Undiagnosed Perihepatic Abscess Revealed at Autopsy of a Patient With COVID-19 Undergoing Prolonged Extracorporeal Membrane Oxygenation (ECMO) Therapy.

The use of extracorporeal membrane oxygenation (ECMO) increased during the COVID-19 pandemic. However, complications associated with the long-term use of ECMO are poorly understood. This case report describes the autopsy findings of a perihepatic abscess in a patient with long-term COVID-19, which could not be diagnosed before death. In cases where the source of infection remains elusive but uncontrolled infections occur, we recommend the combined use of ultrasonography and contrast-enhanced computed tomography (CT) in patients with COVID-19 undergoing prolonged ECMO support, with particular consideration given to the potential development of cholecystitis.

A cluster of Candida parapsilosis displaying fluconazole-trailing in a neonatal intensive care unit successfully contained by multiple infection-control interventions.

Objective: This study aimed to investigate and contain a cluster of invasive candidiasis cases caused by fluconazole-resistant Candida parapsilosis (FRC) in a neonatal intensive care unit. Methods: Active surveillance was initiated. Direct observations of hand-hygiene compliance (HHC) among staff were conducted before and after the implementation of hand-hygiene (HH) education. Thirty-five environmental cultures were obtained. Phylogenetic analysis of FRC was performed using Fourier-transform infrared spectroscopy and microsatellite genotyping. Results: A total of 14 patients (mean birth weight = 860 g, gestational age = 25 weeks) infected with FRC were identified using the fully automated analyzer, including 5 with clinical infection (three with catheter-related bloodstream infection, one with cutaneous infection, and one with fatal peritonitis) and 9 with colonization. The HHC rate in nurses before performing a sterile or aseptic procedure significantly improved after the HH education (P < .05). Sinks near the patients were contaminated with FRC. All FRC strains were confirmed to be susceptible to fluconazole using the CLSI method, and the microdilution procedure indicated a trailing effect. Phylogenetic analysis showed that all the fluconazole-trailing isolates from patients were clustered together and had the same genotype. Sinks were successfully decontaminated using accelerated hydrogen peroxide and drainage pipes were replaced. Ultraviolet-C decontamination was applied in the milk preparation room. No new cases were detected after the education and disinfection interventions. Conclusions: Sinks are an important reservoir of C. parapsilosis. Active surveillance, environmental hygiene, and constant staff education on maintaining a high level of HHC are necessary to limit the spread of C. parapsilosis.

Molecular Epidemiology of Carbapenem-Resistant Klebsiella aerogenes in Japan.

Information regarding Klebsiella aerogenes haboring carbapenemase in Japan is limited. A comprehensive nationwide survey was conducted from September 2014 to December 2022, and 67 non-duplicate strains of carbapenem-resistant K. aerogenes were isolated from 57 healthcare facilities in Japan. Through genetic testing and whole-genome sequencing, six strains were found to possess carbapenemases, including imipenemase (IMP)-1, IMP-6, New Delhi metallo-ß-lactamase (NDM)-1, and NDM-5. The strain harboring blaNDM-5 was the novel strain ST709, which belongs to the clonal complex of the predominant ST4 in China. The novel integron containing blaIMP-1 featured the oxacillinase-101 gene, which is a previously unreported structure, with an IncN4 plasmid type. However, integrons found in the strains possessing blaIMP-6, which were the most commonly identified, matched those reported domestically in Klebsiella pneumoniae, suggesting the prevalence of identical integrons. Transposons containing blaNDM are similar or identical to the transposon structure of K. aerogenes harboring blaNDM-5 previously reported in Japan, suggesting that the same type of transposon could have been transmitted to K. aerogenes in Japan. This investigation analyzed mobile genetic elements, such as integrons and transposons, to understand the spread of carbapenemases, highlighting the growing challenge of carbapenem-resistant Enterobacterales in Japan and underscoring the critical need for ongoing surveillance to control these pathogens.

