[THE EFFICACY OF BRONCHIAL THERMOPLASTY IN LONG-TERM MAINTENANCE OF ADULT PATIENTS WITH MODERATE TO SEVERE ASTHMA].

BACKGROUND AND AIMS: Bronchial thermoplasty (BT) is a bronchoscopic treatment for adult patients with moderate to severe asthma. A systematic review was conducted to examine the efficacy of this treatment. METHODS: Randomized controlled comparing BT to a control in adult patients with moderate to severe asthma were added to the previously conducted systematic review. Literature published prior to July 2022 was selected. RESULTS: Four trials were included in this study. BT resulted in significant improvement in quality of life. However, no significant difference in asthma control was observed. Moreover, the incidence of severe adverse events during the treatment period was increased by BT. Furthermore, BT did not improve lung function, increase withdrawal from oral corticosteroids, reduce frequency of rescue medication usage, or increase the number of symptom-free days. CONCLUSION: From a risk-benefit perspective, there is insufficient evidence to support a recommendation of BT in adult patients with moderate to severe asthma.

C-type lectin receptors of the Dectin-1 cluster: Physiological roles and involvement in disease.

C-type lectin receptors (CLRs) are essential for multicellular existence, having diverse functions ranging from embryonic development to immune function. One subgroup of CLRs is the Dectin-1 cluster, comprising of seven receptors including MICL, CLEC-2, CLEC-12B, CLEC-9A, MelLec, Dectin-1, and LOX-1. Reflecting the larger CLR family, the Dectin-1 cluster of receptors has a broad range of ligands and functions, but importantly, is involved in numerous pathophysiological processes that regulate health and disease. Indeed, these receptors have been implicated in development, infection, regulation of inflammation, allergy, transplantation tolerance, cancer, cardiovascular disease, arthritis, and other autoimmune diseases. In this mini-review, we discuss the latest advancements in elucidating the function(s) of each of the Dectin-1 cluster CLRs, focussing on their physiological roles and involvement in disease.

Mucus plugs and bronchial wall thickening on three-dimensional computed tomography in patients with unexplained chronic cough whose sputum yielded filamentous Basidiomycetes.

OBJECTIVES: This study was conducted in order to identify imaging features on three-dimensional computed tomography (CT) of unexplained chronic cough (UCC) patients with positive sputum cultures for filamentous Basidiomycetes (f-BM). METHODS: UCC outpatients who had been given various questionnaires for cough, pulmonary function tests, and fungal cultures of sputum were evaluated. Multidetector row CT (MDCT) was performed for three-dimensional CT analysis of the lungs. Retrospective analysis was carried out with three groups: f-BM culture-positive group, other fungal culture-positive group, and culture-negative group. The Kruskal-Wallis test, analysis of variance, Fischer exact test, χ2 test, Student's t test, Mann-Whitney U test, Spearman's correlation coefficient, and Dunn-Bonferroni post hoc method were used for statistical analysis. RESULTS: Of the 50 patients, 3 were excluded and the remaining 47 were included in the analysis. There were no significant differences in respiratory function or clinical characteristics among the three groups. The common features on high-resolution CT (HRCT) included tree-in-bud (TIB) pattern, multiple centrilobular nodules, and bronchial wall thickening. Bronchiolar mucus plugs were detected in 7 (15%) of 47 cases. Bronchiole wall thickness and %FEV1 appeared to be slightly correlated (p = 0.033, r = 0.357). The bronchiole walls were significantly thicker when mucus plugs were found (p = 0.010). Bronchiolar walls were the thickest and the score of mucus plugs was the highest in patients with f-BM culture-positive sputum (p = 0.008). CONCLUSIONS: Imaging findings for identifying f-BM culture-positive fungus-associated chronic cough (FACC) patients include high mucus plug scores and bronchiolar wall thickening on three-dimensional CT. KEY POINTS: • Three-dimensional computed tomography helps clinicians assess patients with unexplained chronic cough and identify those with fungus-associated chronic cough. • A retrospective single-center study showed that computed tomography images in patients with filamentous Basidiomycetes cultured from sputum had mucus plugs and bronchiolar wall thickening. • UCC patients with sputum cultures positive for filamentous Basidiomycetes may have fine airway lesions that could not be detected without three-dimensional computed tomography.

Species-specific detection of medically important aspergilli by a loop-mediated isothermal amplification method in chronic pulmonary aspergillosis.

