Published papers

Objective To consider effective measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in medical institutions, this study estimated the SARS-CoV-2 infection rate among healthcare workers (HCWs) in Tokyo, Japan, and determined the specific findings for mild coronavirus disease 2019 (COVID-19) cases. Methods This study analyzed the results of serologic tests to detect immunoglobulin G antibodies against SARS-CoV-2 and evaluated the demographic and clinical characteristics of the faculty and HCWs at a Tokyo medical institution in August 2020. The demographic and clinical characteristics of participants with antibody-positive results were compared to those of participants with antibody-negative results. Patients or Materials This study recruited 2,341 faculty and HCWs at a Tokyo medical institution, 21 of whom had a COVID-19 history. Results Of the 2,320 participants without a COVID-19 history, 20 (0.862%) had positive serologic test results. A fever and dysgeusia or dysosmia occurred with greater frequency among the participants with positive test results than in those with negative results (odds ratio [OR], 5.475; 95% confidence interval [CI], 1.960-15.293 and OR, 24.158; 95% CI, 2.693-216.720, respectively). No significant difference was observed in the positivity rate between HCWs providing medical care for COVID-19 patients using adequate protection and other HCWs (OR, 2.514; 95% CI, 0.959-6.588). Conclusion To reduce the risk of COVID-19 spread in medical institutions, faculty and HCWs should follow standard and necessary transmission-based precautions, and those with a fever and dysgeusia or dysosmia should excuse themselves from work as soon as possible.

Although candiduria is becoming increasingly common among hospitalized patients, Candida lusitaniae is a rare pathogen that account for less than 1% of Candida species isolated from urine. Ascending pyelonephritis and candidemia due to Candida species are uncommon complications. We report herein on a case of acute pyelonephritis and candidemia due to C. lusitaniae. A 66-year-old man presented with a high fever during hospitalization at our hospital following septic shock due to ischial osteomyelitis treated with tazobactam/piperacillin for 29 days. We suspected acute pyelonephritis, and urinary Gram staining showed only yeasts and leucocytes. The next day, blood culture and urine culture tested positive and showed yeast-like fungi. We diagnosed acute pyelonephritis and candidemia due to Candida species and started treatment with fluconazole. C. lusitaniae was identified on the hospital day 34 and treated with fluconazole for 14 days. Candida albicans was the most prevalent species isolated from the urinary tract, however non-albicans Candida species have emerged and are now dominant because of the advent and increasing use of fluconazole. C. lusitaniae is a rare but important pathogen, that is generally susceptible to fluconazole and resistant to amphotericin B. It is necessary to choose an appropriately effective antifungal drug based on identification of the fungal species.

BACKGROUND: Long-term placement of prophylactic drains can result in retrograde infections. AIM: We aimed to investigate the association between the timing of drain removal and clinical outcomes. METHODS: This retrospective, single-center cohort study evaluated 110 patients who underwent elective gastrointestinal or hepatopancreatobiliary surgery and developed subsequent organ/space surgical site infection (SSI) between 2016 and 2020. We evaluated the difference between the culture-positive species of prophylactic drains and direct aspiration, whether the prophylactic drains functioned effectively at the time of SSI diagnosis, and whether the empirical antibiotics administered before drainage were able to treat all the detected bacteria. Finally, clinical outcomes were compared between early (i.e. cases wherein the prophylactic drain had already been removed or replaced at the time of SSI diagnosis) and late (removal after diagnosis) drain removal. FINDINGS: The prophylactic drains functioned effectively in only 27 (25%) patients at the time of SSI diagnosis. Due to the results of direct aspiration cultures, 43% of patients required antibiotic escalation. The median time to drain removal or first replacement was seven postoperative days. The early removal group included 43 patients (39%). Compared with early removal, late removal resulted in a higher frequency of vancomycin use (7.0% versus 22.4%; P = 0.037). CONCLUSIONS: Prolonged prophylactic drain placement is associated with complicated infections requiring vancomycin, therefore, the drains should be removed as soon as possible. Additionally, obtaining the cultures of direct aspiration should be actively considered, as escalation of antimicrobial therapy is often performed based on culture results.

