Search

The clinical features by declining lung function remain uncharacterized in chronic pulmonary aspergillosis (CPA) patients. We investigated the clinical characteristics of CPA patients based on spirometric impairments (restrictive spirometric pattern [RSP] and obstructive spirometric pattern [OSP]) and their severity. We retrospectively analyzed medical records of CPA patients who underwent pulmonary function tests from March 2017 to February 2020. We used Global Lung Initiative 2012 equations with lower limit of normal. The clinical characteristics of patients with RSP were compared to those with OSP. Additionally, RSP patients' characteristics were analyzed according to forced vital capacity (FVC) tertile, and OSP patients' characteristics were analyzed according to forced expiratory volume in 1 second (FEV1) tertile. Among the 112 patients with CPA (52 [46%] with RSP and 60 [54%] with OSP), body mass index (BMI) was significantly lower in patients with RSP than in those with OSP (17.6 kg/m2 versus 20.3 kg/m2; P = 0.003), and non-tuberculous mycobacterial disease was more frequently observed in patients with RSP than in those with OSP (28.8% versus 11.7%; P = 0.004). Additionally, for patients with RSP, younger age and bilateral pulmonary lesions were more frequently observed in the first tertile group than in the other groups (P for trend: 0.025 and 0.001, respectively). For patients with OSP, low BMI, paracavitary infiltrates, and elevated WBC count were more frequently observed in the first tertile group than in the other groups (P for trend: < 0.001, 0.011, and 0.041, respectively). Differences in the clinical features of CPA patients were identified according to heterogeneous spirometric patterns and their severity. Further studies are needed to investigate the clinical significance of these findings., Competing Interests: The authors have declared that no competing interests exist.

Background: Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger)., Methods: C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 μg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined., Results: In comparison to mice challenged only with A. niger, addition of LPS (1 μg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and T H 2 responses while enhancing T H 1 and T H 17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies., Conclusions: In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP., (© 2021. The Author(s).)

Competing Interests: Competing interests: None declared.

This study aimed to evaluate the impact of quantitative baseline Aspergillus-specific immunoglobulin G (IgG) serum levels on weight changes of patients with chronic pulmonary aspergillosis (CPA) under antifungal treatment. We retrospectively reviewed data of patients diagnosed with CPA between April 2015 and March 2018 at the National Aspergillosis Centre (Manchester, UK). All patients were on continued antifungal treatment for 12 months. Data on Aspergillus-specific IgG levels, St George's quality of life (SGQoL) variables and weight at baseline, 6 months and 12 months were extracted. We defined a high serum Aspergillus-specific IgG as ≥ 200 mg/l (Group A) and low level < 200 mg/l (Group B). Forty-nine patients (37 male; 12 female), median age 65 years (range: 29-86) were studied. Overall, 33% (n = 16) of the patients were in Group A. The baseline characteristics between the two groups were similar. The median Charlson comorbidity index was 4 (range: 0-5) and 3 (range: 0-9) for Group A and Group B, respectively (P = .543). There was a sustained decline in median Aspergillus IgG levels from baseline, through 6 month to 12 months of continues therapy from 170 (range: 20-1110) to 121 (range: 20-1126), and finally 107 (15-937) mg/l, respectively (P < .001). Group A patients gained more weight at 6 months (9/15 [60%] vs. 7/33 [21%], P = .012) and at 12 months of treatment (9/15 [60%] vs. 7/33 [22%]), and more patients in Group B lost weight ((13/33 [41%] vs. 1/15 [7%]), P = .015). However, there was no difference in QoL outcomes across groups at 6 (P = .3) and 12 (P = .7) months. A very high Aspergillus IgG may confer a higher likelihood of weight gain as a key, objective marker of clinical response, if patients can tolerate 12 months of antifungal therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Introduction: Chronic pulmonary aspergillosis (CPA) is a fungal disease with high mortality and morbidity. Guidelines suggest treatment with azoles as first-line therapy. However, patients often develop treatment intolerance or increasingly azole resistance., Objectives: This retrospective review assesses outcomes in azole resistant or intolerant patients with CPA treated with cyclical echinocandin therapy., Methods: We retrospectively examined records of 25 patients with CPA treated with cyclical caspofungin, 6 of whom were either azole-resistant or azole intolerant. Baseline characteristics, high-resolution computed tomography severity scores, forced expiratory volume after 1 minute (FEV1), forced vital capacity (FVC), body mass index and serology (Aspergillus fumigatus-specific IgG, Aspergillus fumigatus-specific IgE, total IgE and CRP) were assessed before and after caspofungin., Results: Of the six patients, four (66%) started caspofungin due to intolerance and two (33%) due to pan-azole resistance. On treatment, there was stability in FEV1 with an overall mortality of 33% during the follow-up period with a median survival of 875.5 days (IQR 529-1024). No significant change in serology (A. fumigatus-specific IgG and CRP was seen., Conclusions: With pulsed echinocandin therapy, azole-intolerant or pan-resistant CPA patients have similar mortality rates to azole-naïve CPA patients. Pulsed echinocandin therapy may present a strategy to stabilize CPA in patients with pan resistance or intolerance to, azole therapy., (© 2020 John Wiley & Sons Ltd.)

