Financial Burden as a Potential Barrier to Vaccine Completion in Post-hematopoietic Stem Cell Transplant Patients in Japan.

Introduction The administration of routine vaccinations to patients following hematopoietic stem cell transplantation (HSCT) is highly recommended. However, studies examining reasons for not completing vaccination in post-HSCT patients are lacking. Method We reviewed the medical records of patients who sought vaccination following HSCT from January 2012 to December 2018 at the Center for Infectious Diseases, Nara Medical University. Results Information regarding patients' backgrounds, administered vaccines, and reasons for not administering recommended vaccines was collected for the study. Thirty-five patients (22 men and 13 women) with a median time from HSCT to the first visit of 25 months were enrolled. Vaccine coverage was highest for diphtheria, tetanus, and acellular pertussis (DTaP) at 89% (31 patients), followed by 23-valent pneumococcal, measles/rubella/mumps, and Japanese encephalitis at 71% (25 patients), 71% (25 patients), and 63% (22 persons), respectively. However, vaccine coverage for hepatitis B, 13-valent pneumococcal, and Hib was low at 26% (three patients), 11% (four patients), and 40% (14 patients), respectively. The reason for not completing the recommended vaccination series was not provided for most cases; however, the economic barrier was cited for all vaccines. Discussion This study identified several cases in Japan where individuals stopped completing post-HSCT vaccinations due to financial constraints. Larger-scale studies may be necessary in Japan in the future for further investigation.

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.

Chorioamnionitis and early pregnancy loss caused by ampicillin-resistant non-typeable Haemophilus influenzae.

Haemophilus influenzae can cause intra-amniotic infection and early pregnancy loss. The mode of transmission and risk factors for H. influenzae uterine cavity infections are unknown. Here, we present the case of chorioamnionitis caused by ampicillin-resistant H. influenzae in a 32-year-old Japanese woman at 16 weeks of gestation. Despite empirical treatment, including ampicillin, as recommended by the current guidelines, she had fetal loss. The antimicrobial regimen was changed to ceftriaxone, and the treatment was completed without complications. Although the prevalence and risk factors for chorioamnionitis caused by ampicillin-resistant H. influenzae are unknown, clinicians need to recognize H. influenzae as a potentially drug-resistant and lethal bacterium for pregnant women.

Adverse events after administration of the first and second doses of messenger RNA-based COVID-19 vaccines in Japanese subjects aged 12-18 years.

OBJECTIVE: Using a prospective observational design, we assessed adverse events (AEs) after COVID-19 vaccination in Japanese patients. METHODS: Two doses of the mRNA-1273 (SPIKEVAX®) or BNT162b2 (COMIRNATY®) vaccine were administered to participants aged 12 to 18 years, and AEs after each dose were recorded for 14 days. Data on the duration and nature (local vs. systemic) of AEs were collected using a questionnaire. Sex-based differences in AE frequency were also analyzed. RESULTS: After the first and second doses, 152 and 135 vaccinees were enrolled, respectively. After the first dose, fever (>37.1°C) occurred in 38.9% of males and 50.0% of females, whereas local pain occurred in 89.8% and 97.7% of males and females, respectively (only SPIKEVAX® was used as the first dose). After the second dose, fever (>37.1°C) occurred in 77.8% and 82.6% of males vaccinated with COMIRNATY® and SPIKEVAX®, respectively, and 82.6% of females (all received SPIKEVAX®). The local pain rates in these groups were 80.6%, 76.3%, and 100%, respectively. After the second dose, local pain, fever (>38.1°C) and headache were significantly more common in female participants, and the median symptom duration was 3 days. CONCLUSIONS: AEs were more frequent after the second dose and in females.

Association between history of HBV vaccine response and anti-SARS-CoV-2 spike antibody response to the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine among healthcare workers in Japan: A prospective observational study.

