Search

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Pathogens and Global Health, 117(2), pp.101-103; 2023

Influenza remains a clinically heavy burden worldwide. It is well known that some populations are at high risk of complications from influenza, whereas, even previously healthy people might suffer from severe influenza. The objective of this study was to clarify clinical manifestations of hospitalized patients without risk factors infected with influenza.The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2020 (6 influenza seasons) using an internet-surveillance system. Among them, the patients who had no risk factors of complications from influenza were extracted.Finally, a total of 91 patients (9.0% of all influenza-related hospitalizations) without risk factors were analyzed. The no risk group was younger than the risk group, though other significant differences of clinical characteristics were not recognized between the groups. Pneumonia was the most common cause of hospitalization in the no risk group, and primary influenza viral pneumonia was the most common pneumonia. Antiviral drugs were administered in 96.7% of the no-risk group, and artificial ventilation was performed in 18.7%. In-hospital death was recorded for 3 patients without risk factors.Severe complications of influenza which required hospitalization may occur in a certain degree of patients with no risk factors. Efforts are needed to diagnose and treat influenza appropriately even in previously healthy younger patients. Continuous nationwide surveillance will be required to clarify risk factors for severe influenza even in previously healthy younger patients. (UMIN000015989).

Preventing coronavirus disease (COVID-19) outbreaks and the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from urban areas to less-populated remote islands, many of which may have weak medical systems, is an important issue. Here, we evaluated the usefulness of pre-boarding, saliva-based polymerase chain reaction (PCR) screening tests to prevent the spread of SARS-CoV-2 from Tokyo to the remote island of Chichijima. The infection rate on the island during the study period from September 1, 2020 to March 21, 2021 was 0.015% (2/13,446). Of the 8,910 individuals tested before ship boarding, seven tested positive for COVID-19 (PCR tests of saliva samples). One was confirmed positive by subsequent confirmatory nasopharyngeal swab testing. Based on the testing results, positive cases were denied entry onto the ship to prevent the spread of COVID-19 from Tokyo to Chichijima. This study demonstrated that implementing pre-boarding PCR screening tests is a useful strategy that can be applied to other remote islands with vulnerable medical systems.

Several commercial nucleic acid amplification tests (NAAT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed. We used six kits available in Japan in 13 NAAT-positive specimens with crossing point values >36 and 7 NAAT-negative specimens from patients with coronavirus disease (COVID-19); their results were compared. Specimens positive in ≥2 assays were considered true positive and examined for concordance with specimen results. The SARS-CoV-2 Detection Kit -Multi- (Toyobo M) (Toyobo, Osaka, Japan) using extracted RNA had the highest concordance (κ 1.00). This was followed by the cobas® SARS-CoV-2 (Cobas) (Roche, Basel, Switzerland) (κ 0.79). There was a weak correlation between number of negative results for each kit and days between onset and testing (Spearman rank correlation: ρ= 0.44; p

Tokyo Metropolitan Area is the most populous metropolitan area in the world. While cities around the world are struggling to cope with COVID-19, the number of new positives and deaths in Tokyo has so far been relatively contained compared to other large metropolitan areas. In Japan, infection control measures do not prohibit people from moving around during a COVID-19 outbreak. However, people are not only refraining from travel and social activities at the request of the government, but are also using their own judgment to avoid risk based on information about the infectious disease. This plays an extremely important role in Japans infection control measures. Expectations are high in Japan for maintaining the health care system and minimizing deaths. It is necessary to steadily respond to these expectations while normalizing social functions.

BackgroundEpidemiological data regarding differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination are scarce.MethodsWe repeatedly assessed the anti-spike IgG antibody titers of 2- and 3-dose mRNA vaccine recipients among the staff of a medical and research center in Tokyo. Linear mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last immune-conferred event (vaccination or infection) and compare antibody waning rates across prior infection and vaccination status, and across background factors in infection-naïve participants.ResultsA total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were analyzed. Antibody waning rate (per 30 days [95% CI]) was slower after 3-dose (25% [23–26]) than 2-dose (36% [35–37]). Participants with hybrid immunity (vaccination and infection) had further slower waning rates: 2-dose plus infection (16% [9–22]); 3-dose plus infection (21% [17–25]). Older age, male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were associated with lower antibody titers, whereas these associations disappeared after 3-dose, except for sex (lower in female participants) and immunosuppressant use. Antibody waning was faster in older participants, females, and alcohol drinkers after 2-dose, whereas it did not differ after 3-dose across except sex.ConclusionsThe 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection further enhanced its durability. The antibody levels at a given time point and waning speed after 2-dose differed across background factors; however, these differences mostly diminished after 3-dose.

