Background Information on the incidence and clinical characteristics of respiratory syncytial virus (RSV) infections among adults remains limited in Japan. In this study, we aimed to clarify these aspects among adult outpatients at our institution. Methods This single-center, retrospective observational study included outpatients aged 18 years and older who presented with fever or respiratory symptoms and underwent multiplex PCR testing of nasopharyngeal specimens between April 2021 and March 2025. We assessed the RSV positive rate, underlying comorbidities, and hospitalization rate. For those with pneumonia, we analyzed their imaging findings and sputum culture results. Clinical characteristics were also compared between hospitalized and nonhospitalized patients aged 60 years or older. Results The overall positive rate of RSV infection over the 4 years was 2.3 %. Among individuals aged 60 years and older, the positive rate was 2.3 %. Of the 31 hospitalized cases, 29 were aged 60 years or older, accounting for 36.3 % of all RSV-positive patients in this age group. Age significantly differed between the hospitalized and nonhospitalized groups aged 60 and older. Among 24 patients with pneumonia who underwent computed tomography scans, 11 had positive sputum cultures. Consolidation was significantly more frequent in the 11 culture-positive cases than in the remaining 13 cases. Conclusions RSV infection accounted for 2.3 % of adult outpatient cases, with a notably high hospitalization rate in older adults. These findings highlight RSV as an important respiratory pathogen in older adults, underscoring the need to expand diagnostic testing and preventive strategies in this population.

Early identification of lung fibrosis remains difficult. In Japan, the serum biomarkers surfactant protein-D (SP-D) and KL-6 are commonly used to monitor interstitial lung diseases (ILD) in clinical practice, but their potential role in the early detection of lung fibrosis has not yet been fully clarified. Although chest radiography is also considered a possible tool for identifying subclinical pulmonary fibrosis, detecting early-stage disease remains challenging. A deep learning-based software, BMAX, was recently developed to identify fibrosing ILD on chest radiographs. Its capability to detect lung fibrosis in a health-checkup setting requires validation. Study participants were randomly recruited from individuals undergoing routine health examinations. All participants underwent chest radiography and serum SP-D and KL-6 testing. Those with elevated biomarker levels (≥ 110 ng/mL for SP-D and ≥ 500 IU/mL for KL-6) or radiographic abnormalities were advised to undergo further evaluation with chest computed tomography (CT). Lung fibrosis on CT was assessed independently by one pulmonologist and one thoracic radiologist. BMAX assigned a confidence score for lung fibrosis (ranging from 0 to 1) on each radiograph. In participants who underwent CT, the sensitivity and specificity of BMAX (using a confidence score > 0.3 as the threshold), SP-D, and KL-6 for detecting lung fibrosis were evaluated. Among the 2,751 individuals enrolled, 228 were recommended for CT, and 81 underwent the scan. Lung fibrosis was identified on chest CT in 8 of the 81 participants. The positivity rates for SP-D, KL-6, and BMAX (confidence score > 0.3) were 5.9