INTRODUCTION: Inadequate vaccine response is a common concern among healthcare workers at the frontlines of the COVID-19 pandemic. We aimed to investigate if healthcare workers with history of weak immune response to HBV vaccination are more likely to have weak responses against the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine. METHODS: We prospectively tested 954 healthcare workers for the Anti-SARS-CoV-2 spike (S) protein antibody titers prior to the first and second BNT162b2 vaccination doses and after four weeks after the second dose using Roche's Elecsys® assay. We calculated the percentage of patients who seroconverted after the first and second doses. We estimated the relative risk of non-seroconversion after the first BNT162b2 vaccine (defined as anti-SARS-CoV-2-S titer <15 U/mL) among HBV vaccine non-responders (HBs-Ab titer <10 mIU/mL) and weak responders (≥10 and <100 mIU/mL) compared to normal responders (≥100 mIU/mL). RESULTS: Among 954 healthcare workers recruited between March 9 and March 24, 2021 at Osaka Medical and Pharmaceutical University, weak and normal HBV vaccine responders had comparable S-protein titers after the first BNT162b2 dose (51.4 [95% confidence interval 25.2-137.0] versus 59.7 [29.8-138.0] U/mL, respectively). HBV vaccine non-responders were more likely than normal responders to not seroconvert after a single dose (age and sex-adjusted relative risk 1.85 95% confidence interval [1.10-3.13]) although nearly all participants seroconverted after the second dose. After limiting the analysis to 382 patients with baseline comorbidity data, the comorbidity-adjusted relative risk of non-seroconversion among HBV vaccine non-responders to normal responders was 1.32 (95% confidence interval [0.59-2.98]). DISCUSSION: Long term follow-up studies are needed to understand if protective immunity against SARS-CoV-2 wanes faster among those with history of HBV vaccine non-response and when booster doses are warranted for these healthcare workers.

Newly developed artificial intelligence algorithm for COVID-19 pneumonia: utility of quantitative CT texture analysis for prediction of favipiravir treatment effect.

PURPOSE: Using CT findings from a prospective, randomized, open-label multicenter trial of favipiravir treatment of COVID-19 patients, the purpose of this study was to compare the utility of machine learning (ML)-based algorithm with that of CT-determined disease severity score and time from disease onset to CT (i.e., time until CT) in this setting. MATERIALS AND METHODS: From March to May 2020, 32 COVID-19 patients underwent initial chest CT before enrollment were evaluated in this study. Eighteen patients were randomized to start favipiravir on day 1 (early treatment group), and 14 patients on day 6 of study participation (late treatment group). In this study, percentages of ground-glass opacity (GGO), reticulation, consolidation, emphysema, honeycomb, and nodular lesion volumes were calculated as quantitative indexes by means of the software, while CT-determined disease severity was also visually scored. Next, univariate and stepwise regression analyses were performed to determine relationships between quantitative indexes and time until CT. Moreover, patient outcomes determined as viral clearance in the first 6 days and duration of fever were compared for those who started therapy within 4, 5, or 6 days as time until CT and those who started later by means of the Kaplan-Meier method followed by Wilcoxon's signed-rank test. RESULTS: % GGO and % consolidation showed significant correlations with time until CT (p < 0.05), and stepwise regression analyses identified both indexes as significant descriptors for time until CT (p < 0.05). When divided all patients between time until CT of 4 days and that of more than 4 days, accuracy of the combined quantitative method (87.5%) was significantly higher than that of the CT disease severity score (62.5%, p = 0.008). CONCLUSION: ML-based CT texture analysis is equally or more useful for predicting time until CT for favipiravir treatment on COVID-19 patients than CT disease severity score.

Characteristics and potential quality indicators for evaluating pre-travel consultations in Japan hospitals: the Japan Pretravel consultation registry (J-PRECOR).