The QuantiFERON TB Gold Plus (QFT-Plus) test is a newly approved interferon-gamma releasing assay test for detecting latent tuberculosis. Although blood samples for QFT test can be refrigerated for 48 h in lithium-heparin tubes according to package inserts, no published data are available on the effects of sample refrigeration on the test results. We conducted a clinical study that aimed to elucidate whether sample refrigeration for 48 h affects QFT-Plus test results. We collected 2 blood samples each from 40 participants for QFT-Plus; one sample was refrigerated before incubation for QFT-Plus assay, while the other sample was incubated soon after collection and treated as control. After comparing QFT-Plus test results of refrigerated samples and control samples, the concordance rate and kappa coefficient between them were 95% and 0.90, respectively. Thus, blood samples for QFT-Plus test can be refrigerated for 48 h in lithium-heparin tubes without influencing the test results.

The sufficient dose to obtain an optimal trough concentration of vancomycin (VCM) in patients with non-standard physical types remains controversial. In this study, we examined the relationship between the dose and physical type in patients in whom an optimal trough concentration was obtained among VCM-treated patients. We retrospectively investigated the dose of VCM and physical type in patients treated with VCM between January 2012 and January 2017 at two medical institutions (n = 272). The physical type was classified using the body mass index (BMI). Patients with a BMI of <18.5 kg/m2 were assigned to the lean group, those with a BMI of 18.5-24.9 kg/m2 were assigned to the standard group, and those with a BMI of ≥25 kg/m2 were assigned to the obesity group. The mean doses of VCM per time (mg/kg) to achieve the target trough concentration of VCM, 15-20 μg/mL, were 19.8 ± 4.3, 16.5 ± 3.7, and 13.7 ± 2.7 mg/kg in the lean, standard, and obesity groups, respectively. The dose per time to achieve the target trough concentration decreased significantly in association with an increase of BMI. The upper limit of the recommended dose (15-20 mg/kg) or higher in lean patients, and the lower dose in obese patients than the recommended dose might be appropriate to achieve the target trough concentration when we calculated the dose per time based on actual body weight.

Background: Vancomycin infusion reaction (VIR) is a common adverse reaction to vancomycin. We aimed to investigate the effects of infusion rate, age, infusion time, renal function and history of allergy on the incidence of VIR. Methods: We conducted a single-centre retrospective cohort study with 153 patients (aged 0–92.7 years) who received a single intravenous dose of vancomycin for perioperative prophylaxis. Patients treated for active infections were excluded. Medical records were retrospectively evaluated for VIR occurrence, defined as itching, flushing or rash documentation. Results: VIR incidence was 46.7% (7/15) in patients aged <10 years, 47.4% (9/19) in those aged 10–20 years and 44.4% (4/9) in those aged 20–30 years, versus 2.7% (2/74) in those aged ≥60 years. Multivariable logistic regression identified younger age [adjusted odds ratio (aOR) 0.95, 95% CI 0.93–0.97] and higher weight-adjusted infusion rate (aOR 1.22 per mg/kg/h increase, 95% CI 1.04–1.43) as independent risk factors for VIR. Receiver operating characteristic analysis of the infusion rate by age group showed that the optimal cut-off value for patients aged 30–60 years was 14.8 mg/kg/h, whereas for those aged <30 years, it was 14.0 mg/kg/h. No patients developed VIR when the infusion rate was <9.4 mg/kg/h. Conclusions: Age and higher weight-adjusted infusion rate were key risk factors for VIR. Tailoring infusion rate to age and weight may reduce VIR incidence without unnecessarily prolonging administration time.

Biologic medications have dramatically improved the treatment outcomes of immunological inflammatory diseases, but their immunosuppressive effects put patients at risk for tuberculosis (TB). We investigated the risk factors for developing TB in patients treated for latent tuberculosis infection (LTBI) who also had experience of using biologic medications. At Keio University Hospital, we retrospectively investigated patients treated with anti-mycobacterial drugs before or concurrently with biologic medications from January 2012 to August 2020. Patients in the 'follow-on cases group' who had a positive TB screening test after initiating biologic medications and subsequently started LTBI treatment were excluded. We researched and compared the patient characteristics for TB and non-TB patient groups. Of the 146 eligible patients, 5 (3.4%) developed TB. The incidence rate was 600/100000 person-years. There were no significant differences between TB and non-TB patient groups in the history of TB, interferon-gamma release assay (IGRA), duration of biologic medication therapy, LTBI treatment periods, concomitant use of calcineurin inhibitors or anti-rheumatic drugs. The percentage of patients who received prednisolone at a dose of ≥15 mg for more than 1 month was higher in those who developed TB than in those who did not (40.0 vs. 7.1%, p = 0.054); however, this difference was not statistically significant. Regular monitoring of TB is necessary for long-term concomitant use of high prednisolone doses during and after the administration of biologic medications.

Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

Introduction: Late diagnosis of the human immunodeficiency virus (HIV) is a major concern epidemiologically, socially and for national healthcare systems. Although the association of certain demographics with late HIV diagnosis has been reported in several studies, the association of other factors, including clinical and phylogenetic factors, remains unclear. In the present study, we conducted a nationwide analysis to explore the association of demographics, clinical factors, HIV-1 subtypes/circulating recombinant form (CRFs) and genetic clustering with late HIV diagnosis in Japan, where new infections mainly occur among young men who have sex with men (MSM) in urban areas. Methods: Anonymized data on demographics, clinical factors and HIV genetic sequences from 39.8% of people newly diagnosed with HIV in Japan were collected by the Japanese Drug Resistance HIV-1 Surveillance Network from 2003 to 2019. Factors associated with late HIV diagnosis (defined as HIV diagnosis with a CD4 count <350 cells/μl) were identified using logistic regression. Clusters were identified by HIV-TRACE with a genetic distance threshold of 1.5%. Results: Of the 9422 people newly diagnosed with HIV enrolled in the surveillance network between 2003 and 2019, 7752 individuals with available CD4 count at diagnosis were included. Late HIV diagnosis was observed in 5522 (71.2%) participants. The overall median CD4 count at diagnosis was 221 (IQR: 62–373) cells/μl. Variables independently associated with late HIV diagnosis included age (adjusted odds ratio [aOR] 2.21, 95% CI 1.88–2.59, ≥45 vs. ≤29 years), heterosexual transmission (aOR 1.34, 95% CI 1.11–1.62, vs. MSM), living outside of Tokyo (aOR 1.18, 95% CI 1.05–1.32), hepatitis C virus (HCV) co-infection (aOR 1.42, 95% CI 1.01–1.98) and not belonging to a cluster (aOR 1.30, 95% CI 1.12–1.51). CRF07_BC (aOR 0.34, 95% CI 0.18–0.65, vs. subtype B) was negatively associated with late HIV diagnosis. Conclusions: In addition to demographic factors, HCV co-infection, HIV-1 subtypes/CRFs and not belonging to a cluster were independently associated with late HIV diagnosis in Japan. These results imply the need for public health programmes aimed at the general population, including but not limited to key populations, to encourage HIV testing.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

OBJECTIVE: Cefiderocol, a siderophore cephalosporin, has shown promise against carbapenem-resistant strains such as Pseudomonas aeruginosa and Stenotrophomonas maltophilia species complex. Despite its recent approval in Japan, susceptibility data remain limited. Therefore, this study evaluated the cefiderocol susceptibility of carbapenem-resistant P. aeruginosa and S. maltophilia species complex strains isolated from blood cultures to determine whether cefiderocol can be used as an empirical treatment option. METHODS: Carbapenem-resistant P. aeruginosa and S. maltophilia species complex strains isolated from blood cultures at a university hospital in Japan were included. Minimum inhibitory concentrations (MICs) and inhibition zone diameters were assessed using broth microdilution and disk diffusion methods, respectively. Whole-genome sequencing was conducted to elucidate the genetic backgrounds of the clinical isolates. RESULTS: The MIC50 and MIC90 values for cefiderocol in 65 carbapenem-resistant P. aeruginosa strains were 0.12 and 0.25 µg/mL, and 0.06 and 0.25 µg/mL for 51 S. maltophilia species complex strains, respectively. One S. maltophilia species complex strain exhibited non-susceptibility, with a MIC of 2 µg/mL in broth microdilution, while disk diffusion methods demonstrated susceptibility. A significant negative correlation was observed between MIC values and inhibition zone diameters. Whole-genome sequencing revealed that a limited number of P. aeruginosa strains possessed carbapenemase genes. CONCLUSIONS: The findings of this study support the efficacy of cefiderocol against carbapenem-resistant P. aeruginosa and S. maltophilia species complex, suggesting its potential as an empirical treatment option for bloodstream infection patients in Japan. Continued surveillance is advised to monitor resistance trends with increased cefiderocol use.

