BACKGROUNDThere is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 . Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODSWe conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTSWe detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10 −8 ) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10 −10 ; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10 −8 , respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10 −4 ) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10 −5 ). CONCLUSIONSWe identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

The extensive use of invasive procedures and of long-term norfloxacin prophylaxis in the management of cirrhotic patients may have influenced the epidemiology of bacterial infections in cirrhosis. We conducted a prospective evaluation of all bacterial infections diagnosed in patients with cirrhosis in a Liver Unit between April 1998 and April 2000. A total of 405 patients presented 572 bacterial infections in 507 admissions. Spontaneous bacterial peritonitis was the most frequent infection (138 cases). Gram-positive cocci were responsible for 53% of total bacterial infections in the study, being the main bacteria isolated in nosocomial infections (59%). Patients requiring treatment in an intensive care unit and those submitted to invasive procedures presented a higher rate of infections caused by grampositive cocci (77% vs. 48%, P < .001 and 58% vs. 40%, P < .02, respectively). B acterial infection is one of the most important clinical problems in patients with decompensated cirrhosis. It is present at admission or develops during hospitalization in 20% to 60% of the patients. 1-8 On the other hand, it is a common cause of death. Most studies assessing the etiology and clinical types of bacterial infections in cirrhosis were performed in the 1980s. At that time, the most common infections were urinary tract infections, pneumonia, and spontaneous bacterial peritonitis (SBP); most infections were community acquired; and approximately 70% to 80% of the isolated organisms were gram-negative bacilli (GNB). 1-8 However, during the last decade practice in hepatology has considerably changed and this may have influenced the epidemiology of bacterial infections in liver diseases. Treatment of cirrhotic patients with severe complications in intensive care units has been generalized, particularly with the extension of the liver transplantation programs, and the invasive procedures used in this setting are frequently associated with iatrogenic complications including infections. 9 On the other hand, new invasive treatments have been developed and are extensively used for specific complications of cirrhosis, including variceal ligation, transjugular intrahepatic portosystemic shunt, and arterial embolization or percutaneous ablation of hepatocellular carcinoma. These treatments may be also associated with infections. Finally, long-term selective intestinal decontamination with norfloxacin, which was introduced in 1987, is now widely used for the primary and secondary prophylaxis of SBP and spontaneous bacteremia in cirrhosis. 10,11 Norfloxacin prevents infections caused by GNB but not those caused by gram-positive cocci (GPC). All these features may have changed the type and etiology of acute bacterial infections in cirrhosis. However, there is no study on this topic.Another relevant problem, which has not been adequately evaluated is the clinical relevance of infections caused by quinoloneresistant gram-negative bacilli (QR-GNB) in cirrhosis. It is well known that patients submitted to long-term selective intestinal deconta...