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1.
Med J Aust ; 216(7): 349-356, 2022 04 18.
Article in English | MEDLINE | ID: covidwho-1716042

ABSTRACT

OBJECTIVE: To examine associations between area-level socio-economic factors and the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Victoria during 2020. DESIGN, SETTING: Population-level ecological study of the incidence of SARS-CoV-2 infections in Victoria, by postcode, 1 March - 13 August 2020. MAIN OUTCOME MEASURES: Relationships between the incidence of SARS-CoV-2 infections by postcode (Department of Health and Human Services data published on The Age website), and demographic, education level, ethnic background, economic and employment-related factors, housing-related factors, and social disadvantage (Australian Bureau of Statistics data for 2014-19), expressed as incidence rate ratios (IRRs). RESULTS: During the study period, 15 482 SARS-CoV-2 infections with associated postcodes were recorded in Victoria. Incidence was higher for metropolitan than regional postcodes (418.3 v 62 infections per 100 000 population; IRR, 6.2; 95% CI, 4.6-8.2). In regional postcodes, incidence rose with mean household size (per person: IRR, 7.30; 95% CI, 4.37-12.2), unemployment proportion (per percentage point: IRR, 1.50; 95% CI, 1.33-1.69), and proportions for whom rent (IRR, 1.15; 95% CI, 1.07-1.22) or mortgage repayments (IRR, 1.22; 95% CI, 1.15-1.28) exceeded 30% of household income. In metropolitan areas, incidence increased with unemployment proportion (IRR, 1.14; 95% CI, 1.05-1.23) and proportion without paid leave (IRR, 1.22; 95% CI, 1.02-1.45). Incidence also increased with proportion speaking languages other than English at home (regional: IRR, 1.08; 95% CI, 1.06-1.11; metropolitan: IRR, 1.01; 95% CI, 1.002-1.02) and with Indigenous Australian proportion (metropolitan only: IRR, 1.91; 95% CI, 1.10-2.73). CONCLUSIONS: Socio-economic factors may have contributed to the non-homogeneous incidence of SARS-CoV-2 infections across Victoria during 2020.


Subject(s)
COVID-19 , Australia , COVID-19/epidemiology , Economic Factors , Humans , Incidence , SARS-CoV-2
2.
Aust J Gen Pract ; 50(11): 845-849, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1543140

ABSTRACT

BACKGROUND AND OBJECTIVES: The approach to performing COVID-19 testing in general practice has been going through an evolution and is variable. The aim of this study was to determine what underlying factors, if any, impeded onsite COVID-19 testing in general practices for patients during the second wave of the pandemic in Victoria. METHOD: This study was conducted during August 2020 and October 2020. Fourteen semi-structured interviews with general practitioners, practice nurses and practice managers were conducted. RESULTS: Barriers to performing onsite testing for COVID-19 were identified as: 1) individual, 2) practitioner perception of fear, 3) lack of personal protective equipment, 4) inappropriate clinic design/location, 5) risk of patient avoidance, 6) financial risk, 7) a lack of knowledge and 8) lack of guidelines. DISCUSSION: This study's findings relate to a unique period in Victoria, which at the time accounted for 70% of the nation's total cases and 90% of deaths. Therefore, the barriers identified in this study may help inform policymakers in regard to planning for future responses to similar situations.


Subject(s)
COVID-19 , General Practice , General Practitioners , COVID-19 Testing , Humans , SARS-CoV-2
3.
Cytokine ; 144: 155593, 2021 08.
Article in English | MEDLINE | ID: covidwho-1242912

ABSTRACT

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1ß, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Cytokine Release Syndrome , Influenza A Virus, H1N1 Subtype/immunology , SARS-CoV-2/immunology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/mortality , COVID-19/pathology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Disease-Free Survival , Humans , Influenza, Human/drug therapy , Influenza, Human/immunology , Influenza, Human/mortality , Influenza, Human/pathology , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Lymphocytes/immunology , Lymphocytes/pathology , Survival Rate
4.
Life Sci ; 264: 118617, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-880558

ABSTRACT

BACKGROUND: COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. MAIN BODY: The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.


Subject(s)
COVID-19/immunology , COVID-19/physiopathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/pathogenicity , Thrombosis/complications , Thrombosis/physiopathology , Alveolar Epithelial Cells/physiology , Blood Platelets/physiology , COVID-19/complications , COVID-19/drug therapy , Cytokines/physiology , Endothelial Cells/physiology , Humans , Macrophages, Alveolar/physiology , Neutrophils/physiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Thrombosis/immunology
5.
Life Sci ; 262: 118541, 2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-816772

ABSTRACT

The possibility is examined that immunomodulatory pharmacotherapy may be clinically useful in managing the pandemic coronavirus disease 2019 (COVID-19), known to result from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus. The dominant route of cell entry of the coronavirus is via phagocytosis, with ensconcement in endosomes thereafter proceeding via the endosomal pathway, involving transfer from early (EEs) to late endosomes (LEs) and ultimately into lysosomes via endolysosomal fusion. EE to LE transportation is a rate-limiting step for coronaviruses. Hence inhibition or dysregulation of endosomal trafficking could potentially inhibit SARS-CoV-2 replication. Furthermore, the acidic luminal pH of the endolysosomal system is critical for the activity of numerous pH-sensitive hydrolytic enzymes. Golgi sub-compartments and Golgi-derived secretory vesicles also depend on being mildly acidic for optimal function and structure. Activation of endosomal toll-like receptors by viral RNA can upregulate inflammatory mediators and contribute to a systemic inflammatory cytokine storm, associated with a worsened clinical outcome in COVID-19. Such endosomal toll-like receptors could be inhibited by the use of pharmacological agents which increase endosomal pH, thereby reducing the activity of acid-dependent endosomal proteases required for their activity and/or assembly, leading to suppression of antigen-presenting cell activity, decreased autoantibody secretion, decreased nuclear factor-kappa B activity and decreased pro-inflammatory cytokine production. It is also noteworthy that SARS-CoV-2 inhibits autophagy, predisposing infected cells to apoptosis. It is therefore also suggested that further pharmacological inhibition of autophagy might encourage the apoptotic clearance of SARS-CoV-2-infected cells.


Subject(s)
Antiviral Agents/pharmacology , Autophagy/drug effects , COVID-19/drug therapy , COVID-19/virology , Endosomes/drug effects , Lysosomes/drug effects , SARS-CoV-2/drug effects , Azithromycin/adverse effects , Azithromycin/pharmacology , Azithromycin/therapeutic use , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Pandemics
6.
Life Sci ; 258: 118166, 2020 Oct 01.
Article in English | MEDLINE | ID: covidwho-703163

ABSTRACT

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Respiratory Distress Syndrome/physiopathology , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/pathology , Animals , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Humans , Immunity, Innate , Inflammation/etiology , Inflammation/immunology , Inflammation/physiopathology , Inflammation/therapy , Macrophage Activation , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Neutrophil Activation , Pandemics , Platelet Activation , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Thrombophilia/etiology , Thrombophilia/immunology , Thrombophilia/physiopathology , Thrombophilia/therapy
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