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Chronic pulmonary aspergillosis (CPA) is a challenging respiratory infection caused by the environmental fungus Aspergillus. CPA has a poor prognosis, with reported 1-year mortality rates ranging from 7% to 32% and 5-year mortality rates ranging from 38% to 52%. A comprehensive understanding of the pathogen, pathophysiology, risk factors, diagnosis, surgery, hemoptysis treatment, pharmacological therapy, and prognosis is essential to manage CPA effectively. In particular, Aspergillus drug resistance and cryptic species pose significant challenges. CPA lacks tissue invasion and has specific features such as aspergilloma. The most critical risk factor for the development of CPA is pulmonary cavitation. Diagnostic approaches vary by CPA subtype, with computed tomography (CT) imaging and Aspergillus IgG antibodies being key. Treatment strategies include surgery, hemoptysis management, and antifungal therapy. Surgery is the curative option. However, reported postoperative mortality rates range from 0% to 5% and complications range from 11% to 63%. Simple aspergilloma generally has a low postoperative mortality rate, making surgery the first choice. Hemoptysis, observed in 50% of CPA patients, is a significant symptom and can be life-threatening. Bronchial artery embolization achieves hemostasis in 64% to 100% of cases, but 50% experience recurrent hemoptysis. The efficacy of antifungal therapy for CPA varies, with itraconazole reported to be 43–76%, voriconazole 32–80%, posaconazole 44–61%, isavuconazole 82.7%, echinocandins 42–77%, and liposomal amphotericin B 52–73%. Combinatorial treatments such as bronchoscopic triazole administration, inhalation, or direct injection of amphotericin B at the site of infection also show efficacy. A treatment duration of more than 6 months is recommended, with better efficacy reported for periods of more than 1 year. In anticipation of improvements in CPA management, ongoing advances in basic and clinical research are expected to contribute to the future of CPA management.

Influenza A H1N1 2009 virus caused the first pandemic in an era when neuraminidase inhibitor antiviral drugs were available in many countries. The experiences of detecting and responding to resistance during the pandemic provided important lessons for public health, laboratory testing, and clinical management. We propose recommendations for antiviral susceptibility testing, reporting results, and management of patients infected with 2009 pandemic influenza A H1N1. Sustained global monitoring for antiviral resistance among circulating influenza viruses is crucial to inform public health and clinical recommendations for antiviral use, especially since community spread of oseltamivir-resistant A H1N1 2009 virus remains a concern. Further studies are needed to better understand influenza management in specific patient groups, such as severely immunocompromised hosts, including optimisation of antiviral treatment, rapid sample testing, and timely reporting of susceptibility results.

Significance Preexisting secretory IgA (S-IgA) antibodies can provide immediate immunity via their unique capability to eliminate a pathogen before it passes the mucosal barrier. Several clinical trials have reported that S-IgA against influenza virus was induced by intranasal administration of an inactivated influenza vaccine. S-IgA in mucosa consists predominantly of dimers rather than tetramers, as revealed by ultracentrifugation almost 50 years ago. However, direct evidence concerning the quaternary architectures and the physiological function of polymers larger than dimers has not been reported in healthy humans. The present study revealed, for the first time to our knowledge, the existence of large polymeric IgA in the healthy human upper respiratory mucosa, as well as the physiological functions of these molecules in protecting against viral infection in humans. Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures, which are minor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses compared with dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S-IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract.

Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO 2 :FiO 2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability.

Background It is challenging to diagnose infected aneurysm in the early phase. This study aimed to describe the clinical and microbiological characteristics of infected aneurysm, and to elucidate the difficulties in diagnosing the disease. Methods Forty-one cases of infected aneurysm were diagnosed in Nagasaki University Hospital from 2005 to 2019. Information on clinical and microbiological characteristics, radiological findings, duration of onset, and type of initial computed tomography (CT) imaging conditions were collected. Factors related to diagnostic delay were analyzed by Fisher’s exact test for categorical variables or by the Wilcoxon rank-sum test for continuous variables. Results Pathogens were identified in 34 of 41 cases; the pathogens were Gram-positive cocci in 16 cases, Gram-negative rods in 13 cases, and others in five cases. Clinical characteristics did not differ in accordance with the identified bacteria. At the time of admission, 16 patients were given different initial diagnoses, of which acute pyelonephritis (n = 5) was the most frequent. Compared with the 22 patients with an accurate initial diagnosis, the 19 initially misdiagnosed patients were more likely to have been examined by plain CT. The sensitivities of plain CT and contrast-enhanced CT were 38.1% and 80.0%, respectively. Conclusions In cases of infected aneurysm, diagnostic delay is attributed to non-specific symptoms and the low sensitivity of plain CT. Clinical characteristics of infected aneurysm mimic various diseases. Contrast-enhanced CT should be considered if infected aneurysm is suspected.

