The potential public health impact of the respiratory syncytial virus prefusion F protein vaccine in people aged ≥60 years in Japan: results of a Markov model analysis.

BACKGROUND: Respiratory syncytial virus (RSV), a common respiratory pathogen, can lead to severe symptoms, especially in older adults (OA). A recently developed RSV prefusion F protein (RSVPreF3 OA) vaccine confers high protection against RSV lower respiratory tract disease (LRTD) over two full RSV seasons. The aim of this study was to assess the potential public health impact of RSVPreF3 OA vaccination in the Japanese OA population. RESEARCH DESIGN AND METHODS: A static Markov model was used to estimate the number of symptomatic RSV cases, hospitalizations and deaths in the Japanese population aged ≥ 60 years over a 3-year time horizon. Japan-specific RSV epidemiology and healthcare resource use parameters were used; vaccine efficacy was derived from a phase 3 randomized study (AReSVi-006, NCT04886596). Vaccination coverage was set to 50%. RESULTS: Without vaccination, >5 million RSV acute respiratory illness (ARI) would occur (2.5 million LRTD and 2.8 million upper respiratory tract infections) leading to ~ 3.5 million outpatient visits, >534,000 hospitalizations and ~ 25,500 RSV-related deaths over 3 years. Vaccination could prevent > 1 million RSV-ARI cases, 728,000 outpatient visits, 143,000 hospitalizations and 6,840 RSV-related deaths. CONCLUSIONS: RSVPreF3 OA vaccination is projected to have a substantial public health impact by reducing RSV-related morbidity and mortality in the OA population.

Respiratory syncytial virus (RSV) is one of the most frequent disease-causing agents that leads to common cold symptoms. In older adults, infection with RSV can result in severe complications including bronchitis/bronchiolitis, lung infection (pneumonia) and in rare cases death. Older people and people with chronic heart or lung disease are more likely to experience complications. We estimated that more than 5 million RSV cases occur in older adults (≥60 years) over a three-year period (1.8 million over one year). Many older adults (≥60 years) will see their treating physician because of an acute RSV infection or will be hospitalized.Recently, a vaccine has been registered which protects older adults against RSV disease: the RSV prefusion F protein Older Adult (RSVPreF3 OA) vaccine. Vaccination with RSVPreF3 OA could prevent RSV infection in the older adult population and reduce the number of outpatient visits and hospitalizations; the impact is particularly high in Japan, where 35% of people are 60 years or older. We used a public health impact model to estimate how many RSV cases, hospitalizations and deaths could be prevented if 50% of people aged ≥ 60 years received the RSVPreF3 OA vaccine: We found that the vaccine could prevent about 1 million RSV infections, more than 728,000 outpatient visits, approximately 143,000 hospitalizations and 6,840 RSV-related deaths over a three-year period.Adding RSVPreF3 OA vaccine to the national immunization program in Japan could protect older adults against RSV disease and reduce the burden on patients and the healthcare system.

Listeria monocytogenes bacteremia developed during treatment of COVID-19.

Listeria monocytogenes is an important pathogen in older patients and immunosuppressed patients, often causing bacteremia. Complications resulting from infections other than COVID-19 must also be considered during COVID-19 treatment.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019-2020: General view of the pathogens' antibacterial susceptibility.

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were ß-lactamase-producing ampicillin resistant and ß-lactamase-negative ampicillin resistant, respectively. Extended-spectrum ß-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-ß-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

Targeted Literature Review of the Burden of Respiratory Syncytial Infection among High-Risk and Elderly Patients in Asia Pacific Region.

INTRODUCTION: The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. RESULTS: A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78% (71.43-88.12%) in Japan, 48.00% (3.64-80.00%) in China, 41.67% (33.33-50.00%) in Taiwan, 38.61% in Australia, and 28.57% (22.76-33.33%) in South Korea. RSV was associated with a high clinical burden on those patients with comorbidities such as asthma and chronic obstructive pulmonary disease. In China, inpatients with ARI showed a significantly higher rate of RSV-related hospitalization than outpatients (13.22% versus 4.08%, p < 0.01). The median length of hospital stay among elderly patients with RSV was longest in Japan (30 days) and shortest in China (7 days). Mortality data varied by region with some studies reporting rates as high as 12.00% (9/75) in hospitalized elderly patients. Finally, data on the economic burden was only available for South Korea, with the median cost of a medical admission for an elderly patient with RSV being US dollar (USD) 2933. CONCLUSION: RSV infection is a major source of disease burden among elderly patients, especially in regions with aging populations. It also complicates the management of those with underlying diseases. Appropriate prevention strategies are required to reduce the burden among the adult, especially the elderly, population. Data gaps regarding economic burden of RSV infection in the Asia Pacific region indicates the need for further research to increase our understanding on the burden of this disease in this region.