Objectives: The treatment response in chronic pulmonary aspergillosis (CPA) is usually assessed based on the improvement in clinical and imaging findings. Herein, we evaluate serum Aspergillus fumigatus-specific IgG, serum galactomannan, weight change, and lung function for assessing treatment response in subjects with CPA., Methods: We categorized treatment response as favourable (improved or stable clinical response with radiologically improved or stable disease) or unfavourable (worsening of symptoms or radiological progression) after 6 months of treatment with antifungal azoles. We measured A. fumigatus-specific IgG, serum galactomannan, weight, and lung function at baseline, 3 months, and 6 months in those with favourable and unfavourable treatment response., Results: One hundred and twenty-six consecutive treatment-naïve subjects (53.2% (67/126) males; mean ± SD age, 42.3 ± 14.7 years) with CPA were included. One hundred and six and 20 were classified as having favourable and unfavourable response, respectively. After 6 months of treatment, the decline in serum A. fumigatus-specific IgG (n = 119) was similar in those with favourable or unfavourable response (mean ± SD, -26.3 ± 45.5 mgA/L vs. -3.4 ± 65.6 mgA/L; p 0.20). There was no significant change in the serum galactomannan (favourable vs. unfavourable: mean ± SD, -0.11 ± 2.8 vs. -0.62 ± 2; p 0.92) or FEV1 (favourable vs. unfavourable: mean ± SD, 24 ± 250 mL vs. -62 ± 154 mL; p 0.19) after 6 months of treatment. There was significant loss of weight (mean ± SD, -2.5 ± 4.5 kg) in subjects with unfavourable response., Conclusion: Serum A. fumigatus-specific IgG and serum galactomannan inconsistently decrease following treatment and may not be useful indicators for monitoring treatment response in CPA. Similarly, there is little change in pulmonary function following treatment. A gain in body weight is seen in those with favourable response., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

A 64-year-old man who presented with repeated bouts of pneumothorax was admitted to our hospital because of gradually progressive dyspnea and repeated episodes of a fever. The physiological, radiological and pathological findings were consistent with pleuroparenchymal fibroelastosis (PPFE). In addition, the serum-specific precipitating antibody for Aspergillus was positive. After the administration of voriconazole, a marked improvement was observed in the imaging and physiological findings. Given this clinical course, we diagnosed the patient with PPFE secondary to aspergillosis. The present case suggests that a therapeutic approach based on the cause of secondary PPFE may improve the prognosis of PPFE.

Aspergillus colonization of the lower respiratory airways is common in normal people, and of little clinical significance. However, in some patients, colonization is associated with severe disease including poorly controlled asthma, allergic bronchopulmonary aspergillosis (ABPA) with sputum plugs, worse lung function in chronic obstructive pulmonary aspergillosis (COPD), invasive aspergillosis, and active infection in patients with chronic pulmonary aspergillosis (CPA). Therefore, understanding the pathophysiological mechanisms of fungal colonization in disease is essential to develop strategies to avert or minimise disease. Aspergillus cell components promoting fungal adherence to the host surface, extracellular matrix, or basal lamina are indispensable for pathogen persistence. However, our understanding of individual differences in clearance of A. fumigatus from the lung in susceptible patients is close to zero., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Coexistence of aspergilloma and allergic bronchopulmonary aspergillosis (ABPA) has rarely been reported. Although the treatment for ABPA includes administration of corticosteroids and antifungal agents, little is known about the treatment for coexisting aspergilloma and ABPA. Furthermore, the impact of surgical resection for aspergilloma on ABPA is not fully understood. Here, we present an interesting case of recurrent ABPA with long-term follow-up after surgical resection of aspergilloma., Case Presentation: A 53-year-old man with a medical history of tuberculosis was referred to our hospital with cough and dyspnea. Imaging revealed multiple cavitary lesions in the right upper lobe of the lung, with a fungus ball and mucoid impaction. The eosinophil count, total serum immunoglobulin E (IgE), and Aspergillus-specific IgE levels were elevated. Specimens collected on bronchoscopy revealed fungal filaments compatible with Aspergillus species. Based on these findings, a diagnosis of ABPA with concomitant aspergilloma was made. Although treatment with corticosteroids and antifungal agents was administered, the patient's respiratory symptoms persisted. Therefore, he underwent lobectomy of the right upper lobe, which resulted in a stable condition without the need for medication. Twenty-three months after discontinuation of medical treatment, his respiratory symptoms gradually worsened with a recurrence of elevated eosinophil count and total serum IgE. Imaging revealed recurrent bronchiectasis and cavities with mucoid impaction in the right lower lobe, suggesting relapse of aspergilloma and ABPA. Corticosteroids and antifungal agents were re-administered; aspergilloma improved slightly over a 5-year period, and ABPA remained well controlled with low-dose prednisolone (5 mg/day)., Conclusions: We describe the long-term follow-up outcomes of a patient with concomitant ABPA and aspergilloma, who underwent surgical resection for aspergilloma. Physicians should carefully monitor patients with coexisting ABPA and aspergilloma, as the condition may relapse after remission, even despite surgical resection for aspergilloma. Additionally, surgical resection for aspergilloma could result in resolution of ABPA.

