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Background: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies., Methods: We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (μCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed., Findings: We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection., Interpretation: Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA., Funding: This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114 N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123 N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://doi.org/10.54499/PTDC/MED-OUT/1112/2021), and 2022.06674.PTDC (http://doi.org/10.54499/2022.06674.PTDC); and the "la Caixa" Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN)., Competing Interests: Declaration of interests SF declares having received travel support for conference attendance by Pfizer and Gilead, and a speaker fee from The Healthbook Company Ltd. JW declares having received investigator-initiated grants, speakers’ fees and travel support by Pfizer and Gilead, outside the scope of this manuscript. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

The filamentous fungus Aspergillus causes a wide spectrum of diseases in the human lung, with Aspergillus fumigatus being the most pathogenic and allergenic subspecies. The broad range of clinical syndromes that can develop from the presence of Aspergillus in the respiratory tract is determined by the interaction between host and pathogen. In this review, an oversight of the different clinical entities of pulmonary aspergillosis is given, categorized by their main pathophysiological mechanisms. The underlying immune processes are discussed, and the main clinical, radiological, biochemical, microbiological, and histopathological findings are summarized., Competing Interests: None declared. E.V.B. is chair of the Chronic Pulmonary Aspergillosis Network (CPAnet)., (Thieme. All rights reserved.)

Surgery plays a crucial role in the treatment of patients with chronic pulmonary aspergillosis (CPA). However, there is currently limited information available regarding the use of uniportal thoracoscopy (Uni-VATS) in CPA patients. To address this gap, we conducted a retrospective analysis of surgical procedures performed at a single center, aiming to demonstrate the feasibility and safety of Uni-VATS for patients with CPA. We collected basic information and surgical data from patients who underwent surgery for CPA at our hospital between January 2018 and June 2022. All patients received voriconazole antifungal medication for 3-6 months post-surgery and were monitored for a minimum of 6 months. A total of 110 patients, comprising 59 cases in the traditional open chest incision group and 51 cases in the Uni-VATS group, met the inclusion criteria. Among those who underwent surgery, 70% were male (77/110). The median age (IQR) of all enrolled patients was 55 (46-62) years. There were no statistically significant differences in general information, such as age, sex, comorbidities, BMI, FEV1, FVC, clinical symptoms, location of the disease, and duration of voriconazole antifungal medication, between the OS group and the Uni-VATS group (p > 0.05). The postoperative complication rates were 40.7% (24/59) for the traditional open chest incision group and 17.6% (9/51) for the Uni-VATS group. Through univariate analysis, we identified sex and operative approach as risk factors for postoperative complications. Multivariate logistic analysis confirmed that male and OS procedures were the independent risk factors for postoperative complications. There were statistically significant differences in operative time, intraoperative blood loss volume, postoperative drainage volume, pain scores, postoperative drainage tube removal time, postoperative hospital stay time between the OS group and the Uni-VATS group (p < 0.05). Uni-VATS is a feasible and safe surgical procedure for patients with CPA, and we recommend it as a preferred option for selected patients with CPA., (© 2023. Springer Nature Limited.)

Background: The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) is poorly elucidated., Method: We identified all patients with COVID-19 treated with VV-ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age., Results: Fifty patients, median age 53 years (interquartile range [IQR] 45-59), 66% male, were included. Median time on VV-ECMO was 14.5 days (IQR 6.3-23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9-257, p = .05), whereas we found no associations between other superinfections and risk of death., Conclusion: Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID-19 patients treated with VV-ECMO., (© 2023 CHIP, Centre of Excellence for Health, Immunity and Infections, Rigshospitalet. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

As the global SARS-CoV-2 pandemic continues to plague healthcare systems, it has become clear that opportunistic pathogens cause a considerable proportion of SARS-CoV-2-associated mortality and morbidity cases. Of these, Covid-Associated Pulmonary Aspergilliosis (CAPA) is a major concern with evidence that it occurs in the absence of traditional risk factors such as neutropenia and is diagnostically challenging for the attending physician. In this review, we focus on the immunopathology of SARS-CoV-2 and how this potentiates CAPA through dysregulation of local and systemic immunity as well as the unintended consequences of approved COVID treatments including corticosteroids and IL-6 inhibitors. Finally, we will consider how knowledge of the above may aid in the diagnosis of CAPA using current diagnostics and what treatment should be instituted in probable and confirmed cases.