A web-based genome-wide association study reveals the susceptibility loci of common adverse events following COVID-19 vaccination in the Japanese population.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. To prevent its spread, mRNA-based vaccines made by Pfizer/BioNTech (BNT162b1) and Moderna (mRNA-1273) have been widely used, including in Japan. Various adverse events have been reported following the COVID-19 mRNA vaccination, with differences observed among individuals. However, analyses of the genetic background associated with the susceptibility to side effects have been limited. In the present study, we performed genome-wide association studies (GWAS) for self-reported adverse events of the COVID-19 mRNA vaccination in 4545 Japanese individuals and identified 14 associated loci. Among these, 6p21 was associated with 37.5 °C or higher fever, 38 °C or higher fever, and muscle pain. HLA allele association analysis revealed that various HLA alleles were associated with the adverse effects; HLA-DQA1*03:01 and HLA-A*11:01 were more reliably associated with the adverse effects. Our results may enable the preparation and management of adverse effects by identifying the susceptibility to these adverse events. Furthermore, we obtained valuable data that may lead to a better understanding of the mechanisms of action of the COVID-19 mRNA vaccines.

Epidemiological Characteristics of Carbapenem-Resistant Enterobacterales in Japan: A Nationwide Analysis of Data from a Clinical Laboratory Center (2016-2022).

In Japan, nationwide epidemiological surveys on carbapenem-resistant Enterobacterales (CREs), including comprehensive information, are scarce, with most data available only through public reports. This study analyzed data on the Enterobacterales family collected from nationwide testing centers between January 2016 and December 2022, focusing on isolates that met the criteria for CRE in Japan based on drug susceptibility. We investigated 5,323,875 Enterobacterales isolates of 12 different species; among 4696 (0.09%) CRE strains, the proportion of major CRE isolates was as follows: Escherichia coli, 31.3%; Klebsiella pneumoniae, 28.0%; Enterobacter cloacae, 18.5%; and Klebsiella aerogenes, 6.7%. Moreover, over a 7-year period, Providencia rettgeri, E. cloacae, K. aerogenes, and K. pneumoniae demonstrated relatively high CRE percentages of 0.6% (156/26,185), 0.47% (869/184,221), 0.28% (313/110,371), and 0.17% (1314/780,958), respectively. The number of CRE strains isolated from different samples was as follows: urine, 2390; respiratory specimens, 1254; stool, 425; blood, 252; others, 375. In the broader context, including colonization, the predominant isolates of CREs collected at nationwide testing centers are E. coli and K. pneumoniae. Furthermore, recently, attention has been directed toward less common CRE species, such as Klebsiella oxytoca and Providencia rettgeri, and thus, it might be necessary to continue monitoring these less common species.

Role of the contaminated environment in transmission of multidrug-resistant organisms in nursing homes and infection prevention.

BACKGROUND: With aging of the population in the United States, there are more people in long-term care facilities than in hospitals. Nursing home residents have a high prevalence of colonization with multidrug-resistant organisms (MDROs). A shared environment with vulnerable patients can facilitate intra- and inter-facility transmission of MDROs. The aim of this paper is to examine the role of the nursing home environment in MDRO transmission and provide infection prevention strategies. METHODS: We searched the published literature and reviewed selected articles on contamination, transmission, and infection associated with the nursing home environment. RESULTS: Nursing home residents were frequently colonized with MDROs, leading to contamination of the surrounding environment with the same pathogen. Surface contamination with MDROs was common in nursing home patient rooms, and to a substantial but lesser frequency in common rooms. Shared rooms were a risk factor for MDRO transmission between patients. CONCLUSIONS: Since outbreaks and infections via the environmental contamination cause substantial burden of morbidity and mortality in the nursing home residents, it is essential for healthcare personnel to recognize the role of the nursing home environment in infection transmission and adhere to the current infection prevention guidelines for cleaning and disinfection of environmental surfaces.

Screening for Metallo-Beta-Lactamases Using Non-Carbapenem Agents: Effective Detection of MBL-Producing Enterobacterales and Differentiation of Carbapenem-Resistant Enterobacterales.

Metallo-beta-lactamases (MBLs) are enzymes that break down carbapenem antibiotics, leading to carbapenem-resistant organisms. Carbapenemase-resistant Enterobacterales (CRE) is one of them. Outbreaks of CRE infection can occur in healthcare facilities and lead to increased deaths, illness, and medical costs. This study was conducted to detect MBLs using non-carbapenem agents and exclude MBLs among CRE isolates. A total of 3776 non-duplicate sequential Enterobacterales isolates from a single facility were screened between January 2019 and December 2022 using non-carbapenem agents, ceftazidime and cefoperazone/sulbactam. Positive 153 isolates (4.0%) were further tested using carbapenemase-confirmation tests and verified through polymerase chain reaction (PCR) testing. Fifteen imipenemase (IMP)-type MBL-producing Enterobacterales (0.4%) including one susceptible to carbapenems were identified. Moreover, 160 isolates (4.2%) meeting the criteria for CRE were directly subjected to PCR testing. All fourteen CRE isolates with MBLs identified through PCR testing were found to be the same strains screened using ceftazidime and cefoperazone/sulbactam. Screening using ceftazidime and cefoperazone/sulbactam can effectively detect MBL-producing Enterobacterales strains. This screening method showed comparable results to screening with meropenem, potentially serving as a supplementary approach and contributing to differentiating between MBL- and non-MBL-producing CRE strains. Our findings support these screening methods, particularly in regions where IMP-type MBLs are prevalent.