Background Mycobacterium abscessus subsp. massiliense (MMA) comprises a group of non-tuberculous, rapidly growing mycobacteria. Although MMA can cause pulmonary diseases, surgical site infections, and disseminated diseases, aortic endograft infection has not been reported. Here, we describe the first case of aortic endograft infection caused by MMA. Case presentation Two months after stent-graft insertion for an abdominal aortic aneurysm, an 85-year-old man was admitted with fever and abdominal pain and was diagnosed with aortic endograft infection. Despite 14 days of meropenem and vancomycin intravenous administration, periaortic fluid pooling increased as compared to that before antibiotic administration. The abscess was drained, and fluorescent acid-fast staining of the abscess fluid revealed bacilli. The organism was identified as MMA by genetic testing. Intravenous imipenem–cilastatin (IPM/CS), amikacin (AMK), and oral clarithromycin (CAM) were administered. After 2 months, oral CAM and sitafloxacin were administered because the abscess had decreased in size. However, after 6 weeks, the abscess increased in size again. Antimicrobial susceptibility testing of the drainage fluid from the abscess resulted in the isolation of an MMA strain that had acquired resistance to CAM. Intravenous IPM/CS, AMK, and oral linezolid were added to the treatment regimen along with oral CAM and STFX. However, he was not fully cured and died 6 months later. Neither the full-length erythromycin ribosome methyltransferase (erm)(41) gene nor the rrl or rpIV gene mutations were found by Sanger sequencing in the pre- and post-treatment strains. Whole-genome sequence analysis of the post-treatment strain revealed mutations in genes with no previous reports of association with macrolide resistance. Conclusions Aortic endograft infection caused by MMA strain is extremely rare; nonetheless, MMA should be suspected as the causative microorganism when broad-spectrum antimicrobials are ineffective.

ImportanceInvestigating the role of pre-infection humoral immunity against Omicron BA.5 infection risk and long COVID development is critical to inform public health guidance.ObjectiveTo investigate the association between pre-infection immunogenicity after the third vaccine dose and the risks of Omicron BA.5 infection and long coronavirus disease.Design, Setting, and ParticipantsThis nested case-control analysis was conducted among tertiary hospital staff in Tokyo, Japan who donated blood samples in June 2022 (1 month before Omicron BA.5 dominant wave onset [July–September 2022]) approximately 6 months after receiving the third dose of the historical monovalent coronavirus disease 2019 mRNA vaccine.ExposuresLive virus-neutralizing antibody titers against Wuhan and Omicron BA.5 (NT50) and anti-SARS-CoV-2 spike protein antibody titers with Abbott (AU/mL) and Roche (U/mL) assays at pre-infection.Main Outcomes and MeasuresSymptomatic SARS-CoV-2 breakthrough infections during the Omicron BA.5 dominant wave vs. undiagnosed controls matched using a propensity score. Incidence of long COVID (persistent symptoms ≥4 weeks after infection) among breakthrough infection cases.ResultsAnti-spike antibody titers were compared between 243 breakthrough infection cases and their matched controls among the 2360 staff members who met the criteria. Neutralizing antibodies in 50 randomly selected matched pairs were measured and compared. Pre-infection anti-spike and neutralizing antibody titers were lower in breakthrough cases than in undiagnosed controls. Neutralizing antibody titers against Wuhan and Omicron BA.5 were 64% (95% CI: 42–77) and 72% (95% CI: 53–83) lower, respectively, in breakthrough cases than in undiagnosed controls. Individuals with previous SARS-CoV-2 infections were more frequent among undiagnosed controls than breakthrough cases (19.3% vs. 4.1%), and their neutralizing antibody titers were higher than those of infection-naïve individuals. Among the breakthrough cases, pre-infection antibody titers were not associated with the incidence of long COVID.Conclusions and RelevancePre-infection immunogenicity against SARS-CoV-2 may play a role in protecting against the Omicron BA.5 infection, but not in preventing long COVID.Key PointsQuestionDoes pre-infection anti-SARS-CoV-2 humoral immunity protect against Omicron BA.5 infection and long-COVID development?FindingsPre-infection neutralizing antibody titers against Omicron BA.5 were lower in subsequent Omicron BA.5 breakthrough infection cases than in matched controls in this nested case-control study of healthcare workers who received the third dose of historical COVID-19 mRNA vaccines approximately 6 months prior. Pre-infection antibody titers could not predict the incidence of long COVID among breakthrough infection cases.MeaningHigher pre-infection humoral immunity approximately 6 months after the third vaccination may correlate with protection against Omicron BA.5 infection but not against long-COVID development.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be detected in the stool samples of patients with coronavirus disease 2019 (COVID-19), and this virus can be transmitted via the oral-fecal route. However, there are only few reports on the viral load in the stool samples. In this pilot study, we aimed to evaluate the clinical characteristics and viral load of SARS-CoV-2 in the stool samples of 13 patients with confirmed COVID-19 using pepper mild mottle virus as a control, which has been proposed as a potential marker of human feces contamination in the environmental water bodies. SARS-CoV-2 RNA was detected in the stool samples of four patients (31%), and among them, three exhibited symptoms of diarrhea. One patient who suffered from long-term diarrhea (22 days) exhibited highest level of viral RNA in the stool sample (8.28 log10 copies/g). However, we could not harvest SARS-CoV-2 from the stool sample of any patient, even after culturing with VeroE6/TMPRESS2 cells for four weeks. Our results suggest that SARS-CoV-2 RNA can be detected in the stool samples of patients with COVID-19 suffering from diarrhea. However, further studies elucidating the relationship between SARS-CoV-2 viral load in the stool samples and symptoms of diarrhea in large cohorts and upon adjusting other causative factors and virus infectivity are still warranted.