Thoracic air leak syndromes (TALS) are very rare among the noninfectious pulmonary complications (PCs). They can either be idiopathic or have several risk factors such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), graft versus host disease and rarely pulmonary aspergillosis. We present a 14-year-old girl with hypoplastic myelodysplastic syndrome who developed graft versus host disease on day 60, TALS on day 150, bronchiolitis obliterans syndrome on day 300, pulmonary aspergillosis on day 400 and COVID-19 pneumonia on day 575 after allo-HSCT. This is the first report of a child who developed these subsequent PCs after allo-HSCT. Therefore, the manifestations of these unfamiliar PCs like TALS and COVID-19 pneumonia, and concomitant pulmonary aspergillosis with management options are discussed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Between April and July 2020, and, therefore, prior to the broad recommendation of corticosteroids for severe COVID-19, a total of 50 full autopsies were performed in Manaus. We confirmed two invasive cases of aspergillosis through histopathology and gene sequencing (4%) in our autopsy series. The confirmed invasive aspergillosis incidence seems much lower than expected based on the "probable and possible" definitions, and an individualized approach should be considered for each country scenario. Interestingly, a prolonged length of stay in the intensive care unit was not observed in any of the cases. Timely diagnosis and treatment of fungal infection can reduce mortality rates.

Purpose: Invasive pulmonary aspergillosis (IPA) after liver transplantation (LT) is most often fatal. We analyzed the outcomes of IPA in a single center., Methods: We reviewed, retrospectively, the medical records of recipients of living donor LT (LDLT) or deceased donor LT (DDLT) performed between 1995 and 2019 at our institute. We analyzed the incidence of IPA and assessed the treatment courses of patients treated successfully and those not treatment successfully., Results: Among 326 recipients, IPA was diagnosed in 6 (1.8%). The incidence of IPA was significantly higher in patients with acute liver failure (ALF, 9.8%) than in those without ALF (0.4%), after DDLT (8.8%) than after LDLT (1.0%), and in recipients who received preoperative steroid pulse therapy (16.0%) than in those who did not (0.7%). Complete cure of IPA was achieved in the most recent three patients, by administering voriconazole immediately after the diagnosis of IPA and performing lung resection, while the IPA lesion was single and localized., Conclusions: Patients with risk factors for IPA must be monitored closely. Our three successfully treated cases demonstrate that initiating immediate voriconazole treatment and making a calculated decision about lung resection can contribute to a favorable outcome., (© 2021. Springer Nature Singapore Pte Ltd.)

Severe COVID-19 patients complicated with aspergillosis are increasingly reported. We present a histopathological proven case of fatal COVID-19-associated pulmonary aspergillosis (CAPA), due to Aspergillus flavus. This report and existing published literature indicate diagnostic challenges and poor outcomes of CAPA in ICU patients., (© 2021 Wiley-VCH GmbH.)

Abstract: This study to analyze the clinical characteristics of patients with invasive pulmonary aspergillosis (IPA) following influenza A (H1N1) infection.We retrospectively analyzed 10 cases with IPA following H1N1 infection. The clinical manifestations, laboratory examination results, chest computed tomography, and treatments were analyzed.Clinical manifestations: all 10 cases had typical flu-like symptoms at the onset of the disease, among which 7 patients developed dyspnea in the late stage, and 8 patients had hemoptysis. Laboratory examination: the absolute and percentage of peripheral blood lymphocytes in all 10 patients were declined, among which 5 cases were with decreased CD3+ CD4+ T cells/lymphocytes; 9 cases with increased bronchoalveolar lavage fluid galactomannan; 6 cases with increased serum galactomannan; 1 case with bronchoalveolar lavage fluid cultured aspergillus fumigatus; and 2 cases with aspergillus by second-generation sequencing. Chest computed tomography: all patients showed multiple diffused ground-glass opacities at the beginning, along with linear or reticular interstitial changes. Two cases had multiple subarachnoid nodules with halo signs, 3 cases had consolidation in multiple segments of both lungs, 2 cases had cavities, and 4 cases were with pleural effusion. Treatment: 10 patients were treated with antiviral and anti-Aspergillus drugs after admission. Four patients received respiratory support. All 10 cases were cured and discharged.Early diagnosis of IPA in influenza A (H1N1) patients is the key to successful treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Our aim was to evaluate the performance of two galactomannan (GM) assays (Platelia Aspergillus EIA, Bio-Rad ® , and Aspergillus GM LFA, IMMY ® ) in tracheal aspirate (TA) samples of consecutive critically ill patients with COVID-19., Methods: We included critically ill patients, performed GM-EIA and GM-Lateral Flow Assay (GM-LFA) in TA and followed them until development of COVID-19-associated pulmonary aspergillosis (CAPA) or alternate diagnosis. CAPA was defined according to the modified AspICU criteria in patients with SARS-CoV-2 infection. We estimated sensitivity, specificity, positive and negative predictive values for GM-EIA, GM-LFA, the combination of both or either positive results for GM-EIA and GM-LFA. We explored accuracy using different breakpoints, through ROC analysis and Youden index to identify the optimal cut-offs. We described antifungal treatment and 30-day mortality., Results: We identified 14/144 (9.7%) patients with CAPA, mean age was 50.35 (SD 11.9), the median time from admission to CAPA was 8 days; 28.5% received tocilizumab and 30-day mortality was 57%. ROC analysis and Youden index identified 2.0 OD as the best cut-off, resulting in sensitivity and specificity of 57.1% and 81.5% for GM-EIA and 60% and 72.6% for GM-LFA, respectively., Conclusions: The diagnostic performance of GM in tracheal aspirates improved after using a cut-off of 2 OD. Although bronchoalveolar lavage testing is the ideal test, centres with limited access to bronchoscopy may consider this approach to identify or rule out CAPA., (© 2020 Wiley-VCH GmbH.)

