Unfractionated Heparin Safety in COVID-19: Incidence and Risks of Bleeding Complications in Japan.

AIM: Several studies have shown the efficacy and safety of low-molecular-weight heparin use in coronavirus disease 2019 (COVID-19), but that of unfractionated heparin (UFH) has not been investigated. We investigated the prevalence of bleeding complications during UFH administration, its impact on mortality, and the risk factors of bleeding outcomes associated with UFH. METHODS: This retrospective cohort study was conducted at a single-center tertiary care hospital, including hospitalized patients with COVID-19. The primary outcomes were measured as the prevalence of bleeding complications during hospitalization, and the secondary outcomes were thromboembolic events and 60-day mortality rates. Logistic regression analysis and propensity score matching were used to assess risk factors for bleeding complications and their impact on mortality. RESULTS: Among 1035 included patients, 516 patients were treated with UFH. Twelve (2.3%) patients in the UFH group experienced major bleeding. The prevalence of major bleeding in patients treated with therapeutic-dose UFH was 9.2%. Logistic regression analysis showed that age ≥ 60 years (adjusted odds ratio [aOR], 3.89; 95% confidence interval [CI], 1.01-15.0; P＜.05) and COVID-19 severity (aOR, 35.9; 95% CI, 4.57-282; P ＜.05) were associated with major bleeding complications. After propensity score matching, 11 major and 11 non-major bleeding cases (including minor bleeding) were matched. The 60-day cumulative mortality rate between the two groups did not differ significantly (P=.13, log-rank test). CONCLUSIONS: The incidence of major bleeding in COVID-19 patients using therapeutic-dose UFH was relatively high. Critical COVID-19 and older age were risk factors for bleeding complications.

Development of a partnership between academia, community, and government in response to the 2022 mpox outbreak in Japan.

Objectives　In response to the steady rise in the number of cases of mpox in nonendemic countries, starting with an outbreak in the United Kingdom in May 2022, the World Health Organization declared a public health emergency of international concern on July 23, 2022. As of November 13, 2022, seven cases of mpox have been reported in Japan.Methods　A community engagement approach was applied to prevent the spread of mpox in Japan.Results　A tripartite partnership between academia, community, and government (ACG) was established to promote multisectoral communication between vulnerable communities, medical personnel involved in diagnosis and treatment, public health specialists at public health centers, epidemiologists at the National Institute of Infectious Diseases (NIID), and government and public administration. Through information sharing, this ACG partnership can translate accurate information into effective infection control measures.Conclusion　By developing and maintaining the ACG partnership, an environment will be created that allows an immediate response to future public health crises affecting vulnerable communities. This Practice Report describes the process of establishing an ACG partnership.

Infectious virus shedding duration reflects secretory IgA antibody response latency after SARS-CoV-2 infection.

Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.

Trends in teicoplanin loading dose implementation from 2010 to 2019 and evaluation of safety and efficacy factors: a retrospective cohort study based on a Japanese administrative claims database.

BACKGROUND: The loading dose of teicoplanin (TEIC) is recommended for implementation. However, there is significant discrepancy between the dose settings in the package insert and, in the guidelines, and the actual status of loading doses in Japan is unclear. Furthermore, TEIC causes liver injury as side effect. Although the risk of developing liver injury has not been reported to be increased following a loading dose based on the guidelines, there is a lack of reports in large populations. Therefore, we evaluated the trend in the loading dose and factors affecting the efficacy and safety of TEIC administration. METHODS: A Japanese administrative claims database was used in this study. Trends in loading doses were evaluated in target populations administered TEIC between 2010 and 2019. Patient characteristics were adjusted by propensity score matching based on the guideline group (total dose of 3 days > 1,600 mg) and non-guideline group (≤ 1,600 mg) of the loading dose. Finally, univariable and multivariable conditional logistic regression analysis was performed to evaluate factors affecting 30-day mortality and liver injury. RESULTS: A total of 10,030 patients were selected based on these criteria. The proportion of loading doses based on the recommended guidelines showed an increase over time, regardless of the implementation of therapeutic drug monitoring (TDM), but especially so in cases where TDM was implemented, the loading doses were administered in accordance with the recommendations of the guidelines. Conditional logistic regression analysis showed a relationship between drug management and guidance fees (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.36‒0.55), a reimbursement indicating pharmacist intervention, and a reduction in 30-day mortality. In addition, loading doses based on the recommended guidelines had no influence on liver injury, and other factors were not significantly associated with increased incidence of liver injury. CONCLUSION: Thus, this study implies the benefits of pharmacological management as indicated by drug management and guidance fee and supports the implementation of loading doses based on the guideline on TEIC administration.

