Assessment of clinical relevance of antigen improves diagnostic accuracy of hypersensitivity pneumonitis.

BACKGROUND: Exposure assessment is integral to the diagnosis of hypersensitivity pneumonitis (HP). Although the clinical relevance of exposed antigens is essential for the assessment, many of the previous guidelines or reports have only evaluated simple exposure histories or immunological tests. To overcome this problem, the Exposure Assessment Form (EAF) was developed as an assessment tool for classifying the exposure grade from G0 to G4. The EAF was modified from the description in the Japanese clinical practice guide 2022 for HP published by the Japanese Respiratory Society. METHODS: One hundred and seventy-two consecutive patients with interstitial lung disease who underwent multidisciplinary discussion (MDD) at our hospital were retrospectively examined. We assessed whether the use of the EAF improved the diagnostic performance of the international guideline of HP. We also evaluated whether the exposure grade affected the prognosis of HP. RESULTS: Even when a HP diagnosis was made with a confidence of 70% or higher according to the international guideline, less than half of these cases resulted in a final diagnosis of HP when the exposure grades were lower than G3. When the result of the EAF was integrated into the exposure definition of the international guideline, the specificity of the diagnostic performance improved, while sensitivity was maintained. Furthermore, HP patients with an exposure grade of G3 or higher showed a tendency to take a longer time to initiate medication. CONCLUSIONS: This is the first study to evaluate the clinical relevance of possible antigens using the EAF. Assessing the exposure grade prevents overdiagnosis and improves the diagnostic performance of the international guideline.

Interplay between social isolation and loneliness and chronic systemic inflammation during the COVID-19 pandemic in Japan: Results from U-CORONA study.

In the face of the global coronavirus disease 2019 (COVID-19) pandemic, billions of people were forced to stay at home due to the implementation of social distancing and lockdown policies. As a result, individuals lost their social relationships, leading to social isolation and loneliness. Both social isolation and loneliness are major risk factors for poor physical and mental health status through enhanced chronic inflammation; however, there might be an interplay between social isolation and loneliness on the association with chronic inflammation. We aimed to clarify the link between social relationships and inflammation in the context of the COVID-19 pandemic by distinguishing whether social isolation only, loneliness only, or both were associated with chronic inflammation markers among community-dwelling adults. The data of 624 people (aged 18-92 years, mean 51.4) from the Utsunomiya COVID-19 seROprevalence Neighborhood Association (U-CORONA) study, which targeted randomly sampled households in Utsunomiya city, Japan, were analyzed. Social isolation was assessed as a structural social network by asking the number of social roles they have on a daily basis. Loneliness was measured with the UCLA loneliness scale. As chronic inflammation biomarkers, neutrophil-to-lymphocyte ratio (NLR) and the concentration of high-sensitivity C-reactive protein (CRP) were measured. Generalized estimating equations method was employed to take into account the correlations within households. Isolated-Lonely condition (i.e., being both socially isolated and feeling lonely) was associated with higher NLR among men (B = 0.141, 95%CI = -0.01 to 0.29). Interestingly, Nonisolated-Lonely condition (i.e., not socially isolated but feeling lonely) was associated with lower CRP among women (B = -0.462, 95%CI = -0.82 to -0.10) and among the working-age population (B = -0.495, 95%CI = -0.76 to -0.23). In conclusion, being both socially isolated and feeling lonely was associated with chronic inflammation. Assessing both social isolation and loneliness is critical for proper interventions to mitigate the impact of poor social relationships on health, especially in the context of the COVID-19 pandemic.

Analysis of synergy between beta-lactams and anti-methicillin-resistant Staphylococcus aureus agents from the standpoint of strain characteristics and binding action.