Background Several studies have investigated whether pregnancy is a risk factor for developing severe coronavirus disease 2019 (COVID-19); however, the results remain controversial. In addition, the information regarding risk factors for developing severe COVID-19 in pregnant women is limited. Methods A retrospective cohort study analyzing the data from the nationwide COVID-19 registry in Japan was conducted. Propensity score–matched analysis was performed to compare COVID-19 severity between pregnant and nonpregnant women. Multivariate analysis was also conducted to evaluate risk factors for developing moderate-to-severe COVID-19 in pregnant women. Results During the study period, 254 pregnant and 3752 nonpregnant women of reproductive age were identified. After propensity score matching, 187 pregnant women and 935 nonpregnant women were selected. A composite outcome of moderate-to-severe COVID-19 was more frequently observed in pregnant women than that of nonpregnant women (n = 18 [9.6%] vs n = 46 [4.9%]; P = .0155). In multivariate analysis, the presence of underlying diseases and being in the second-to-third trimester of pregnancy were recognized as risk factors for moderate-to-severe COVID-19 in pregnant women (odds ratio [95% confidence interval]: 5.295 [1.21–23.069] and 3.871 [1.201–12.477], respectively). Conclusions Pregnancy could be a risk factor for moderate-to-severe COVID-19 for women in Japan. In addition to the presence of comorbidities, advanced pregnancy stages may contribute to greater risks for developing moderate-to-severe COVID-19 in pregnant women.

Introduction: Old age is an independent risk factor (RF) for severe COVID-19; evidence for clinico-epidemiological characteristics among elderly COVID-19 patients is scarce. We aimed to analyze clinical and epidemiological characteristics and comorbidities associated with COVID-19 inpatients in age-stratified populations of an elderly COVID-19 cohort. Methods: We conducted a retrospective cohort study, using nationwide registry data of COVID-19 patients hospitalized before October 31, 2020 (major information entered in the registry as of December 28, 2020). Participants were divided by age according to the Japan Geriatrics Society and the Japan Gerontological Society: pre-old (65–74 years), old (75–89 years), and super-old (≥90 years). Multivariable logistic regression (MLR) analyses were conducted to identify stratified risk and relationships with comorbidities associated with worse outcomes in different age-groups of elderly patients. Demographics and supportive care were evaluated by category. Results: Data of 4,701 patients from 444 hospitals were included. Most patients (79.3%) had at least one comorbidity; the proportion of patients with hypertension was high in all categories. The proportion of patients with dementia, cardiovascular disease, and cerebrovascular disease increased with age. The percentage of patients who underwent invasive mechanical ventilation/extracorporeal membrane oxygenation was lower in the super-old group. In total, 11.5% of patients died (5.3%, pre-old; 15.2%, old; and 22.4%, super-old). MLR showed that the risk of critical illness differed among age-groups. Male sex was a significant RF in all ages. Collagen disease, moderate to severe renal disorder, and dialysis were significant RFs in older patients, while hematological malignancies and metastatic tumors were more important RFs for severe disease in relatively younger patients. Most of the RFs for critical illnesses were associated with death. Conclusion: Differences in the epidemiological and clinical characteristics among the different age-groups were found.

Introduction In response to global outbreaks of infectious diseases, the need for support from organizations such as the World Health Organization Global Outbreak Alert and Response Network (GOARN) is increasing. Identifying the obstacles and support needs for applicants could increase GOARN deployments from Japan. Methods This cross-sectional study involved a web-based, self-administered questionnaire survey targeting Japanese participants in the GOARN Tier 1.5 training workshop, held in Tokyo in December 2019. Results All 47 Japanese participants in the workshop responded to the survey. Most responders were male and in their 30s and 40s. Participants specialized in case management (42.6%), infection prevention and control (25.6%), epidemiology and surveillance (19.1%). Only two participants (4.6%) had experienced a GOARN deployment. Their motivations for joining the GOARN training workshop were “Desire to be part of an international emerging infectious disease response team” (44.6%), “Interest in making an international contribution” (19.1%), and “Interest in working for the Japanese government in the field of international infectious diseases” (14.9%). Obstacles to GOARN deployments were “Making time for deployments” (45.7%) and “Lack of required professional skills and knowledge” (40.4%). The support needs for GOARN deployments constituted “Periodic simulation training” (51.1%), “Financial support during deployments” (44.7%), and “Technical support for deployments” (40.4%). Conclusions Our study revealed the obstacles and support needs of Japanese candidates for GOARN deployment. Making time and upskilling for GOARN deployment were the main obstacles. More practical training (like GOARN Tier 2.0) with other supports are needed. The national framework is desirable to realize these supports.

Background While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infection. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. Methods We describe incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2415 fully vaccinated staff (BNT162b2) for breakthrough infection and selected 3 matched controls. We measured post-vaccination neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the 2 groups. Results No COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and participants had returned to work early. There was no measurable difference between cases and controls in post-vaccination neutralizing antibody titers against the wild-type, Alpha, Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. Conclusions Post-vaccination neutralizing antibody titers were not decreased among patients with breakthrough infection relative to their controls under the Delta variant outbreak. The result points to the importance of infection-control measures in the post-vaccination era, irrespective of immunogenicity profile.