Molecular Evolution of the Pseudomonas aeruginosa DNA Gyrase gyrA Gene.

DNA gyrase plays important roles in genome replication in various bacteria, including Pseudomonasaeruginosa. The gyrA gene encodes the gyrase subunit A protein (GyrA). Mutations in GyrA are associated with resistance to quinolone-based antibiotics. We performed a detailed molecular evolutionary analyses of the gyrA gene and associated resistance to the quinolone drug, ciprofloxacin, using bioinformatics techniques. We produced an evolutionary phylogenetic tree using the Bayesian Markov Chain Monte Carlo (MCMC) method. This tree indicated that a common ancestor of the gene was present over 760 years ago, and the offspring formed multiple clusters. Quinolone drug-resistance-associated amino-acid substitutions in GyrA, including T83I and D87N, emerged after the drug was used clinically. These substitutions appeared to be positive selection sites. The molecular affinity between ciprofloxacin and the GyrA protein containing T83I and/or D87N decreased significantly compared to that between the drug and GyrA protein, with no substitutions. The rate of evolution of the gene before quinolone drugs were first used in the clinic, in 1962, was significantly lower than that after the drug was used. These results suggest that the gyrA gene evolved to permit the bacterium to overcome quinolone treatment.

Effectiveness of neutralizing antibody cocktail in hemodialysis patients: a case series of 20 patients treated with or without REGN-COV2.

The number of patients with SARS-CoV-2 infection continues to increase, and it has become a global pandemic. Although there is an urgent need to establish an effective treatment, the medication available for dialysis patients has been limited. An antibody cocktail containing two SARS-CoV-2-neutrarizing antibodies, REGN-COV2 has been granted special approval for COVID-19 in Japan, since July 2021, and this intravenous preparation can be used for dialysis patients. At our hospital, we had 22 hemodialysis patients with COVID-19, and five of them were treated with REGN-COV2. On admission, four of the five patients had moderate disease (pneumonia but O2 inhalation) and one patient had mild disease (not having pneumonia). The mean duration of hospitalization treated with REGN-COV2 was 10.2 ± 2.86 days (mean ± SD), which was less than half, compared to patients untreated of similar severity on admission (22.12 ± 15.5). The time to fever resolution was average 7 days, and no cases progressed to severe illness or death. Among these patients, no obvious adverse reactions were shown. Although more studies with a larger number of patients could be needed for a rigorous evaluation of the effect, our result suggests that REGN-COV2 may be safe and having the possibilities in preventing severe disease in hemodialysis patients. Given the difficulty in securing inpatient beds tend to be in short supply, the strategy combined with neutralizing antibody could be beneficial for end-stage kidney disease (ESKD) patients with hemodialysis who are at high risk of severe disease.

Detailed Analyses of Molecular Interactions between Favipiravir and RNA Viruses In Silico.

There are currently no antiviral agents for human metapneumovirus (HMPV), respiratory syncytial virus (RSV), mumps virus (MuV), or measles virus (MeV). Favipiravir has been developed as an anti-influenza agent, and this agent may be effective against these viruses in vitro. However, the molecular mechanisms through which the agent affects virus replication remain to be fully elucidated. Thus, to clarify the detailed molecular interactions between favipiravir and the RNA-dependent RNA polymerase (RdRp) of HMPV, RSV, MuV, MeV, and influenza virus, we performed in silico studies using authentic bioinformatics technologies. As a result, we found that the active form of favipiravir (favipiravir ribofuranosyl-5'-triphosphate [F-RTP]) can bind to the RdRp active sites of HMPV, RSV, MuV, and MeV. The aspartic acid residue of RdRp active sites was involved in the interaction. Moreover, F-RTP was incorporated into the growing viral RNA chain in the presence of nucleotide triphosphate and magnesium ions. The results suggested that favipiravir shows two distinct mechanisms in various viruses: RdRp active site inhibition and/or genome replication inhibition.

Occurrence and disease burden of respiratory syncytial virus and other respiratory pathogens in adults aged ≥65 years in community: A prospective cohort study in Japan.