Background: COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as an invasive fungal disease, often affecting previously immunocompetent, mechanically ventilated, intensive care unit (ICU) patients. Incidence rates of 3.8%-33.3% have been reported depending on the geographic area, with high (47%) mortality., Objectives: Here, we describe a single-centre prospective case series with CAPA cases from both the first (March-May, n = 5/33) and second (mid-September through mid-December, n = 8/33) COVID-19 wave at a 500-bed teaching hospital in the Netherlands., Patients/methods: In the first COVID-19 wave, a total of 265 SARS-CoV-2 PCR-positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, 508 SARS-CoV-2 PCR-positive patients were admitted of whom 33 needed mechanical ventilation. Data were prospectively collected., Results: We found a significant decrease in COVID-19 patients needing mechanical ventilation in the ICU in the second wave (p < .01). From these patients, however, a higher percentage were diagnosed with CAPA (24.2% vs 15.2%), although not significant (p = .36). All CAPA patients encountered in the second wave received dexamethasone. Mortality between both groups was similarly high (40%-50%). Moreover, we found environmental TR 34 /L98H azole-resistant Aspergillus fumigatus isolates in two separate patients., Conclusions: In this series, 19.7% (n = 13/66) of mechanically ventilated SARS-CoV-2 patients were diagnosed with CAPA. In addition, we found a significant reduction in COVID-19 patients needing mechanical ventilation on the ICU in the second wave. Numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS-CoV-2 therapy., (© 2021 The Authors. Mycoses published by Wiley-VCH GmbH.)

Recurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.

Competing Interests: The authors have declared that no competing interests exist.

Purpose: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment., Methods: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018., Results: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59)., Conclusion: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

Purpose: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies., Methods: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus., Results: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung., Conclusion: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.

Invasive pulmonary aspergillosis is a complication in critically ill patients with acute respiratory distress syndrome, especially those with severe influenza pneumonia. We report a fatal case of invasive pulmonary aspergillosis in an immunocompetent patient in France who had severe coronavirus disease-associated pneumonia.

Background and Objective: Chronic pulmonary aspergillosis (CPA) is associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). However, the clinical significance of the positivity of Aspergillus precipitating antibody (APAb), a serodiagnostic test for pulmonary aspergillosis (PA), at the time of MAC-LD diagnosis is unknown. The objective of this study was to investigate the effects of APAb test results on the clinical outcomes of patients with MAC-LD., Methods: We retrospectively analyzed patients who were newly diagnosed as having MAC-LD between 2007 and 2014 in our hospital and checked for APAb at the time of diagnosis., Results: We enrolled 131 patients in this study. Of these patients, 20 (15.3%) tested positive for APAb at the diagnosis of MAC-LD. The APAb-positive patients were more frequently male (70.0% vs. 37.8%, P = 0.013) and more frequently had pulmonary emphysema (60.0% vs. 13.5%, P < 0.001) and interstitial pneumonia (15.0% vs. 1.8%, P = 0.025) compared with the APAb-negative patients. During a median follow-up period of 4.0 years, PA developed in 12 of the APAb-positive patients (60.0%, CPA: 9 and allergic bronchopulmonary aspergillosis: 3) and 12 APAb-negative patients (10.8%, CPA: 12) (P < 0.001). The APAb-positive patients had a significantly higher rate of mortality than did the APAb-negative patients (P = 0.004). A multivariate analysis indicated that older age, lower albumin, fibrocavitary or fibrocavitary and nodular/bronchiectatic radiographic features, and APAb positivity were negative prognostic factors., Conclusions: APAb-positive patients with MAC-LD more frequently develop PA and may have an unfavorable prognosis., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Chronic pulmonary aspergillosis (CPA) is an underdiagnosed and misdiagnosed disease and now increasingly recognised. However, the diagnosis of CPA remains challenging. In this study, we aimed to investigate the diagnostic values of serum Aspergillus-specific IgG, IgA and IgM antibodies in patients with CPA., Methods: The prospective study was performed at Chinese People's Liberation Army General Hospital in Beijing, from January 2017 to December 2017. Adult patients with lung lesions presented as cavity, nodule, mass, bronchiectasis or severe fibrotic destruction with at least two lobes in CT imaging were enrolled. One hundred healthy persons were also enrolled as additional controls. The serum levels of Aspergillus-specific IgG, IgA and IgM antibodies and galactomannan (GM) levels were measured simultaneously by plate ELISA kit., Results: A total of 202 patients were enrolled in this study, including 42 CPA patients, 60 non-CPA patients and 100 healthy persons. The most common underlying lung diseases in CPA patients were bronchiectasis (28.6%) and COPD (19.0%). The most common symptoms in the CPA patients were cough (76.2%), sputum (71.4%), and fever (45.2%); chest pain (4.8%) was infrequent. Receiver operating characteristic (ROC) curve analysis revealed that the optimal CPA diagnostic cut-off of Aspergillus-specific IgG, IgA and IgM assays and GM test were 89.3 AU/mL, 8.2 U/mL, 73.3 AU/mL and 0.5μg/L, respectively. The serum levels of Aspergillus-specific IgG and IgA in CPA patients were higher than these in non-CPA patients or healthy persons. The sensitivities and specificities of Aspergillus-specific IgG, IgA, IgM tests and GM test were 78.6 and 94.4%, 64.3 and 89.4%, 50.0 and 53.7% and 71.4 and 58.1%, respectively., Conclusions: The sensitivity and specificity of serum Aspergillus-specific IgG assay are satisfactory for diagnosing CPA, while the performance of Aspergillus-specific IgA assay is moderate. Aspergillus-specific IgM assay and serum GM test have limited value for CPA diagnosis., Trial Registration: NCT03027089 . Registered 20 January 2017.

