Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Development of a rapid, user-friendly, diagnostic test for Taenia solium cysticercosis

In this presentation we would like to introduce a novel diagnostic tool for Taenia solium cysticercosis in the porcine host. This tool is a rapid, user-friendly lateral flow format assay utilising the HP10 monoclonal antibody. We will describe the production of this assay, its performance as judged using a Bayesian nogold-standard analysis and discuss the utility of such a test in the field. Neurocysticercosis, the development of the larval stage of this parasite within the central nervous system of man, is a leading cause of acquired epilepsy in the developing world. The parasite is sustained in a population by factors intrinsically linked with poverty: low-input free-range pig husbandry, poor latrine provision, lack of formal pig slaughter and meat inspection and low levels of education or awareness of hygienic meat preparation techniques. In order to assist the affected communities, who are by definition often those with scare resources, it is imperative that cost-effective and easy-to-use diagnostic assays are made available. Although checking the tongue of a pig for cysts has been recommended as a low-cost screening method for T. solium, the sensitivity of this test is notoriously poor. Several antibody and antigen ELISA assays have been developed, but the time, equipment and skills required to perform them makes them unsuitable for many of the situations where diagnostics are required. To rectify this situation work has been ongoing to develop a rapid, user-friendly, antigen detection test for use in the field. We believe that such an assay has a real utility both as a tool for epidemiological studies and within intervention strategies as we work towards control of this important parasitic disease

Epidemiology of bacterial infections in livestock and their human keepers in Western Kenya

We report on the results of work on three bacterial zoonoses arising as part of a large project dealing with zoonotic infections amongst livestock and the farmers who keep them. Domestic livestock are an important source of zoonotic infections to humans, particularly in rural parts of Africa. Understanding the interactions between people and their domestic animals, and the transmission of zoonoses between them, is of vital importance in creating the evidence-based disease control policies that are required to protect both human and animal health. The wider project addresses the impact of co-factors (a condition that influences the effects of another condition) on the epidemiology of, and burden imposed by, these diseases. We describe the results of an analysis of three bacterial infections of major public health significance (q-fever, brucellosis and tuberculosis), with a focus on infection in both domestic cattle and humans. In particular, we explore the spatial distribution of these infections in Western Kenya, and explore patterns of infection at the household level in both species (n=450 households). In addition, using multivariate methods, we examine non-zoonotic co-factors as explanatory variables for the individual pathogens, and quantify the risk of co-infections with multiple bacterial zoonoses. We use our wealth of ancillary risk factor data to explain the patterns observed

Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS”, a multinational observational cohort study and ESICM Trials Group Project

Purpose: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. Conclusion: This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection. © 2019, The Author(s)