BACKGROUND: The frequency and clinical profile of respiratory syncytial virus (RSV)-acute respiratory disease (ARD) in older adults in Japan has not been well-characterized. METHODS: This was a multicenter prospective observational cohort study to evaluate the occurrence rate of ARD in 1000 older adult participants (≥65 years) for 52 weeks during the 2019 to 2020 season. A multiplex polymerase chain reaction panel was used for pathogen detection in nasopharyngeal swab from participants diagnosed with ARD. Symptoms and impact of ARD was assessed using the Respiratory Infection Intensity and Impact Questionnaire (RiiQ™). The study was registered at UMIN (https://www.umin.ac.jp/ctr/): UMIN000037891. RESULTS: RSV-ARD was detected in 24/1000 (2.4%) participants and RSV-lower respiratory tract disease in 8/1000 (0.8%) participants. The median duration of RSV-ARD was 18 days. All 24 participants had utilized the medical services of outpatient visits and only 1 (4.2%) participant was hospitalized for RSV-ARD. The most common viruses other than RSV that caused ARD (detected in >10 participants) were human rhinovirus/enterovirus, parainfluenza 3, coronavirus OC43, human metapneumovirus, and influenza A/H1. The most frequent symptoms of RSV-ARD were cough, sore throat, nasal congestion, and expectoration. CONCLUSIONS: RSV was reported as a major pathogen for respiratory infections in older adults in Japan.

Efficacy and Safety of Weekly Ultraviolet Germicidal Irradiation for the Reuse of N95 Filtering Respirators.

Background During the ongoing coronavirus disease (COVID-19) pandemic, N95 filtering facepiece respirators (N95 respirators) are in short supply in many countries. Considering this, the Centers for Disease Control and Prevention suggested reusing N95 respirators and recommended the use of ultraviolet germicidal irradiation (UVGI) for sterilizing the respirators. However, only a few reports have described UVGI protocols for sterilizing the N95 respirators for reuse. Therefore, in this study, we aimed to develop and evaluate a novel method for the reuse of N95 respirators after sterilization by UVGI. Methods Before conducting the study, the function of N95 respirators after multiple UVGI with a total dose of up to 10 J (1 J/cm2 or more per dose) was assessed by measuring the particle collection efficiency and ventilation resistance. The participants used N95 respirators during work if they passed the fit test. After use, the respirators were sterilized using UVGI (1 J/cm2) and stored in a breathable paper bag for a week. The procedure was repeated up to three times after confirming the successful results of the fit tests. Results The particle collection efficiency without UVGI was 96.7%, while those after one, five, and 10 cycles of UGVI were 96.8%, 97.2%, and 97.2%, respectively. Ventilation resistance without UVGI was 42 Pa, and 43 Pa, 42 Pa, and 41 Pa after one, five, and 10 cycles of UVGI, respectively, which satisfied the Japanese national certification standard DS2. All 43 participants passed the fit test before the first reuse, and 39 participants (90.7%) completed the entire study protocol. The results of this study showed that N95 respirators could be used safely after repeated UVGI treatment. Conclusions This study developed a novel method for reusing the N95 respirators. A few cycles of UV radiation N95 masks retain their functionalities and can be reused with proper UVGI.

Clinical Surveillance of Candidemia at Our Hospital.

Treatment of Candidemia has become increasingly complicated as more and more non-albicans Candida species are being isolated in recent years.We launched an investigation of the species, the MIC value, and the state of administration of antifungal drugs for all the cases with Candida spp. confirmed by blood cultures for the 7-year period from 2012 to 2018 at our hospital. In total, 192 cases were found and 206 strains of Candida species were isolated. Overall, 49.5% of the 206 isolated strains were Candida albicans (102 strains), followed by Candida glabrata (40 strains, 19.4%), and Candida parapsilosis (38 strains, 18.4%). The most frequently used antifungal drug for the initial dose was MCFG (120 cases, 59.2%), while the most frequently switched antifungal agent was L-AMB. Cases with an inappropriate end-of-treatment time represented 58.7% of all the cases.We investigated the Candidemia situation at our hospital for a period of seven years. We believe that it is important for medical institutions to gather detailed data on candidemia at their own hospitals. Likewise, the hospital's Infection Control Team/Antimicrobial Stewardship Team should inform the physicians-in-charge about the appropriate diagnosis and treatment based on the data obtained.

Reusing N95 Respirators at Weekly Intervals During the COVID-19 Pandemic.