Necessity for a System Implementing Therapeutic Drug Monitoring in Outpatient Settings Based on the Actual Use of Voriconazole Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan: A Descriptive Epidemiological Study.

Voriconazole (VRCZ) is an antifungal drug that necessitates therapeutic monitoring (TDM). Typically, TDM is recommended for patients undergoing long-term outpatient treatment. However, in Japan, insurance reimbursement for TDM is only permitted for inpatients. There is a concern that VRCZ use is growing among outpatients, although information regarding this issue remains unavailable. Therefore, we aimed to clarify the use of VRCZ by utilizing data from the National Database of Health Insurance Claims and Specific Health Checkups in Japan. The use of branded and generic oral VRCZ from 2013 to 2019 was calculated using the defined daily doses/1000 inhabitants/d (DID) for each receipt type. Oral VRCZ was used more frequently in the outpatient setting than that in the inpatient setting, with use increasing over time. The use of generic drugs began in 2016 and accounted for 52.5% of the use in 2019 among outpatients. Considering outpatient prescriptions, 76.4-81.0% were dispensed at insurance pharmacies, indicating the need for community pharmacist involvement. Accordingly, the appropriate use of VRCZ in ambulatory care should be promoted in collaboration with community pharmacists, and a reimbursement system should be established to implement TDM in ambulatory care.

A nationwide cross-sectional study using a web-based questionnaire survey of the duration of isolation of COVID-19 inpatients with cancer at Japanese cancer centers.

There is no clear consensus regarding the optimal isolation duration for immunocompromised patients with coronavirus disease 2019 (COVID-19). Therefore, we conducted a questionnaire survey at eight Japanese cancer centers to investigate the practices of infectious disease specialists regarding the duration of isolation for COVID-19 inpatients with cancer. For asymptomatic to severely ill COVID-19 inpatients without severe immunodeficiency, four centers reported at least 10 days of isolation without testing, and two reported at least 20 days. Two centers incorporated polymerase chain reaction (PCR) as a criterion for terminating the isolation of inpatients without severe immunodeficiency. For severely immunocompromised COVID-19 inpatients, at least 20 days of isolation were required in seven facilities, regardless of illness severity. Additionally, seven centers had implemented Ct or antigen quantification test values as criteria for de-isolating severely immunocompromised inpatients. No cases caused nosocomial outbreaks after isolation was terminated based on each facility's criteria for isolation termination. Thus, cancer patients required longer isolation periods than the general population in most facilities, and for those with severe immunodeficiency, the isolation periods were longer and more tightly controlled with tests.

Effectiveness of inactivated influenza and COVID-19 vaccines in hospitalized children in 2022/23 season in Japan - The first season of co-circulation of influenza and COVID-19.

We have analyzed the inactivated vaccine effectiveness (VE)for preventing influenza hospitalization by test-negative design in the 2022/23 season. This is the first season of co-circulation of influenza and COVID-19, and a unique period because all inpatients received COVID-19 screening. Among 536 children hospitalized with fever, none were positive for both influenza and SARS-CoV-2. The adjusted VE for preventing influenza A for all children, the 6-12-year-old group, and those with underlying diseases was 34 % (95 ％CI, -16 %-61 %, n = 474), 76 % (95 ％ CI, 21 %-92 %, n = 81), and 92 % (95 ％ CI, 30 %-99 %, n = 86), respectively. Only 1 out of 35 hospitalized cases with COVID-19, and 42 out of 429 controls, had been immunized with COVID-19 vaccine. This is the first report showing influenza VE by age group in children in this limited season. We still recommend the inactivated influenza vaccine for children based on the significant VE in subgroup analysis.

Investigation of oral macrolide prescriptions in Japan using a retrospective claims database, 2013-2018.

