Successful management of persistent COVID-19 using combination antiviral therapy (nirmatrelvir/ritonavir and remdesivir) and intravenous immunoglobulin transfusion in an immunocompromised host who had received CD20 depleting therapy for follicular lymphoma.

The management of persistent symptomatic coronavirus disease 2019 (COVID-19) infections in immunocompromised patients remains unclear. Here, we present the first case of successful antiviral therapy (nirmatrelvir/ritonavir and remdesivir) in combination with intravenous immunoglobulin (IVIg) in a patient who had received CD20 depleting therapy for follicular lymphoma and experienced recurrent COVID-19 relapses. After the patient received IVIg treatment, the viral load decreased without recurrence. Subsequently, it was found that the anti-spike antibody titer in the administered immunoglobulin was high at 9528.0 binding antibody units/mL. Our case highlights the potential of combination therapy with selective IVIg and antiviral drugs for relapsed immunocompromised COVID-19 patients who have received CD20 depleting therapy.

Autopsy of tetanus with foot gangrene as portal of entry.

Non-traumatic chronic skin lesions are the second most common cause of tetanus. Herein, we describe an 85-year-old woman who presented with a chronically infected skin lesion. She developed tetanus while in hospital and died of respiratory failure, after refusing mechanical ventilation. Routine immunization against tetanus began in Japan during 1968; hence many people born before 1968 are unvaccinated. Mortality due to tetanus is high and the proportion with protective antibodies is low in older adults. Therefore, we recommend tetanus vaccination for older persons in Japan who have chronic skin lesions and have never been vaccinated.

Real-world effectiveness of full and booster mRNA vaccination for coronavirus disease 2019 against disease severity during the delta- and omicron-dominant phases: A propensity score-matched cohort study using the nationwide registry data in Japan.

BACKGROUND: To date, few studies from the Asian region have reported the effectiveness of messenger ribonucleic acid coronavirus disease 2019 (COVID-19) vaccines against disease progression and death after hospitalization. METHODS: We evaluated the data from the COVID-19 registry in Japan during the delta- and omicron-dominant phases. A propensity score-matched cohort study was conducted between the incompletely (0-1 dose) and fully (2 doses) vaccinated groups during the delta-dominant phase and among the incompletely, fully, and booster (3 doses) vaccinated groups during the omicron-dominant phase. RESULTS: In the delta-dominant phase, 411 pairs were matched. The fully vaccinated group showed a significantly lower oxygen supplementation rate (24.1 % vs. 41.1 %, p < 0.001) but little difference in the mortality rate (2.2 % vs. 2.9 %, p = 0.66). In the omicron-dominant phase, 1494 pairs from the incompletely and fully vaccinated groups, and 425 pairs from the fully and booster vaccinated groups were matched. Full vaccination reduced both the oxygen supplementation rate (18.6 % vs 25.7 %, p < 0.001) and mortality rate (0.7 % vs 2.3 %, p < 0.001). Booster vaccination showed little difference in either the rate of oxygen supplementation (21.2 % vs. 24.7 %, p = 0.25) or mortality (1.2 % vs. 2.6 %, p = 0.21) compared with full vaccination. CONCLUSIONS: Full vaccination reduced disease severity during the delta- and omicron-dominant phases; booster vaccination did not further enhance the protective effects against disease progression during the omicron-dominant phase compared to full vaccination. Future vaccine strategies and policy decisions should consider preventing infection or disease progression in the target population, as well as the characteristics of the dominant variant in that phase.

Trends of participants in convalescent plasma donation for COVID-19 in Japan as the pandemic evolved.

Background: We aimed to investigate chronological changes in the characteristics of participants in a coronavirus disease 2019 convalescent plasma donation study that may benefit optimal collection methods in the future. Methods: Data from a convalescent plasma donation study from April 30, 2020 to November 5, 2021 were collected and analyzed. After August 23, 2021, an interim analysis of factors linked to higher antibody titers led us to restrict our participant recruitment criteria to participants who were within 4 months of disease onset and to patients who were otherwise most likely to have sufficiently high antibody titers. Overall, 1299 samples from 1179 patients were analyzed. Results: Over the duration of the study, 35.9% of the samples were deemed eligible for convalescent plasma collection. The overall eligibility rate initially declined, dipping to <20% after one year. During this period, the proportion of enrolled samples from patients who had severe illness also declined, and the proportion of samples from participants who were >120 days post disease onset increased. After the addition of days from onset and vaccination status to our participant recruitment criteria, the eligibility rate improved significantly. Conclusions: As outbreaks of emerging infectious disease occur, it is desirable to construct and implement a scheme for convalescent plasma donation promptly and to monitor the eligibility rate over time. If it declines, promptly analyze and resolve the associated factors. Additionally, vaccine development and infection prevalence are likely to influence the effective recruitment of participants with high antibody titers.