BACKGROUND: Awareness of pre-travel consultations (PTCs) and prevention methods for overseas travel-related diseases, and the understanding of PTCs among Japanese travelers and medical professionals remains low in Japan. A multicenter registry was established to examine PTCs in Japan. This study assessed the PTC implementation rate and examined the indicators of PTCs that can be used as criteria for evaluating quality. METHODS: Clients who presented for their PTCs at 17 facilities and were registered between February 1, 2018, and May 31, 2020, were included. Medical information was extracted retrospectively via a web-based system. Correlations between vaccination risk categories and advice/intervention proportions by the facility were evaluated using Spearman's ordered phase relations (α = 0.05). RESULTS: Of the 9700 eligible clients (median age, 32 years; 880 [9.1%] aged < 16 years and 549 [5.7%] aged ≥65 years), the most common travel duration was ≥181 days (35.8%); higher among younger clients. The most common reason for travel was business (40.5%); the US (1118 [11.5%]) and Asia (4008 [41.3%]) were the most common destinations and continents, respectively. The vaccine number (median three per person) increased after the PTCs except for the tetanus toxoid. Only 60.8% of the clients recommended for malaria prophylaxis received anti-malarial agents. The gross national income; the incidence of human rabies, typhoid fever, falciparum malaria; and dengue risk category were associated with the percentage of hepatitis-A vaccines; explaining rabies post-exposure prophylaxis, typhoid-fever vaccinations, malaria-prophylaxis prescriptions; and mosquito repellants, respectively. CONCLUSIONS: Although the characteristics of the travelers differed, the quality of the PTCs should be improved to address, for example, the lower rate of acceptance of malaria prophylaxis in Japan.

Effect of the introduction of a management bundle for blood culture collection.

BACKGROUND: Inappropriate blood collection subjected to blood culture (BC) causes BC contamination and may complicate the diagnose is of infectious diseases. Therefore, we developed a bundle based on the guideline recommendations for appropriate blood collection and examined the effects of bundle introduction. METHODS: We performed a retrospective analysis of BC samples to determine the contamination rates before and after introducing the BC bundle. We also analyzed the correlation between the compliance rate of the bundle and contamination rate, and between each bundle element and contamination. RESULTS: After the introduction of the bundle, the contamination rate was significantly reduced from 5.4% ± 0.9% to 1.7± 0.7% (P < .01). The compliance rate of the bundle was significantly associated with a lower contamination rate (P < .01). Multivariable logistic regression showed that collection from superficial veins of the cubital fossa (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.13-0.51, P < .01) and disinfection of the skin at the blood collection site with 1% chlorhexidine alcohol swab (OR, 0.41; 95% CI, 0.25-0.68, P < .01) were significantly associated with lower contamination. CONCLUSIONS: This study suggests that the introduction of the BC bundle significantly reduced the contamination rate, and bundle compliance was associated with a lower contamination rate.

Young Healthy Patient With Severe COVID-19 and Fulminant Community-Acquired Pseudomonas aeruginosa Pneumonia: A Case Report.

Community-acquired pneumonia (CAP) caused by Pseudomonas aeruginosa in healthy adults can rapidly lead to severe outcomes. We treated a case of P. aeruginosa-induced CAP and concurrent severe coronavirus disease (COVID-19) in a healthy 39-year-old man without other serious risk factors for severe illness except smoking. Immediately after admission, the patient developed sepsis and received intensive broad-spectrum antibacterial therapy with meropenem and vancomycin, veno-arterial extracorporeal membrane oxygenation (VAECMO), and catecholamine supplementation. Despite receiving multidisciplinary treatment, the patient died within 24 hours. P. aeruginosa with normal antimicrobial susceptibility was identified in blood and sputum cultures of samples taken at admission. Gram staining of the bacteria detected in blood cultures was suspicious for non-glucose-fermenting Gram-negative rods, including P. aeruginosa, and the antimicrobial regimen that was initiated following admission was considered effective. The patient was a plumber and a smoker, which are risk factors for P. aeruginosa-induced CAP, and the clinical course matched those in previous reports of P. aeruginosa-induced CAP, including necrotizing pneumonia with cavities and rapid progression of sepsis. Although COVID-19 can be the sole cause of septic shock, the combination of P. aeruginosa bacteremia and COVID-19 was possibly the cause of septic shock in this case. Even during an infectious disease pandemic, reviewing the patient's occupational history and comorbidities and performing blood and sputum culture tests, including Gram staining, are important for the provision of appropriate treatment.