To describe the trend of cumulative incidence of coronavirus disease 19 (COVID-19) and undiagnosed cases over the pandemic through the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants among healthcare workers in Tokyo, we analysed data of repeated serological surveys and in-house COVID-19 registry among the staff of National Center for Global Health and Medicine. Participants were asked to donate venous blood and complete a survey questionnaire about COVID-19 diagnosis and vaccine. Positive serology was defined as being positive on Roche or Abbott assay against SARS-CoV-2 nucleocapsid protein, and cumulative infection was defined as either being seropositive or having a history of COVID-19. Cumulative infection has increased from 2.0% in June 2021 (pre-Delta) to 5.3% in December 2021 (post-Delta). After the emergence of the Omicron, it has increased substantially during 2022 (16.9% in June and 39.0% in December). As of December 2022, 30% of those who were infected in the past were not aware of their infection. Results indicate that SARS-CoV-2 infection has rapidly expanded during the Omicron-variant epidemic among healthcare workers in Tokyo and that a sizable number of infections were undiagnosed.

The symptoms that persist after an acute coronavirus disease 2019 (COVID-19) are referred to as post-COVID conditions. Although the cause of post-COVID conditions remains unclear, the host immune response to SARS-CoV-2 may be involved. Hence, we aimed to investigate the effect of serum antibody titers against SARS-CoV-2 on the development of post-COVID conditions. We conducted a retrospective observational study of COVID-19-recovered individuals who attended the clinic at the National Center for Global Health and Medicine between January 2020 and April 2021. Serum SARS-CoV-2 anti-spike antibody titers were measured and a questionnaire survey was used to collect information on the presence of post-COVID conditions and demographic characteristics of the participants. Participants were then divided into two groups: high peak antibody titer group [>= 0.759 OD450 value], and low peak antibody titer group [< 0.759 OD450 value] and compared their frequency of post-COVID conditions. Of 526 individuals attending the clinic, 457 (86.9%) responded to the questionnaire. We analyzed the data of 227 (49.7%) participants with measurements of serum antibody titers during the peak period. The incidence of depressed mood was significantly higher in the group with higher antibody titers (odds ratio: 2.34, 95% CI: 1.17-4.67, p = 0.016). There was no significant difference in the frequency of the remaining symptoms between the two groups. Among post-COVID conditions, the depressed mood was more frequent in the group with high serum antibody titers which suggests a difference in pathogenesis between depressive mood and other post-COVID conditions that requires further investigation.

This study aimed to examine the sex-associated differences in the relationship between dyslipidemia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike immunoglobulin (Ig)G antibodies among BNT162b2 vaccine recipients.Participants were staff members (aged 21-75 years) of a medical and research institution who underwent an anti-SARS-CoV-2 spike IgG antibody test after the second (n=1,872) and third doses (n=1,075) of the BNT162b2 vaccine. Dyslipidemia was defined as triglyceride level ≥150 mg/dL, high-density lipoprotein-cholesterol level40 mg/dL, low-density lipoprotein-cholesterol level ≥140 mg/dL, or lipid-lowering medication use. Multivariable linear regression was used to calculate the ratio of means for SARS-CoV-2 spike IgG titer according to dyslipidemia status.The prevalence of dyslipidemia was 38.0% in men and 19.6% in women. The relationship between dyslipidemia and SARS-CoV-2 spike IgG titers after the second dose differed markedly by sex (P for interaction0.001). In men, dyslipidemia was associated with significantly lower IgG titers: ratio of means [95% confidence interval (CI)] was 0.82 (0.72-0.93). However, this association disappeared after the third dose (0.96 [0.78-1.18]). Of dyslipidemia components, hypertriglyceridemia was inversely associated with SARS-CoV-2 spike IgG antibody titer after both the second and third doses [ratio of means: 0.82 (0.70-0.95) and 0.73 (0.56-0.95), respectively]. In women, IgG titers did not differ according to dyslipidemia or hypertriglyceridemia status after either dose.These results suggest a detrimental role of hypertriglyceridemia in the humoral immune response to the BNT162b2 vaccine for COVID-19 in men but not in women. This article is protected by copyright. All rights reserved.

Social contact data in Japan have not been updated since 2011. The main objectives of this study are to report on newly collected social contact data, to study mixing patterns in the context of the COVID-19 pandemic, and to compare the contact patterns during and after mass events like the 2020 Olympic Games, which were held in 2021.We compared the number of contacts per day during and after the Olympic Games and on weekdays and weekends; we also compared them with a pre-COVID-19 pandemic social contact study in Japan. Contact matrices consisting of the age-specific average number of contacted persons recorded per day were obtained from the survey data. Reciprocity at the population level was achieved by using a weighted average.The median number of contacts per day was 3 (interquartile range (IQR) = 1-6). The occurrence of the Olympic Games and the temporal source of data (weekday or weekend) did not change the results substantially. All three matrices derived from this survey showed age-specific assortative mixing patterns like the previous social contact survey.The frequency of social contact in Japan did not change substantially during the Tokyo Olympic Games. However, the baseline frequency of social mixing declined vs those collected in 2011.

We analyzed 2462 episodes of suspected catheter-related bloodstream infection (CRBSI). The sensitivity, specificity, and positive and negative predictive values for detecting Candida CRBSI by gram staining of catheter tips were 66.1%, 99.4%, 84.4%, and 98.4%, respectively. Gram staining may be useful for the early detection of Candida CRBSI.