Summary: Allergic bronchopulmonary mycosis (ABPM) is a clinical syndrome associated with immune sensitivity to various fungi that colonize the airways. Early diagnosis and treatment with systemic corticosteroids is the key in preventing the progression of the disease to irreversible lung fibrosis. Although Aspergillus has progressively gained recognition as a causative agent in past few decades, other fungi, that have been reported to cause ABPM, are not yet widely evaluated. We studied hundred and two patients with asthma for occurrence of ABPM. Patients were tested for cutaneous hypersensitivity and serum precipitin to 12 common fungal antigens. The positive cases were further evaluated for ABPM using standard criteria. Out of 102 asthma patients screened, 18 patients had either skin prick test (SPT) and/or serum precipitin positive. While 14 patients were SPT positive for one or more fungal antigen, two patients were serum precipitin positive for one or more fungi. Two patients had both serum precipitin positive as well as SPT positive. Six (5.8%) patients were diagnosed as ABPM as they fulfilled the criteria. Three of these were because of Aspergillus sp. Two were because of fungi other than Aspergillus namely Schizophyllum and Curvularia. One patient had ABPM because of both Aspergillus and Curvularia. In our study absolute eosinophil count (AEC), total IgE, serum precipitin and SPT had sensitivity of 100%, 100% 50% and 83.3% respectively for diagnosing ABPM. The specificity of these tests was 44.79%, 64.58% 98.96% and 88.54% respectively. Specfic IgE was positive in 50% of patients with either serum precipitin or SPT positivity. SPT or serum precipitin followed by specific IgE had sensitivity of 100% and specificity of 96.88% for diagnosing ABPM. SPT alone followed by Specific IgE had a sensitivity of 83.33% and specificity of 96.88% for diagnosing ABPM. We found that fungi other than Aspergillus such as schizophyllum, and curvularia, can be implicated in ABPM. Multiple fungal agents may be responsible for ABPM in an individual. There is a subset of patients of BA who have fungal sensitization but do not fulfil the criteria for ABPM. SPT was the single most sensitive and specific test, AEC >350 and total IgE more than 417IU were most sensitive tests and SPT followed by specific IgE was most effective strategy for diagnosing ABPM.

The frequency and importance of Aspergillus infections is increasing worldwide. This study aimed to assess the occupational exposure of forklifts and taxi drivers to Aspergillus spp. Nineteen filters from air conditioning system of taxis, 17 from forklifts and 37 from personal vehicles were assessed. Filters extract were streaked onto MEA, DG18 and in azole-supplemented media. Real-time quantitative PCR amplification of selected Aspergillus species-complex was also performed. Forklifts filter samples presented higher median values. Aspergillus section Nigri was the most observed in forklifts filters in MEA (28.2%) and in azole-supplemented media. DNA from Aspergillus sections Fumigati and Versicolores was successfully amplified by qPCR. This study enlightens the added value of using filters from the air conditioning system to assess Aspergillus spp. occupational exposure. Aspergillus azole resistance screening should be included in future occupational exposure assessments.

Progressive fibrobullous changes in the residual lobes are sometimes observed after lobectomy. Aspergillus osteomyelitis is an uncommon infection that rarely occurs sternally. A 70-year-old man who had undergone lobectomy 12 years earlier was admitted to our hospital for chest pain. He was diagnosed with Aspergillus sternomyelitis based on sternal bone culture after an ultrasound-guided percutaneous needle biopsy. The fibrosis and right residual lung apex volume loss had gradually progressed over 12 years, and therefore, chronic pulmonary aspergillosis (CPA) with direct invasion sternal from the CPA was considered. Aspergillus sternomyelitis can develop from CPA as a late complication of lobectomy.