Humans are constantly exposed to the opportunistic mold Aspergillus fumigatus , and disease caused by this pathogen is often determined by the magnitude of local and systemic immune responses. We have previously shown a protective role for interleukin-22 (IL-22) after acute A. fumigatus exposure. Here, employing IL-22 Cre R26R eYFP reporter mice, we identified iNKT cells, γδ T cells, and type 3 innate lymphoid cells (ILC3s) as lung cell sources of IL-22 in response to acute A. fumigatus exposure. As these cells often utilize common γ-chain cytokines for their development or maintenance, we determined the role of IL-7, IL-21, and IL-15 in lung IL-22 induction and A. fumigatus lung clearance. We observed that IL-7, IL-21, and IL-15 were essential for, partially required for, or negatively regulated the production of IL-22, respectively. Deficiency in IL-7 and IL-21, but not IL-15R, resulted in impaired fungal clearance. Surprisingly, however, the absence of IL-7, IL-21, or IL-15R signaling had no effect on neutrophil recruitment. The levels of IL-1α, an essential anti- A. fumigatus proinflammatory cytokine, were increased in the absence of IL-7 and IL-15R but decreased in the absence of IL-21. IL-7 was responsible for maintaining lung iNKT cells and γδ T cells, whereas IL-21 was responsible for maintaining lung iNKT cells and ILC3s. In contrast, IL-15R deficiency had no effect on the absolute numbers of any IL-22 cell source, rather resulting in enhanced per cell production of IL-22 by iNKT cells and γδ T cells. Collectively, these results provide insight into how the IL-22 response in the lung is shaped after acute A. fumigatus exposure., (Copyright © 2018 American Society for Microbiology.)

Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) ( Chia ) deficiency on host defense during acute exposure to the fungal pathogen Aspergillus fumigatus as well as its contribution to A. fumigatus -associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in A. fumigatus conidia, which emerged at the highest level during hyphal transition. In response to acute A. fumigatus challenge, Chia -/- mice unexpectedly demonstrated lower A. fumigatus lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E 2 (PGE 2 ) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronic A. fumigatus exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses., (Copyright © 2018 American Society for Microbiology.)

The pulmonary mucus of cystic fibrosis (CF) patients displays elevated levels of the cathelicidin antimicrobial peptide LL-37, and the aim of this work was to assess the effect of LL-37 on the growth of Aspergillus fumigatus , a common pathogen of CF patients. Exposure of A. fumigatus to LL-37 and its derived fragment RK-31 (1.95 μg/ml) for 24 h had a positive effect on growth (199.94% ± 6.172% [ P < 0.05] and 218.20% ± 4.63% [ P < 0.05], respectively), whereas scrambled LL-37 peptide did not (85.12% ± 2.92%). Exposure of mycelium (preformed for 24 h) to 5 μg/ml intact LL-37 for 48 h increased hyphal wet weight (4.37 ± 0.23 g, P < 0.001) compared to the control (2.67 ± 0.05 g) and scrambled LL-37 (2.23 ± 0.09 g) treatments. Gliotoxin secretion from LL-37 exposed hyphae (169.1 ± 6.36 ng/mg hyphae, P < 0.05) was increased at 24 h compared to the results seen with the control treatment (102 ± 18.81 ng/mg hyphae) and the scrambled LL-37 treatment (96.09 ± 15.15 ng/mg hyphae). Shotgun proteomic analysis of 24-h LL-37-treated hyphae revealed an increase in the abundance of proteins associated with growth (eukaryotic translation initiation factor 5A [eIF-5A] [16.3-fold increased]), tissue degradation (aspartic endopeptidase [4.7-fold increased]), and allergic reactions (Asp F13 [10-fold increased]). By 48 h, there was an increase in protein levels indicative of cellular stress (glutathione peroxidase [9-fold increased]), growth (eIF-5A [6-fold increased]), and virulence (RNase mitogillin [3.7-fold increased]). These results indicate that LL-37 stimulates A. fumigatus growth and that this stimulation can result in increased fungal growth and secretion of toxins in the lungs of CF patients., (Copyright © 2018 American Society for Microbiology.)