Macrolide usage in Japan exceeds that in Europe and the United States. Investigating the actual conditions in which macrolides are used is important for identifying further interventions for appropriate antimicrobial use; however, this situation has not been evaluated in Japan. Therefore, we aimed to clarify the number of macrolide prescriptions and their changes before and after implementation of the Antimicrobial Resistance (AMR) Action Plan. In addition, we also investigated the names of diseases for which macrolides have been prescribed and the number of days of prescription. A retrospective observational study was conducted using JMDC claims data from January 2013 to December 2018. The proportion of all oral antimicrobials and macrolides used during this period and the diseases for which macrolides were used in the 3 years before and after the AMR Action Plan were determined separately for acute (< 14 prescription days) and chronic (> 14 prescription days) diseases. The number of prescriptions for macrolides constituted approximately 30% of those for all oral antimicrobials; of these, clarithromycin accounted for approximately 60%. Most prescriptions for acute diseases were for common cold, whereas allergic and dermatological diseases were included among chronic diseases. The names of these illnesses did not change before and after the AMR Action Plan. Overall, these results indicate that appropriate macrolide use involves a review of their use for common cold along with appropriate evaluation of their long-term use for skin and allergic diseases. They also indicate the need for further fact-finding studies and ongoing AMR measures.

Urinary L-Type Fatty Acid-Binding Protein Predicts Oxygen Demand of COVID-19 in Initially Mild Cases.

Early detection of illness trajectory in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients is crucial for patients and healthcare workers. An effective, noninvasive approach, with simple measurement for decision-making, is necessary in a pandemic to discriminate between high- and low-risk patients, even though both groups may exhibit mild symptoms in the beginning. OBJECTIVES: To predict COVID-19 disease severity within 10 days, distinguishing cases that will progress to moderate or severe versus mild, patient urinary L-type fatty acid-binding protein (L-FABP) was assayed within 4 days of receiving a diagnosis. The study also examined whether L-FABP point of care (POC) test is helpful in risk screening. DESIGN: Symptomatic subjects who tested positive for SARS-CoV-2 and were hospitalized were prospectively enrolled at the National Center for Global Health and Medicine (NCGM), Yamanashi Prefectural Central Hospital (YPCH), and Sinai Hospital in Maryland. The outcome of each case was evaluated 7 days after admission and the diagnostic performance of L-FABP was assessed. SETTING AND PARTICIPANTS: Subjects were treated for COVID-19 at public healthcare centers in Japan from January 31, 2020, to January 31, 2021, to NCGM, YPCH, and at Sinai Hospital in Baltimore, MD, during the same period. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine whether urinary L-FABP within 48 hours of admission can predict the patient's severity of COVID-19 1 week later. We obtained demographic data, information on clinical symptoms, radiographic images, and laboratory data. RESULTS: Diagnostic performance was assessed using receiver operating characteristic analysis. Of the 224 participants in the study, 173 initially had a mild form of COVID-19. The area under the curve (AUC) for a severe outcome was 93.5%. L-FABP POC risk prediction of a severe outcome had an AUC of 88.9%. CONCLUSIONS AND RELEVANCE: Urinary L-FABP can predict patient risk of COVID-19 illness severity. L-FABP POC is implementable for patient management. (ClinicalTrials.gov number, NCT04681040).

Effects of population age structure on parenteral antimicrobial use estimations.

Antimicrobial use (AMU) is conventionally reported as unadjusted defined daily doses (DDDs) or population-adjusted DDDs per 1000 inhabitants per day (DID). DID is frequently used to monitor national AMU trends, this metric does not intrinsically take temporal changes in population age structure into account. We examined the effects of population age structure on DID estimates of parenteral AMU in Japan, and predicted future trends in DDDs based on population projections. Parenteral AMU data from 2013 to 2018 were acquired from a national claims database. We assessed temporal trends in parenteral AMU by age group (children aged < 15 years, working-age persons aged 15-64 years, and older persons aged ≥ 65 years) using both DID and DDDs. In addition, we modeled DDD predictions based on age-specific population projections from 2019 to 2030. DID values for older persons were 8.08-10.15 times and 5.43-5.63 times higher than in children and working-age persons, respectively. DID was stable, but DDDs increased in older persons. The prediction models showed that DDDs will continue to increase until 2030 if DID remains steady or decreases. DID estimates were skewed by the older population. More rigorous antimicrobial stewardship efforts targeting geriatric care are needed to counter the aging-associated increase in AMU.

Diagnostic accuracy of rapid antigen tests in cerebrospinal fluid for pneumococcal meningitis: a systematic review and meta-analysis.