Chronic pulmonary aspergillosis (CPA) is a common subtype of pulmonary aspergillosis and a life-threatening disease. However, its diagnosis remains difficult due to the lack of specific clinical features and radiologic findings, as well as the difficulty of isolating Aspergillus spp. We developed a novel species-specific detection method of medically important aspergilli using a loop-mediated isothermal amplification (LAMP) for CPA. Specific LAMP primer sets for Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, and Aspergillus nidulans were designed. The use of the LAMP assay was validated using respiratory specimens (CPA cases, n = 21; nonaspergillosis cases, n = 23). A total of 15 cases were positive in the CPA group (A. fumigatus, n = 5; A. flavus, n = 1; A. niger, n = 1; A. terreus, n = 7; A. nidulans, n = 1), but only three in the non-CPA group (A. niger, n = 2; A. terreus n = 1). The sensitivity and specificity of the diagnosis of CPA by the LAMP system were 71.4% and 87.0%, respectively. In conclusion, we developed a species-specific detection approach for five medically important aspergilli using the LAMP method. The system showed high sensitivity and specificity for diagnosis of CPA.

Real-Time PCR Detection of the Basidiomycetous Fungus Bjerkandera adusta: A Tool to Identify Itraconazole Responder Patients with Unexplained Chronic Cough.

BACKGROUND: Filamentous basidiomycetes (f-BMs) are involved in some unexplained chronic cough (UCC) cases that can be improved by the administration of antifungal agents. The disease concept was termed fungus-associated chronic cough (FACC). The current diagnostic criteria warrant environmental fungi isolation from respiratory specimens, which is hardly conceivable for such fungi. OBJECTIVES: This study aimed to detect the f-BMs Bjerkandera adusta, the most common pathogen in FACC, from respiratory specimens of patients with UCC using real-time polymerase chain reaction (PCR). It also evaluated the applicability of the PCR system to detect antifungal agent responders among patients with unexplained cough. METHODS: The PCR system specific to B. adusta was developed and its utility was evaluated using sputum samples from 23 patients with chronic cough. RESULTS: B. adusta was detected in 10 out of 14 patients with UCC (71.4%), in contrast to only 2 out of 9 patients with non-UCC (22.2%; p < 0.05 with the Fisher's exact test). The copy number of the samples correlated with the therapeutic impact score for cough symptoms following the oral administration of itraconazole. CONCLUSION: Development of the real-time PCR system enabled us to demonstrate that many patients with UCC might be influenced by B. adusta, a fact evidenced by the improvement of symptoms with itraconazole administration in most PCR-positive patients. This method would help in detecting itraconazole responders among patients with UCC when the isolation of f-BMs is not achievable.

Epidural abscess caused by Schizophyllum commune: A rare case of rhinogenic cranial complication by a filamentous basidiomycete.

Central nervous system (CNS) infections due to filamentous basidiomycetes are extremely rare. We encountered a case of epidural abscess due to Schizophyllum commune that extended from sinusitis. A 53-year-old Japanese man presented at our hospital with a headache. Computed tomography (CT) of the cranium and sinuses showed ethmoid and sphenoid sinusitis with no intracranial abnormalities. The patient was diagnosed with acute sinusitis and underwent antibiotic treatment. However, the symptoms deteriorated, and the patient came to our hospital again with consciousness disturbance. CT scan of the cranium and sinuses showed no improvement of sinusitis after antibiotic therapy and an epidural abscess emerged in the middle cranial fossa. Therefore, emergency craniotomy and endoscopic sinus fenestration were performed. Filamentous fungal elements were observed in both rhinorrhoea and epidural abscess. The symptoms improved after the operation and administration of liposomal amphotericin B. The clinical isolate was identified as S. commune by a molecular-based method. To our knowledge, this is the first report of epidural abscess due to this fungus. Although rare, clinicians should be aware that S. commune could be a causative agent of CNS infections.

Cross-reactivity in Cryptococcus antigen latex agglutination test in two commercial kits.

This article presents an examination of the cross-reactivity of pathogenic fungi with Cryptococcus neoformans in two commercial Cryptococcus antigen latex agglutination tests performed across 39 fungal strains. Some fungi were newly indicated as Cryptococcus cross-reactive, and the two kits showed differences in cross-reactive fungi.

Carbapenem vs. non-carbapenem antibiotics for ventilator-associated pneumonia: A systematic review with meta-analysis.