Influenza is a serious public health problem that causes a contagious respiratory disease. Vaccination is the most effective strategy to reduce transmission and prevent influenza. In recent years, cell-based vaccines have been developed with continuous cell lines such as Madin-Darby canine kidney (MDCK) and Vero. However, wild-type influenza and egg-based vaccine seed viruses will not grow efficiently in these cell lines. Therefore, improvement of virus growth is strongly required for development of vaccine seed viruses and cell-based influenza vaccine production. The aim of our research is to develop novel MDCK cells supporting highly efficient propagation of influenza virus in order to expand the capacity of vaccine production. In this study, we screened a human siRNA library that involves 78 target molecules relating to three major type I interferon (IFN) pathways to identify genes that when knocked down by siRNA lead to enhanced production of influenza virus A/Puerto Rico/8/1934 in A549 cells. The siRNAs targeting 23 candidate genes were selected to undergo a second screening pass in MDCK cells. We examined the effects of knockdown of target genes on the viral production using newly designed siRNAs based on sequence analyses. Knockdown of the expression of a canine gene corresponding to human IRF7 by siRNA increased the efficiency of viral production in MDCK cells through an unknown process that includes the mechanisms other than inhibition of IFN-α/β induction. Furthermore, the viral yield greatly increased in MDCK cells stably transduced with the lentiviral vector for expression of short hairpin RNA against IRF7 compared with that in control MDCK cells. Therefore, we propose that modified MDCK cells with lower expression level of IRF7 could be useful not only for increasing the capacity of vaccine production but also facilitating the process of seed virus isolation from clinical specimens for manufacturing of vaccines.

[Display omitted] •A web-based questionnaire for the survey was performed to registered SOT facilities in Japan.•Pre- and post-transplant vaccination policy adherence in Japan was not up to level.•More educational programs on the importance of pre- and post-transplant vaccination might be needed to increase interest in transplant-related vaccination.•Role of infectious disease physicians for adherence to vaccination maybe important.•Patient co-payments for transplant-related vaccinations needs to be reduced. Pre-transplant vaccination is recommended for patients undergoing solid organ transplantation (SOT). While appropriate vaccination protocols are implemented at some facilities, transplantation is sometimes performed with inadequate preoperative vaccine management. Vaccination rates vary across facilities, but those of SOT centers in Japan have never been investigated. This study aimed to conduct a nationwide questionnaire survey to assess pre- and post-transplant vaccination policies among SOT facilities in Japan. The survey was conducted from September to November 2022. All registered (n = 221) solid organ (namely, the lungs, liver, kidneys, pancreas, heart, and small intestine) transplant facilities were asked to complete a web-based survey. The survey response rate was 70.2 %. Live and inactivated vaccines were recommended at 64.9 % and 68.9 % of the responding facilities, respectively. The following vaccines were incorporated into the vaccination protocols of facilities: pneumococcal vaccine, 31.7 % (13-valent pneumococcal conjugate vaccine) and 65.4 % (23-valent pneumococcal polysaccharide vaccine); hepatitis B virus vaccine, 67.3 %; severe acute respiratory syndrome coronavirus 2 vaccine, 73.1 %; influenza vaccine, 73.1 %; and zoster vaccines, 23.1 %. The reasons for unresponsiveness to vaccinations included inadequate time before transplantation (60.3 %), cost burden (41.1 %), high number of vaccinations (21.9 %), no recognition of the need for vaccination (17.9 %), and the requirement to explain the need for vaccination (15.2 %). Our study revealed gaps in vaccination practices across nationwide facilities in Japan. The findings indicate the importance of promoting scheduled efficiency and encouraging the national health system to reduce vaccine costs with the support of public subsidies.