Background: The number of patients with pulmonary nontuberculous mycobacterial disease complicated by chronic pulmonary aspergillosis (CPA) has been increasing. Additionally, CPA is reportedly associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). In the present study, we aimed to identify risk factors for developing CPA and stratify the risk for CPA development in patients with MAC-LD., Methods: We retrospectively examined 361 patients newly diagnosed with MAC-LD. Risk factors for CPA development were examined using multivariate Cox proportional hazards regression analyses. A risk stratification system was established using the risk factors and receiver operating characteristic curve analyses., Results: CPA developed in 20 (5.5%) of the 361 patients. Independent risk factors for CPA development included the presence of pulmonary emphysema, baseline steroid use, a serum albumin level <3.5 g/dL, and the presence of MAC-LD cavities. A 4-point scoring system was established to stratify patients into low-risk (0-1 point) and high-risk (2-4 points) groups. The 5-year incidence rates of CPA were 2.2% and 31% in the low- and high-risk groups, respectively (P < 0.001)., Conclusions: We identified independent predictors of CPA development and established a simple risk stratification system for identifying patients with MAC-LD who were at a high risk of developing CPA., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Pulmonary non-tuberculous mycobacterial disease (PNTM) is a known risk factor for chronic pulmonary aspergillosis (CPA). However, few studies have focused on the prognosis of PNTM-associated CPA. In the present investigation, we aimed to elucidate the clinical course and prognostic factors of CPA in patients with PNTM., Methods: We retrospectively investigated the medical records of 62 patients with CPA and a history of PNTM who were admitted to Kinki-chuo Chest Medical Center between 2010 and 2015. Co-morbidities, causative microorganisms, radiological findings, and outcomes were evaluated., Results: The patients' median age was 69.5 years, and the median follow-up period was 4.2 years. The major underlying diseases, other than PNTM and CPA, were old pulmonary tuberculosis, chronic obstructive pulmonary disease, and interstitial pneumonia. The most common causative NTM species were Mycobacterium avium complex (MAC; 37 patients; 59.7%) and Mycobacterium kansasii (20 patients; 32.3%). Survival was 83% after 1 year and 61% after 5 years. Use of systemic corticosteroids (hazard ratio: 3.32, 95% confidence interval: 1.23-9.51; P=0.00177) and C-reactive protein levels ≥ 5.0 mg/dL (hazard ratio: 8.96, 95% confidence interval: 2.15-62.9; P=0.0014) at the time of CPA diagnosis were associated with increased over-all mortality., Conclusions: CPA frequently developed in patients with MAC and M. kansasii PNTM. The treatment course of PNTM was not associated with all-cause mortality. However, systemic corticosteroid use and high CRP levels were negative prognostic factors of CPA in patients with PNTM. Since the prognosis is poor, early diagnosis and treatment of CPA are important in patients with PNTM., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Sarcoidosis is a granulomatous disease of unknown cause, occurs worldwide and has a highly variable prevalence. The disease is typically dominant in the lungs, although it can affect virtually any organ and is unpredictable in its clinical course. The severity of pulmonary sarcoidosis ranges from incidentally discovered radiographic abnormalities in asymptomatic patients to a chronic progressive disease that is refractory to treatment. Mortality from sarcoidosis appears to have increased in the past three decades, with respiratory failure being the most common cause of sarcoidosis-related death. Pulmonary fibrosis, extensive disease on high-resolution chest CT, impaired lung function, and pulmonary hypertension are well established predictors of poor clinical outcomes. In patients who need systemic therapy to control their disease, corticosteroids are the most commonly used first-line treatment, with antimetabolites generally representing an alternative for patients who are unresponsive to corticosteroids or who cannot tolerate them. Indeed, corticosteroid therapy is associated with toxic effects that correlate with both the cumulative dose and duration of treatment. The scarcity of truly effective therapies and shortage of reliable predictors of the unpredictable development of disease in individual patients greatly contribute to making sarcoidosis such a difficult disease to manage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Aspergillomas occur due to colonization of a pre-existing pulmonary, bronchial or pleural cavity by Aspergillus spp. Often asymptomatic, this pathology can reveal itself by recurrent haemoptysis or when bacterial superinfections occur. Aspergillomas occurring in post-traumatic cavities are rare and their management is poorly codified., Case Report: A child suffered from a chest wound at the age of 13 years. Two years later, investigation of recurrent haemoptysis revealed a residual pneumatocele in the right lower lobe colonized by Aspergillus spp. Initial treatment with systemic azole antifungals was unsuccessful because of digestive and ophthalmological intolerance. Surgical treatment by right lower lobectomy was finally decided on by the multidisciplinary team. This revealed an intrabronchial foreign body of vegetal type with cellulosic reinforcement, causing a polymorphic granulomatous reaction around, and associated with a proliferation of filamentous fungi including Aspergillus fumigatus. Surgery was followed by liposomal amphotericin B treatment for three weeks with a favourable outcome., Conclusions: This clinical case illustrates the benefits of surgical management of post-traumatic aspergillomas, even in children, in order to eradicate the aspergillus implant and to remove any foreign body to prevent recurrence., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Hemoptysis is a symptom that can be caused by airway disease, pulmonary parenchymal disease, or pulmonary vascular disease, or it can be idiopathic. Infection is the most common cause of hemoptysis, accounting for 60% to 70% of cases. Hemoptysis is also an initial symptom of diffuse alveolar hemorrhage syndrome, although it may be absent at presentation in one-third of patients. Diffuse alveolar hemorrhage is characterized by disruption of the alveolar-capillary basement membranes because of either injury or inflammation of the arterioles, venules, or capillaries, resulting in bleeding in alveolar spaces. To date, no study in the literature has investigated the cause of hemoptysis in renal transplant patients. In this retrospective study, we aimed to investigate the causes of hemoptysis in renal recipients., Materials and Methods: The data included in this study were obtained from 352 renal transplant patients who were consulted by the pulmonology department regarding hemoptysis between 2011 and 2017 at Baskent University. Patient medical records were reviewed for demographic, clinical, radiographic, bronchoscopic features, and microbiology data. Immunosuppressive drugs and clinical outcome data were also noted., Results: This study included 352 renal transplant patients (139 male patients with mean age of 34.9 ± 7 years and 113 female patients with mean age of 31.1 ± 5 years). Hemoptysis was detected in 17 patients (4.8%),with 3 (0.85%) having massive hemoptysis as a result of diffuse alveolar hemorrhage syndrome. Fourteen of our patient group (4%) had pneumonia, and Aspergillus species was detected in 5 patients (1.4%). The only reason for diffuse alveolar hemorrhage was immunosuppressive agents, including sirolimus and mycophenolate mofetil., Conclusions: Hemoptysis is an important respiratory symptom in renal transplant patients. Although community- or hospital-acquired pneumonia may result in hemoptysis, drug-induced diffuse alveolar hemorrhage and Aspergillus infection should be considered for causes in renal transplant patients.