BACKGROUND: Carbapenem is recommended as one of the first-line regimens for ventilator-associated pneumonia (VAP), but no recent systematic review has fully investigated its efficacy. This systematic review aims to evaluate the efficacy of carbapenem compared with non-carbapenem for VAP treatment. METHODS: We performed a systematic review and meta-analysis of studies comparing the efficacy and the safety between carbapenem and non-carbapenem with activity to Pseudomonas aeruginosa in the treatment for VAP. The main outcome was mortality, and the additional outcomes were the clinical cure of pneumonia, length of intensive care unit stay, recurrence, adverse effects, and the development of resistant bacteria. This study was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of the initial 1,730 publications, 9 randomized control trials were enrolled. In the meta-analysis, no difference was observed between the carbapenem and non-carbapenem regimens in improving mortality (odds ratio, 0.83; 95 % confidence interval (CI) 0.67-1.02). While the carbapenem regimen was superior to the non-carbapenem regimen in studies reporting the resolution of pneumonia (odds ratio, 1.09; 95 % CI 1.01-1.17), the effectiveness of carbapenem treatment was not evident in studies assessing the other outcomes. CONCLUSIONS: Carbapenem might have no superiority in survival when treating VAP. Moreover, non-carbapenem antibiotics with activities to P. aeruginosa have a potential option to avoid inducing carbapenem-resistant pathogens.

Bacterial profiles detected in ventilator-associated pneumonia in Japan: A systematic review.

The primary objective of this study was to identify the predominant organisms associated with ventilator-associated pneumonia (VAP) in Japan. Studies on VAP conducted in Japan were systematically reviewed, and seven studies with a total of 374 cases were included. The detection rate of each bacterium and multidrug-resistant (MDR) pathogen was analyzed using the inverse variance method. Pseudomonas aeruginosa was identified as the predominant pathogen in 29.2 % of cases, followed by methicillin-resistant Staphylococcus aureus (MRSA) (12.0 %), and Klebsiella spp. (9.5 %). An integrated analysis revealed a detection rate of 57.8 % (95 % confidence interval: 48.7%-66.8 %) for MDR pathogens. This review highlights P. aeruginosa and MRSA as the predominant VAP-associated organisms in Japan, with a significant prevalence of MDR pathogens. This analysis provides valuable insights based on the regional distribution of bacteria detected in VAP, which is critical for selecting appropriate empirical therapy.

COVID-19-Associated Pulmonary Aspergillosis Complicated by Severe Coronavirus Disease: Is Detection of Aspergillus in Airway Specimens Before Disease Onset an Indicator of Antifungal Prophylaxis?

A 55-year-old man was admitted for coronavirus disease 2019 (COVID-19)-related respiratory failure. He was treated with corticosteroids and tocilizumab in the intensive care unit. Aspergillus fumigatus (A. fumigatus) was isolated from his sputum on admission. However, no radiological findings suggesting pulmonary aspergillosis were seen on chest computed tomography (CT). Since the fungus had merely colonized in airways, antifungal drugs were not administered immediately. On day 19 of hospitalization, a high (1→3)-ß-D-glucan (BDG) level was noted. A CT scan on day 22 revealed consolidations with a cavity in the right lung. A. fumigatus was isolated from his sputum again. Thus, we diagnosed the patient with COVID-19-associated pulmonary aspergillosis (CAPA) and started voriconazole. After the treatment, BDG levels and radiological findings were noted to improve. In this case, tocilizumab probably had a critical role in developing the disease. Although antifungal prophylaxis therapy for CAPA is not well established, this case shows that detecting Aspergillus in airway specimens before the disease onset possibly implies a high risk of developing CAPA and is an indicator of antifungal prophylaxis.

Clinical features of organizing pneumonia in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders.

BACKGROUND: Anti-aquaporin-4 (AQP4) antibody is an autoantibody marker often observed in patients with neuromyelitis optica spectrum disorder (NMOSD). The pathological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD remains unclear. We aimed to assess the clinical and histological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD. METHODS: We retrospectively reviewed the medical records of 52 patients with anti-AQP4 antibody-positive NMOSD and conducted immunohistochemical evaluations of the lung biopsy specimens. RESULTS: Among 52 patients with anti-AQP4 antibody-positive NMOSD, 4 patients showed pulmonary involvement with a diagnosis of organizing pneumonia (OP). The proportion of males was larger (75% vs. 12.5%; p = 0.013) and creatine kinase levels were higher (458.3 U/L vs. 83.9 U/L; p = 0.003) in patients with OP than in those without OP. OP development preceded or coincided with the NMOSD symptoms. Chest computed tomography findings were consistent with OP in all four patients. Bronchoalveolar lavage fluid predominantly contained lymphocytes. Transbronchial lung biopsy revealed intraluminal plugs of inflammatory debris within the alveoli. Alveolar epithelial cells covering the OP lesions exhibited AQP4 loss, immunoglobulin G deposition, and complement activation. Corticosteroid treatment resulted in clinical improvement of OP. CONCLUSION: OP may be considered a pulmonary manifestation of anti-AQP4 antibody-positive NMOSD beyond the central nervous system. Complement-dependent cytotoxicity of the lung epithelial cells caused by anti-AQP4 antibody is at least partly involved in OP development. When diagnosing NMOSD, the possibility of OP should be carefully evaluated based on the detailed history and chest imaging findings.