Determining the appropriate therapy for patients with interstitial pneumonia with autoimmune features (IPAF) is a clinical challenge. Although IPAF patients may benefit from immunomodulation, as seen in autoimmune interstitial lung diseases (ILDs), broad use of immunosuppression in idiopathic pulmonary fibrosis (IPF) increases risk without clear benefit. Recent data from our lab suggests that protein expression profiling in the lung microenvironment can identify molecular endotypes across idiopathic ILDs. This study leverages a supervised proteomics analysis of bronchoalveolar lavage fluid (BALF) across IPF and IPAF patients to identify unique protein expression profiles that distinguish these groups. We leveraged pre-treatment BALF samples collected at the Sapporo Medical University Hospital that were stored for a prospective research study. Label-free, quantitative proteomics was performed on BALF supernatant from each patient. Proteins were extracted and analyzed by LC-MS/MS using Thermo Fisher Orbitrap Ascend Tribrid mass spectrometer. Differential expression analysis included proteins with <25% missing values and applied significance thresholds of fold change ≥2 and p ≤ 0.05. Ingenuity Pathway Analysis (IPA) was used to explore pathways related to significantly different proteins. The cohort included 65 patients (IPAF n=33, IPF n=32). The IPAF group had a significantly higher proportion of women (53% vs. 18%, p<0.01) and a higher forced vital capacity percent predicted (94.5 ± 21.6% vs. 83.7 ± 15.5%, p=0.03) compared to the IPF group. No significant differences were observed in age (p=0.9), smoking status (p=0.1), pack years (p=0.2), diffusion capacity for carbon monoxide (p=0.2), or GAP scores (p=0.3). Of the 1293 proteins detected, 524 were expressed in at least 75% of samples in each group and included in the analysis. Significant differences in the lung microenvironment were found with 124 proteins showing increased expression and 75 proteins with decreased expression in IPAF compared to IPF. Pathway analysis of differentially expressed proteins revealed pathways associated with inflammatory processes such as complement cascade, acute phase response, and scavenger receptor signaling suggesting a distinct immune profile. Our findings support the paradigm that IPAF represents a crucial distinction within idiopathic ILDs as patients with IPAF exhibit increased expression of autoinflammatory proteins in the lung microenvironment. This heightened inflammatory profile supports the potential responsiveness of IPAF to immunomodulatory therapies, providing a foundation for more targeted, precision-based approaches to treatment. These results advocate for further research to identify and validate these potential protein markers in IPAF lung microenvironment, with the aim of refining therapeutic strategies and improving outcomes for IPAF patients.

OBJECTIVES:We aimed to compare the clinical features in patients with streptococcal toxic shock syndrome (STSS) caused by the three β-hemolytic streptococci (BHS): Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae subsp. equisimilis (SDSE). METHODS:Overall, 301 adult patients with STSS with S. pyogenes (32.9%), S. agalactiae (17.6%), and SDSE (49.5%) in Japan were enrolled between 2016 and 2021. Data were analyzed to identify differences in clinical characteristics among the three BHS. Bacterial isolates were examined for emm or capsular typing. RESULTS:The incidence of STSS with S. pyogenes declined during the COVID-19 pandemic, but STSS with S. agalactiae and SDSE did not. Patients with SDSE were the oldest (median age, 81 years; interquartile range, 70-88 years) followed by those with S. agalactiae (76 years; 67-85 years) and S. pyogenes (66 years; 58-78 years). The case fatality rates (CFRs) of STSS caused by the three BHS were not significantly different, ranging from 48-59%; however, the CFR significantly increased with age in patients with SDSE (P <0.05). CONCLUSIONS:The characteristics of STSS differed among the three BHS. Clinicians should be aware of poor outcomes in patients with STSS, and provide appropriate treatment at an early stage.

As the increase in infections due to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), monitoring of colonization in healthy population is becoming more significant. From nasal cavity of two preclinical medical students who were originally healthy and had neither foreign travel history nor contact with animals, methicillin-resistant S. aureus (MRSA) strains were isolated. For these MRSA, the genotypes, prevalence of virulence factors and antimicrobial resistance determinants were analyzed, along with antimicrobial susceptibility test. These strains were genotyped as (i) ST8-SCCmec-IVl, which was "CA-MRSA/J" clone, known as a unique Panton-Valentine leukocidin (PVL)-negative ST8 MRSA in Japan, and (ii) ST1930-SCCmec-IVa, which belonged to CC96, one of the livestock-associated MRSA, while being a rare type in humans (first detection in Japan). Both strains were susceptible to most antimicrobials, except for oxacillin, and continued to colonize the students for 1 year. These MRSA strains were successfully decolonized by the treatment with nasal ointment of mupirocin, and the eradication of ST8 MRSA strain was confirmed for at least 1 year. The present study revealed the persistent colonization of the rare CA-MRSA clones in healthy adults with unknown route of transmission, suggesting the importance to screen CA-MRSA and its decolonization in healthy individuals.