Background Neutralizing antibody therapy such as casirivimab/imdevimab is known to significantly reduce the viral load of SARS-CoV-2, but there is limited study on the clinical prognosis of neutralizing antibody therapy, especially in Asia, and the dynamics of cytokines is unknown worldwide. Several cytokines have been investigated as biomarkers to predict oxygen demand, among which CCL17 and INF3 have received approved and covered by the national health insurance in Japan. Methods Between July 2021 - December 2021, patient’s demographic, laboratory, radiological findings, prognosis, and cytokine kinetics (IFN-λ3, CCL17) at National Center for Global Health and Medicine, Tokyo, Japan, were analyzed using medical charts and serum samples. Univariate analysis was performed using Fisher's exact probability test and Mann-Whitney U test to evaluate the clinical characteristics of the group with oxygen demand compared with those of the group without oxygen demand. Results Thirty-four patients were analyzed. The median age of the cohort was 57.5 years (IQR 52.8-67.3), and 25 (73.5%) were male. Eight patients (23.5%) had been fully vaccinated and three patients (8.8%) had been vaccinated once. The severity of disease before casirivimab/imdevimab was asymptomatic in two (5.9%), mild in 12 (35.3%), moderate in 20 (58.8%) cases. Of the 17 cases in which mutant strains were identified, 16 were delta strains. The IFN-λ3 level (pg/mL) before casirivimab/imdevimab was significantly higher (7.6 vs. 17.2, p = 0.005), while the CCL17 level (pg/mL) was significantly lower (148.8 vs. 64.2, p = 0.036) in the group with oxygen demand during the therapeutic course compared to those in the group without oxygen demand. After casirivimab/imdevimab was administered, the IFN-λ3 level decreased to a median of 0.0 (IQR 0.0-0.3), while the CCL17 level increased to median of 220.3 (IQR 135.8-304.8), with no statistically significant differences between both groups (Figure 1). None of the patients became seriously ill. Figure 1A and 1B show the changing of the cytokine dynamics in COVID-19 patients who were treated with casirivimab/imdevimab on IFN-λ3 level and CCL17 level, respectively. Conclusion There was a statistically significant difference between IFN-λ3 and CCL17 levels before casirivimab/imdevimab in both groups. Our results suggest that casirivimab/immudevimab may improve the clinical prognosis for COVID-19 patients with delta strains. Disclosures All Authors: No reported disclosures.

Background Methicillin-susceptible Staphylococcus aureus (MSSA) is the most common causative microorganism of pyogenic vertebral osteomyelitis (VO). Oral antimicrobial therapy with first-generation cephalosporins can treat MSSA infection, but data on pyogenic VO are scarce. Methods This retrospective study included adult patients treated with oral cephalexin as the completing treatment for pyogenic VO with bacteremia due to MSSA at the National Center for Global Health and Medicine Hospital, Japan from 2012 to 2020. Treatment effectiveness of cephalexin was evaluated by comparing the improvement in symptoms and laboratory and imaging results after intravenous (IV) administration of antimicrobial agents and after oral cephalexin treatment, using a 5-point scale (Table). A score of 4 or 5 indicated treatment success. Results This study included 15 patients (8 [53%] females), with median age 75 years (interquartile range [IQR], 67.5–80.5), median body weight 57.0 kg (IQR, 45.5–62.5), and median Charlson comorbidity index score 2 (IQR, 0–4). Ten patients (67%) had lesions in the lumbar spine. Six patients had lesions at multiple sites (cervical and thoracic, n=1; cervical and lumbar, n=2; thoracic and lumbar, n=1; and lumbar and sacral, n=2). Twelve patients (80%) had spinal abscesses and four (27%) had remote abscesses, but none had concomitant endocarditis. In 11 patients with normal renal function, 1,500–2,000 mg/day of cephalexin was administered. Surgical intervention was performed in five cases (33%). The median duration of IV antibiotics, cephalexin, and total treatment was 36 (IQR, 32–61; range, 21–86), 29 (IQR, 19–82; range, 8–251), and 86 (IQR, 59–125; range, 37–337) days, respectively. Majority patients (≥80%) received either cefazolin or ceftriaxone as IV therapy. Two patients used oral antimicrobials other than cephalexin outside of the cephalexin treatment period. Treatment success rate after cephalexin therapy was 87%. None of the patients had recurrence during a median follow-up of 119 days (IQR, 48.5-350). Conclusion In patients with bacteremic VO due to MSSA, completing treatment with cephalexin is a reasonable option, even in cases with spinal abscess, if at least 3 weeks of effective IV antimicrobial therapy is provided. Disclosures All Authors: No reported disclosures.