Pancreatic tuberculosis in an immunocompetent young female mimicking a malignant tumor: A case report and diagnostic radiological investigation.

Tuberculosis remains the leading cause of infectious disease related death worldwide with extrapulmonary tuberculosis being particularly difficult to diagnose. Here, we report a case of pancreatic tuberculosis (PTB) in an immunocompetent young female, which mimicked a malignant tumor diagnosed by endoscopic ultrasound-guided fine needle aspiration and biopsy (EUS-FNAB). A 19-year-old Japanese female with no prior medical history presented with abdominal epigastralgia and appetite loss lasting 2 months. A solid lobular mass was observed in the pancreatic head with enhanced abdominal computed tomography and magnetic resonance imaging suggested it was a malignant pancreatic tumor. Using EUS-FNAB, granulomas with caseous necrosis and acid-fast bacilli were observed. Polymerase chain reaction results were positive for Mycobacterium tuberculosis but negative for Mycobacterium avium complex. Therefore, the patient was diagnosed with PTB. Her symptoms and radiological findings improved with a standard antituberculosis therapy. PTB is difficult to differentiate from other pancreatic diseases with Magnetic resonance imaging (MRI) patterns of T1, T2 weighted, or diffusion-weighted image (DWI) images. To investigate novel radiological diagnostics for PTB, we focused on MRI apparent diffusion coefficient (ADC) values, which have not been investigated in this context. The present case showed 0.52 × 10-3 mm2/s; additionally, the mean value of other mass-forming pancreatic diseases, such as pancreatic cancer was 1.592 × 10-3 mm2/s (the range: 1.015-3.025 × 10-3 mm2/s). The range does not overlap with the present PTB case or other pancreatic diseases. Therefore, ADC values may be useful as a noninvasive radiological diagnostic method for PTB.

[A case of tuberculous pleurisy developing contralateral effusion during anti-tuberculosis chemotherapy].

A 55-year-old woman was admitted to our hospital because of chest pain, fever, and right pleural effusion that was exudative and lymphocyte-dominant with a high level of adenosine deaminase (ADA). Since her blood QuantiFERON-TB 3G test (QFT) was positive, she was diagnosed with tuberculous pleurisy. After initiation of anti-tuberculosis chemotherapy with isoniazid, rifampicin, ethambutol, and pyrazinamide, her symptoms improved. Later, liquid culture of the pleural effusion turned positive for Mycobacterium tuberculosis. On the 18th day of treatment, her chest X-ray and computed tomography exhibited pleural effusion in a moderate amount in the left thorax, with subsiding pleural effusion in the right thorax. Thoracocentesis demonstrated that the left thorax effusion was also exudative and lymphocyte-dominant, with elevated QFT response and high ADA concentration, suggesting tuberculous pleurisy. Mycobacterium tuberculosis was detected in the culture of a left pleural biopsy specimen obtained by thoracoscopy. We assumed that the left pleural effusion was due to paradoxical worsening because (1) on admission no effusion or lung parenchymal lesion was detected in the left hemithorax, (2) on the 14th day of treatment she was afebrile without pleural effusion on both sides, and (3) the bacilli were sensitive to the drugs she had been taking regularly. We performed drainage of the left effusion and continued the same anti-tuberculosis drugs, which led to the elimination of all her symptoms and of the pleural effusion on both sides. In conclusion, paradoxical worsening should be included in the differential diagnosis when contralateral pleural effusion is detected during the treatment of tuberculosis.

Iliopsoas gravity abscess secondary to a tuberculous empyema.

A 29-year-old Japanese man with a history of right-sided tuberculous pleurisy presented with fever and right flank pain. Computed tomography images revealed a right pleural effusion and an area of low attenuation in the right iliopsoas muscle. Percutaneous drainage of the iliopsoas lesion resulted in a bloody pyogenic discharge that tested positive for Mycobacterium tuberculosis by both acid-fast staining and polymerase chain reaction. Enhanced fluoroscopy revealed a perforation of the diaphragm between the thoracic region and the psoas muscle. The patient was diagnosed with an iliopsoas abscess secondary to tuberculous empyema.