In light of the increasing number of clinical cases resistant to traditional monotherapies and the lack of novel antimicrobial agents, combination therapy is an appealing solution for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we evaluated the efficacy of anti-MRSA agents, such as vancomycin (VAN), daptomycin (DAP), and linezolid (LZD), in conjunction with 13 beta-lactams and non-beta-lactams. We assessed the in vitro activities of the various combinations against 40 MRSA strains based on the maximum synergistic effect (MSE), an index calculated from the MIC change with a combination agent. Nearly all the anti-MRSA agents, which were combined with beta-lactams as well as VAN and DAP, showed a synergistic effect with arbekacin. VAN also exhibited varying degrees of synergy depending on the type of beta-lactam, whereas DAP and LZD showed similar synergy with different beta-lactams. These effects were confirmed by antibiotic kill curves, except for the apparent interaction between LZD and beta-lactams. The MSE results were analyzed according to strain characteristics including susceptibility to combination agents, staphylococcal cassette chromosome mec type, and presence of the blaZ gene; however, no obvious correlations were observed. In a fluorescence binding assay, the fluorescence intensity of boron-dipyrromethene (BODIPY)-VAN decreased, whereas that of BODIPY-DAP increased in combination with a beta-lactam agent. These findings suggest that beta-lactam combinations are promising treatment options for MRSA infections and that the type of beta-lactam combined with VAN is important for the synergistic effect.

Changes in the Genotypic Characteristics of Community-Acquired Methicillin-Resistant Staphylococcus aureus Collected in 244 Medical Facilities in Japan between 2010 and 2018: a Nationwide Surveillance.

Although community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged worldwide, no nationwide CA-MRSA surveillance has been conducted in Japan to determine the changes in its molecular characteristics over time. We aimed to characterize the molecular epidemiology of Panton-Valentine leucocidin (PVL)-positive CA-MRSA strains collected from across Japan in the past decade. We isolated 1,770 MRSA strains from the skin and pus samples of outpatients of 244 medical facilities in 31 prefectures between 2010 and 2018 (2010, 2012, 2014, 2016, and 2018). Regions, hospitals, and periods in which strains were isolated and patient age group and sex were tabulated. Staphylococcal cassette chromosome mec (SCCmec) typing, detection of virulence factor genes, and antimicrobial susceptibility testing were performed. Whole-genome analysis was performed for the PVL-positive strains isolated in 2018. All strains harbored the mecA gene. Compared to that in 2010, the percentage of SCCmec type IV increased in 2018, with a corresponding increase in the proportion of PVL-positive strains (10% to 26%). Of the isolates obtained in 2018, clonal complex 8 (CC8) was dominant among PVL-positive strains. Core-genome single-nucleotide polymorphism analysis, using whole-genome sequencing, suggested that the CC8 PVL-positive strains spread throughout Japan over the last decade. Furthermore, a unique ST22 clone carrying both the PVL- and toxic shock syndrome toxin-1-encoding genes has emerged. We demonstrated that the molecular epidemiology of CA-MRSA in Japan differs from that in Europe and the United States; thus, it is crucial to monitor the trend of changes in CA-MRSA characteristics in Japan. IMPORTANCE Community-associated MRSA, which is a multidrug-resistant organism and can cause infections in otherwise-healthy individuals, has become a global problem. This paper describes a nationwide surveillance conducted in Japan to investigate changes in molecular epidemiological characteristics of CA-MRSA over the past decade and provides a detailed review of the characteristics of Panton-Valentine leucocidin (PVL)-positive strains isolated in 2018. Although CA-MRSA is rare in Japan to date, we found that the isolation of PVL-positive strains has been increasing over the past decade. In particular, the PVL-positive strains wherein CC8 was dominant exhibited high interstrain similarity, suggesting that a limited number of clones have spread over the past decade. Furthermore, a unique ST22 clone carrying both PVL-encoding and toxic shock syndrome toxin-1-encoding genes has emerged. This study shows that various changes can be observed when molecular epidemiological analysis, combined with next-generation sequencing, is conducted over a long period.