Objectives A surge in the demand for N95 filtering facepiece respirators (N95 respirators) due to the worldwide spread of coronavirus disease 2019 (COVID-19) has resulted in a global shortage of N95 respirators. This study was performed to evaluate the clinical validation of reusing N95 respirators following stringent fit test protocols. Methods After passing the first fit test, we prospectively enrolled healthcare workers who used N95 respirators for two hours per shift (duckbill-shaped HPR-R/HPR-S, dome-shaped Hi-Luck 350, and three-panel flat-fold respirators 9211) in settings such as bronchoscopy or respiratory specimen sampling. These procedures were repeated for up to three weeks, with the fit test performed every week. At each timing of the fit test, we used a fit-testing system for quantitatively evaluating particle leakage. Results A total of 41 participants were enrolled, including 24 doctors and 17 nurses, of whom 25 were women. The pass rate of successful reuse over three observational weeks using four fit tests was 85.4%, which was comparable among the three types of N95 respirators. Six (14.6%) participants failed the fit test, while no participants dropped out of protocol due to either N95 respirator damage or contamination. Among the six dropped out participants, four reused the duckbill-shaped type and two reused the three-panel flat-fold type. All participants using the cup-shaped type mask successfully completed the protocol. However, the passing rate of this study was not statistically different among the three types of N95 respirators. Conclusion This study shows that N95 respirators can be safely reused for a short period irrespective of their type, as quantitatively assessed by fit tests.

Ruxolitinib inhibits poly(I:C) and type 2 cytokines-induced CCL5 production in bronchial epithelial cells: A potential therapeutic agent for severe eosinophilic asthma.

RATIONALE: Severe eosinophilic asthma is characterized by airway eosinophilia and corticosteroid-resistance, commonly overlapping with type 2 inflammation. It has been reported that chemokine (C-C motif) ligand 5 (CCL5) is involved in the exacerbation of asthma by RNA virus infections. Indeed, treatment with a virus-associated ligand and a T helper type 2 cell (Th2) cytokine can synergistically stimulate CCL5 production in bronchial epithelial cells. We aimed to evaluate the mechanisms underlying CCL5 production in this in vitro model and to assess the potential of Janus kinase 1 (JAK1) as a novel therapeutic target via the use of ruxolitinib. METHODS: We stimulated primary normal human bronchial epithelial (NHBE) cells and BEAS-2B cells with poly(I:C) along with interleukin-13 (IL-13) or IL-4, and assessed CCL5 production. We also evaluated the signals involved in virus- and Th2-cytokine-induced CCL5 production and explored a therapeutic agent that attenuates the CCL5 production. RESULTS: Poly(I:C) stimulated NHBE and BEAS-2B cells to produce CCL5. Poly(I:C) and IL-13 increased CCL5 production. Poly(I:C)-induced CCL5 production occurred via the TLR3-IRF3 and IFNAR/JAK1-phosphoinositide 3-kinase (PI3K) pathways, but not the IFNAR/JAK1-STATs pathway. In addition, IL-13 did not augment poly(I:C)-induced CCL5 production via the canonical IL-13R/IL-4R/JAK1-STAT6 pathway but likely via subsequent TLR3-IRF3-IFNAR/JAK1-PI3K pathways. JAK1 was identified to be a potential therapeutic target for severe eosinophilic asthma. The JAK1/2 inhibitor, ruxolitinib, was demonstrated to more effectively decrease CCL5 production in BEAS-2B cells than fluticasone propionate. CONCLUSION: We have demonstrated that JAK1 is a possible therapeutic target for severe corticosteroid-resistant asthma with airway eosinophilia and persistent Th2-type inflammation, and that ruxolitinib has potential as an alternative pharmacotherapy.

A case of infective endocarditis caused by "Neisseria skkuensis".

"Neisseria skkuensis" is a gram-negative coccus that is endemic in the human oral cavity, with only few reports of infection in humans. Herein, we report a case of a male patient in his sixties presenting with infective endocarditis (IE) caused by "N. skkuensis". To our knowledge, this is the second case of IE confirmed using 16S rRNA gene to have been caused by "N. skkuensis". The accurate diagnosis of rare or difficult-to-identify pathogens is a major challenge for clinical microbiological laboratories. Although Neisseria spp. are common in the oral cavity and are often seen in routine tests, identification of their biochemical properties and mass spectrometric analysis are difficult. In this case report, we describe the accurate identification of "N. skkuensis" by 16S rRNA gene sequencing analysis compared to other identification methods. Further cases of "N. skkuensis" are needed to fully evaluate the clinical approach of this detection method.

Evidence of the Sequential Changes of Lung Sounds in COVID-19 Pneumonia Using a Novel Wireless Stethoscope with the Telemedicine System.

