Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Chronic pulmonary aspergillosis - a guide for the general physician.

This collaborative article presents a review of chronic pulmonary aspergillosis (CPA) from the perspective of a multidisciplinary team comprising of respiratory physicians, radiologists, mycologists, dietitians, pharmacists, physiotherapists and palliative care specialists. The review synthesises current knowledge on CPA, emphasising the intricate interplay between clinical, radiological, and microbiological aspects. We highlight the importance of assessing each patient as multidisciplinary team to ensure personalised treatment strategies and a holistic approach to patient care.

Management of non-cystic fibrosis bronchiectasis.

Bronchiectasis is a common respiratory condition, characterised by abnormal bronchial dilatation, that often leads to recurrent airway infection and inflammation. It is an increasingly recognised respiratory condition, both as a primary lung disease but also co-existing with other respiratory diseases, such as chronic obstructive pulmonary disease and asthma. Diagnosis can have important treatment implications. There are shared systematic approaches to treatment, such as sputum clearance techniques, prompt treatment of exacerbations and, in certain circumstances, regular antibiotic therapy. It is vital to target antibiotic therapy appropriately, and knowledge of the patient's airway microbiology can assist with this. Certain infective and colonising organisms, such as Pseudomonas aeruginosa, cause worse patient outcomes and so need prompt treatment with appropriate antibiotics. In addition to this general management approach, there are many different underlying causes of bronchiectasis that should be identified wherever possible, to support more targeted therapy and prevent disease progression. This article provides a guide to the key principles of diagnosing and managing bronchiectasis, and outlines situations where more specialist respiratory support is required.

Receiver operating characteristic curve analysis of four Aspergillus-specific IgG assays for the diagnosis of chronic pulmonary aspergillosis.

Measurement of Aspergillus-specific IgG is central to the diagnosis of chronic pulmonary aspergillosis (CPA), but manufacturers' guidance on test interpretation is based on unpublished data. We performed the first receiver operating characteristic (ROC) area under the curve (AUC) analysis to identify optimal cut-offs for this test in relation to European controls. Aspergillus-specific IgG levels were measured in sera from British adults with CPA and European healthy controls by ImmunoCAP, Immulite, Serion and Bio-Rad assays. ROC AUC analysis was performed to identify optimal cut-offs. ROC AUC results were; Bio-Rad 0.955, Immulite 0.948, ImmunoCAP 0.956 and Serion 0.944. Optimal diagnostic cut-offs were 1.5 AU/mL for Bio-Rad (93% sensitive, 98% specific), 25 mg/L for Immulite (93% sensitive, 99% specific), 50 mg/L for ImmunoCAP (84% sensitive, 96% specific) and 50 U/mL for Serion (84% sensitive, 91% specific). These cut-offs differ from manufacturers' guidance and from those previously calculated in relation to Ugandan controls.

Novel immunologic classification of aspergillosis in adult cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) demonstrate a wide range of hypersensitivity responses to Aspergillus, beyond allergic bronchopulmonary aspergillosis, which require classification. OBJECTIVE: This study integrated 2 new methods of Aspergillus detection-sputum galactomannan (GM) and real-time PCR-alongside established serologic markers, to reclassify aspergillosis in CF. METHODS: A total of 146 adult patients with CF had serologic tests (ImmunoCap total IgE, specific Aspergillus fumigatus IgE, and specific A fumigatus IgG), sputum real-time Aspergillus PCR, and sputum GM. Patients were classified by using latent class analysis. RESULTS: Both RT-PCR and GM were more sensitive than culture in detecting Aspergillus in sputum (culture 37%, RT-PCR 74%, and GM 46%). Intraassay and interassay reproducibility of PCR and GM was excellent. Latent class analysis of triazole-naive patients identified a nondiseased group and 3 disease classes: class 1 (n = 49, 37.7%) represented patients with or without positive RT-PCR but no immunologic response to A fumigatus and negative GM (nondiseased); class 2 (n = 23, 17.7%) represented patients with positive RT-PCR, elevated total and specific A fumigatus IgE/IgG, and positive GM (serologic allergic bronchopulmonary aspergillosis); class 3 (n = 19, 14.6%) represented patients with or without positive RT-PCR, elevated A fumigatus IgE (not IgG), and negative GM (Aspergillus sensitized); and class 4 (n = 39, 30%) represented patients with positive RT-PCR, elevated A fumigatus IgG (not IgE), and positive GM (Aspergillus bronchitis). CONCLUSIONS: Three distinct classes of aspergillosis in CF were identified by latent class analysis by using serologic, RT-PCR, and GM data. This novel classification will facilitate improved phenotyping, pathogenesis studies, and management evaluations.

Intravenous antibiotics reduce the presence of Aspergillus in adult cystic fibrosis sputum.