Validity of Clinical Symptoms Score to Discriminate Patients with COVID-19 from Common Cold Out-Patients in General Practitioner Clinics in Japan.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has spread worldwide, including Japan. However, little is known about the clinical symptoms which discriminate between COVID-19 and non-COVID-19 among outpatients in general practitioner clinics, which is important for efficient case detection. The aim of this study was to investigate the clinical symptoms to discriminate between COVID-19 and non-COVID-19 cases among outpatients in general practitioner clinics during the second wave of the COVID-19 pandemic in Japan in August 2020. METHODS: The records of 360 patients who visited a clinic with suspicion of infectious disease and underwent COVID-19 PCR test between 1 and 14 August 2020 were used. The patients filled out a questionnaire on possible clinical symptoms and transmission routes. Multivariate logistic regression was used to investigate the association between clinical symptoms and COVID-19 status. RESULTS: COVID-19-positive patients were 17 (4.7%). Multiple logistic regression analyses showed that anosmia (odds ratio (OR), 25.94 95% confidence interval (CI), 7.15-94.14; p < 0.001), headache (OR, 3.31 95% confidence interval (CI), 0.98-11.20; p = 0.054), sputum production (OR, 3.32 CI, 1.01-10.90; p = 0.048) and history of visiting an izakaya or bar (OR, 4.23 CI, 0.99-18.03; p = 0.051) were marginally significantly associated withbeing COVID-19 positive. This model showed moderate predictive power (area under receiver operating characteristic curve = 0.870 CI, 0.761 to 0.971). CONCLUSIONS: We found that anosmia, headache, sputum production, history of visiting an izakaya or bar were associated with COVID-19, which can be used to detect patients with COVID-19 in out-patient clinics in Japan. The findings of this study need to be verified in other clinics and hospitals in Japan and other countries with universal healthcare coverages.

Seroprevalence of SARS-CoV-2 in Utsunomiya City, Greater Tokyo, after the first pandemic in 2020.

BACKGROUND: A seroepidemiological study was conducted on a random sample of households in Utsunomiya City, Tochigi Prefecture, Greater Tokyo, Japan, to assess the seroprevalence of SARS-CoV-2. METHODS: The level of IgG antibodies in the blood of the recruited subjects was assessed using chemiluminescence immunoassay analysis. In addition, the population-based prevalence of SARS-CoV-2 was estimated. RESULTS: Three positive afebrile cases were confirmed. The estimated unweighted prevalence and weighted prevalence of SARS-CoV-2 infection were 0.40% and 1.23%, respectively. CONCLUSIONS: This study suggests that the prevalence of SARS-CoV-2 may have been underestimated. Wider testing strategies may lead to revealing more SARS-CoV-2 cases.

Association between Social Integration and Face Mask Use Behavior during the SARS-CoV-2 Pandemic in Japan: Results from U-CORONA Study.

Face mask use is a critical behavior to prevent the spread of SARS-CoV-2. We aimed to evaluate the association between social integration and face mask use during the COVID-19 pandemic in a random sample of households in Utsunomiya City, Greater Tokyo, Japan. Data included 645 adults in the Utsunomiya COVID-19 seROprevalence Neighborhood Association (U-CORONA) study, which was conducted after the first wave of the pandemic, between 14 June 2020 and 5 July 2020, in Utsunomiya City. Social integration before the pandemic was assessed by counting the number of social roles, based on the Cohen's social network index. Face mask use before and during the pandemic was assessed by questionnaire, and participants were categorized into consistent mask users, new users, and current non-users. Multinomial logistic regression analysis was used to examine the association between lower social integration score and face mask use. To account for possible differential non-response bias, non-response weights were used. Of the 645 participants, 172 (26.7%) were consistent mask users and 460 (71.3%) were new users, while 13 (2.0%) were current non-users. Lower social integration level was positively associated with non-users (RRR: 1.76, 95% CI: 1.10, 2.82). Social integration may be important to promote face mask use.

Morphological and Biological Characteristics of Staphylococcus aureus Biofilm Formed in the Presence of Plasma.