Evaluation of potential rabies exposure among Japanese international travelers: A retrospective descriptive study.

BACKGROUND: Although Japan has been a rabies-free country for >50 years, a few cases have been reported among people traveling abroad. This study aimed to investigate animal exposure among Japanese travelers using the Japanese Registry for Infectious Diseases from Abroad (J-RIDA). METHOD: In this retrospective analysis, we examined Japanese overseas travelers with animal exposure, as included the J-RIDA database, reported from October 1, 2017, to October 31, 2019, with a focus on pre-exposure prophylaxis (PrEP) administration and the animals to which the patients were exposed. RESULTS: Among the 322 cases included in the analysis, 19 (5.9%) patients received PrEP and 303 did not. The most common purpose of travel was a non-package tour (n = 175, 54.3%). Most trips (n = 213, 66.1%) were to a single country for <2 weeks. Most patients (n = 286, 87.9%) traveled to countries with a rabies risk. The majority of patients with and without PrEP were injured in rabies-risk countries [n = 270 (89.1%) for non-PrEP and n = 16 (84.2%) for PrEP]. Animals associated with injuries included dogs (55.0%), cats (25.5%), and monkeys (15.5%). Most patients were classified as World Health Organization Category II/III for contact with suspected rabid animals (39.5% and 44.1% for categories II and III, respectively) and had exposure within 5 days of travel. Southeast Asia (n = 180, 55.9%) was the most common region in which travelers were exposed to animals. CONCLUSIONS: Japanese overseas travelers had contact with animals that could possibly transmit the rabies virus, even on short trips. Promoting pre-travel consultation and increasing awareness of the potential for rabies exposure are important for prevention of rabies among Japanese international travelers.

Clinical outcomes and epidemiological characteristics of bacteremia in the older Japanese population.

BACKGROUND: The characteristics and clinical consequences of bacteremia in older people, who are highly susceptible to infections, need to be clarified. This study aimed to determine the epidemiological characteristics, prognosis, and predictors of 7-day mortality in patients with community-acquired (CA), healthcare-associated (HCA), and hospital-onset (HO) bacteremia in older adults aged ≥65 years. METHODS: Patients aged ≥65 years with positive blood cultures between April 1, 2015, and March 31, 2018, were divided into three groups: pre-old (65-74 years), old (75-89 years), and super-old (≥90 years). Characteristics based on medical exposure, including CA, HCA, and HO, were also compared and factors related to mortality were identified. RESULTS: Overall, 1716 episodes of bacteremia were identified in 1415 patients. Of the 1211 episodes without contamination, 32.8%, 54.3%, and 12.9% occurred in pre-old, old, and super-old patients. Central line-associated bloodstream infections were more common in pre-old patients and urinary tract infections in the old and super-old. The 7-day mortality rates in the pre-old, old, and super-old groups were 7.4%, 5.8%, and 14.2% (P = 0.002), respectively. Multivariable logistic regression showed that super-old age (adjusted odds ratio, aOR: 2.09 [1.13-3.88], P = 0.019) and HO bacteremia (aOR: 1.97 [1.18-3.28], P = 0.010) were independent risk factors for 7-day mortality. Infectious disease consultation had a protective effect on 7-day mortality (aOR: 0.59 [0.35-0.99], P = 0.047). CONCLUSIONS: The epidemiology of bacteremia differs among older people; thus, they should not be treated as a single entity. A careful approach is needed for the optimal management of bacteremia in these vulnerable patients.

Imported severe Plasmodium falciparum infection in the first trimester of pregnancy complicated by post-artemisinin delayed hemolysis and intrauterine fetal death, a case report.