Background Pharmacists play an important role in infection control and antimicrobial stewardship teams in hospitals and the community. The need for education on antimicrobial resistance (AMR) and clinical infectious diseases (CID) is increasing. However, the status of Japanese pharmaceutical education on CID and AMR is unclear. Methods We conducted a nationwide cross-sectional survey of pharmaceutical department in Japanese universities between February and March 2022. Data on the following were collected using questionnaires: 1) basic information; 2) number of faculty members with experience in CID; 3) lecture times for CID and AMR; 4) self-evaluation of CID and AMR education; and 5) the most important issues in CID and AMR education. Descriptive analyses were conducted. Results Among the 74 participating universities, 44 (59.5%) universities responded. The median number [IQR] of faculties of infectious disease education was 7 [4–12], and clinical faculties was 3 [1–6]. Twenty-seven (62.8%) of the universities had faculties with clinical experience in infectious diseases. Lectures time for CID and AMR varied among the universities. Respondents indicated that CID and AMR lectures were insufficient, compared to microbiology basic lectures. Additionally, insufficient lecture time and specialists were the most common responses as the most important issues in CID and AMR education. University background and questions regarding CID and AMR lectures (N=44) Boxplot of lectures time for clinical infectious disease and antimicrobial resistance education Self-evaluation of clinical infectious disease and antimicrobial resistance education Conclusion This study revealed that educational status and resources for CID and AMR education varied widely, and that practical lectures on CID and AMR may be insufficient. We suggest that the entire core curriculum and resources, including the number of faculties, needs to be examined and improved. The most important issues in clinical infectious disease and antimicrobial resistance education. Disclosures All Authors: No reported disclosures.

Background Japan has one of the most aging societies in the world. Urinary tract infection (UTI) is a common disease in the elderly, and the incidence of hospitalization owing to UTI is increasing with the aging population. Here, we examined the length of hospital stay, differences in the Barthel index (BI), activities of daily living score (ADLs) at admission and discharge, and medical costs of UTI in elderly patients. Methods We retrospectively included hospitalized UTI patients in our center between January 1, 2013 and March 31, 2019. The inclusion criteria were as follows: (1) urine culture positive for Escherichia coli (over 104 colony forming units/mL) within 48 h of admission, and (2) the presence of at least one of the following: fever ≥ 38°C, costovertebral angle tenderness, suprapubic tenderness, and dysuria at the time of admission. We classified the enrolled patients into four groups according to age: young adults (20–64 years), pre-old (65–74 years), old (75–84 years), and super-old (≥ 85 years). Patient characteristics were compared across groups using the Mann–Whitney U test, Fisher’s exact test, and Kruskal-Wallis test. The Bonferroni corrected P < 0.05 was considered statistically significant. Results This study enrolled 393 cases, including 112 (28.4%) young adults, 72 (18.3%) pre-old, 130 (33.2%) old, and 79 (20.1%) super-old. The lengths of hospital stay were 10.8, 17.9, 17.2, and 21.6 days in young adults, pre-old, old, and super-old, respectively (P < 0.05). Differences in the BI were 1.2, 4.2, 5.2, and 5.2 in young adults, pre-old, old, and super-old, respectively (P < 0.05). However, no significant differences in these values were noted among the pre-old, old, and super-old groups. The medical costs were 6,054, 8,310, 10,129, and 12,577-USD (1USD = 128 yen) in young adults, pre-old, old, and super-old, respectively (P < 0.05). Nevertheless, a comparison of the medical costs per day showed no significant differences among the groups. Conclusion UTI in elderly patients were associated with ADLs decline, longer hospital stays, and higher medical costs than those in younger patients; however, no significant differences were found among those aged ≥ 65 years. Disclosures Sho Saito, MD, PhD, DAIICHI SANKYO: Grant/Research Support|EVEC: Grant/Research Support|EVEC: Patents obtained through collaborative research|SHIONOGI: Grant/Research Support|Takeda: Advisor/Consultant.

Background Two years have passed since the global outbreak of COVID-19 began. Vaccines and many therapeutic agents have now been developed, and treatment is being conducted in accordance with guidelines. In general, it takes a long time for guidelines to be established, as a large amount of clinical data is required. Therefore, in the early and middle stages of an epidemic, treatment is often based on experience at individual centers. This study focuses on two drugs, Favipiravir and Steroid, and investigates how trends in drug use changed in different regions. Methods We compared the proportion of drug administered patients in the COVID-19 Registry Japan (COVIREGI-JP). Data from four COVID-19 epidemic waves, from January 2020 to June 2021, were included for the analysis. To compare regional trends, 10 categories were used based on existing classifications. In addition, Tokyo and Osaka were accounted for separately, for a total of 12 regions. Severity of each case was divided into mild, moderate 1, moderate 2 and severe based on the condition on admission, and the proportion of Favipiravir or Steroid administered cases was calculated for moderate 2 and severe cases. Results Favipiravir was administered to more than 50-100% of patients in the first wave. Thereafter, it declined nationwide, with sharp falls in Tokyo (34.9%, 16.5% and 4.3%) and Osaka (48.8%, 41.8% and 8.0%). In Hokkaido, on the other hand, 82.4%, 53.7% and 59.8% of the cases still continued to receive Favipiravir. In the first wave, Steroid was administered to 20-40% of cases. The proportion gradually increased, with 50-80% in the second wave, and 85.5% in Tokyo, 93.4% in Osaka and 90.2% in Hokkaido in the fourth wave, the majority of cases. Changes over time in the proportions of cases treated with Favipiravir and Steroid in each region. The top four and middle four panels show the proportion of cases treated with Favipiravir and Steroid, respectively. The lower epi-curve shows the number of COVID-19 cases in Japan. Conclusion We confirmed that the more effective treatment was rapidly spreading throughout the country. More information is available in areas with a large number of cases, such as Tokyo and Osaka, and in facilities that see a large number of cases. On the other hand, it may be difficult for smaller facilities or facilities that do not see many COVID-19 cases. Information from registry studies would be useful in making more effective treatments available earlier and more widely. We believe that further use of COVIREGI-JP would promote standardization of treatment. Disclosures All Authors: No reported disclosures.