Chronic pulmonary aspergillosis (CPA) is an overlooked disease category in which delay of diagnosis and treatment is associated with increased mortality. A prerequisite for prognostic optimization of CPA is an increased focus on predisposing factors and patients at risk. Diagnosis of CPA is challenging and requires a systematic approach to assessment and interpretation of findings, both of which are necessary for correct disease classification and selection of targeted antifungal treatment and duration.

Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT) and bis-methyl-gliotoxin (bmGT) are secondary metabolites produced by Aspergillus during invasive, hyphal growth and may prove diagnostically useful. Because IA pathophysiology and GT's role in virulence vary depending on the underlying host immune status, we hypothesized that GT and bmGT production in vivo may differ in three mouse models of IA that mimic human disease. We defined temporal kinetics of GT and bmGT in serum, bronchoalveolar lavage fluid (BALF) and lungs of A. fumigatus-infected chronic granulomatous disease (CGD), hydrocortisone-treated, and neutropenic mice. We harvested lungs for assessment of fungal burden, histology and GT/bmGT biosynthetic genes' mRNA induction. GT levels were higher in neutropenic versus CGD or steroid-treated lungs. bmGT was persistently detected only in CGD lungs. GT, but not bmGT, was detected in 71% of sera and 50% of BALF of neutropenic mice; neither was detected in serum/BALF of CGD or steroid-treated mice. Enrichment of GT in Aspergillus-infected neutropenic lung correlated with fungal burden and hyphal length but not induction of GT biosynthetic genes. In summary, GT is detectable in mouse lungs, serum and BALF during neutropenic IA, suggesting that GT may be useful to diagnose IA in neutropenic patients.

We present a fatal case of Aspergillus-associated lung failure in a patient with necrotizing fasciitis. The cause of the fasciitis was a retroperitoneal perforation of a colon carcinoma. Being already a rare condition, the fasciitis did not manifest as Fournier's gangrene like similar described cases illustrate, but instead travelled along the fasciae and subcutaneous fat tissue cranially into the thoracic cavity, ultimately leading to a disseminated infection of the lungs. The lethal outcome was thus caused by respiratory failure at a time when the primary focus was already successfully treated, contrary to typical cases of necrotizing fasciitis. This case report depicts the importance of acknowledging opportunistic fungal infections in the practice of emergency surgery. Contributing factors, pathogenesis and possible prevention measures are discussed., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Case Presentation: An African American man in his late 30s was referred to the pulmonary clinic for evaluation of a persistent cough of several weeks' duration. Cough was productive of mucopurulent sputum mixed with blood. He also noted generalized weakness and dyspnea with minimal exertion., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Invasive pulmonary aspergillosis (IPA) is one of the major complications in immunocompromised patients. The mainstay of diagnostic imaging is non-enhanced chest-computed-tomography (CT), for which various non-specific signs for IPA have been described. However, contrast-enhanced CT pulmonary angiography (CTPA) has shown promising results, as the vessel occlusion sign (VOS) seems to be more sensitive and specific for IPA in hematologic patients. The aim of this study was to evaluate the diagnostic accuracy of CTPA in a larger cohort including non-hematologic immunocompromised patients. CTPA studies of 78 consecutive immunocompromised patients with proven/probable IPA were analyzed. 45 immunocompromised patients without IPA served as a control group. Diagnostic performance of CTPA-detected VOS and of radiological signs that do not require contrast-media were analyzed. Of 12 evaluable radiological signs, five were found to be significantly associated with IPA. The VOS showed the highest diagnostic performance with a sensitivity of 0.94, specificity of 0.71 and a diagnostic odds-ratio of 36.8. Regression analysis revealed the two strongest independent radiological predictors for IPA to be the VOS and the halo sign. The VOS is highly suggestive for IPA in immunocompromised patients in general. Thus, contrast-enhanced CTPA superior over non-contrast&#95;enhanced chest-CT in patients with suspected IPA.