BACKGROUND: Post-artemisinin delayed hemolysis (PADH) is a serious complication in patients who recover from severe malaria after receiving artemisinin-based combined therapy (ACT), including artemether-lumefantrine. In Japan, among the antimalarial drugs recommended by the World Health Organization (WHO) guideline for severe malaria, intravenous quinine gluconate is available only in 29 designated hospitals, and intravenous artesunate is unavailable. Therefore, oral artemether-lumefantrine is occasionally administered as an alternative, even though it may be a suboptimal treatment. In non-endemic settings like Japan, a lack of knowledge of malaria and the side effects, such as post-artemisinin delayed hemolysis caused by the ACT, can have critical consequences. Like our patient, being a primigravida in the early stages of pregnancy is a serious risk factor for severe malaria and must be carefully monitored. CASE PRESENTATION: This report describes a severe case of imported Plasmodium falciparum malaria complicated by fetal loss and prolonged anemia, requiring frequent blood transfusions. The patient was a previously healthy pregnant Japanese female in her 30 s. She developed a high fever 2 days after returning from Nigeria. The patient fulfilled the severe malaria criteria by WHO. On arrival, an abdominal ultrasound incidentally revealed a fetus of 5 week gestational age with a heartbeat in the uterus. Given her pregnancy and the severity of the disease, she was administered intravenous quinine 16 mg/kg as a loading dose. However, the second dose of quinine was not administered due to frequent vomiting and QTc prolongation. We initiated treatment with oral artemether-lumefantrine, and clearance of parasitemia was confirmed by microscopic observation on day 4. Miscarriage was noted on day 6 after admission. Moreover, the patient became feverish again up to 39 °C, and from days 14 to 22, the patient required multiple blood transfusions due to PADH. On day 40, follow-up was discontinued as the hemoglobin level exceeded 10 g/dL. CONCLUSIONS: In patients who recover from severe malaria after ACT treatment, monitoring the hemoglobin level for at least a month is strongly recommended for prompt identification of PADH. Travelers to malaria-endemic countries, especially primigravida women, should be provided with adequate information on the risk and prevention of infection.

Potential usage of anterior nasal sampling in clinical practice with three rapid antigen tests for SARS-CoV-2.

INTRODUCTION: Anterior nasal sampling (AN) might be more convenient for patients than NP sampling to diagnose coronavirus disease. This study investigated the feasibility of rapid antigen tests for AN sampling, and the factors affecting the test accuracy. METHODS: This single-center prospective study evaluated one qualitative (ESP) and two quantitative (LUMI and LUMI-P) rapid antigen tests using AN and NP swabs. Symptomatic patients aged 20 years or older, who were considered eligible for reverse-transcription quantitative polymerase chain reaction using NP samples within 9 days of onset were recruited. Sensitivity, specificity, and positive and negative concordance rates between AN and NP samples were assessed for the rapid antigen tests. We investigated the characteristics that affected the concordance between AN and NP sampling results. RESULTS: A total of 128 cases were recruited, including 28 positive samples and 96 negative samples. The sensitivity and specificity of AN samples using ESP were 0.81 and 1.00, while those of NP samples were 0.94 and 1.00. The sensitivity of AN and NP samples was 0.91 and 0.97, respectively, and specificity was 1.00, for both LUMI and LUMI-P. The positive concordance rates of AN to NP sampling were 0.87, 0.94, and 0.85 for ESP, LUMI, and LUMI-P, respectively. No factor had a significant effect on the concordance between the sampling methods. CONCLUSIONS: ESP, LUMI, and LUMI-P showed practical diagnostic accuracy for AN sampling compared to NP sampling. There was no significant factor affecting the concordance between AN and NP sampling for these rapid antigen tests.

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.

First nationwide survey of infection prevention and control among healthcare facilities in Japan: impact of the national regulatory system.

