Unveiling the role of preceding seasonal influenza in the development of bacteremic pneumococcal pneumonia in older adults before the COVID-19 pandemic in Japan.

OBJECTIVE: We aimed to investigate the impact of preceding seasonal influenza on the clinical characteristics of adult patients with invasive pneumococcal disease (IPD) in Japan. METHODS: Data for 1722 adult patients with IPD were analyzed before (2017-2019) and during the COVID-19 pandemic (2020-2022). RESULTS: The seasonal influenza epidemic disappeared soon after the emergence of the pandemic. Compared with that before the pandemic (66.7%), we observed a lower bacteremic pneumonia proportion in patients with IPD during the pandemic (55.6%). The clinical presentations of IPD cases significantly differed between those with and without preceding influenza. The proportion of bacteremic pneumonia was higher in IPD patients with preceding influenza than in those without in both younger (44.9% vs 84.2%) and older adults (65.5% vs 87.0%) before the pandemic. The case fatality rate was significantly higher in IPD patients with preceding influenza (28.3%) than in those without (15.3%) in older adults before the pandemic (P = 0.020). Male and aging are high risk factors for death in older patients with IPD who had preceding influenza. CONCLUSION: Our study reveals that preceding seasonal influenza plays a role in the development of bacteremic pneumococcal pneumonia, increasing the risk of death in older adults.

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.

Acute acalculous cholecystitis following extended administration of nirmatrelvir/ritonavir for persistent SARS-CoV-2 infection.

Immunocompromised patients with hematologic malignancies, particularly those treated with anti-CD20 antibodies such as rituximab and obinutuzumab, are known to be at risk of prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prolonged administration or combination therapy with antiviral medications reportedly yields favorable outcomes in these patients. However, knowledge regarding the adverse events associated with such therapeutic approaches is limited. Herein, we report a case of acute acalculous cholecystitis (AAC) following extended administration of nirmatrelvir/ritonavir (NMV/r) in a 68-year-old Japanese man with persistent SARS-CoV-2 infection. The patient had received obinutuzumab and bendamustine for follicular lymphoma and was diagnosed with coronavirus disease 2019 (COVID-19) approximately one year after treatment initiation with these drugs. Subsequently, he was admitted to a different hospital, where he received antiviral drugs, monoclonal antibodies, and steroids. Despite these interventions, the patient relapsed and was subsequently transferred to our hospital due to persistent SARS-CoV-2 infection. Remdesivir administration was ineffective, leading to the initiation of extended NMV/r therapy. One week later, he exhibited elevated gamma-glutamyl transpeptidase (GGT) levels, and one month later, he developed AAC. Cholecystitis was successfully resolved via percutaneous transhepatic gallbladder drainage and administration of antibiotics. We speculate that extended NMV/r administration, in addition to COVID-19, may have contributed to the elevated GGT and AAC. During treatment of persistent SARS-CoV-2 infection with extended NMV/r therapy, patients should be carefully monitored for the appearance of findings suggestive of biliary stasis and the development of AAC.

Isolation of Aspergillus udagawae in Canaliculitis: A Case Report.

Aspergillus udagawae is a cryptic species of Aspergillus section Fumigati. Here, we report a case of canaliculitis with isolated A. udagawae. Fungal canaliculitis is a rare lacrimal disease, and its clinical features are poorly understood. The causative fungus was initially misclassified as Aspergillus thermomutatus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) but was finally identified as A. udagawae by ß-tubulin genetic analysis. The patient showed rapid improvement and did not experience relapse after drainage alone, without antifungal therapy. A. udagawae has low virulence, which may be related to the minimally invasive nature of the infection.

Sputum Gram stain of hypervirulent Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae has virulence genes relevant to capsule overproduction, which could lead to the finding of thick transparent area ("halo") in Gram stain. In sputum Gram stain, observation of a large Gram-negative rod with a thick capsule may not only indicate that it is K. pneumoniae but also that it is a highly virulent strain.

Genetic relatedness of third-generation cephalosporin-resistant Escherichia coli among livestock, farmers, and patients in Japan.

