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

Two cases of culture proven Mycobacterium tuberculosis presenting with a broad-complex tachycardia and non-caseating granulomas

Tuberculosis is a leading cause of death worldwide. It affects pulmonary and extra-pulmonary sites with a multitude of differing presentations. In this report, we describe two cases in which TB causes myopericarditis and presents with a broad-complex tachycardia that did not respond typically to standard anti-arrhythmic therapy; a very rare presentation with limited description in the literature. Both patients required extensive investigation culminating in identifying lymph nodes amenable to biopsy under endobronchial ultrasound guidance. It was not until both patients received anti-tuberculous chemotherapy alongside anti-arrhythmic management that any improvement to their condition was witnessed. Therefore, we recommend that the clinician should have a high index of suspicion for TB in any patient presenting with a broad-complex tachycardia that is not responding to standard first line management, especially if the patient is from a high risk background. We recommend an active diagnostic pursuit, and lymph node biopsy under endobronchial ultrasound guidance

TIMP-1 is a key factor of fibrogenic response to bleomycin in mouse lung.

International audiencePulmonary fibrosis is characterized by the excessive deposition of extracellular matrix in the interstitium, resulting in respiratory failure. The role of remodeling mediators such as metalloproteinases (MMPs) and their inhibitors (TIMPs) in the fibrogenic process remains misunderstood. We investigated MMP-9, MMP-2, TIMP-1, TIMP-2 and TIMP-3 in the fibrotic response to bleomycin of fibrosis prone C57BL/6J and fibrosis resistant BALB/c mice. Mice were administered with 0.1 mg bleomycin by intranasal administration. Either 24 h or 14 days after, the mice were anesthetized and underwent either bronchoalveolear lavage (BAL) or lung removal. Collagen deposition in lung tissue was determined by hydroxyproline measurement, MMP activity was analyzed by zymography, and other mediators were analyzed by ELISA. TIMP-1 was localized in lung sections by immunohistochemistry and real time PCR was performed to gene expression in lung. Non parametric Mann-Whitney and Spearman tests were used for statistical analysis. Fourteen days after bleomycin administration, hydroxyproline assay and histological study revealed that BALB/c mice developed significantly less fibrosis compared to C57BL/6J mice. At day 1, bleomycin enhanced TIMP-1, MMP-2 and MMP-9 protein levels in BALF, and induced corresponding genes in lung tissue of both strains. The rise of Timp-1, Mmp-9 and Mmp-2 gene levels were significantly stronger in lungs of C57BL/6J, whereas gelatinase activities of MMP-2 and MMP-9 were similar. Immunohistochemistry revealed that TIMP-1 macrophages and epithelial cells were prominent TIMP-1 producers in both strains. At day 14, neither MMP-2 nor MMP-9 levels exhibited strain-dependent protein level or gene expression, although TIMP-1 was strongly associated with fibrosis. Interestingly, bleomycin induced neither Timp-2 nor Timp-3 in lung tissue at any time of the study. The present study shows that early altered regulation of TIMP-1 following bleomycin administration may be involved in bleomycin-induced pulmonary fibrosis