Multiplex Hybrid Capture Improves the Deep Detection of Antimicrobial Resistance Genes from Wastewater Treatment Plant Effluents to Assess Environmental Issues.

Metagenomic sequencing (mDNA-seq) is one of the best approaches to address antimicrobial resistance (AMR) issues and characterize AMR genes (ARGs) and their host bacteria (ARB); however, the sensitivity provided is insufficient for the overall detection in wastewater treatment plant (WWTP) effluents because the effluent is well treated. This study investigated the multiplex hybrid capture (xHYB) method (QIAseq × HYB AMR Panel) and its potential to increase AMR assessment sensitivity. The mDNA-Seq analysis suggested that the WWTP effluents had an average of 104 reads per kilobase of gene per million (RPKM) for the detection of all targeted ARGs, whereas xHYB significantly improved detection at 601,576 RPKM, indicating an average 5,805-fold increase in sensitivity. For instance, sul1 was detected at 15 and 114,229 RPKM using mDNA-seq and xHYB, respectively. The blaCTX-M, blaKPC, and mcr gene variants were not detected by mDNA-Seq but were detected by xHYB at 67, 20, and 1,010 RPKM, respectively. This study demonstrates that the multiplex xHYB method could be a suitable evaluation standard with high sensitivity and specificity for deep-dive detection, highlighting a broader illustration of ongoing dissemination in the entire community.

Clinical Features Comparing Arterial Thrombosis and Venous Thromboembolism in Hospitalized Patients with COVID-19: Result from the CLOT-COVID Study.

Objectives: This study aimed to investigate the clinical features of arterial thrombosis and venous thromboembolism (VTE) in coronavirus disease 2019 (COVID-19). Methods: The CLOT-COVID Study was a retrospective, multicenter cohort study that enrolled 2,894 consecutively hospitalized patients with COVID-19 among 16 centers in Japan from April 2021 to September 2021. We compared the clinical features of arterial thrombosis and VTE. Results: Thrombosis was observed in 55 patients (1.9%) during hospitalization. Arterial thrombosis and VTE occurred in 12 (0.4%) and 36 (1.2%) patients, respectively. Among the 12 patients with arterial thrombosis, 9 (75%), 2 (17%), and 1 developed ischemic cerebral infarction, myocardial infarction, and acute limb ischemia, respectively, and there were five patients (42%) without comorbidities. Among 36 patients with VTE, 19 (53%) and 17 (47%) developed pulmonary embolism (PE) and deep vein thrombosis (DVT), respectively. PE was common in the early stages of hospitalization; whereas, DVT was common beyond the early stages of hospitalization. Conclusion: Among patients with COVID-19, arterial thrombosis was less common than VTE, although ischemic cerebral infarction seemed to be relatively common, and a certain number of patients developed arterial thrombosis even in the absence of known atherosclerosis risk factors.

Circulating Extracellular Vesicle Levels in Patients with Coronavirus Disease 2019 Coagulopathy: A Prospective Cohort Study.

Coronavirus disease 2019 (COVID-19) is associated with coagulopathy. However, the underlying mechanisms are not completely understood. We evaluated the association between COVID-19 coagulopathy and extracellular vesicle (EV) levels. We hypothesized that several EV levels would be higher in COVID-19 coagulopathy patients than in non-coagulopathy patients. This prospective observational study was conducted in four tertiary care faculties in Japan. We enrolled 99 COVID-19 patients (48 with coagulopathy and 51 without coagulopathy) aged ≥20 years who required hospitalization, and 10 healthy volunteers; we divided the patients into coagulopathy and non-coagulopathy groups according to the D-dimer levels (≥1 µg/mL and <1 µg/mL, respectively). We used flow cytometry to measure the tissue-factor-bearing, endothelium-derived, platelet-derived, monocyte-derived, and neutrophil-derived EV levels in platelet-free plasma. The EV levels were compared between the two COVID-19 groups as well as among the coagulopathy patients, non-coagulopathy patients, and healthy volunteers. No significant difference was found in EV levels between the two groups. Meanwhile, the cluster of differentiation (CD) 41 + EV levels were significantly higher in COVID-19 coagulopathy patients than in healthy volunteers (549.90 [255.05-984.65] vs. 184.3 [150.1-254.1] counts/µL, p = 0.011). Therefore, CD41+ EVs might play an essential role in COVID-19 coagulopathy development.