BACKGROUND: Streptococcus pneumoniae is a leading cause of bacterial meningitis worldwide. Conventional microbiological assays take several days and require the use of various drugs for empirical treatment. Rapid antigen tests in cerebrospinal fluid (CSF) may be useful to triage pneumococcal meningitis immediately. OBJECTIVES: To elucidate whether rapid antigen tests in CSF are useful in the triage of pneumococcal meningitis. METHODS: Data sourcesCochrane CENTRAL, MEDLINE, EMBASE, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov databases were searched. Study eligibility criteriaAll types of cohort studies except multiple-group studies, where the sensitivity and specificity of rapid antigen tests in CSF compared with CSF culture can be extracted. ParticipantsPatients with suspected meningitis. TestsRapid antigen tests in CSF. Reference standardsOne or more of the following: blood culture, CSF culture, and polymerase chain reaction in CSF. Assessment of risk of biasThe methodological quality of the included studies was assessed using QUADAS-2. Methods of data synthesisWe used a random-effects bivariate model for the meta-analysis. We conducted a subgroup analysis by dividing studies into types of antigen tests, adults and children, low-income and high-income countries, and with or without exposure to antibiotics before lumbar puncture. RESULTS: Forty-four studies involving 14 791 participants were included. Most studies had a moderate-to-low methodological quality. Summary sensitivity and specificity were 99.5% (95% confidence interval (CI), 92.4-100%) and 98.2% (95% CI, 96.9-98.9%), respectively. Positive predictive values and negative predictive values at the median prevalence (4.2%) in the included studies were 70.8% (95% CI, 56.6-79.9%) and 100% (95% CI, 99.7-100%), respectively. The diagnostic accuracy was consistent across the various subgroups, except for slightly reduced sensitivity in high-income countries. CONCLUSIONS: Rapid antigen tests in CSF would be useful in triaging pneumococcal meningitis. Further studies are warranted to investigate the clinical benefit of ruling out pneumococcal meningitis based on the results of rapid antigen tests.

A case of prosthetic joint infection caused by Mycobacterium tuberculosis complicated secondary bacterial infection after knee joint replacement surgery.

Mycobacterium tuberculosis (M. tuberculosis) is a rare cause of prosthetic joint infection (PJI). Previous studies have reported that many cases of PJI caused by M. tuberculosis have no medical history of active tuberculosis (TB) or other localization, which contributes to diagnostic difficulties. Furthermore, owing to the limited number of studies on treatment, appropriate treatment strategies, such as the duration of anti-tuberculosis (anti-TB) drugs and surgical indications, remain unclear. We report a case of PJI caused by M. tuberculosis and secondary pyogenic arthritis caused by Staphylococcus aureus and Streptococcus dysgalactiae in a 67-year-old man after knee joint replacement surgery in Japan, which was a moderately endemic country until 2020 and a low endemic country since 2021. Although he had no past medical history or close contact with TB, he was diagnosed with PJI caused by M. tuberculosis, following the culture of a synovectomy specimen. He underwent two-stage surgery and was treated with anti-TB drugs for a total of 12 months and recovered without recurrence. Based on our case and previous studies, there are three points of clinical significance for PJI caused by M. tuberculosis. First, about one year of anti-TB drugs with two staged joint revision resulted in a good course of treatment. Second, surgical treatment might be considered in cases complicated by secondary bacterial infection. Third, because the diagnosis of PJI caused by M. tuberculosis is difficult, TB should be considered in the differential diagnosis of routine bacterial culture-negative PJI, especially in endemic areas.

Lack of clinical evidence of antiviral therapy for human monkeypox: A scoping review.

Since May 2022, many human monkeypox cases have been reported from non-endemic countries. This systematic review aimed to evaluate and summarize the existing research on the efficacy and safety of tecovirimat, brincidofovir, and cidofovir for patients with monkeypox. We searched studies that reported the efficacy and adverse events of tecovirimat, brincidofovir, or cidofovir for patients with human monkeypox in several databases including preprint servers. Only five studies were included. The efficacy and adverse events were assessed in only five and four patients, respectively. Regarding tecovirimat, all two patients recovered from monkeypox. One had no adverse event and the other has no description of an adverse event. Regarding brincidofovir, all three patients recovered from monkeypox but all of them had increased alanine transaminase, and one had nausea and abdominal discomfort. There was no study on treatment with cidofovir. Based on past studies and our results, tecovirimat might be the best choice due to ease of administration (oral drug), fewer side effects, and past treatment results for human monkeypox administration. However, very few studies were included in this scoping review. Therefore, further studies are needed to assess their efficacy and safety as possible treatments for human monkeypox.

Effect of the COVID-19 pandemic and state of emergency declarations on the relative incidence of legionellosis and invasive pneumococcal disease in Japan.