BackgroundLiposomal amphotericin B (L-AMB), a broad-spectrum antifungicidal drug, is often used to treat fungal infections. However, clinical evidence of its use in patients with renal dysfunction, especially those receiving renal replacement therapy (RRT), is limited. Therefore, we evaluated the usage and occurrence of adverse reactions during L-AMB therapy in patients undergoing RRT.MethodsUsing claims data and laboratory data, we retrospectively evaluated patients who were administered L-AMB. The presence of comorbidities, mortality rate, treatment with L-AMB and other anti-infective agents, and the incidence of adverse reactions were compared between patients receiving RRT, including continuous renal replacement therapy (CRRT) and maintenance hemodialysis (HD), and those that did not receive RRT.ResultsIn total, 900 cases met the eligibility criteria: 24, 19, and 842 cases in the maintenance HD, CRRT, and non-RRT groups, respectively. Of the patients administered L-AMB, mortality at discharge was higher for those undergoing either CRRT (15/19; 79%) or maintenance HD (16/24; 67%) than for those not receiving RRT (353/842; 42%). After propensity score matching, the average daily and cumulative dose, treatment duration, and dosing interval for L-AMB were not significantly different between patients receiving and not receiving RRT. L-AMB was used as the first-line antifungal agent for patients undergoing CRRT in most cases (12/19; 63%). Although the number of subjects was limited, the incidence of adverse events did not markedly differ among the groups.ConclusionL-AMB may be used for patients undergoing maintenance HD or CRRT without any dosing, duration, or interval adjustments.

Manufactured influenza vaccines have to contain a defined amount of hemagglutinin (HA) antigen. Therefore, vaccine viruses with a high HA antigen yield (HAY) are preferable for manufacturing vaccines, particularly vaccines in response to a pandemic, when vaccines need to be rapidly produced. However, the viral properties associated with a high HAY have not yet been fully clarified. To identify the HAY-associated traits, we first propagated 26 H5 candidate vaccine viruses (CVVs) in eggs, which were previously developed based on genetic reassortment methods using master viruses, to determine their total protein yield (TPY), ratio of HA to total viral protein (%-HA content) and HAY. The results revealed that the HAY was correlated with the TPY but not with the %-HA content. We further found that altering the sequences of the 3’ noncoding region of HA vRNA or replacing the master virus improved the HAYs and TPYs of the low-HAY CVVs to approximately double the values of the original CVVs but did not change the %-HA content, which a previous study suggested was associated with the HAY. Analyses based on real-time PCR assays and scanning electron microscopy revealed that the virus samples with an improved HAY contained more copies of the virus genome and viral particles than the original samples. The results suggest that an improvement in virus growth (i.e., an increase in the amount of viral particles) leads to an increase in the TPY and thus in the HAY, regardless of the %-HA content. The approximately twofold increase in the HAY shown in this study may not appear to represent a large improvement, but the impact will be significant given the millions of chicken eggs used to produce vaccines. These findings will be informative for developing high-HAY vaccine viruses.

Data on the clinical effectiveness and adverse events of daptomycin in pediatric patients, considering dosage and renal function, are limited. In this study, we aimed to investigate the clinical effectiveness of daptomycin, incidence of related adverse events, and associations between clinical outcomes and risk factors, including dosage and renal function, in pediatric patients. Medical records of pediatric patients treated with daptomycin between September 2011 and December 2022, were retrospectively reviewed. Clinical effectiveness was categorized as cure, improvement, failure, or non-evaluable. The clinical success rate was defined as the sum of cured and improved cases. We classified doses based on the approved ranges: underdose (>1 mg/kg less than the approved dose), adequate dose (approved dose ±1 mg/kg), and overdose (>1 mg/kg more than the approved dose). Obesity was defined as a body mass index ≥ 30 kg/m2, with adjusted body weight used for dosing in these patients. We enrolled 54 patients, achieving a clinical success rate of 91%. Four (7%) patients died, particularly those with microbiological failure (P = 0.004) and underdosing (P < 0.001). The underdose group comprised a higher proportion of younger patients (P = 0.020). Additionally, seven (13%) patients experienced daptomycin-related adverse events, including creatine phosphokinase elevation, eosinophilic pneumonia, rhabdomyolysis, liver failure, and drug fever, occurring regardless of renal function. Five patients received an approved dose, while two received an overdose. Adequate daptomycin dosing improved clinical effectiveness and the mortality rate. However, continuous monitoring of adverse events remains critical for patients receiving the approved dose, including those with a normal renal function.