Highly sensitive detection of antimicrobial resistance genes in hospital wastewater using the multiplex hybrid capture target enrichment.

Wastewater can be useful in monitoring the spread of antimicrobial resistance (AMR) within a hospital. The abundance of antibiotic resistance genes (ARGs) in hospital effluent was assessed using metagenomic sequencing (mDNA-seq) and hybrid capture (xHYB). mDNA-seq analysis and subsequent xHYB targeted enrichment were conducted on two effluent samples per month from November 2018 to May 2021. Reads per kilobase per million (RPKM) values were calculated for all 1,272 ARGs in the constructed database. The monthly numbers of patients with presumed extended-spectrum ß-lactamase (ESBL)-producing and metallo-ß-lactamase (MBL)-producing bacteria, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE) were compared with the monthly RPKM values of blaCTX-M, blaIMP, mecA, vanA, and vanB by xHYB. The average RPKM value for all ARGs detected by xHYB was significantly higher than that of mDNA-seq (665, 225, and 328, respectively, and P < 0.05). The average number of patients with ESBL producers and RPKM values of blaCTX-M-1 genes in 2020 were significantly higher than that in 2019 (17 and 13 patients per month and 921 vs 232 per month, respectively, both P < 0.05). The average numbers of patients with MBL-producers, MRSA, and VRE were 1, 28, and 0 per month, respectively, while the average RPKM values of blaIMP, mecA, vanA, and vanB were 6,163, 6, 0, and 126 per month, respectively. Monitoring ARGs in hospital effluent using xHYB was found to be more useful than conventional mDNA-seq in detecting ARGs including blaCTX-M, blaIMP, and vanB, which are important for infection control.IMPORTANCEEnvironmental ARGs play a crucial role in the emergence and spread of AMR that constitutes a significant global health threat. One major source of ARGs is effluent from healthcare facilities, where patients are frequently administered antimicrobials. Culture-independent methods, including metagenomics, can detect environmental ARGs carried by non-culturable bacteria and extracellular ARGs. mDNA-seq is one of the most comprehensive methods for environmental ARG surveillance; however, its sensitivity is insufficient for wastewater surveillance. This study demonstrates that xHYB appropriately monitors ARGs in hospital effluent for sensitive identification of nosocomial AMR dissemination. Correlations were observed between the numbers of inpatients with antibiotic-resistant bacteria and the ARG RPKM values in hospital effluent over time. ARG surveillance in hospital effluent using the highly sensitive and specific xHYB method could improve our understanding of the emergence and spread of AMR within a hospital.

Clinical Features and Outcomes of Persistent Candidemia Caused by Candida albicans versus Non-albicans Candida Species: A Focus on Antifungal Resistance and Follow-Up Blood Cultures.

The clinical distinctions among variations in Candida species, antifungal resistance (AFR), and clearance status of hospital-acquired persistent candidemia (HA-PC) remain uncertain. This secondary analysis of a retrospective cohort study aimed to assess the differences in HA-PC based on different Candida species, AFR, and persistent candidemia (PC) clearance status. A retrospective review was conducted using medical records from Tohoku University Hospital of patients for whom blood cultures were performed between January 2012 and December 2021. PC cases were categorized into groups based on Candida species, azole, or echinocandin resistance, as well as PC-clearance status, and the respective characteristics were analyzed. The HA-PC non-clearance group had a tendency toward higher 30-90-day and 90-day mortality rates compared to the HA-PC-clearance group in both the susceptible and resistant strain groups, with the former group demonstrating a statistically significant difference (odds ratio = 19, p = 0.028). The high mortality rate observed in the Candida non-albicans and resistant strain groups necessitates a more meticulous therapeutic management approach for PC. Follow-up blood cultures and confirmation of PC clearance are useful for improving the survival rates of both the HA-PC-susceptible and -resistant strain groups.

Novel Virus Air Sampler Based on Electrostatic Precipitation and Air Sampling of SARS-CoV-2.