INTRODUCTION: During the COVID-19 pandemic, the incidence of many droplet-transmitted infections decreased due to increased mask-wearing and social distancing. Contrastingly, there has been concern that COVID-19 countermeasures, such as lockdowns, may increase legionellosis incidence via water stagnation. During the pandemic in Japan, four state of emergency declarations were imposed between 2020 and 2021, which makes it particularly suitable to test this hypothesis. METHODS: We use country-level surveillance data from the National Institute of Infectious Diseases to track the relative incidence of legionellosis compared to invasive pneumococcal disease (IPD) during the COVID-19 pandemic in Japan, with a focus on the periods just after state of emergency declarations were lifted. RESULTS: The absolute number of legionellosis and IPD cases decreased in 2020 and 2021 compared to previous years. The average relative incidence of legionellosis as well as the variance of the relative incidence significantly increased during the pandemic compared to previous years. There were no increases in the relative incidence of legionellosis during the periods immediately following emergency declaration liftings, but the relative incidence did increase considerably during the first two states of emergency. CONCLUSIONS: COVID-19 countermeasures appear more effective at decreasing the incidence of human-to-human transmitted infections, such as IPD, compared to environmentally-transmitted infections, such as legionellosis. Though no evidence was found to suggest that legionellosis cases increased after state of emergency declarations, public health efforts should continue to emphasize the importance of routine sanitation and water system maintenance to prevent water stagnation and Legionella spp. contamination.

Recent changes in the reporting of STIs in Japan during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic has had variable effects on the rates of STIs reported across the globe. This study sought to assess how the number of STI reports changed during the pandemic in Japan. METHODS: We used national infectious disease surveillance data from the National Institute of Infectious Diseases (Tokyo, Japan) for the period between January 2013 and December 2021. We compared reported rates of chlamydia, gonorrhoea, condyloma acuminata and genital herpes, as well as total notifications for HIV/AIDS and syphilis during the pandemic versus previous years in Japan. We used a quasi-Poisson regression to determine whether any given week or month between January 2018 and December 2021 had a significant excess or deficit of STIs. Notification values above or below the 95% upper and lower prediction thresholds were considered as statistically significant. The start of the pandemic was defined as January 2020. RESULTS: Chlamydia generally remained within predicted range during the pandemic period. Reporting of gonorrhoea was significantly higher than expected throughout early-to-mid 2021 but otherwise generally remained within predicted range prior to 2021. Condyloma, herpes and HIV/AIDS reporting were transiently significantly lower than expected throughout the pandemic period, but no significant periods of higher-than-expected reporting were detected. Syphilis showed widespread evidence of significantly lower-than-predicted reporting throughout 2020 but eventually reversed, showing significantly higher-than-predicted reporting in mid-to-late 2021. CONCLUSIONS: The COVID-19 pandemic was associated with variable changes in the reporting of STIs in Japan. Higher-than-predicted reporting was more likely to be observed in the later phases of the pandemic. These changes may have been attributable to pandemic-related changes in sexual behaviour and decreased STI clinic attendance and testing, but further research on the long-term impact of the pandemic on STIs is necessary.

Nationwide Descriptive Epidemiological Study of Patients with COVID-19 Evacuated from Wuhan, China to Japan from January to February, 2020.

We investigated the epidemiological findings regarding the route of coronavirus disease 2019 (COVID-19) and infection prevention and control (IPC) measures among returnees in the emergency evacuation from Wuhan, China to Japan during the COVID-19 outbreak in 2020. A total of 12 of the 14 returnees (median age [range]: 49.5 years [29-65 years]; 9 men [75%]) had confirmed COVID-19. The proportion of returnees with COVID-19 was 12/566 (2.1%) in Flights 1-3 and 2/263 (0.8%) in Flights 4 and 5. Six patients were asymptomatic on admission, while 3 patients developed symptoms thereafter. None of the participants reported a specific history of contact with animals, going to seafood markets, or visiting medical facilities. Two patients were in contact with an individual who was confirmed or suspected of having COVID-19. Most patients resided in hotels in the center of Wuhan City, taking taxis and trains for commute. Patients relatively adhered to IPC measures such as wearing a mask and hand hygiene. However, emphasis on IPC measures such as universal masking and more rigorous avoidance of exposure risk might have been necessary to prevent infection. In addition, forced social distancing due to lockdown might have contributed to the lower infection rates in Flights 4 and 5, compared to Flights 1-3.