Objectives: The third-generation cephalosporin (3GC)-resistant E. coli strains have been detected worldwide in humans and animals. Hence, in this study, we evaluated the prevalence and genetic characteristics of 3GC-resistant E. coli in livestock, farmers, and patients to further analyse if livestock serves as a potential reservoir of antimicrobial-resistant bacteria. Methods: Faecal samples were collected from 330 healthy livestock (216 cattle and 114 swine), 61 healthy livestock farmers (52 cattle farmers and 9 swine farmers), and 68 non-duplicate 3GC-resistant E. coli isolates were also obtained from the clinical specimens of patients in Japan between 2013 and 2015. Genes associated with resistance in 3GC-resistant E. coli were identified using polymerase chain reaction (PCR) and DNA sequencing. Genotypic diversity was determined by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Results: We obtained 39 and 17 non-duplicated 3GC-resistant E. coli strains from healthy livestock (33 cattle and six swine) and livestock farmers, respectively. All isolates carried either CTX-M-type extended-spectrum ß-lactamase or plasmid-mediated AmpC ß-lactamase genes, with CTX-M-14 being the most frequent. CTX-M producers from livestock and patients belonged to 22 and 19 different sequence types (STs), respectively, and only three STs were the same. Among the 3GC-resistant E. coli from livestock and farmers, three types of CTX-M producers have shown similar characteristics (CTX-M genotype, ST, PFGE patterns, and antimicrobial susceptibilities) and were identified as clonal isolates shared among their farms. Conclusions: Our study findings indicate that CTX-M-14 is predominant in Japan. No distinct relationship was observed between the 3GC-resistant E. coli isolated from livestock and patients; however, some clonal relatedness was observed between the isolates from livestock and farmers due to their close contact.

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.

A Sublatissimus Dorsi Abscess Due to Pasteurella multocida Caused by a Cat Scratch.

We encountered a 51-year-old male patient who was not immunocompromised. Thirteen days before his admission, his right forearm was scratched by his pet cat. Swelling, redness, and purulent discharge appeared at the site, but he did not seek medical attention. He developed a high fever and was hospitalized with a diagnosis of septic shock, respiratory failure, and cellulitis on plain computed tomography. After admission, the swelling on his forearm was relieved with empirical antibiotics, but the symptoms spread from his right axilla to his waist. We suspected necrotizing soft tissue infection and made a trial incision in the lateral chest up to the latissimus dorsi, but were unable to prove it. However, an abscess was later found under the muscle layer. Second incisions were made to allow the abscess to drain. The abscess was relatively serous, and no tissue necrosis was observed. The patient's symptoms improved rapidly. In retrospect, the patient probably already had the axillary abscess on admission. It may have been detected at this point if contrast-enhanced computed tomography had been performed, and early axillary drainage may have accelerated the patient's recovery, which could also have prevented the formation of the latissimus dorsi muscle abscess. In conclusion, the Pasteurella multocida infection on the patient's forearm induced a very unusual presentation and caused an abscess to form under the muscle, unlike necrotizing soft tissue infections. Early contrast-enhanced computed tomography may aid earlier and more appropriate diagnosis and treatment in such cases.

Clinical characteristics of patients with coronavirus disease 2019-associated pulmonary aspergillosis on mechanical ventilation: A single-center retrospective study in Japan.

BACKGROUND: Aspergillus is one of the important pathogens that contribute to high mortality in patients with coronavirus disease 2019 (COVID-19) in intensive care units (ICUs). Although incidence rates of Aspergillus coinfection are high globally, a Japanese national survey reported a low incidence. This study aimed to describe the clinical characteristics of patients with COVID-19-associated pulmonary aspergillosis at our institute. METHODS: We identified patients with microbiologically confirmed COVID-19 on mechanical ventilation in the ICU. Of these patients, we identified patients in whom Aspergillus was cultured from the respiratory specimen. RESULTS: Of a total of 169 patients, seven had aspergillosis (4.1%), which included three patients, three patients, and one patient with possible, probable, and proven aspergillosis, respectively, according to the criteria of the European Confederation of Medical Mycology International Society. All patients received systemic steroid therapy. Two patients (one each with proven and probable aspergillosis) had tracheobronchitis diagnosed by bronchoscopy. All patients in whom Aspergillus was repeatedly isolated from samples died. The mortality rates for all cases and probable and proven cases were 57% (4/7) and 75% (3/4), respectively. CONCLUSIONS: The incidence rate of aspergillosis in patients with COVID-19 in the ICU was higher in our institute than that reported by a Japanese national survey (4.1% vs. 0.5%). Repeated detection of Aspergillus might suggest a true Aspergillus infection, such as chronic aspergillosis, rather than colonization. In patients with severe COVID-19 patients, it is important to always keep CAPA in mind.

Invasive Haemophilus influenzae disease among adults in Japan during 2014-2018.