BACKGROUND: Pseudomonas aeruginosa and Aspergillus fumigatus frequently co-colonise the airways of patients with cystic fibrosis (CF). This study aimed to assess the impact of short-term administration of intravenous antipseudomonal antibiotics during CF exacerbations on the presence of Aspergillus. METHODS: Pre- and post-antibiotic sputum samples from 26 adult patients with CF and chronic Pseudomonas colonisation were analysed for the presence of Aspergillus by fungal culture, real-time PCR and galactomannan antigen (GM). Lung function (forced expiratory volume in 1 s and forced vital capacity % predicted) and blood levels of total IgE, specific A fumigatus IgE and specific A fumigatus IgG were measured at the start and end of antibiotics. Respiratory viral real-time PCR and bacterial community profiling using ribosomal intergenic spacer analysis (RISA) were performed to estimate concurrent changes in the lung microbiome. RESULTS: Aspergillus PCR and GM were more sensitive than culture in detecting Aspergillus species (culture 8%, GM 31%, PCR 77%). There was a significant decline in the presence of Aspergillus, measured both by PCR and GM index, following antibacterial therapy (PCR: median increase in crossing threshold 1.7 (IQR 0.5-3.8), p<0.001; GM: median fall in GM index 0.7 (IQR 0.4-1.6), p=0.016). All patients improved clinically with a significant increase in lung function (p<0.0001). RISA community analysis showed large changes in bacterial community similarity in 67% of patients following antibiotics. Viral RT-PCR demonstrated the presence of a concurrent respiratory virus in 27% of patients. CONCLUSIONS: Intravenous antibiotics targeting Pseudomonas during CF pulmonary exacerbations have a negative impact on the presence of Aspergillus in sputum samples.

IgE-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis.

BACKGROUND: The recovery of Aspergillus and Candida from the respiratory secretions of patients with cystic fibrosis (CF) is common. Their relationship to the development of allergic sensitization and effect on lung function has not been established. Improved techniques to detect these organisms are needed to increase knowledge of these effects. METHODS: A 2-year prospective observational cohort study was performed. Fifty-five adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profile (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years. RESULTS: Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus. There was no association between the recovery of either organism and the presence of specific IgE responses. There was no difference in lung function decline for patients with Aspergillus or Candida colonization compared with those without (FEV1 percent predicted, P = .41 and P = .90, respectively; FVC % predicted, P = .87 and P = .37, respectively). However, there was a significantly greater decline in FEV1 and increase in IV antibiotic days for those sensitized to Aspergillus (FEV1 decline, P = .03; IV antibiotics days, P = .03). CONCLUSIONS: Allergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations.

Aspergillus bronchitis without significant immunocompromise.

Aspergillus bronchitis is poorly understood and described. We extracted clinical data from more than 400 referred patients with persistent chest symptoms who did not fulfill criteria for allergic, chronic, or invasive aspergillosis. Symptomatic patients with a positive culture or real-time PCR for Aspergillus spp. were reviewed. Seventeen patients fulfilled the selected criteria. Fourteen were women, with a mean age of 57 years (range 39-76). Sixteen of the patients had productive cough, eight had voluminous tenacious sputum, and seven had recurrent chest infections. Eight patients had Medical Research Council dyspnea scores of 4-5; 12 had bronchiectasis; and 13 patients grew A. fumigatus, 3 A. niger, and 1 A. terreus. Twelve of the 17 patients (71%) had elevated Aspergillus IgG (47-137 mg/L, mean 89.2) and 5 (29%) had elevated Aspergillus precipitins. Six of 12 (50%) had a major response to antifungal therapy and five of 12 (42%) patients relapsed, requiring long-term therapy. Aspergillus bronchitis is a discrete clinical entity in patients with structural lung disease but who are not significantly immunocompromised. It is distinct from asymptomatic fungal colonization and other forms of aspergillosis, and may respond to antifungal therapy.

Peripheral neuropathy in patients on long-term triazole antifungal therapy.

