective Surgical Procedures , Health Care Rationing , Pandemics , Patient Selection , Pneumonia, Viral , COVID-19 , Decision Making , Elective Surgical Procedures/methods , Humans , SARS-CoV-2 , Triage/methods
8.
World Neurosurg ; 140: e367-e372, 2020 08.
Article in English | MEDLINE | ID: covidwho-401403

ABSTRACT

BACKGROUND: The coronavirus identified in 2019 (COVID-19) pandemic effectively ended all major spine educational conferences in the first half of 2020. In response, the authors formed a "virtual" case-based conference series directed at delivering spine education to health care providers around the world. We herein share the technical logistics, early participant feedback, and future direction of this initiative. METHODS: The Virtual Global Spine Conference (VGSC) was created in April 2020 by a multiinstitutional team of spinal neurosurgeons and a neuroradiologist. Biweekly virtual meetings were established wherein invited national and international spine care providers would deliver case-based presentations on spine and spine surgery-related conditions via teleconferencing. Promotion was coordinated through social media platforms such as Twitter. RESULTS: VGSC recruited more than 1000 surgeons, trainees, and other specialists, with 50-100 new registrants per week thereafter. An early survey to the participants, with 168 responders, indicated that 92% viewed the content as highly valuable to their practice and 94% would continue participating post COVID-19. Participants from the United States (29%), Middle East (16%), and Europe (12%) comprised the majority of the audience. Approximately 52% were neurosurgeons, 18% orthopedic surgeons, and 6% neuroradiologists. A majority of participants were physicians (55%) and residents/fellows (21%). CONCLUSIONS: The early success of the VGSC reflects a strong interest in spine education despite the COVID-19 pandemic and social distancing guidelines. There is widespread opinion, backed by our own survey results, that many clinicians and trainees want to see "virtual" education continue post COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections , Orthopedic Surgeons/statistics & numerical data , Pandemics , Pneumonia, Viral , Spine/virology , COVID-19 , Europe , Health Personnel/education , Health Personnel/statistics & numerical data , Humans , SARS-CoV-2 , Spine/surgery , Surveys and Questionnaires , Telecommunications , Training Support/statistics & numerical data
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