Background: A previous study explored factors discriminating colonization and true infection among non-transplant, non-neutropenic patients with repeated Aspergillus spp. isolation from lower respiratory samples. The present study explored the evolution of patients with Aspergillus colonization in that study to determine the percentage of cases progressing to aspergillosis and time to development., Methods: Clinical records were retrospectively reviewed (for each patient from his end date in the past study) and data from all respiratory processes suffered by patients up to April 2015 were recorded. Comparisons of variables were performed between colonized patients that developed aspergillosis and those that did not. A Kaplan-Meier curve was used to describe time to development of aspergillosis in chronic obstructive pulmonary disease (COPD) patients for II-IV stages of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification., Results: Sixty seven colonized patients were followed, 12 of them (17.9%) developed aspergillosis. Diagnoses included six tracheobronchitis (4 invasive, 2 simple tracheobronchitis), four pulmonary disease (2 invasive pulmonary aspergillosis, 2 chronic pulmonary aspergillosis), one allergic bronchopulmonary aspergillosis and one pulmonary aspergilloma. Up to 47 (70.4%) of the study patients presented COPD. Among patients developing aspergillosis COPD was more frequent (100%) than among those that did not develop aspergillosis (35 out of 55; 63.6%) (p = 0.012), as well as GOLD IV patients were more frequent among COPD patients developing aspergillosis than among COPD patients that did not (50.0 vs. 26.1%, p = 0.046). Mean time to development of aspergillosis was 18.4 months (median: 8.5) with a wide range (1-58). Overtime, the percentage of patients developing aspergillosis was significantly higher among GOLD IV patients than among GOLD II-III patients (p = 0.032)., Conclusions: The high percentage of cases progressing to aspergillosis among colonized patients, especially among those with COPD (25.5%), stresses the importance of colonization as risk factor, and creates awareness of the possible change from colonization to invasive disease in GOLD IV patients.

Background: Aspergillus fumigatus is frequently recovered from respiratory secretions of cystic fibrosis (CF) patients. Azole resistance has been increasingly reported., Objectives: To assess the prevalence of azole resistance in A. fumigatus isolates from patients followed by two CF centers of northern Italy., Methods: 423 isolates (220 patients) were screened for azole resistance. Resistance was confirmed with the EUCAST method and cyp51A gene sequencing. Microsatellite genotyping was performed and results were compared with those of environmental resistant isolates., Results: No resistance was detected in one center, while 8.2% of the patients of the other center harbored resistant isolates. The TR 34 /L98H alteration in the cyp51A gene, present in seven cases, resulted associated with poor in-vitro activity of all tested azoles., Conclusions: The environmental origin of the resistance seems to be probable since azole resistance was found also in naïve patients and an identical microsatellite genotype in clinical and environmental isolates was observed., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

We present a case of a patient who following chemotherapy developed semi-invasive pulmonary aspergillosis and an aspergilloma in a lung cavity previously formed by microwave ablation (MWA). A 55-year-old woman presented with cough and shortness of breath after finishing three cycles of chemotherapy for a metastatic nerve sheath tumour. She had been treated by MWA for pulmonary metastases 2 years previously which resulted in a residual right apical lung cavity. Postchemotherapy imaging showed that this cavity had enlarged, developed a thicker wall and contained lobulated soft tissue with a crescent sign on coronal reformats. In addition, the patient's Aspergillus-specific IgG was markedly raised. Treatment with itraconazole improved the symptoms and reduced the cavity size and wall thickness. This case shows that persisting lung cavities after MWA are a potential site for semi-invasive aspergillosis and has implications for the timing of chemotherapy in patient with metastatic lung disease., (2016 BMJ Publishing Group Ltd.)

Patients with cystic fibrosis (CF) suffer from chronic lung infection and airway inflammation. Respiratory failure secondary to chronic or recurrent infection remains the commonest cause of death and accounts for over 90% of mortality. Bacteria as Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia complex have been regarded the main CF pathogens and their role in progressive lung decline has been studied extensively. Little attention has been paid to the role of Aspergillus spp. and other filamentous fungi in the pathogenesis of non-ABPA (allergic bronchopulmonary aspergillosis) respiratory disease in CF, despite their frequent recovery in respiratory samples. It has become more apparent however, that Aspergillus spp. may play an important role in chronic lung disease in CF. Research delineating the underlying mechanisms of Aspergillus persistence and infection in the CF lung and its link to lung deterioration is lacking. This review summarizes the Aspergillus disease phenotypes observed in CF, discusses the role of CFTR (cystic fibrosis transmembrane conductance regulator)-protein in innate immune responses and new treatment modalities., (Copyright © 2016. Published by Elsevier Ltd.)