Standardized, one-size-fits-all COVID-19 booster schedules may be suboptimal due to individual variation in immune backgrounds, particularly prior infection, which induces robust hybrid immunity. This study estimated optimal booster timing by modeling antibody decay in relation to surrogate correlates of protection (CoP). In a prospective cohort of 177 Japanese healthcare workers, we longitudinally monitored anti-spike receptor-binding domain (S-RBD) antibody titers following BNT162b2 vaccination. Participants were stratified into SARS-CoV-2-naïve and previously infected groups. Mixed-effects models were developed to predict when antibody titers would decline below predefined CoP thresholds. The model estimated optimal booster timing after a two-dose primary series to be 3–5 months for naïve individuals and approximately one year for those with prior infection. Following a third dose, the estimated interval extended to 8–12 months for the naïve group and 1.5–2 years for the previously infected group. These substantial differences underscore the limitations of uniform booster schedules. Our findings provide a quantitative framework for personalized vaccination strategies based on individual antibody profiles and immune status, thereby optimizing protection.

Bacteria continually evolve. Previous studies have evaluated bacterial evolution in retrospect, but this approach is based on only speculation. Cohort studies are reliable but require a long duration. Additionally, identifying which genetic mutations that have emerged during bacterial evolution possess functions of interest to researchers is an exceptionally challenging task. Here, we establish a Rapid and Integrated Bacterial Evolution Analysis (RIBEA) based on serial passaging experiments using hypermutable strains, whole-genome and transposon-directed sequencing, and in vivo evaluations to monitor bacterial evolution in a cohort for one month. RIBEA reveals bacterial factors contributing to serum and antimicrobial resistance by identifying gene mutations that occurred during evolution in the major respiratory pathogen Klebsiella pneumoniae. RIBEA also enables the evaluation of the risk for the progression and the development of invasive ability from the lung to blood and antimicrobial resistance. Our results demonstrate that RIBEA enables the observation of bacterial evolution and the prediction and identification of clinically relevant high-risk bacterial strains, clarifying the associated pathogenicity and the development of antimicrobial resistance at genetic mutation level.

Background: Interstitial lung disease (ILD) is characterized by pulmonary inflammation and fibrosis associated with persistent and refractory cough that significantly hinders quality of life. Conventional treatments for ILD-associated cough have shown limited efficacy, necessitating alternative therapeutic approaches. Gefapixant, a P2X3 receptor antagonist, can potentially alleviate chronic cough by inhibiting the ATP-mediated activation of sensory C-fibers, but its efficacy in ILD-associated cough remains unclear. This study observed the effects of gefapixant on ILD-associated refractory chronic cough. Methods: This prospective study enrolled patients with ILD-associated refractory chronic cough who received gefapixant at Sapporo Medical University Hospital between July 2022 and November 2023. Cough frequency, Leicester Cough Questionnaire (LCQ) score, cough severity visual analog scale (Cough VAS), and taste VAS were evaluated at baseline and at 2, 4, and 8 weeks after gefapixant administration. Results: Six patients completed the study. Their ILD subtypes included idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), and connective tissue disease-associated ILDs (CTD-ILDs). After 8 weeks, the cough frequency decreased from 88.5 to 44.3 episodes per 30 min, LCQ scores increased from 8.3 to 13.6, and cough VAS scores decreased from 75.8 to 40.2. However, statistical significance was not reached due to high interindividual variability, with gefapixant being effective in some and ineffective in others. The most common adverse event was taste disorder, leading to discontinuation in one patient, but symptoms tended to lessen over the course of treatment. Conclusions: Gefapixant appears to be effective in reducing refractory cough related to ILD, although these results were not statistically significant because its effectivity widely varied across individuals. Further investigation is needed to identify patient subgroups with the greatest potential for treatment responsiveness.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival. Methods We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan–Meier method and the log-rank test. Results Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at − 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs. Conclusions In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

Background:Idiopathic interstitial pneumonias (IIPs), such as idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features, present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Methods:Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared with controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles that were then analysed to predict survival outcomes and investigate associated pathways. Results:Proteomic profiling successfully differentiated IIP from controls. k-means clustering based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology index (concordance index 0.794 versus 0.709). The cluster with the worst prognosis featured decreased inflammatory signalling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B-cell-mediated immunity. Conclusions:The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalised treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