The assessment of airborne viruses in air is a critical step in the design of appropriate prevention and control measures. Hence, herein, we developed a novel wet-type electrostatic air sampler using a viral dissolution buffer containing a radical scavenging agent, and verified the concentration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the air of hospital rooms inhabiting coronavirus disease 2019 (COVID-19) patients and public areas. RNA damage caused by corona discharge was negligible when Buffer AVL was used as the collecting electrode. The viral RNA concentration in the air of the room varied by patient: 3.9 × 103 copy/m3 on the 10th day after onset in a mild case and 1.3 × 103 copy/m3 on the 18th day in a severe case. Viral RNA levels were 7.8 × 102 and 1.9 × 102 copy/m3 in the air of the office and food court, respectively, where people removed their masks when eating and talking, but it remained undetected in the station corridor where all the people were wearing masks. The assessment of airborne SARS-CoV-2 RNA using the proposed sampler can serve as a basis for the safe discontinuation of COVID-19 isolation precautions to identify exposure hotspots and alert individuals at increased infection risks.

Clinical Characteristics and Outcomes of Persistent Staphylococcal Bacteremia in a Tertiary Care Hospital.

Clinical outcomes of persistent staphylococcal bacteremia vary depending on the causative organism. This secondary data analysis study compared the clinical characteristics of persistent Staphylococcus aureus (S. aureus)- and coagulase-negative staphylococci (CoNS)-caused bacteremia, focusing on the methicillin-resistant status. This study used data collected from patients who underwent blood cultures between January 2012 and December 2021 at Tohoku University Hospital, Japan. Patients with persistent staphylococcal bacteremia were divided into groups based on the pathogen and methicillin-resistant status, and their characteristics were analyzed. The primary outcomes were early (30-day), late (30-90 days), and 90-day mortality rates. The early, late, and 90-day mortality rates were similar between the persistent CoNS and S. aureus bacteremia groups. Patients with persistent methicillin-resistant S. aureus (MRSA) bacteremia tended to have higher early, late, and 90-day mortality rates than those with persistent methicillin-susceptible S. aureus bacteremia (not statistically significant). No differences were observed between the methicillin-resistant and-susceptible CoNS groups. In patients with persistent CoNS bacteremia, mortality tended to increase, especially in debilitated or immunocompromised patients with distant metastases, underscoring the importance of infection source control. Mortality tended to be high in patients with persistent MRSA bacteremia, especially when persistent bacteremia clearance was not confirmed, illustrating the need for careful therapeutic management.

Clinical and Epidemiological Characteristics of Persistent Bacteremia: A Decadal Observational Study.

Background: Bloodstream infections (BSIs), including persistent bacteremia (PB), are a leading source of morbidity and mortality globally. PB has a higher mortality rate than non- PB, but the clinical aspects of PB in terms of the causative pathogens and the presence of clearance of PB are not well elucidated. Therefore, this study aimed to describe the clinical and epidemiological characteristics of PB in a real-world clinical setting. Methods: We performed a retrospective observational survey of patients who underwent blood culture between January 2012 and December 2021 at Tohoku University Hospital. Cases of PB were divided into three groups depending on the causative pathogen: gram-positive cocci (GPC), gram-negative rods (GNRs), and Candida spp. For each group, we examined the clinical and epidemiological characteristics of PB, including differences in clinical features depending on the clearance of PB. The main outcome variable was mortality, assessed as early (30-day), late (30-90 day), and 90-day mortality. Results: Overall, we identified 31,591 cases of single bacteremia; in 6709 (21.2%) cases, the first blood culture was positive, and in 3124 (46.6%) cases, a follow-up blood culture (FUBC) was performed. Of the cases with FUBCs, 414 (13.2%) were confirmed to be PB. The proportion of PB cases caused by Candida spp. was significantly higher (29.6%, 67/226 episodes) than that for GPC (11.1%, 220/1974 episodes, p < 0.001) and GNRs (12.1%, 100/824 episodes, p < 0.001). The Candida spp. group also had the highest late (30-90 day) and 90-day mortality rates. In all three pathogen groups, the subgroup without the clearance of PB tended to have a higher mortality rate than the subgroup with clearance. Conclusions: Patients with PB due to Candida spp. have a higher late (30-90 day) and 90-day mortality rate than patients with PB due to GPC or GNRs. In patients with PB, FUBCs and confirming the clearance of PB are useful to improve the survival rate.