Endobronchial aspergilloma is a rare and unusual presentation of lung aspergilloma; the natural history for such rare diseases is poorly understood. This report presents two cases of endobronchial aspergilloma complicated by primary and metastatic lung cancer, and summarizes previous reports that suggest that an endobronchial lung cancer lesion may promote the colonialization and growth of Aspergillus species in the bronchus. Therefore, if endobronchial aspergilloma is found, the complication of primary or metastatic endobronchial lung cancer should be carefully considered., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

A 50-year-old man with hemoptysis, given a diagnosis of left upper lobe pulmonary aspergilloma with cavity and fungus ball by computed tomography. He has a history of typeⅠ diabetes mellitus due to traumatic injury of pancreas and underwent diaphragm plasty. Despite of systemic anti-fungal medication, symptom and radiological findings were not progressed and surgical intervention was planned. Before surgery we performed intercostal artery embolization, in order to minimize bleeding on dissecting adhesion between the chest wall and the lobe with aspergilloma. Left upper lobectomy with muscle-flap prombage was done safely with a blood loss of 450 ml. Postoperative course was favorable. Intercostal artery embolization with N-butyl-2cyanoacrylate is an effective way to minimize hemorrhage during surgical resection for pulmonary aspergillosis with sever adhesion.

Background: With advancements in anti-fungal drugs, it has become more important to correctly diagnose chronic pulmonary aspergillosis (CPA); however, it is not easy to distinguish CPA from colonization when Aspergillus species are isolated from respiratory samples. The aim of the study was to clarify the particular clinical characteristics of patients with CPA vs. those with colonization., Methods: We retrospectively reviewed the medical records of 110 patients with Aspergillus species isolation from respiratory samples, to analyze and compare the differences between CPA and colonization of the Aspergillus species., Results: The median age of all analyzed was 71 years (range: 31-92 years); 64 were female (58%). The most frequently cultured Aspergillus species was Aspergillus fumigatus (48.3%), followed by A. niger (29.2%). Thirty patients (27.4%) were diagnosed with CPA, vs. 75 (68.2%) with colonization and 5 (4.5%) with allergic bronchopulmonary aspergillosis. Compared with the colonization group, the CPA group included more males (CPA vs. colonization: 49.3% vs. 13.3%) and subjects with a low body mass index (18.45 kg/m2 vs. 21.09 kg/m2). As for the underlying pulmonary diseases, the patients with CPA showed a significantly higher prevalence of sequelae of pulmonary tuberculosis (40% vs. 8%) and a history of thoracic surgery (43% vs. 13%) than those with colonization. Asthma was less frequent in the CPA group than in the colonization group (0% vs. 20%). We found no significantly important underlying extrapulmonary diseases., Conclusions: Patients with CPA display clinical characteristics distinct from those seen in subjects with colonization., (Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Chronic pulmonary aspergillosis (CPA) is an emerging complication after lobectomy for lung cancer. This retrospective study aimed to determine the incidence, main risk factors and clinical features of postoperative CPA in lung cancer patients., Methods: This study included lung cancer patients treated by lobectomy and with no previous history of thoracic surgery or coexistent aspergillosis at the time of surgery. The cumulative incidence of CPA was determined using death as a competing risk. Furthermore, the identified lung cancer patients were divided into CPA and non-CPA groups to compare their preoperative clinical features and to identify the risk factors of postoperative CPA by univariable and multivariable analyses. We also analysed the clinical features of CPA patients after diagnosis., Results: We included 475 lung cancer patients. Of these, 17 patients (3.6%) developed CPA after the lobectomy. The cumulative postoperative incidence rate of CPA was 2.3% [95% confidence interval (CI), 0.8-3.8%] at 5 years and 7.9% (95% CI, 3.0-13.0%) at 10 years. There were significantly more men (P = 0.007), smokers (P = 0.002) and comorbid chronic obstructive pulmonary disease (COPD) (P = 0.008) and interstitial lung disease (ILD) (P = 0.009) patients in the CPA group than in the non-CPA group. Multivariable analysis identified comorbid COPD (P = 0.0019) and ILD (P = 0.0003) as significant risk factors. An antifungal treatment response was obtained in 6 patients (35%). The 1-year survival rate was 47% (follow-up periods, interquartile range: 3-78 months), and 5 of the total of 11 deaths were due to CPA., Conclusions: Through the present retrospective study, CPA seems to be a common sequel to lobectomy in lung cancer patients, and COPD and ILD represent strong risk factors of postoperative CPA. Because of the poor clinical outcome of lung cancer patients who develop CPA after lobectomy, careful follow-up using several examinations and chest radiographs to make CPA diagnosis may be essential., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)