Multiple Cardiovascular Diseases or Risk Factors Increase the Severity of Coronavirus Disease 2019.

BACKGROUND: This study aimed to determine whether disease severity varied according to whether coronavirus disease 2019 (COVID-19) patients had multiple or single cardiovascular diseases and risk factors (CVDRFs).Methods and Results:COVID-19 patients with single (n=281) or multiple (n=412) CVDRFs were included retrospectively. Multivariable logistic regression showed no significant difference in the risk of in-hospital death between groups, but patients with multiple CVDRFs had a significantly higher risk of acute respiratory distress syndrome (odds ratio: 1.75, 95% confidence interval: 1.09-2.81). CONCLUSIONS: COVID-19 patients with multiple CVDRFs have a higher risk of complications than those with a single CDVRF.

Travelers' vaccines and their adverse events in Nara, Japan.

BACKGROUND: It is important to analyze the types of vaccines in travel clinics to determine the focus points in future practice. METHODS: We retrospectively reviewed the electronic medical records of all patients who visited the travel clinic of Nara Medical University between June 2013 and December 2019 to determine their background and the vaccines administered. The information regarding adverse events of the unapproved vaccines in Japan (Havrix®, Verorab®, Boostrix®, Priorix®, Typhim Vi®, and Mencevax®) was also collected. RESULTS: Of 645 patients, 58.6% were men and the median age was 31 years. Business was the most common travel purpose (34.9%), and Southeast Asia was the most common destination (40.2%). More than 80% of travelers to low- and middle-income countries were vaccinated against hepatitis A, while the rabies vaccination rate was approximately 50%. Typhoid vaccination coverage among travelers to South Asia was approximately 50%. The incidence of adverse events requiring medical consultation, telephonic consultation, or prolonged stay in the examination room was less than 5% for all unapproved vaccines in Japan. CONCLUSION: More patient education is needed to increase the vaccination rate of rabies and typhoid vaccines. Adverse events to unapproved vaccines in Japan were not high and were well-tolerated.

A case of cryptococcal necrotizing fasciitis and immune reconstitution inflammatory syndrome in a renal transplantation recipient.

INTRODUCTION AND IMPORTANCE: Immunocompromised patients are at high risk of unexpectedly serious infections caused by uncommon bacteria or fungi. We experienced a case of Cryptococcus neoformans-induced necrotizing fasciitis (NF) of the lower extremities. The progress so far has been reported by the urology department [1]. Moreover, after the NF had been treated, the patient developed immune reconstitution inflammatory syndrome (IRIS). We report from surgeon's view point. CASE PRESENTATION: A 51-year-old male renal transplant patient complained of pain in both lower extremities (LE). After the initial debridement, periodic acid-Schiff after diastase digestion (D-PAS) staining confirmed the diagnosis. No symptoms were seen in the lungs or cerebrospinal system. The patient was reluctant to undergo surgical treatment but several debridement improved patient's condition. After the LE wound healed, prednisolone was discontinued, then painful nodules appeared on both LE. Based on the negative culture results and the fact that the patient had been treated with flucytosine and fluconazole, we suspected that the nodules had been caused by IRIS. CLINICAL DISCUSSION: It was difficult to diagnose Cryptococcus-induced NF and paradoxical IRIS. Cooperation from other specialists was essential. CONCLUSION: We think this patient needed earlier and more definitive debridement. Fortunately, we were able to save the patient's life and maintain his LE function. In immunocompromised patients, cryptococcus can be a pathogen. In addition, IRIS can occur during treatment. Management of IRIS is the capital point of sepsis management, careful anti-inflammatory drug control by specialists is required.