OBJECTIVES: Triazole antifungal drugs are the mainstay of treatment for patients with chronic pulmonary aspergillosis and are often used as steroid-sparing agents in patients with allergic aspergillosis. Peripheral neuropathy (PN) is a rare but reported side effect of triazole therapy in the acute management of invasive fungal infections, but its incidence during long-term triazole treatment for chronic aspergillosis is unknown. The goal of this study was to determine the incidence of PN in this context. PATIENTS AND METHODS: A retrospective cohort study was carried out to collect data on all patients with chronic aspergillosis commenced on long-term triazole therapy at the National Aspergillosis Centre in Manchester between 2007 and 2010. RESULTS: Two hundred and twenty-two patients were commenced on triazole therapy. Ten percent developed PN after an average of 4 months. Seventeen percent of patients taking itraconazole, 9% taking voriconazole and 3% taking posaconazole developed PN. This is the first report of posaconazole-induced PN. Twenty-two episodes of PN presented as numbness or tingling in the extremities, while four episodes presented as predominant leg weakness. The majority of cases were axonal, length-dependent neuropathies that recovered after triazole medication was discontinued. Two patients had non-progressive but irreversible PN. Two patients were diagnosed with mononeuropathies. CONCLUSIONS: A 10% incidence of PN was observed for patients commenced on triazole therapy for chronic aspergillosis. Patients on long-term triazole therapy should be monitored for neurological symptoms. If PN is suspected, diagnosis should include nerve conduction studies, exclusion of other causes and consideration of dose reduction or cessation of therapy.

Pulmonary aspergillosis: an alternative diagnosis to lung cancer after positive [18F]FDG positron emission tomography.

[(18)F]Fluorodexyglucose (FDG) positron emission tomography (PET) scans have significantly improved the diagnosis and staging of lung cancer, but false-positive scans are known to occur due to inflammatory and infectious diseases. Recognition of the conditions leading to false-positive scans is important. Single or multiple pulmonary nodules, with or without cavitation, are classical findings in acute and chronic pulmonary aspergillosis. Clinical features of pulmonary aspergillosis are very similar to those of lung cancer. This report highlights pulmonary aspergillosis as an alternative diagnosis to lung cancer in patients with positive [(18)F]FDG PET scans and the need to strive for presurgical histological diagnosis.

Homogenisation of cystic fibrosis sputum by sonication--an essential step for Aspergillus PCR.

The importance of Aspergillus as a lung pathogen in cystic fibrosis (CF) is becoming increasingly recognised. However, fungal culture of CF sputum is unreliable and there is no consensus for identifying phenotypes beyond ABPA that may benefit from antifungal therapy. There are no published studies using real-time PCR to detect Aspergillus in CF sputum. The major barrier to sensitive detection of Aspergillus using PCR is sputum homogenisation. This study aimed to optimise sputum homogenisation utilising sonication to improve Aspergillus DNA extraction. Sonication amplitude and duration that enabled sputum homogenisation but ensured preservation of DNA integrity were first determined. 160 sputum samples were collected from CF patients. 49 of the sputum samples were split, one half was used for standard culture and the other half was homogenised with NALC-NaOH before undergoing DNA extraction. The subsequent 111 samples were homogenised with dithiothreitol plus sonication prior to culture and DNA extraction. Real-time PCR targeting a portion of the 18S rDNA of Aspergillus was performed on all DNA extractions. In the 49 samples with no sonication 8 (16%) were culture positive but only 4 of these were PCR positive. However, PCR was positive in 11 culture negative samples. PCR after sonication showed a significant improvement in sensitivity: 33 (30%) were culture and PCR positive, 48 (43%) were culture negative, but PCR positive (p<0.0001) and 30 (27%) were culture and PCR negative. The combination of dithiothreitol and sonication to homogenise sputum increases PCR yield, with PCR being substantially more sensitive than culture.

Efficacy and safety of posaconazole for chronic pulmonary aspergillosis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is a severe, progressive respiratory infection characterized by multiple pulmonary cavities and increased levels of antibodies to Aspergillus species. We report the first use of posaconazole in patients with CPA. METHODS: A retrospective study was performed. A composite clinical and radiological evaluation was used to assess response to posaconazole therapy. The rates of clinical response and failure after 6 and 12 months of therapy were determined. Kaplan-Meier survival models were developed to describe the time to clinical response and failure. The underlying diagnosis, the type of therapy (primary or salvage), Aspergillus antibody titer, and posaconazole serum concentrations were assessed as covariates. Aspergillus species were identified and minimum inhibitory concentrations (MICs) of triazoles were determined using standard techniques. RESULTS: There were 79 patients that initially received posaconazole 400 mg twice per day. The median age of patients was 61 years, and 57% were male. Response to posaconazole was observed in 61% of patients at 6 months and in 46% at 12 months. Kaplan-Meier plots showed that the first response to posaconazole was observed in some patients only after approximately 1 year of therapy. Covariates were not significant. Adverse reactions were observed in 12 patients (15%) (nausea in 5, rash in 5, headache in 1, and lethargy in 1), leading to withdrawal of treatment for 9 patients. Aspergillus species were recovered from 22 patients. A posaconazole MIC of >8 mg/L was found in 4 isolates; in 1 of these isolates, this emerged during therapy. Treatment failed in all 4 patients from whom these 4 isolates had been recovered. CONCLUSION: Posaconazole is a safe and partially effective treatment for CPA. Prospective comparative studies are now required.