Rationale: Little is known about the role of Aspergillus precipitating antibody (APAb) in patients with Mycobacterium avium complex lung disease (MAC-LD)., Objectives: We investigated the clinical characteristics of patients with MAC-LD positive for APAb., Methods: We conducted a cross-sectional study targeting patients with MAC-LD. APAb was checked in all participants. Clinical variables included laboratory data, pulmonary function, high-resolution computed tomography findings, and health-related quality of life., Results: We analyzed 109 consecutive patients. Their median age was 68 years, and the median duration of MAC-LD was 4.8 years. Twenty (18.3%) patients tested positive for APAb. APAb-positive patients had significantly longer duration of MAC-LD (9.4 vs. 4.0 years, P = 0.017), more severe bronchiectasis evaluated by modified Reiff score (6.5 vs. 4, P = 0.0049), and lower forced expiratory volume in 1 s (%FEV 1 ) (75.1% vs. 86.2%, P = 0.013) than APAb-negative patients. Analysis of covariance adjusted for background factors and underlying pulmonary disease revealed that %FEV 1 was also significantly lower in patients with APAb (P = 0.045). Ten patients were newly diagnosed with chronic pulmonary aspergillosis (N = 5) or allergic bronchopulmonary aspergillosis (N = 5)., Conclusions: APAb is associated with lower pulmonary function, and observed especially in patients with longer duration of MAC-LD and severe bronchiectasis, even in the absence of cavitary lesions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A 68-year-old man, presented with 3 week history of infective symptoms and mild haemoptysis. Past medical history included severe emphysema and a chronic right upper lobe (RUL) cavity. He was discharged from follow-up a year ago in view of clinical and radiological stability; previous bronchoscopic examinations yielded no specific diagnosis. CT scan on admission confirmed complex cavitary consolidation of RUL. He developed massive haemoptysis requiring intubation and ventilation. CT pulmonary angiogram (CTPA) revealed 16 mm RUL pulmonary artery (PA) aneurysm which was successfully embolized. Sputum cultures, aspergillus antigen and rapidity of clinical progression suggested a diagnosis of subacute invasive aspergillosis (SAIA), prompting treatment with Voriconazole. Bronchoscopy showed blood ooze from RUL even after embolization. Unfortunately, patient continued to deteriorate and succumbed to profound septicaemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To explore the clinical efficacy of sequential therapy with voriconazole on chronic obstructive pulmonary disease (COPD) patients in acute phase with pulmonary aspergillosis and its effects on cytokines and pulmonary functions., Patients and Methods: A total of 110 COPD patients in acute phase with pulmonary aspergillosis who were admitted to the hospital between February 2015 and November 2016 were enrolled. We divided them randomly into two groups, i.e., the control group (n = 55) and the treatment group (n = 55). Patients in the control group took itraconazole capsules orally (200 mg/time, twice per day for three days followed by once per day). Patients in treatment group underwent sequential treatment with voriconazole through intravenous infusion at a dose of 5 mg/kg/time twice a day for 3 days followed by a dose of 4 mg/kg/time, twice a day for 8 days. Then, patients took voriconazole orally at a dose of 150 mL/time, twice a day for 6 days. Patients in two groups received the treatment for a total of 14 days. After treatment, we evaluated the levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-8. The total lung capacity (TLC), diffusing capacity of the lung for carbon monoxide (DLco), and arterial oxygen saturation (SaO2), were measured as well., Results: The total effectiveness rates of the treatment group and the control group were 83.63% and 61.82%. The differences had statistical significance (p < 0.01). After treatment, the incidence of chest pain, cough, sputum-coughing, hemoptysis, cyanosis, and dyspnea in the treatment group was significantly fewer than that in the control group (p < 0.05). TCL, DLco, and SaO2 in the two groups were significantly ameliorated by treatment (p < 0.05). The amelioration in the treatment group was more prominent than that in the control group (p < 0.05). The levels of TNF-α, IL-8, and IL-6 in the two groups were decreased dramatically by the treatments. The decrease in the treatment group was significantly lower than those in the control group (p < 0.05). Occurrence of adverse reactions in treatment group and control group were 8.33% and 6.25%, respectively; (p > 0.05)., Conclusions: Sequential therapy with voriconazole exhibits promising clinical efficacy in COPD patients in acute phase with pulmonary aspergillosis. The treatment ameliorated the clinical symptoms and vital signs of patients significantly. It also improved the pulmonary functions and inhibited the inflammatory responses of patients with evident clinical efficacy.

Bronchiectasis is a chronic irreversible airway abnormality associated with infectious agents that either cause or superinfect the airways. While the role of bacteria is well studied, much remains to be determined about fungi in both cystic fibrosis- and non-cystic fibrosis-related bronchiectasis. The airway is constantly exposed to inhaled ambient moulds of which Aspergillus represent the most ubiquitous. In a normal healthy host, this situation is of little consequence. The presence of anatomical or immunological abnormalities such as those in bronchiectasis leads to a range of fungal-related pathologies from asymptomatic airway colonization to fungal sensitization, allergic bronchopulmonary aspergillosis or chronic pulmonary aspergillosis. These entities are difficult to recognize, diagnose and treat due in part to a lack of validated biomarkers. Our true understanding of the complex relationships that regulate fungal-host interactions is still in its infancy and, several questions remain. This includes if fungal epidemiology in bronchiectasis is uniform across countries, and to what extent immunopathological mechanisms-related to fungal airway infections-occurs in different disease states. Specific triggers to allergic or infectious responses to Aspergillus require further exploration. How transition occurs between allergic and invasive phenotypes and their respective biomarkers is also important. Whether anti-fungal treatment is warranted in all cases and what the optimal management strategy is, particularly when treatment should commence and its expected duration remains unclear. Further research is clearly necessary and should be prioritized to better understand the clinical effects and impact of Aspergillus in the setting of bronchiectasis.