Factors associated with viral clearance periods from patients with COVID-19: A retrospective observational cohort study.

INTRODUCTION: Knowledge is limited on the virologic course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, particularly the time taken for viral clearance and the optimal time to discontinue isolation. This study aims to identify the clinical and demographic factors influencing the time taken for viral clearance in patients with COVID-19 to determine the optimal isolation period. METHODS: This two-center retrospective observational cohort study was conducted between March 1 and June 31, 2020. Patients with COVID-19, which was confirmed by real-time reverse transcription polymerase chain reaction, were included. Data were extracted from medical records. The positive duration, which was defined as the period from the day of symptom onset to the negative conversion day, was assessed using a generalized linear model. RESULTS: We included 63 patients. The mean positive duration was 20 days. The positive duration was significantly shorter for patients younger than 30 years of age and those between 30 and 60 years of age than for patients older than 60 years of age. We observed a more scattered distribution of the positive duration in older patients than in younger patients. CONCLUSIONS: Younger patients who recovered from COVID-19 took less time to clear SARS-CoV-2 than older patients; thus, a classification of the isolation periods based on age could be considered. A uniform viral clearance period for older patients may be difficult to determine because of biases such as underlying medical conditions. Further surveillance measures are recommended to determine the viral clearance time and the optimal isolation period.

Epidemiological trends of imported infectious diseases in Japan: Analysis of imported 2-year infectious disease registry data.

INTRODUCTION: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information. METHODS: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis. RESULTS: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever. CONCLUSIONS: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Necessity to screen and treat latent tuberculosis before ruxolitinib treatment-Ruxolitinib-associated disseminated tuberculosis: A case report and literature review.

Ruxolitinib, a Janus kinase inhibitor, considerably improves symptoms of patients with polycythemia vera and primary or secondary myelofibrosis. However, its association with the development of infectious complications is a concern. Herein, we report the case of an 80-year-old man with primary myelofibrosis who developed disseminated tuberculosis during treatment with ruxolitinib at 15 mg twice daily and prednisone at 5 mg. We also reviewed the literature on patients who developed tuberculosis during treatment with ruxolitinib. There are 13 case reports of patients who developed tuberculosis during treatment with ruxolitinib, including our case. Disseminated tuberculosis manifestations were observed in 84.6 % of the patients and 50 % of them died. Although the interferon-gamma release assay was performed for seven of the patients with six positive results at the time of tuberculosis diagnosis, none were tested before the commencement of ruxolitinib. We suggest taking a history of tuberculosis and screening for and treating latent tuberculosis before administering ruxolitinib, especially in areas where the risk of tuberculosis is high.

Spinal epidural abscess caused by non-typhoidal Salmonella: A case report and literature review.

Non-typhoidal Salmonellae are Gram negative bacilli commonly causing self-limiting gastroenteritis, representing a public health issue particularly in tropical countries. Further, the epidemiology of invasive infection by non-typhoidal Salmonella species is poorly understood. Herein, we presented a case of an unusual Salmonella enterica subsp. enterica serovar Altona epidural abscess that cause osteomyelitis and psoas abscess in a 52-year-old Japanese man. To ensure adequate antibiotics penetration into the epidural space, the patient was treated with antibiotics in doses similar to those administered for meningitis. We also reviewed the literature on patients who developed non-typhoidal Salmonella epidural abscesses, and we found 10 other previously reported cases. Salmonella Enteritidis was the pathogen most commonly identified, similar to gastroenteritis. More surveillance of non-typhoidal Salmonella serovars, especially in cases of severe infection, and investigation of antibiotic penetration rate into the epidural space are warranted to decide the best treatment course.