Background: We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods: We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results: Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions: We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

Objectives The incidence of nontuberculous mycobacteria (NTM) infections has increased globally. We describe clinical characteristics and outcomes of extrapulmonary NTM disease. Methods This multicenter retrospective study included adult patients with extrapulmonary NTM disease at five Japanese tertiary hospitals (2012-2020), confirmed by culture or polymerase chain reaction tests from non-pulmonary specimens. Clinical characteristics, antimicrobial therapy, source control, treatment outcomes, and mortality were evaluated. Results Seventy patients were included: 49 with rapidly growing mycobacteria (RGM) and 21 with slowly growing mycobacteria (SGM) infections. Median age was 70; 52.9% were male. Prosthetic devices were present in 38.6% of cases, more frequent in RGM than SGM (51% vs. 10%). Antimicrobials were administered to 70.0%, and 62.9% underwent source control. Treatment duration was longer for SGM (435 vs. 132 days), particularly for bone, joint, and disseminated infections. Cure/improvement occurred in 53 patients (75.7%), with similar outcomes for RGM and SGM. Among RGM infections, lack of source control in device-related cases was associated with poor treatment outcomes. Fifteen patients died during the observation period; two were NTM-related. Conclusions Most extrapulmonary NTM cases respond to antimicrobial therapy and source control. RGM infections involving prosthetic devices without source control remain challenging, warranting further research into optimized management.

The novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 is a major threat to humans. Recently, we encountered two seemingly separate COVID-19 clusters in a tertiary care medical center. Whole viral genome sequencing detected the haplotype of the SARS-CoV-2 genome and the two clusters were successfully distinguished by the viral genome haplotype. Concurrently, there were nine COVID-19 patients clinically unlinked to clusters #1 or #2 that necessitated the determination of the source of infection. Such patients had similar haplotypes to that in cluster #2 but were devoid of two rare mutations characteristic to cluster #2. This suggested that these nine cases of "probable community infection" indeed had community infection and were not derived from cluster #2. Whole viral genome sequencing of SARS-CoV-2 is a powerful measure not only for monitoring the global trend of SARS-CoV-2 but also for identifying the source of infection of COVID-19 at a level of institution.

After publication of the original article [1], we were notified that units of testosterone in main text and abstract and units of DHEA-S in Fig. 1 and Table 4 are incorrect.

BACKGROUND: An early report has shown the clinical benefit of the asymptomatic preoperative SARS-CoV-2 screening test and some clinical guidelines recommended it; however, the cost-effectiveness of asymptomatic screening was not evaluated. We aimed to investigate the cost-effectiveness of universal preoperative screening of asymptomatic patients for SARS-CoV-2 using polymerase chain reaction (PCR) testing. METHODS: We evaluated the cost-effectiveness of asymptomatic screening using a decision tree model from a payer perspective, assuming that the test-positive rate was 0.07% and the screening cost was 8,500 Japanese yen (JPY) (∼7,601 USD). The input parameter was derived from the available evidence reported in the literature. A willingness-to-pay threshold was set at 5,000,000 JPY/quality-adjusted life years (QALY). RESULTS: The incremental cost of one death averted was 74,469,236 JPY (∼566,048 USD) and 291,123,368 JPY/QALY (∼2,212,856 USD/QALY), which was above the 5,000,000 JPY/QALY willingness-to-pay threshold. The incremental cost-effectiveness ratio fell below 5,000,000 JPY/QALY only when the test-positive rate exceeded 0.739%; however, when the probability of developing a postoperative pulmonary complication among SARS-CoV-2-positive patients was below 0.22, asymptomatic screening was never cost-effective, regardless how high the test-positive rate became. CONCLUSIONS: Asymptomatic preoperative universal SARS-CoV-2 PCR screening is not cost-effective in the base case analysis. The cost-effectiveness mainly depends on the test-positive rate, the frequency of postoperative pulmonary complications, and the screening costs; however, no matter how high the test-positive rate, the cost-effectiveness is poor if the probability of developing postoperative pulmonary complications among patients positive for SARS-CoV-2 is sufficiently reduced.