The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The first case of third-generation cephalosporins resistant Kluyvera ascorbata biliary tract infection in Japan: A case report and review of the literature

Introduction: Kluyvera ascorbata is a gram-negative, catalase-positive, oxidase-negative, aerobic fermentative bacterium with flagella. This organism colonizes in the human body and its pathogenicity is extremely low; few clinical cases of K. ascorbata infection have been reported. Presentation of case: We report on a patient who experienced severe sepsis and acute cholangitis due to K. ascorbata bacteremia and was treated with levofloxacin following antibiotic susceptibility testing. To our knowledge, this is the first case report of third-generation cephalosporins resistant K. ascorbata infection in Japan. Discussion: Although this pathogen produces innate CTX-M type β-lactamases and is generally resistant to first- and second-generation penicillins and cephalosporins, multi-drug resistant K. ascorbata infection, including ceftriaxone resistant infection has seldom been reported. Conclusion: The increase of drug-resistant pathogens is of concern; in such cases, rapid microbial identification and appropriate antibiotic selection are crucial for successful treatment. Keywords: Kluyvera ascorbata, Cholangitis, Bacteremia, CTX-M type β-lactamas

Co-infection with Neisseria mucosa in a patient with tuberculous otitis media

Tuberculous otitis media (TOM) is a rare manifestation caused by Mycobacterium tuberculosis with low incidence rates among extrapulmonary tuberculosis cases. Diagnosis is often delayed because of the presence of several clinical manifestations and the high prevalence of secondary bacterial infections. Few reports have attributed secondary bacterial infections in patients with TOM to commensal Neisseria. Thus, understanding the pathogenic mechanisms and clinical features of commensal Neisseria is important, considering its recent presentation as an infection-causing pathogen. Neisseria mucosa is a commensal inhabitant in humans and is generally considered non-pathogenic but can cause infection in rare cases. Here, we report an atypical secondary infection caused by Neisseria mucosa in an 81-year-old woman with TOM being treated for pulmonary tuberculosis. Direct purulent otorrhea smear microscopy revealed no acid-fast bacilli using Ziehl-Neelsen staining, whereas the phagocytosis of gram-negative cocci by white blood cells was confirmed using Gram staining. Otorrhea culture revealed the growth of N. mucosa. Subsequently, M. tuberculosis infection in the otorrhea was identified using a culture-based method. Vigilance is critical for the early detection of TOM to prevent further complications. This report raises awareness regarding TOM and provides insight into the pathogenicity of N. mucosa in otitis media

Two cases of acute respiratory failure following SARS‐CoV‐2 vaccination in post‐COVID‐19 pneumonia

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination is a very effective method of preventing infection and is recommended for people having recovered from coronavirus disease 2019 (COVID‐19). In this novel case report, we describe two patients with post‐COVID‐19 pneumonia who experienced acute respiratory failure and new bilateral ground‐glass opacities several days after receiving SARS‐CoV‐2 vaccination. Both patients were treated with methylprednisolone pulse therapy and recovered from the disease successfully. Indeed, post‐COVID‐19 patients can gain benefits from the vaccine, but vaccination at the early stage of recovery from COVID‐19 might be a risk for certain populations. These cases highlight a potential association between vaccination, interstitial lung disease and worsening of post‐COVID‐19 pneumonia. Further investigation and research examining the relationship between the timing of SARS‐CoV‐2 vaccination and potential risks in post‐COVID‐19 patients is recommended

Diminishment of Carbapenemase-Producing Enterobacterales from Sink Outlets Using a Steam Cleaner

In 2016, Tosei General Hospital, a tertiary emergency medical facility with 633 beds in Japan, experienced a large nosocomial outbreak of carbapenemase-producing Enterobacterales (CPE) that had spread to numerous sink outlets. Based on our experience with using steam cleaners to suppress CPE on environmental surfaces, we report the efficacy of steam cleaners in the disinfection of sink outlets. Steam cleaners were used to disinfect 22 target areas. CPE disappeared in 90.9% of the sink outlets within the first two months after disinfection, and, after 12 months, 54.5% of the sink outlets remained negative throughout the remainder of the study period. This study demonstrates the effectiveness of using steam cleaners to disinfect sink outlets contaminated with CPE

Impact of rapid identification of positive blood cultures using the Verigene system on antibiotic prescriptions: A prospective study of community-onset bacteremia in a tertiary hospital in Japan.

Rapid identification of positive blood cultures is important for initiation of optimal treatment in septic patients. Effects of automated, microarray-based rapid identification systems on antibiotic prescription against community-onset bacteremia (COB) remain unclear.We prospectively enrolled 177 patients with 185 COB episodes (occurring within 72 h of admission) over 17 months. Bacteremia episodes due to gram-positive bacteria (GP) and gram-negative bacteria (GN) in the same patient were counted separately. For GP bacteremia, patients with ≥2 sets of positive blood cultures were included. The primary study objective was evaluating the rates of antibiotic prescription changes within 2 days of rapid identification using the Verigene system.Bacteremia due to GN and GP included 144/185 (77.8%) and 41/185 (22.2%) episodes, respectively. Antibiotic prescription changes occurred in 51/185 cases (27.6% [95%CI:21.3-34.6%]) after Verigene analysis and 70/185 cases (37.8% [30.8-45.2%]) after conventional identification and susceptibility testing. Prescription changes after Verigene identification were more frequent in GP (17/41[41.5%]) than in GN (34/144[23.5%]). Among bacteremia due to single pathogen targeted by Verigene test, bacterial identification agreement between the two tests was high (GP: 38/39[97.4%], GN: 116/116[100%]). The Verigene test correctly predicted targeted antimicrobial resistance. The durations between the initiation of incubation and reporting of the results for the Verigene system and conventional test was 28.3 h (IQR: 25.8-43.4 h) and 90.6 h (68.3-118.4 h), respectively. In only four of the seven episodes of COB in which two isolates were identified by conventional tests, the Verigene test correctly identified both organisms.We observed a high rate of antibiotic prescription changes after the Verigene test in a population with COB especially in GP. The Verigene test would be a useful tool in antimicrobial stewardship programs among patients with COB