A 60-year-old woman was admitted to our hospital due to coronavirus disease 2019 (COVID-19) pneumonia with a chief complaint of persistent low-grade fever and dry cough for two weeks. Thoracic computed tomography demonstrated a crazy paving pattern in the bilateral lower lobes. In a COVID-19 ward, we used a novel wireless stethoscope with a telemedicine system and successfully recorded and shared the lung sounds in real-time between the red and green zones. The fine crackles at the posterior right lower lung fields changed from mid-to-late (day 1) to late inspiratory crackles (day 3), which disappeared at day 5 along with an improvement in both the clinical symptoms and thoracic CT findings.

Reactive arthritis after COVID-19 infection.

Reactive arthritis (ReA) is typically preceded by sexually transmitted disease or gastrointestinal infection. An association has also been reported with bacterial and viral respiratory infections. Herein, we report the first case of ReA after the he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This male patient is in his 50s who was admitted with COVID-19 pneumonia. On the second day of admission, SARS-CoV-2 PCR was positive from nasopharyngeal swab specimen. Despite starting standard dose of favipiravir, his respiratory condition deteriorated during hospitalisation. On the fourth hospital day, he developed acute respiratory distress syndrome and was intubated. On day 11, he was successfully extubated, subsequently completing a 14-day course of favipiravir. On day 21, 1 day after starting physical therapy, he developed acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon, without rash, conjunctivitis, or preceding diarrhoea or urethritis. Arthrocentesis of his left ankle revealed mild inflammatory fluid without monosodium urate or calcium pyrophosphate crystals. Culture of synovial fluid was negative. Plain X-rays of his ankles and feet showed no erosive changes or enthesophytes. Tests for syphilis, HIV, anti-streptolysin O (ASO), Mycoplasma, Chlamydia pneumoniae, antinuclear antibody, rheumatoid factor, anticyclic citrullinated peptide antibody and Human Leukocyte Antigen-B27 (HLA-B27) were negative. Gonococcal and Chlamydia trachomatis urine PCR were also negative. He was diagnosed with ReA. Nonsteroidal Anti-Inflammatory Drug (NSAID)s and intra-articular corticosteroid injection resulted in moderate improvement.

Molecular evolution of the hemagglutinin-neuraminidase (HN) gene in human respirovirus 3.

Human respirovirus 3 (HRV3) is a major causative agent of acute respiratory infections in humans. HRV3 can manifest as a recurrent infection, although exactly how is not known. In the present study, we conducted detailed molecular evolutionary analyses of the major antigen-coding hemagglutinin-neuraminidase (HN) gene of this virus detected/isolated in various countries. We performed analyses of time-scaled evolution, similarity, selective pressure, phylodynamics, and conformational epitope prediction by mapping to HN protein models. In this way, we estimated that a common ancestor of the HN gene of HRV3 and bovine respirovirus 3 diverged around 1815 and formed many lineages in the phylogenetic tree. The evolutionary rates of the HN gene were 1.1 × 10-3 substitutions/site/year, although the majority of these substitutions were synonymous. Some positive and many negative selection sites were predicted in the HN protein. Phylodynamic fluctuations of the gene were observed, and these were different in each lineage. Furthermore, most of the predicted B cell epitopes did not correspond to the neutralization-related mouse monoclonal antibody binding sites. The lack of a link between the conformational epitopes and neutralization sites may explain the naturally occurring HRV3 reinfection.

Pilot study for risk assessment of aspiration pneumonia based on oral bacteria levels and serum biomarkers.

BACKGROUND: Aspiration pneumonia is a serious problem among elderly patients; it is caused by many risk factors including dysphagia, poor oral hygiene, malnutrition, and sedative medications. The aim of this study was to define a convenient procedure to objectively evaluate the risk of aspiration pneumonia in the clinical setting. METHODS: This prospective study included an aspiration pneumonia (AP) group, a community-acquired pneumonia (CAP) group, and a control (Con) group (patients hospitalized for lung cancer chemotherapy). We used the Oral Health Assessment Tool (OHAT), which assesses oral hygiene, and evaluated performance status, body mass index, serum albumin levels, substance P values in plasma, and oral bacterial counts. RESULTS: The oral health as assessed by the OHAT of the aspiration pneumonia group was significantly impaired compared with that of the CAP group and the control (5.13 ± 0.18, 4.40 ± 0.26, 3.90 ± 0.22, respectively; p < 0.05). The oral bacterial count in the aspiration pneumonia group (7.20 ± 0.11) was significantly higher than that in the CAP group (6.89 ± 0.12), consistent with the OHAT scores. Oral bacterial count was significantly reduced by oral care. CONCLUSIONS: OHAT and oral bacterial counts can be a tool to assess the requirement of taking oral care and other preventive procedures in patients at high risk of aspiration pneumonia.