MelLec Exacerbates the Pathogenesis of Aspergillus fumigatus-Induced Allergic Inflammation in Mice.

Environmental factors, particularly fungi, influence the pathogenesis of allergic airway inflammation, but the mechanisms underlying these effects are still unclear. Melanin is one fungal component which is thought to modulate pulmonary inflammation. We recently identified a novel C-type lectin receptor, MelLec (Clec1a), which recognizes fungal 1,8-dihydroxynaphthalene (DHN)-melanin and is able to regulate inflammatory responses. Here we show that MelLec promotes pulmonary allergic inflammation and drives the development of Th17 T-cells in response to spores of Aspergillus fumigatus. Unexpectedly, we found that MelLec deficiency was protective, with MelLec-/- animals showing normal weight gain and significantly reduced pulmonary inflammation in our allergic model. The lungs of treated MelLec-/- mice displayed significantly reduced inflammatory foci and reduced bronchial wall thickening, which correlated with a reduced cellular influx (particularly neutrophils and inflammatory monocytes) and levels of inflammatory cytokines and chemokines. Notably, fungal burdens were increased in MelLec-/- animals, without apparent adverse effects, and there were no alterations in the survival of these mice. Characterization of the pulmonary T-cell populations, revealed a significant reduction in Th17 cells, and no alterations in Th2, Th1 or Treg cells. Thus, our data reveal that while MelLec is required to control pulmonary fungal burden, the inflammatory responses mediated by this receptor negatively impact the animal welfare in this allergic model.

Enhancing melting curve analysis for the discrimination of loop-mediated isothermal amplification products from four pathogenic molds: Use of inorganic pyrophosphatase and its effect in reducing the variance in melting temperature values.

Loop-mediated isothermal amplification (LAMP) is widely used for differentiating causative agents in infectious diseases. Melting curve analysis (MCA) in conjunction with the LAMP method reduces both the labor required to conduct an assay and contamination of the products. However, two factors influence the melting temperature (Tm) of LAMP products: an inconsistent concentration of Mg2+ ion due to the precipitation of Mg2P2O7, and the guanine-cytosine (GC) content of the starting dumbbell-like structure. In this study, we investigated the influence of inorganic pyrophosphatase (PPase), an enzyme that inhibits the production of Mg2P2O7, on the Tm of LAMP products, and examined the correlation between the above factors and the Tm value using MCA. A set of LAMP primers that amplify the ribosomal DNA of the large subunit of Aspergillus fumigatus, Penicillium expansum, Penicillium marneffei, and Histoplasma capsulatum was designed, and the LAMP reaction was performed using serial concentrations of these fungal genomic DNAs as templates in the presence and absence of PPase. We compared the Tm values obtained from the PPase-free group and the PPase-containing group, and the relationship between the GC content of the theoretical starting dumbbell-like structure and the Tm values of the LAMP product from each fungus was analyzed. The range of Tm values obtained for several fungi overlapped in the PPase-free group. In contrast, in the PPase-containing group, the variance in Tm values was smaller and there was no overlap in the Tm values obtained for all fungi tested: the LAMP product of each fungus had a specific Tm value, and the average Tm value increased as the GC% of the starting dumbbell-like structure increased. The use of PPase therefore reduced the variance in the Tm value and allowed the differentiation of these pathogenic fungi using the MCA method.

Detection of Fungi from an Indoor Environment using Loop-mediated Isothermal Amplification (LAMP) Method.

　Loop-mediated isothermal amplification (LAMP) is a useful DNA detection method with high specificity and sensitivity. The LAMP reaction is carried out within a short time at a constant temperature without the need for thermal cycling. We developed a LAMP primer set for detecting a wide range of fungi by aligning the sequences of the large subunit ribosomal RNA gene of Candida albicans (Ascomycota), Cryptococcus neoformans (Basidiomycota), and Mucor racemosus (Mucorales). The threshold of C. albicans rDNA as template with our LAMP primer set was in the range of 10-100 copies per a reaction. In this study, we evaluated the correlation between colony forming units (CFU) and LAMP detection rate using the LAMP method for environmental fungi. The LAMP method should be a useful means of detecting fungi in indoor environments, disaster areas, or even in confined manned spacecraft to prevent allergies or infections caused by fungi.