BACKGROUND: Infection prevention and control (IPC) measures in Japan are facilitated by a financial incentive process at the national level, where facilities are categorized into three groups (Tier 1, Tier 2, or no financial incentive). However, its impact on IPC at the facility level using a validated tool has not been measured. METHODS: A nationwide cross-sectional study was conducted from August 2019 to January 2020 to evaluate the situation of IPC programs in Japan, using the global IPC Assessment Framework (IPCAF) developed by the World Health Organization. Combined with the information on the national financial incentive system, the demographics of facilities and each IPCAF item were descriptively analyzed. IPCAF scores were analyzed according to the facility level of care and the national financial incentive system for IPC facility status, using Dunn-Bonferroni and Mann-Whitney U tests. RESULTS: Fifty-nine facilities in Japan responded to the IPCAF survey: 34 private facilities (57.6%) and 25 public facilities (42.4%). Of these, 11 (18.6%), 29 (49.2%), and 19 (32.3%) were primary, secondary, and tertiary care facilities, respectively. According to the national financial incentive system for IPC, 45 (76.3%), 11 (18.6%), and three (5.1%) facilities were categorized as Tier 1, Tier 2, and no financial incentive system, respectively. Based on the IPCAF total score, more than half of the facilities were categorized as "Advanced" (n = 31, 55.3%), followed by "Intermediate" (n = 21, 37.5%). The IPCAF total score increased as the facility level of care increased, while no statistically significant difference was identified between the secondary and tertiary care facilities (p = 0.79). There was a significant difference between Tier 1 and Tier 2 for all core components and total scores. Core components 5 (multimodal strategies for implementation of IPC interventions) and 6 (monitoring/audit of IPC and feedback) were characteristically low in Japan with a median score of 65.0 (interquartile range 40.0-85.0) and 67.5 (interquartile range 52.5-87.5), respectively. CONCLUSIONS: The national financial incentive system was associated with IPC programs at facility level in Japan. The current financial incentive system does not emphasize the multimodal strategy or cover monitoring/audit, and an additional systematic approach may be required to further promote IPC for more practical healthcare-associated infection prevention.

Surveillance and risk assessment of health screening for vaccine-preventable diseases among international students in Japan: A cross-sectional study in 2020.

We conducted a cross-sectional study using a structured questionnaire in three major Japanese cities from August 03 to 24, 2020 to clarify the current situation of health checkups, including vaccine-preventable diseases (VPDs), among international students at Japanese universities (JUs) and Japanese language schools (JLSs). The total response rate was 36%: 69 JUs (31%) and 137 JLSs (39%). Over 90% of these institutions conducted chest X-ray screening for tuberculosis among their students, whereas only 24.6% of JUs and 15.3% of JLSs performed general blood tests for health screening. Only 14.5% and 2.2% of the JUs and JLSs, respectively, required the submission of vaccination or antibody certificates for admission. The difficulties in requesting vaccination certificates from international students are due to poor legal requirements and concerns about rising costs for schools. From 2017 to 2019, 183 international students, principally from East Asia and Southeast Asia, were infected with VPDs, particularly tuberculosis (99 cases) and varicella (71 cases). Whereas the majority of Japanese educational institutions screen international students for tuberculosis (TB) at admission, only a few institutions request proof of antibody testing relating to other VPDs or of vaccination. These findings will help formulate guidelines for checkups related to vaccination for international students required to protect the educational institutions in Japan from the spread of VPDs. In addition, providing multifaceted social support, including financial compensation for institutions and enhanced international students' health issues, would be helpful.

Impact of the COVID-19 pandemic on racial and ethnic minorities in Japan.

This study compared clinico-epidemiological characteristics between Japanese and non-Japanese coronavirus disease 2019 (COVID-19) patients under the pandemic in Japan. We retrospectively analysed nationwide data of hospitalised COVID-19 patients before 31 March 2021. Epidemic curves were constructed to identify the case distribution over time. A total of 28 093 patients were Japanese and 1335 patients were non-Japanese. The major racial and ethnic minorities were East Asians (n = 521), South Asians (n = 260) and Latin Americans (n = 270). Non-Japanese patients were younger and more likely to travel to COVID-19 endemic countries (7.7%), had meals with other people (17.8%), stayed in crowded places (17.9%) and worked mainly in restaurants (6.6%) and service facilities in nightlife businesses (5.2%). In the matched cohorts, we found no clear disparities in time to admission and clinical prognoses. The epidemic curve for non-Japanese patients showed a small peak in the first wave and no definite waves for the second or third waves. Racial and ethnic minorities were at less risk of severe disease but were at a greater risk of COVID-19 exposure; however, the healthcare system in Japan may provide them with equal opportunities to access inpatient care with Japanese. Further research on their social determinants of health in Japan is required.