Introduction The automated quantitative antigen test (QAT), which detects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is suitable for mass screening. However, its diagnostic capability differentiated by time from onset and potential contribution to infectivity assessment have not been fully investigated. Methods A retrospective, observational study using nasopharyngeal swab specimens from coronavirus disease (COVID-19) inpatients was conducted using LumipulseⓇ SARS-CoV-2 antigen test. Diagnostic accuracy was examined for the early (up to 10 days after onset) and late (over 10 days after onset) stages. Time-course QAT changes and reverse‐transcription quantitative polymerase chain reaction tests results were displayed as locally estimated scatterplot smoothing curve, and receiver operating characteristic curve (ROC) analysis was used to determine the appropriate cutoff value for differentiating the early and late stages. Results We obtained 100 specimens from 68 COVID-19 patients, including 51 early-stage and 49 late-stage specimens. QAT sensitivity and specificity were 0.82 (0.72–0.90) and 0.95 (0.75–0.99) for all periods, 0.93 (0.82–0.98) and 1.00 (0.39–1.00) for the early stage, and 0.66 (0.48–0.82) and 0.93 (0.69–0.99) for the late stage, respectively. The ROC analysis indicated an ideal cutoff value of 6.93 pg/mL for distinguishing early-from late-stage specimens. The sensitivity, specificity, positive predictive value, and negative predictive value for predicting the late stage were 0.76 (0.61–0.87), 0.76 (0.63–0.87), 0.76 (0.61–0.87), and 0.76 (0.63–0.87). Conclusions QAT has favorable diagnostic accuracy in the early COVID-19 stages. In addition, an appropriate cutoff point can potentially facilitate rapid identification of noncontagious patients.

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

Introduction Many articles have reported that the coronavirus disease 2019 (COVID-19) causes coagulation abnormalities and pulmonary thrombosis, contributing to a poorer prognosis. The study aimed to evaluate whether pre-admission anticoagulation and antiplatelet therapy prevented severe COVID-19 illness or not. Materials and methods We conducted a study to determine whether taking antiplatelet or anticoagulation agents before admission affected the severity on admission using a large nationwide cohort of hospitalized COVID-19 patients in Japan. We analyzed a large nationwide cohort of hospitalized COVID-19 patients in Japan from February 9 to July 31, 2020. Results and conclusion A total of 4265 patients from 342 facilities in Japan were included. Their use was associated with a slight reduction in the disease severity on admission in a propensity score-matched analysis which controlled for underlying diseases. However, this difference was not statistically significant.

We report the case of a 67-year-old woman with disseminated Streptococcus anginosus invasive infection. Even under a maximal dose of susceptible antibiotics, her condition was complicated by pulmonary septic emboli and intracranial subdural abscess. Effective antibiotics and emergent surgical drainage were performed, but the sequelae of aphasia and hemiplegia remained. Underlying immunocompromised conditions of diabetes mellitus and monoclonal gammopathy of unknown significance might partially affect the clinical course of invasive S. anginosus infection. Once the infection becomes invasive, it can be refractory and difficult to treat. Clinicians should acknowledge the characteristics of invasive S. anginosus infection.

Background Healthcare-associated infections (HAIs), including bloodstream infections (BSIs) in the intensive care unit (ICU), are growing global public health problems. While high-income countries have reported the burden of HAIs precisely, low- and middle-income countries (LMICs), including Vietnam, often lack surveillance systems for HAIs. In Vietnam, few reports described HAI-associated BSIs. Therefore, in this study, we aim to clarify the characteristics of HAI-associated BSI in an adult ICU. Materials and methods We conducted a retrospective cohort study of HAI-associated BSI in the adult ICU of Bach Mai Hospital (BMH), Vietnam, between December 2013 and August 2015. For every case identified with bacteremia, we collected characteristics and laboratory findings of the case and followed the length of hospital stay and seven-day and 30-day survival. Predictors of 30-day mortality were analyzed using univariate and multivariate analyses. Results Among the 90 cases identified, the median age of the study cohort was 57 (range: 18-90) years, and 59 (65.6%) were male. Chronic heart disease was the most frequent comorbidity (n = 26, 28.9%). The pathogens isolated were mostly

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: 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.

BackgroundBoth physicians and patients are proactive towards managing seasonal influenza in Japan and six drugs are approved. We aimed to clarify the status of anti-influenza drug use by analyzing real-world data.MethodsThis retrospective study analyzed open data from the National Database of Health Insurance Claims and Specific Health Checkups, which covers most claims data from national health insurance. We estimated the annual number of patients prescribed anti-influenza drugs, their age and sex distribution, drug costs, and regional disparities for the period 2014-2020.ResultsFor 2014-2019, an estimated 6.7-13.4 million patients per year were prescribed anti-influenza drugs, with an annual cost of 22.3-48.0 billion JPY (Japanese Yen). In addition, 21.1-32.0 million rapid antigen tests were performed at a cost of 30.1-47.1 billion JPY. In 2017, laninamivir was the most frequently prescribed anti-influenza drug (48%), followed by oseltamivir (36%), while in 2018, the newly introduced baloxavir accounted for 40.8% of prescriptions. After the emergence of COVID-19, the number of patients prescribed anti-influenza drugs in 2020 dropped to just 14,000. In 2018, 37.6% of prescriptions were for patients aged < 20 years compared with 12.2% for those aged ≥ 65 years. Prescriptions for inpatients accounted for 1.1%, and the proportion of prescriptions for inpatients increased with age. Male were more likely than female to be prescribed anti-influenza drugs for inpatient.ConclusionsBased on our clarification of how influenza is clinically managed in Japan, future work should evaluate the clinical and economic aspects of proactively prescribing anti-influenza drugs.