Characterization of extended-spectrum ß-lactamase-producing Escherichia coli isolated from municipal and hospital wastewater in Japan.

OBJECTIVES: The purpose of this study was to characterize the strains of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) isolated from municipal and hospital wastewater by detecting antibiotic resistance genes (ARGs) as well as antibiotic susceptibility. To identify the source of ESBL-EC, multi-locus sequence typing and typing plasmids that may carry ESBL-producing genes were conducted. METHODS: Wastewater was sampled twice a month from February 2019 to February 2020 from a municipal wastewater treatment plant and hospital located in a city in northeastern Japan. Throughout the study period, 279 and 37 strains of ESBL-EC were isolated from municipal and hospital wastewater, respectively. RESULTS: All 316 isolates were resistant to ampicillin and cefotaxime and susceptible to imipenem and tigecycline. Almost all (98.1%) of the ESBL-EC isolates possessed blaCTX-M, and the blaCTX-M-9 group was detected most frequently (62.3%). Multi-locus sequence typing revealed a higher diversity of sequence types (STs) in the isolates from municipal wastewater than in those from hospital wastewater; although ST131, which recently caused nosocomial- and community-associated infections worldwide, was dominant in both types of wastewater. All ST131 isolates possessed the IncFII plasmid, which is often reported to carry blaCTX-M. CONCLUSIONS: These results demonstrated that healthy people carry clinically important antibiotic-resistant bacteria and ARGs, motivating routine monitoring of municipal wastewater to detect such antibiotic-resistant bacteria and ARGs from a variety of sources supported by the high diversity of STs in the present study.

Impact of Persistent Multidrug-Resistant Gram-Negative Bacteremia on Clinical Outcome and Mortality.

The clinical aspects of persistent bacteremia (PB) caused by gram-negative rods (GNRs) in terms of antimicrobial resistance (AMR) and PB clearance status are unclear. This secondary analysis of a retrospective cohort study investigated differences in PB caused by Enterobacterales and glucose non-fermentative GNRs (NF-GNRs) based on AMR and PB clearance. We retrospectively surveyed medical records at Tohoku University Hospital. Patients for whom blood cultures were performed between January 2012 and December 2021 were recruited. PB cases were grouped based on AMR and PB clearance; the characteristics of PB due to each bacterial pathogen were examined. The main outcome variable was mortality. The late (30-90-day) mortality rate was significantly higher in the multidrug-resistant (MDR) group than in the non-MDR group for Enterobacterales. However, no significant difference was noted in mortality rates between NF-GNRs with and without AMR. Mortality rates tended to be higher in the non-PB-clearance group than in the clearance group for both Enterobacterales and NF-GNRs. Since the mortality rate was higher in the MDR group in the case of Enterobacterales PB, more careful management is necessary for this condition. Follow-up blood cultures and confirming the clearance of PB are useful for improving the survival rate.

Statistical Analysis of Mortality Rates of Coronavirus Disease 2019 (COVID-19) Patients in Japan Across the 4C Mortality Score Risk Groups, Age Groups, and Epidemiological Waves: A Report From the Nationwide COVID-19 Cohort.

Background: The mortality rates of coronavirus disease 2019 (COVID-19) have been changed across the epidemiological waves. The aim was to investigate the differences in mortality rates of COVID-19 patients in Japan across the 6 epidemiological waves stratified by age group and Coronavirus Clinical Characterisation Consortium (4C) mortality score risk group. Methods: A total of 56 986 COVID-19 patients in the COVID-19 Registry Japan from 2 March 2020 to 1 February 2022 were enrolled. These patients were categorized into 4 risk groups based on their 4C mortality score. Mortality rates of each risk group were calculated separately for different age groups: 18-64, 65-74, 75-89, and ≥90 years. In addition, mortality rates across the wave periods were calculated separately in 2 age groups: <75 and ≥75 years. All calculated mortality rates were compared with reported data from the United Kingdom (UK) during the early epidemic. Results: The mortality rates of patients in Japan were significantly lower than in the UK across the board, with the exception of patients aged ≥90 years at very high risk. The mortality rates of patients aged ≥75 years at very high risk in the fourth and fifth wave periods showed no significant differences from those in the UK, whereas those in the sixth wave period were significantly lower in all age groups and in all risk groups. Conclusions: The present analysis showed that COVID-19 patients had a lower mortality rate in the most recent sixth wave period, even among patients ≥75 years old at very high risk.