Correction: Conjunctivitis, the key clinical characteristic of adult rubella in Japan during two large outbreaks, 2012-2013 and 2018-2019.

[This corrects the article DOI: 10.1371/journal.pone.0231966.].

A Case of Vascular Graft Infection Caused by Haemophilus parainfluenzae.

Haemophilus parainfluenzae is a gram-negative coccobacillus that is a part of the normal flora in the human upper airway and sometimes causes infective endocarditis. We present a case of a 68-year-old Japanese man who had vascular graft infection caused by H. parainfluenzae 4 years after surgery for chronic aortic dissection.

A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT).

BACKGROUND: Coronavirus disease 2019 is a global public health concern. As of December 2020, the therapeutic agents approved for coronavirus disease 2019 in Japan were limited to two drugs: remdesivir, an antiviral drug, granted a Special Approval for Emergency on 7 May 2020, and dexamethasone, which has an anti-inflammatory effect. The aim of this study is to evaluate the efficacy of convalescent plasma collected from donors who recovered from coronavirus disease 2019. METHODS: This is an open-label, randomized controlled trial comprising two groups: a convalescent plasma and a standard-of-care group. Plasma administered to patients with coronavirus disease 2019 randomized in the convalescent plasma group of this trial will be plasma that has been collected and stored in an associated study. Patients with a diagnosis of mild coronavirus disease 2019 will be included in this trial. The efficacy of convalescent plasma transfusion will be evaluated by comparing the convalescent plasma group to the standard-of-care group (without convalescent plasma transfusion) with respect to changes in the viral load and other measures. The primary endpoint will be time-weighted average changes in the SARS-CoV-2 virus load in nasopharyngeal swabs from day 0 to days 3 and 5. It is hypothesized that the intervention should result in a decrease in the viral load in the convalescent plasma group until day 5. This endpoint has been used as a change in viral load has and been used as an index of therapeutic effect in several previous studies. DISCUSSION: The proposed trial has the potential to prevent patients with mild COVID-19 from developing a more severe illness. Several RCTs of convalescent plasma therapy have already been conducted in countries outside of Japan, but no conclusion has been reached with respect to the efficacy of convalescent plasma therapy, which is likely in part because of the heterogeneity of the types of target patients, interventions, and endpoints among trials. Actually, previous clinical trials on plasma therapy have shown inconsistent efficacy and are sometimes ineffective in COVID-19 patients with severe disease, which is due to unmeasured neutralizing antibody titer in the COVID-19 convalescent plasma. To improve this issue, in this study, we measure neutralizing activity of convalescent plasma before administration and provide the plasma with high neutralizing activity to the subjects. It is hoped that this study will further evidence to support the role of convalescent plasma therapy in COVID-19.

Impact of prioritized vaccinations for the elderly on the COVID-19 pandemic in Japan.

The Japanese government implemented a large-scale vaccination policy against the coronavirus disease 2019 (COVID-19) pandemic, primarily using messenger RNA vaccines in 2021. Its hallmark was prioritized vaccination for the elderly after healthcare workers in a short period of time. Vaccination for the elderly, vulnerable to infection and severe disease, was carried out rapidly in approximately 4 months since April 2021. We evaluated the impact of Japan's vaccination policy against COVID-19 during the pandemic, with a particular focus on how prioritized vaccination for the elderly affected the pandemic. We observed a remarkable decrease in the number of infections, cluster events in long-term care facilities, and severe disease among the elderly during the fifth wave (August 2021) despite rising incidence of infections in the overall population. In conclusion, we think that prioritized vaccination for the elderly was efficacious in preventing infections and severe COVID-19 among the elderly during the fifth wave in Japan.

Case Report: Leptospirosis by Wild Rat Bite in Winter in Tokyo Metropolitan Area, Japan.

We report a case of leptospirosis in Tokyo in winter due to a rat bite, an uncommon cause of Leptospira infection. In Japan, many cases due to exposure to fresh water have been reported from domestic southwest islands in summer. However, a previous report on leptospirosis in Tokyo documented several cases occurring in winter. The main route of infection in the Tokyo metropolitan area during winter was attributed to the increased chance of direct rat exposure. Rapid and feasible diagnostic methods are needed to elucidate its epidemiology and provide prompt treatment.

Disseminated Streptococcus anginosus invasive infection with intracranial subdural abscess formation.

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.