To elucidate the current practices of infectious disease management in home care settings in Japan, we sent a questionnaire to 36 physicians working at 13 clinics that specialize in providing care to patients in their homes or residential care facilities. The questionnaire described three hypothetical scenarios (aspiration pneumonia, pyelonephritis, and neoplastic fever) in older patients with terminal cancer, and 25 respondents answered questions on testing and treatment strategies. Most respondents chose to obtain cultures for aspiration pneumonia (sputum) and for pyelonephritis (urine), although fewer respondents chose to obtain blood cultures. For neoplastic fever, most of respondents elected to continue observation without antibiotic treatment. The most frequently selected antibiotics were cephalosporins and quinolones. The results indicated that most respondents would perform bacterial culture tests before prescribing antibiotics and observe patients when bacterial infections are not suspected. Standardized guidelines are needed to optimize infectious disease management in home care.

The aim of this study was to determine the efficacy and safety of ciclesonide in the treatment of novel coronavirus disease 2019 (COVID-19) as gauged by pneumonia progression. This multi-center, open-label randomized trial was conducted with patients recruited from 22 hospitals across Japan. Participants were patients admitted with mild or asymptomatic COVID-19 without signs of pneumonia on chest X-rays. Asymptomatic participants were diagnosed after identification through contact tracing. Trial participants were randomized to either the ciclesonide or control arm. Participants in the treatment arm were administered 400 µg of ciclesonide three times a day over seven consecutive days. The primary endpoint was exacerbated pneumonia within seven days. Secondary outcomes were changes in clinical findings, laboratory findings, and changes over time in the amount of the viral genome. In the treatment group, 16 patients (39.0%) were classified as having exacerbated pneumonia compared to 9 (18.8%) in the control group. The risk ratio (RR) was 2.08 (95% confidence interval (CI): 1.15-3.75), indicating a worsening of pneumonia in the ciclesonide group. Significant differences were noted in participants with a fever on admission (RR: 2.62, 90% CI: 1.17-5.85, 95% CI: 1.00-6.82) and individuals 60 years of age or older (RR: 8.80, 90% CI: 1.76-44.06, 95% CI: 1.29-59.99). The current results indicated that ciclesonide exacerbates signs of pneumonia on images in individuals with mild or asymptomatic symptoms of COVID-19 without worsening clinical symptoms.

Background: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab–cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab–cilgavimab in preventing progression to severe COVID-19 or death. Methods: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab–cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394. Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p Interpretation: A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.

To compare the characteristics and clinical course of patients with coronavirus disease (COVID-19) according to the healthcare level of the admitted hospital, to provide an insight into determining the appropriate level of care for each patient.This retrospective, observational study utilized data from the COVID-19 Registry Japan (COVIREGI-JP), the largest Japanese registry of hospitalized patients with COVID-19. Datasets were obtained from reports filed as of May 31, 2022.A total of 59,707 patients (2004 in the primary care group, 41,420 in the secondary care group, and 16,283 in the tertiary care group) from 585 facilities were included in the analysis. Patients with established risk factors for severe disease, such as old age and the presence of comorbidities, were treated at higher care facilities and had poorer initial conditions and in-hospital clinical course, as well as higher mortality. Analysis of the fatality rates for each complication suggested that patients with complications requiring procedures (e.g. pleural effusions, myocardial ischemia, and arrhythmia) may have better survival rates in facilities with specialist availability. The number of deaths and severe COVID-19 cases in this study were notably less than those reported overseas.Our results showed that more difficult COVID-19 cases with poor outcomes were treated at higher care level facilities in Japan. Attending to possible complications may be useful for selecting an appropriate treatment hospital. Healthcare providers need to maintain a broad perspective on the distribution of medical resources.

This multicenter, double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor, in Japanese patients with mild-to-moderate coronavirus disease 2019 (COVID-19) or asymptomatic ARSCoV- 2 infection. Sixty-nine patients were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily, or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was the change from baseline in the SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.0 to 40.4 years). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], –2.42 [1.42]; P = 0.0712) and 250 mg (–2.81 [1.21]; P = 0.0083) versus placebo (–1.54 [0.74]); ensitrelvir treatment reduced SARS-CoV-2 RNA by –1.4 to –1.5 log10 copies/ mL versus placebo. The viral titer and viral RNA were similar across groups on and after day 6. The median time to infectious viral clearance decreased by approximately 50 h with ensitrelvir treatment. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated (Japan Registry of Clinical Trials identifier: jRCT2031210350)., Antimicrobial Agents and Chemotherapy, 66(10), art. no. e0069722; 2022