Chronic pulmonary aspergillosis (CPA) has recently been recognized as a significant global health burden. In China, the diagnosis of CPA is still unfamiliar to most doctors. The aim of this study was to demonstrate the clinical manifestations and diagnoses of CPA in China.A multidisciplinary team of doctors retrospectively screened 690 records of patients diagnosed with pulmonary aspergillosis from January 2000 to December 2016 at Peking Union Medical College Hospital, Beijing, China. Of these, 69 patients were diagnosed with CPA. The patients' clinical characteristics were then retrieved and analyzed. Demographic, laboratory, and radiological data for these patients were compared by CPA type.Of the 69 patients diagnosed with CPA, 10 patients were diagnosed with chronic cavitary pulmonary aspergillosis (CCPA), 15 patients with semi-invasive aspergillosis (SAIA), 41 patients with simple aspergilloma, and 3 patients with Aspergillus nodule. Further, 53.3% of the SAIA patients were obviously immunocompromised, and 60% of the CCPA patients, 26.7% of the SAIA patients, 7.3% of the simple aspergilloma cases were mildly immunocompromised. Previous underlying lung abnormalities were observed in 20% of CCPA patients, 53.3% of SAIA patients, and 80.5% of simple aspergilloma patients. The most common symptoms in the CPA patients were cough (92.8%), hemoptysis (63.8%), chronic sputum (23.2%), and fever (17.4%). The most common computerized tomography abnormalities were cavities (94.2%), nodule (84.1%), consolidation (4.3%), pleural thickening (2.9%), and infiltration (2.9%). CCPA, SAIA and simple aspergilloma patients were significantly different with respect to their course before diagnosis, constitutional symptoms, fever, hemoptysis, breathlessness, white blood cell count, erythrocyte sedimentation rate, high-sensitivity C-reactive protein count, presence of nodule, and presence of a solitary lesion (all P < .05). Furthermore, SAIA patients had a significantly shorter course before diagnosis and a significantly higher white blood cell count compared with CCPA patients (both P < .01).In China, underlying systemic immunocompromising conditions and lung diseases with mechanical impediments contribute to CPA. Simple aspergillosis was the most common diagnosis in CPA patients. The imaging characteristics of simple aspergillosis and Aspergillus nodules were quite discriminable, while CCPA, and SAIA were similar in their clinical and radiological features. Distinguishing between CCPA and SAIA depends mainly on the physician's clinical judgment.

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.)

Chronic pulmonary aspergillosis (CPA) complicating sarcoidosis (SA) is associated with high mortality, and there is a lack of clarity regarding the relative contributions of SA or CPA.This was a retrospective single-centre study on CPA-SA.In total, 65 patients (44 men), aged 41.4±13.5 and 48.3±11.9 years at the time of SA and CPA diagnoses, respectively, were included between 1980 and 2015. Of these, 64 had fibrocystic SA, most often advanced, with composite physiological index (CPI) >40 (65% of patients) and pulmonary hypertension (PH) (31%), and 41 patients (63%) were treated for SA (corticosteroids or immunosuppressive drugs). Chronic cavitary pulmonary aspergillosis (CCPA) was the most frequent CPA pattern. Regarding treatment, 55 patients required long-term antifungals, 14 interventional radiology, 11 resection surgery and two transplantation. Nearly half of the patients (27; 41.5%) died (mean age 55.8 years); 73% of the patients achieved 5-year survival and 61% 10-year survival. Death most often resulted from advanced SA and rarely from haemoptysis. CPI, fibrosis extent and PH predicted survival. Comparison with paired healthy controls without CPA did not show any difference in survival, but a higher percentage of patients had high-risk mould exposure.CPA occurs in advanced pulmonary SA. CPA-SA is associated with high mortality due to the underlying advanced SA rather than to the CPA. CPI, fibrosis extent and PH best predict outcome., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Rationale: Pulmonary aspergillosis is a lethal mold infection in the immunocompromised host. Understanding initial control of infection and how this is altered in the immunocompromised host are key goals for comprehension of the pathogenesis of pulmonary aspergillosis., Objectives: To characterize the outcome of human macrophage infection with Aspergillus fumigatus and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants., Methods: We defined the outcome of human macrophage infection with A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies., Measurements and Main Results: Macrophage phagocytosis of A. fumigatus enabled control of 90% of fungal germination. However, fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell-cell transfer of A. fumigatus between macrophages, which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein envelope. Its relevance to the control of fungal germination was also shown by direct visualization in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506 (tacrolimus) reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and also resulted in hyphal escape., Conclusions: These observations identify programmed, necrosis-dependent lateral transfer of A. fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host.