IntroductionPatients with COVID-19 have dysbiosis of the intestinal microbiota with altered metabolites in the stool. However, it remains unclear whether the differences among SARS-CoV-2 variants lead to differences in intestinal microbiota and metabolites. Thus, we compared the microbiome and metabolome changes for each SARS-CoV-2 variant in patients with COVID-19.Materials and methodsWe conducted a multicenter observational study of patients with COVID-19 and performed fecal microbiome, metabolome, and calprotectin analyses and compared the results among the different SARS-CoV-2 variants.ResultsTwenty-one patients with COVID-19 were enrolled and stratified according to the SARS-CoV-2 strain: six with the Alpha, 10 with the Delta, and five with the Omicron variant. Fecal microbiome analysis showed that α-diversity was reduced in the order of the Omicron, Delta, and Alpha variants (p = 0.07). Linear discriminant analysis revealed differences in the abundance of short-chain fatty acid-producing gut microbiota for each SARS-CoV-2 variant. Fecal metabolome analysis showed that the Omicron and Delta variants had markedly reduced propionic and lactic acid levels compared to the Alpha strain (p < 0.05).ConclusionThe intestinal microbiota of patients with COVID-19 varies depending on the SARS-CoV-2 variant. Dysbiosis of the intestinal microbiota due to differences in SARS-CoV-2 variants causes a decrease in intestinal short-chain fatty acids.

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 COVID19 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. (c) 2024 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Abstract Background/Introduction Coronary microvascular dysfunction (CMD) is a condition in which the distal microvasculature is compromised, resulting in inadequate blood flow to the subsequent arteries and myocardial ischemia. Index of microvascular resistance (IMR), which can quantify CMD, is becoming the standard for the diagnosis of CMD. Patients with CMD have a 4 to 5 times greater risk of cardiovascular death and myocardial infarction than patients without heart disease and similar cardiovascular risk. Early diagnosis of CMD may reduce cardiovascular risk and improve quality of life with therapeutic intervention. Pericoronary adipose tissue mean attenuation (PCATMA) is an indirect measure of adipocyte size and lipid content around coronary artery, reflecting inflammation status. Previous studies have shown that both PCATMA and CMD are associated with the functional severity of coronary artery disease, but no study has yet examined the relationship between PCATMA and CMD. Purpose We conducted a study comparing PCATMA in patients with and without CMD. Methods Between September 2022 and October 2023, 25 patients without significant stenosis (<50% stenosis) who underwent IMR measurement on invasive coronary angiography and coronary CT angiography (CCTA) were included. CMD was diagnosed when the IMR exceeded 25 as measured by a pressure wire inserted into the left anterior descending artery after invasive coronary angiography had excluded significant stenosis. PCATMA was measured on CCTA using the average of the values of right coronary artery, left anterior descending artery, and left circumflex artery. Multivariable logistic regression analysis with stepwise forward selection was used to assess predictors for patients with abnormal IMR. The following variables were included for adjustment: PCATMA, age, sex, diabetes, dyslipidemia, hypertension. Results The mean age of 25 patients in this study was 63 years, 48.0% were female, 29.2% had diabetes, 62.5% had dyslipidemia and 66.7% had hypertension. PCATMA was significantly higher in patients with abnormal IMR (IMR>25) (-79.6 [IQR: -82.1, -74.6] HU vs -86.3 [IQR: -89.8, -78.9] HU, p = 0.043). Multivariate logistic regression analysis demonstrated that PCATMA remained an independent predictor of patients with abnormal IMR (OR 1.27 [95% CI: 1.05–1.65], p = 0.039). Optimal cut-off value of PCATMA for predicting patients with abnormal IMR by Youden index was -82.1 HU (AUC = 0.75 [95% CI: 0.55-0.95]). Conclusions In patients without significant coronary artery stenosis, PCATMA on CCTA may be used to predict the patients with CMD, noninvasively.