Characteristics of Staphylococcus aureus infections include biofilm formation, leading to the spread of bacteria to the bloodstream causing sepsis and metastatic infections. In particular, in methicillin-resistant S. aureus (MRSA) infections, biofilm formation critically hampers treatment and causes poor prognosis. We explored the biofilm formation of MRSA in the presence or absence of plasma and compared morphological characteristics, accumulation of antibiotics, and resistance to bactericidal activity, using continuous optimizing confocal reflection microscopy. Addition of plasma significantly increased biofilm formation, which is characterized by an uneven surface and aggregation of bacteria (hereafter plasma biofilm). The flow-cell system, which enabled a continuous supply of plasma, accelerated biofilm formation in both the tested strains of MRSA (BAA1556 and N315). Accumulation of green fluorescence-labeled vancomycin was observed within 5 minutes in the plasma-free biofilm, but not in the plasma biofilm. Delay of accumulation was also observed for daptomycin in plasma biofilm. Plasma biofilm bacteria were more resistant to anti-MRSA antibiotics than plasma-free biofilm bacteria. These data demonstrate that the plasma biofilm of S. aureus is substantially different from the plasma-free biofilm. Plasma biofilm, especially in the flow-cell system, could be a clinically relevant model to analyze MRSA infections and treatment.

Evidence of latent molecular diversity determining the virulence of community-associated MRSA USA300 clones in mice.

INTRODUCTION: The USA300 clone of community-associated MRSA is reported to be hypervirulent and epidemic in the United States. This clone causes a variety of diseases from lethal pneumonia to mild skin infections. We hypothesized that evolutionary diversity may exist among USA300 clones, which may link virulence traits with host responses and mortality rates. METHODS: USA300 isolates from severe pneumonia (IP) and skin infection (IS) were characterized by pulsed-field gel electrophoresis (PFGE) and next-generation sequencing. Their virulence traits and host responses were compared in a lung infection model. RESULTS: The two USA300 isolates were found to be identical in genomic analysis. Robust IL-6 production, aggregation of bacteria, and hemorrhaging were observed in IP-infected lungs, which were associated with a higher rate of mortality than that observed with strain IS. Few neutrophils were detected in the lungs infected with strain IP, even at high bacterial loads. Massive production of α-toxin and coagulase were evident during the early phase of IP infection, and robust gene expression of hla (α-toxin) and lukS-PV (Panton-Valentine leukocidin), but not coa, agrA, or rnaIII, was confirmed in vitro. Strain IP also induced strong hemolysis in red blood cells. CONCLUSIONS: The present data demonstrated latent diversity in the virulence of USA300 clones. Unknown regulatory mechanisms, probably involving a host factor(s) as a trigger, may govern the virulence expression and resultant high mortality in certain sub-clones of USA300.

Penicilliosis marneffei complicated with interstitial pneumonia.

A 71-year-old man with interstitial pneumonia was hospitalized due to a pulmonary infection. He had been living in Thailand and had returned to Japan three months earlier. Antibiotic therapy initially cleared the infection; however, the patient's condition relapsed. Pseudomonas aeruginosa and Penicillium sp. were both detected in sputum and bronchial lavage fluid cultures and Penicillium sp. was identified to be P. marneffei. The infiltration observed on chest radiographs improved following treatment with itraconazole and tazobactam/piperacillin, and no relapse occurred. We herein report the first case of a non-HIV patient with P. marneffei infection in Japan.

Bilateral pleural fluid caused by a pancreaticopleural fistula requiring surgical treatment.

A 53-year-old man developed bilateral pleural effusion with respiratory failure. The amylase level in the pleural effusion was elevated. He had neither abdominal symptoms nor abdominal physical findings. Abdominal computed tomography (CT) also showed no abnormalities. Magnetic resonance cholangiopancreatography (MRCP) was non-diagnostic, but endoscopic retrograde cholangiopancreatography (ERCP) and subsequent CT showed a fistula connecting the pancreatic duct with the right pleural cavity. The pleural effusion was refractory to drug therapy, leading to the need for surgical intervention. The pathological findings revealed chronic pancreatitis without pseudocysts. The elevated pancreatic amylase in the pleural effusion offered an important clue to the correct diagnosis.