PURPOSE: We describe the epidemiology of invasive Haemophilus influenzae disease (IHD) among adults in Japan. METHODS: Data for 200 adult IHD patients in 2014-2018 were analyzed. The capsular type of H. influenzae was determined by bacterial agglutination and polymerase chain reaction (PCR), and non-typeable Haemophilus influenzae (NTHi) was identified by PCR. RESULTS: The annual incidence of IHD (cases per 100,000 population) was 0.12 for age 15-64 years and 0.88 for age ≥ 65 years in 2018. The median age was 77 years, and 73.5% were aged ≥ 65 years. About one-fourth of patients were associated with immunocompromising condition. The major presentations were pneumonia, followed by bacteremia, meningitis and other than pneumonia or meningitis (other diseases). The case fatality rate (CFR) was 21.2% for all cases, and was significantly higher in the ≥ 65-year group (26.1%) than in the 15-64-year group (7.5%) (p = 0.013). The percentage of cases with pneumonia was significantly higher in the ≥ 65-year group than in the 15-64-year group (p < 0.001). The percentage of cases with bacteremia was significantly higher in the 15-64-year group than in the ≥ 65-year group (p = 0.027). Of 200 isolates, 190 (95.0%) were NTHi strains, and the other strains were encapsulated strains. 71 (35.5%) were resistant to ampicillin, but all were susceptible to ceftriaxone. CONCLUSION: The clinical presentations of adult IHD patients varied widely; about three-fourths of patients were age ≥ 65 years and their CFR was high. Our findings support preventing strategies for IHD among older adults, including the development of NTHi vaccine.

Transition of Antibody Titers after SARS-CoV-2 mRNA Vaccination in Japanese Healthcare Workers.

Since February 2021, healthcare workers in Japan have been preferentially vaccinated with a messenger RNA vaccine (BNT162b2; Pfizer/BioNTech) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While many studies have confirmed that this vaccine is highly effective in reducing hospitalization and deaths from coronavirus disease 2019 (COVID-19), antibody titers tend to decline at 3 months after vaccination, leading to a risk of breakthrough infections. Thus, information is needed to support the decision regarding the 3rd vaccination. In this study, we investigated the transition of anti-SARS-CoV-2 spike protein receptor-binding domain (RBD) IgG and neutralizing antibody titers in 37 vaccinated Japanese healthcare workers. Samples were collected 6 times starting before vaccination until 6 months after the second vaccination. The levels of anti-SARS-CoV-2 RBD IgG peaked 1 week after the 2nd vaccination, then declined over time and decreased to < 10% at 6 months after the 2nd vaccination. Additionally, approximately one-third of the healthcare workers were seronegative for the Omicron variant 6 months after the 2nd vaccination. Workers with low anti-SARS-CoV-2 RBD IgG levels also had low neutralizing antibody titers. These data support booster dose administration for healthcare workers, especially those with low anti-SARS-CoV-2 RBD IgG levels.

Sensitivity and specificity analyses of COVID-19 screening protocol for emergency medical services: A STARD-compliant population-based retrospective study.

During the novel coronavirus disease (COVID-19) pandemic, emergency medical services (EMS) has borne a huge burden in transporting emergency patients. However, the protocol's effect on identifying emergency patients who are likely to have COVID-19 is unknown. We aimed to evaluate the diagnostic accuracy of a prehospital COVID-19 screening protocol for EMS. We conducted this population-based retrospective study in Nara Prefecture, Japan. The Nara Prefectural Government implemented a screening protocol for COVID-19 comprising the following symptom criteria (fever, cough, sore throat, headache, malaise, dysgeusia, or anosmia) and epidemiological criteria (contact history with confirmed COVID-19 cases or people with upper respiratory symptoms, or travel to areas with high infection rate). A patient meeting at least one criterion of each class was considered positive. We evaluated all 51,351 patients from the regional EMS database of the Nara Prefecture (emergency Medical Alliance for Total Coordination of Healthcare) who were registered from June 15, 2020 to May 31, 2021 and had results of COVID-19 reverse transcription polymerase chain reaction (RT-PCR) tests. We assessed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this protocol. We also assessed how these outcomes changed by adding vital signs and conducted a 10-fold and 100-fold prevalence simulation. The screening protocol was used for 246/51351 patients (0.5%). Among them, 31 tested positive after EMS transportation. This protocol's sensitivity, specificity, PPV, and NPV were 40.8%, 99.6%, 12.6%, and 99.9%, respectively. With the addition of ≥2 vital signs (body temperature ≥37.5 °C, respiratory rate ≥20 breaths/minute, and oxygen saturation <90%), sensitivity and PPV changed to 61.8% and 1.0%, respectively, while NPV remained 99.9%. With a 10-fold and 100-fold increase in disease, the protocol PPV would be 59.0% and 94.3%, and NPV would be 99.1% and 90.7%, respectively, and with additional vital signs, PPV would be 8.9% and 53.1%, and NPV would be 99.4% and 93.2%, respectively. This COVID-19 screening protocol helped enable EMS transport for patients with COVID-19 with a PPV of 12.6%. Adding other vital sign variables may improve its diagnostic value if the prevalence rate increases.

A survey of healthcare workers' recommendations about human papillomavirus vaccination.