Introduction: Fatigue is a prominent disabling symptom in several pulmonary diseases. Its impact on health status in patients with chronic pulmonary aspergillosis (CPA) has not been investigated., Methods: A total of 151 CPA patients attending the National Aspergillosis Centre completed Manchester COPD Fatigue Scale (MCFS), St. George's Respiratory Questionnaire (SGRQ) and Medical Research Council (MRC) dyspnoea score. Lung function and BMI were measured. Univariate, multivariate linear and binary analyses, and principal component analysis (PCA) were used., Results: Female patients accounted for 44%. The mean (range) of age was 59.6 (31-83) years, FEV1% was 64 (14-140), BMI was 23.6 (16.3-43.4), SGRQ total score was 56 (4-96.2) and MCFS total score was 30.6 (0-54). PCA showed that 27 items of MCFS loaded on three components; physical, psychosocial and cognitive fatigue, explaining 78.4% of fatigue variance. MCFS score correlated strongly with total SGRQ score (r = 0.83, p < 0.001). Using linear multivariate analysis, fatigue was the strongest factor (beta = 0.7 p < 0.0001) associated with impaired health status, after adjusting for age, BMI, FEV1%, and MRC dyspnoea score. Using patients' 5 self-assessment grades of their health, one-way ANOVA showed that those with "very poor" health status had the highest fatigue scores (45 (±6) (p < 0.001)). Logistic regression analysis showed that fatigue score (OR = 0.9, 95% CI 0.84-0.97; p = 0.005) and FEV1% (OR = 1.03, 95% CI 1.01-1.07, p = 0.02) are significantly associated with self-assessed impaired health status after correcting for age, gender and DLCO%., Conclusion: Fatigue is a major component of impaired health status of CPA patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

With intensified antibiotic therapy and longer survival, patients with cystic fibrosis (CF) are colonized with a more complex pattern of bacteria and fungi. However, the clinical relevance of these emerging pathogens for lung function remains poorly defined. The aim of this study was to assess the association of bacterial and fungal colonization patterns with lung function in adolescent patients with CF. Microbial colonization patterns and lung function parameters were assessed in 770 adolescent European (German/Austrian) CF patients in a retrospective study (median follow-up time: 10years). Colonization with Pseudomonas aeruginosa and MRSA were most strongly associated with loss of lung function, while mainly colonization with Haemophilus influenzae was associated with preserved lung function. Aspergillus fumigatus was the only species that was associated with an increased risk for infection with P. aeruginosa. Microbial interaction analysis revealed three distinct microbial clusters within the longitudinal course of CF lung disease. Collectively, this study identified potentially protective and harmful microbial colonization patterns in adolescent CF patients. Further studies in different patient cohorts are required to evaluate these microbial patterns and to assess their clinical relevance., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Chronic pulmonary aspergillosis (CPA) is a refractory disorder that needs long-term antifungal treatment and occasionally results in fatal respiratory failure and hemoptysis. However, the pathological features of the disorder have not been thoroughly delineated. Thirty cases were therefore analyzed clinically and histologically to elucidate the pathophysiology of CPA. The subjects comprised 14 individuals who underwent surgical removal and 16 patients who died. No subject exhibited a severely immunocompromised state. The main symptoms included cough, hemosputum, and dyspnea. Chest computed tomography (CT) findings revealed a cavity, fungus ball, and consolidation and/or ground glass opacity (GGO); 27 serial CT scans showed enlarged consolidation and/or GGO (70%), dilatation of the cavity (26%), and extension to the opposite lung (22%). Histopathological findings revealed a cavity with ulceration, bronchitis, and various degrees of organizing pneumonia (OP) that were correlated with the area of consolidation and GGO on the CT scan. The essential pathophysiology of CPA can be understood as an active state of ulceration of the cavity and/or erosive bronchitis caused by contact with the fungus ball, which may play a significant role in the development of OP. Consequently, OP is thought to reflect respiratory failure that relates to the prognosis of CPA.

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF.Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life.Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150-0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484-1.612; p<0.001).Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF., (Copyright ©ERS 2015.)

Purpose: There have been scarce data evaluating the differences of clinical characteristics and prognosis of chronic pulmonary aspergillosis (CPA) depending on underlying pulmonary diseases. We tried to clarify them in CPA patients who had pulmonary emphysema or previous pulmonary tuberculosis., Methods: We reviewed and evaluated CPA patients diagnosed between 2007 and 2013 with pulmonary emphysema (PE group; n = 29), with previous pulmonary tuberculosis (PT group; n = 47) and with combination of these 2 underlying conditions (CTE group; n = 24)., Results: In CT findings, fungus balls were rare in PE group (7% in PE group and 36% in PT group; p = 0.006). Compared with PT group, PE group patients exhibited more frequent preceding antibiotics administration (45% vs 11%; p = 0.002) and fever (52% vs 17%; p = 0.002), less frequent hemosputum (24% vs 57%; p = 0.008), and more frequent consolidations in imaging (79% vs 38%; p = 0.001) and respiratory failure (34% vs 13%; p = 0.020), possibly suggesting more acute clinical manifestations of CPA in emphysematous patients. Trend of the differences between PT and PE group was not changed when patients with fungal balls were excluded. Multivariate Cox regression analysis of risks for all-cause mortality revealed age (HR, 1.079; p = 0.002) and emphysema (HR, 2.45; p = 0.040) as risk factors., Conclusions: Assessment of underlying lung diseases is needed when we estimate prognosis and consider treatment of CPA patients. Particularly, emphysematous patients can be presented as refractory pneumonia and show poor prognosis., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Thoracoplasty is a technique used to obliterate residual intrapleural spaces after lung resection for infection or other causes. It involves multiple osteotomies on several ribs and then collapsing them into the space to be obliterated; however, this results in a distorted and asymmetrical chest wall. We report a case of a 34-year-old female with completely destroyed right upper lobe secondary to chronic Aspergillus infection. She underwent a completion right upper lobectomy and modified thoracoplasty with the use of a breast implant to obliterate the residual pleural space without any distortion of the chest wall, with an excellent outcome., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aim: This retrospective study evaluated the clinical presentation, underlying lung disease, surgical indications, technique, treatment outcomes, and postoperative complications of pulmonary aspergilloma., Materials and Methods: We evaluated 77 patients who underwent pulmonary resection of an aspergilloma at Atatürk Chest Diseases and Thoracic Surgery Research and Training Hospital between January 2000 and December 2013. The initial operations were 4 pneumonectomies, 24 lobectomies, 9 lobectomy plus myoplasties, 10 segmental resections, and 30 wedge resections. Six reoperations were carried out to deal with postoperative complications: 1 myoplasty, 2 completion lobectomies plus myoplasties, 2 myoplasties with rib resections, and 1 completion lobectomy., Results: The subjects comprised 53 males (mean age: 44.26 (range: 10-73) years) and 24 females (mean age: 48.25 (range: 26-70) years). The most common indication for surgery was hemoptysis in 52 patients (67.53%). The most common underlying lung disease was tuberculosis in 37 patients (48.05%). Forty patients (51.94%) had a simple pulmonary aspergilloma and 37 (48.05%) had a complex pulmonary aspergilloma. Major complications occurred in 18 patients (23.37%). The postoperative mortality rate was 3.89%, with 3 patients dying., Conclusion: Surgical resection of pulmonary aspergilloma is the best way to prevent recurrent hemoptysis with low morbidity and mortality.

Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2 / Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness., (© 2013 John Wiley & Sons Ltd.)

Case Report: Invasive aspergillosis is a life threatening complication in immune-compromised patients causing lung tissue destruction. Aspergillus empyema requires aggressive multimodality treatment., Material and Method: We present a case of Aspergillus empyema treated by thoracic and plastic surgery preserving the lung function in an 18 year-old male patient suffering dermatomyositis and treated with steroids for a long time. After open window thoracostomy (OWT) we used pedicled musculus latissimus dorsi (MLD) flap and mobilised the anterior serratus muscle to close the pleural cavity., Conclusion: The intrathoracic use of muscle flaps after OWT in case of chronic Aspergillus empyema can preserve the underlying lung tissue. Cooperation of thoracic and plastic surgeons - as in the cases presented - provides an excellent opportunity to treat successfully of otherwise hopeless patients.

Background: Chronic pulmonary aspergillosis (CPA) markedly reduces lung function through progressive lung destruction. To date, however, health status in patients with CPA has not been studied. This is due, in part, to a lack of adequately validated scales. The St. George's Respiratory Questionnaire (SGRQ) is widely used for several chronic respiratory diseases, but not for CPA. We examined the reliability and validity of SGRQ in CPA., Methods: Eighty-eight patients with CPA completed the SGRQ, the Short Form-36 Health Survey (SF-36), and the Medical Research Council (MRC) dyspnea scale. Lung function and BMI were also measured. Pearson correlation, t test, analysis of variance, and their equivalents for nonparametric data and multivariate linear and binary analyses were used., Results: The SGRQ components (symptoms, activity, and impact) and total scores achieved high internal consistency (Cronbach α = 0.77, 0.91, 0.86, and 0.94), and SGRQ components had good intercorrelation (r ≥ 0.41; P &lt; .001) and correlated well with the total score (r ≥ 0.63; P &lt; .001). There were high, intraclass, correlation coefficients for the total SGRQ and its dimensions (≥ 0.92). The SGRQ scores showed significant correlation with the MRC dyspnea scale and SF-36 components and differentiated between all grades of shortness of breath and different bands of disease severity (P &lt; .05). In addition, patients with greater clinician-rated disease severity had more impairment of health status (P &lt; .006). CPA severity was independently associated with impairment in health status, and COPD comorbidity significantly affected the health status in patients with CPA., Conclusions: SGRQ demonstrated a significant level of reliability and validity in measuring health status in CPA.

Immunocompromised mice were infected intranasally with Aspergillus fumigatus as part of a vaccine efficacy study. Although body temperature was measured throughout the study, a formal evaluation of its usefulness as an endpoint criterion was not performed. We retrospectively evaluated survival data and temperature records to determine whether body temperature can be used as an objective predictor of death and included in the humane endpoint criteria for this mouse model. CF1 mice were immunosuppressed with either cortisone acetate or by treatment with antiGR1 (a neutrophil-depleting antibody) and then intranasally challenged with A. fumigatus. Body temperature was measured by using an infrared noncontact thermometer a maximum of 3 times daily until death or euthanasia. A surface body temperature below 29.0 °C was correlated with a poor chance of survival, and using this cutoff point with signs of morbidity (hunched, ruffled fur, respiratory distress) reliably indicates mice for euthanasia without negatively affecting data collection. Using 2 subsequent readings of less than 31.0 °C as an endpoint would have led to premature euthanasia of only one mouse (2.2%). As a single reading, a body temperature of 28.8 °C had a sensitivity of 92.2% and specificity of 90.9%. Hypothermia proved to be a useful addition to the humane endpoint criteria for this mouse model, and veterinary and research groups should discuss their study needs in relation to animal welfare to best determine the most appropriate means of including this parameter.

