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

Clinical, haematological, cytokine and acute phase protein changes during experimental Babesia gibsoni infection of beagle puppies

Babesia gibsoni is a haemoprotozoan parasite of emerging global importance. The clinical presentation of babesial infections is diverse and the systemic inflammatory response induced by infection is considered to be a major feature of the pathophysiology of canine babesiosis. An experimental case-controlled longitudinal study was conducted to assess the clinical, haematological, cytokine and acute phase protein changes that occur during experimental B. gibsoni infection of beagle puppies. Infected dogs became transiently pyrexic and anaemic, intermittently neutropenic and transiently, but profoundly, thrombocytopenic, although this had no apparent adverse clinical effect. Experimental B. gibsoni infection also induced an acute phase response, characterised by a marked increase in the concentration of C-reactive protein, which was delayed in onset following infection but preceded the detection of peripheral parasitaemia. Experimental B. gibsoni infection was also associated with marked increases in the concentration of multiple cytokines which were also delayed in onset following infection and occurred subsequent to the detection of peripheral parasitaemia and the acute phase response. This study furthers our understanding of the immune response that occurs during babesial infections and the role that systemic inflammation plays in the pathophysiology of canine babesiosis

Platelet function and activation in Cavalier King Charles Spaniels with subclinical chronic valvular heart disease

OBJECTIVE To assess platelet closure time (CT), mean platelet component (MPC) concentration, and platelet component distribution width (PCDW) in dogs with subclinical chronic valvular heart disease. ANIMALS 89 Cavalier King Charles Spaniels (CKCSs) and 39 control dogs (not CKCSs). PROCEDURES Platelet count, MPC concentration, PCDW, and Hct were measured by use of a hematology analyzer, and CT was measured by use of a platelet function analyzer. Murmur grade and echocardiographic variables (mitral valve regurgitant jet size relative to left atrial area, left atrial-to-aortic diameter ratio, and left ventricular internal dimensions) were recorded. Associations between explanatory variables (sex, age, murmur grade, echocardiographic variables, platelet count, and Hct) and outcomes (CT, MPC concentration, and PCDW) were examined by use of multivariate regression models. RESULTS A model with 5 variables best explained variation in CT (R2, 0.74), with > 60% of the variance of CT explained by mitral valve regurgitant jet size. The model of best fit to explain variation in MPC concentration included only platelet count (R2, 0.24). The model of best fit to explain variation in PCDW included platelet count and sex (R2, 0.25). CONCLUSIONS AND CLINICAL RELEVANCE In this study, a significant effect of mitral valve regurgitant jet size on CT was consistent with platelet dysfunction. However, platelet activation, as assessed on the basis of the MPC concentration and PCDW, was not a feature of subclinical chronic valvular heart disease in CKCSs