Purpose: The human papillomavirus (HPV) vaccine is safe and effective for preventing HPV-related diseases. However, HPV vaccination rates in Japan are low because the "Ministry of Health, Labour and Welfare" had stopped recommending vaccination. We assessed healthcare workers' (HCWs) current recommendations regarding the HPV vaccine and how the provision of information about HPV vaccination affected their recommendations. Materials and Methods: A survey was conducted among nurses and physicians in Nara prefecture from March 2021 to July 2021. The questionnaire asked about their understanding, recommendations, and opinions regarding HPV vaccination. Before answering the last two questions (optional), the HCWs read evidence-based information quantifying the risks and benefits of HPV vaccination. Results: A total of 441 HCWs completed the questionnaire. Only 19% of HCWs always recommended HPV vaccination for girls aged 12-16 years. The evidence-based information significantly improved the percentage of HCWs who would "always recommend" vaccination. Conclusion: This study showed that the proportion of HCWs who recommend HPV vaccination to adolescent girls remains low in Japan. However, we found that evidence-based information describing the causal relationship between adverse events and vaccination, quantifying the risks and benefits, noting the importance of HCW communications with families, and reporting the recommendations of national societies, might increase HCWs' recommendations for HPV vaccination.

Invasive Streptococcus oralis Expressing Serotype 3 Pneumococcal Capsule, Japan.

We report 2 adult cases of invasive disease in Japan caused by Streptococcus oralis that expressed the serotype 3 pneumococcal capsule and formed mucoid colonies. Whole-genome sequencing revealed that the identical serotype 3 pneumococcal capsule locus and hyl fragment were recombined into the genomes of 2 distinct S. oralis strains.

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.

Clinical characteristics and treatment outcomes of carbapenem-resistant Enterobacterales infections in Japan.

OBJECTIVES: The dissemination of difficult-to-treat carbapenem-resistant Enterobacterales (CRE) is of great concern. We clarified the risk factors underlying CRE infection mortality in Japan. METHODS: We conducted a retrospective, multicentre, observational cohort study of patients with CRE infections at 28 university hospitals from September 2014 to December 2016, using the Japanese National Surveillance criteria. Clinical information, including patient background, type of infection, antibiotic treatment, and treatment outcome, was collected. The carbapenemase genotype was determined using PCR sequencing. Multivariate analysis was performed to identify the risk factors for 28-day mortality. RESULTS: Among the 179 patients enrolled, 65 patients (36.3%) had bloodstream infections, with 37 (20.7%) infections occurring due to carbapenemase-producing Enterobacterales (CPE); all carbapenemases were of IMP-type (IMP-1: 32, IMP-6: 5). Two-thirds of CPE were identified as Enterobacter cloacae complex. Combination therapy was administered only in 46 patients (25.7%), and the 28-day mortality rate was 14.3%. Univariate analysis showed that solid metastatic cancer, Charlson Comorbidity Index ≥3, bloodstream infection, pneumonia, or empyema, central venous catheters, mechanical ventilation, and prior use of quinolones were significant risk factors for mortality. Multivariate analysis revealed that mechanical ventilation (OR: 6.71 [1.42-31.6], P = 0.016), solid metastatic cancers (OR: 5.63 [1.38-23.0], P = 0.016), and bloodstream infections (OR: 3.49 [1.02-12.0], P = 0.046) were independent risk factors for 28-day mortality. CONCLUSION: The significant risk factors for 28-day mortality in patients with CRE infections in Japan are mechanical ventilation, solid metastatic cancers, and bloodstream infections.

Dynamic changes in clinical characteristics and serotype distribution of invasive pneumococcal disease among adults in Japan after introduction of the pediatric 13-valent pneumococcal conjugate vaccine in 2013-2019.

Nationwide population-based surveillance for invasive pneumococcal disease (IPD) is being conducted in few Asian countries. We aimed to evaluate the clinical characteristics and serotype distribution among Japanese adult patients with IPD after introduction of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) in 2013. IPD surveillance was conducted among adults between 2013 and 2019, and 1,995 patients were analyzed by time period (early, 2013-2015; middle, 2016-2017; late, 2018-2019). We found that the period of 2018-2019 was independently associated with a lower risk of fatal outcome, compared with the period of 2013-2015. The proportion of those with serotype PCV13-nonPCV7 decreased significantly in patients aged 15-64 years and in those aged ≥ 65 years within 3 years after the introduction of pediatric PCV13. By contrast, the proportion of those with nonvaccine serotype increased significantly in those aged ≥ 65 years, but not in those aged 15-64 years. No significant change was found in the proportion of 23-valent polysaccharide pneumococcal vaccine (PPSV23)-nonPCV13 in both of adults aged 15-64 years and ≥ 65 years. The proportions of PCV15-, PCV20- and PCV24-covered serotypes were 38%, 56% and 58% in adult patients with IPD aged ≥ 65 years during the late period. Our data on the serotype distribution support an indirect effect from pediatric PCV13 use among adults, and afford a basis for estimates of protection against IPD by vaccination with newly developed PCVs in older adults in Japan.