Purpose of Review: Aspergillus fumigatus is frequently isolated from cystic fibrosis (CF) patients and is notorious for its role in the debilitating condition of allergic bronchopulmonary aspergillosis (ABPA). Although CF patients suffer from perpetual microorganism-related lung disease, it is unclear whether A. fumigatus colonization has a role in causing accelerated lung function decline and whether intervention is necessary., Recent Findings: A. fumigatus morbidity appears to be related to cystic fibrosis transmembrane conductance regulator-dependant function of the innate immune system. A. fumigatus-colonized patients have a lower lung capacity, more frequent hospitalizations and more prominent radiological abnormalities than noncolonized patients. Treatment with antifungal agents can be of value but has several drawbacks and a direct effect on lung function is yet to be shown., Summary: A. fumigatus appears to have an important role in CF lung disease, not exclusive to the context of ABPA. However, a causal relationship still needs to be confirmed. Study observations and trends indicate a need to further elucidate the mechanisms of A. fumigatus interactions with the host innate immune system and its role in CF lung morbidity.

Indoleamine 2,3-dioxygenase (IDO) suppresses the functions of CD4(+) T cells through its ability to metabolize the essential amino acid tryptophan. Although the activity of IDO is required for the immunosuppression of allergic airway disease by the Toll-Like-Receptor 9 (TLR9) agonist, oligonucleotides comprised of cytosine and guanine nucleotides linked by phosphodiester bonds (CpG) DNA, it is unclear whether IDO expression by resident lung epithelial cells is sufficient to elicit these effects. Therefore, we created a transgenic mouse inducibly overexpressing IDO within nonciliated airway epithelial cells. Upon inhalation of formalin-fixed Aspergillus fumigatus hyphal antigens, the overexpression of IDO from airway epithelial cells of these mice reduced the number of CD4(+) T cells within the inflamed lung and impaired the capacity of antigen-specific splenic CD4(+) effector T cells to secrete the cytokines IL-4, IL-5, IL-13, and IFN-γ. Despite these effects, allergic airway disease pathology was largely unaffected in mice expressing IDO in airway epithelium. In support of the concept that dendritic cells are the major cell type contributing to the IDO-inducing effects of CpG DNA, mice expressing TLR9 only in the airway epithelium did not augment IDO expression subsequent to the administration of CpG DNA. Furthermore, the systemic depletion of CD11c(+) cells rendered mice incapable of CpG DNA-induced IDO expression. Our results demonstrate that an overexpression of IDO within the airway epithelium represents a novel mechanism by which the number of CD4(+) T cells recruited to the lung and their capacity to produce cytokines can be diminished in a model of allergic airway disease, and these results also highlight the critical role of dendritic cells in the antiasthmatic effects of IDO induction by CpG DNA.

Introduction: Invasive aspergillosis is a major cause of mortality in allogeneic bone marrow transplant recipients and patients treated for blood malignancies. The diagnostic tools, treatments and preventive strategies, essentially developed for neutropaenic patients, have not been assessed in populations whose immune systems are considered to be competent., State of the Art: Beside the standard picture of chronic Aspergillus infection, the incidence of invasive aspergillosis is increasing in non neutropaenic patients, such as those with chronic lung diseases or systemic disease treated with long-term immunosuppressive drugs and solid organ transplant recipients. This study reviews the specific features of invasive aspergillosis in non neutropaenic subjects (NNS) and discusses the value of the diagnostic tools and treatment in this population., Prospects: A better understanding of the pathophysiology and the epidemiological characteristics of invasive aspergillosis would provide a means of adapting the staging and classification of the disease for NNS., Conclusions: Invasive aspergillosis is under diagnosed in NNS who may already be colonised when they receive immunosuppressive treatment; this can lead to an adverse outcome in patients who are considered to be a moderate risk population., (Copyright © 2010. Published by Elsevier Masson SAS.)

Aspergillus can cause several forms of pulmonary disease ranging from colonization to invasive aspergillosis and largely depends on the underlying lung and immune function of the host. This article reviews the clinical presentation, diagnosis, pathogenesis, and treatment of noninvasive forms of Aspergillus infection, including allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and chronic pulmonary aspergillosis (CPA). ABPA is caused by a hypersensitivity reaction to Aspergillus species and is most commonly seen in patients who have asthma or cystic fibrosis. Aspergillomas, or fungus balls, can develop in previous areas of cavitary lung disease, most commonly from tuberculosis. CPA has also been termed semi-invasive aspergillosis and usually occurs in patients who have underlying lung disease or mild immunosuppression.

Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patients were in their fourth decade. Episodic hemoptysis was the commonest mode of presentation (85.4%). Forty aspergillomas were complex, occurring in cavitatory lesions (82.9%) or in bronchiectasis (14.6%). Simple aspergilloma was seen as an incidental finding in only one. Tuberculosis was the etiological factor in 31 patients, producing cavitatory or bronchiectatic lesions; other causes were chronic lung abscess and bronchiectasis (unrelated to tuberculosis). Surgical resections are endorsed in view of high risk of unpredictable, life-threatening hemoptysis.