Mariko Siyue Koh

Is bronchial thermoplasty cost‐effective as treatment for problematic asthma patients? Singapore's perspective on a global model

Bronchial thermoplasty (BT) has been shown to be effective at reducing asthma exacerbations and improving asthma control for patients with severe persistent asthma but it is also expensive. Evidence on its cost‐effectiveness is limited and inconclusive. In this study, we aim to evaluate the incremental cost‐effectiveness of BT combined with optimized asthma therapy (BT‐OAT) relative to OAT for difficult‐to‐treat and severe asthma patients in Singapore, and to provide a general framework for determining BTs cost‐effectiveness in other healthcare settings.

Sensitization to Aspergillus species is associated with frequent exacerbations in severe asthma

Background Severe asthma is a largely heterogeneous disease with varying phenotypic profiles. The relationship between specific allergen sensitization and asthma severity, particularly in Asia, remains unclear. We aim to study the prevalence of specific allergen sensitization patterns and investigate their association with outcomes in a severe asthma cohort in an Asian setting. Methods We conducted a cross-sectional study of patients receiving step 4 or 5 Global Initiative for Asthma treatment. Univariate and multivariate analyses were performed to assess the association between sensitization to a specific identifiable allergen by skin prick test (SPT) and uncontrolled asthma (defined in our study as the use of ≥2 steroid bursts or hospitalization in the past year, a history of near-fatal asthma or evidence of airflow obstruction on spirometry). Results Two hundred and six severe asthma patients (mean age 45±17 years, 99 [48.1%] male) were evaluated. Of them, 78.2% had a positive SPT to one or more allergens. The most common allergen to which patients were sensitized was house dust mites (Blomia tropicalis, Dermatophagoides pteronyssinus and Dermatophagoides farinae). Also, 11.7% were sensitized to Aspergillus species. On multivariate analysis, Aspergillus sensitization was associated with uncontrolled asthma (odds ratio 6.07, 95% confidence interval 1.80–20.51). In particular, Aspergillus sensitization was independently associated with the use of ≥2 steroid bursts in the past year (odds ratio 3.05, 95% confidence interval 1.04–8.95). No similar associations of uncontrolled asthma with sensitization to any other allergens were found. Conclusion High allergen, specifically Aspergillus sensitization was observed in the Asian population with severe asthma by SPT. Aspergillus sensitization was specifically associated with frequent exacerbations and a greater corticosteroid requirement. An improved understanding of the severe asthma with Aspergillus sensitization phenotype is warranted, which is likely a subgroup of severe asthma with fungal sensitization.

Understanding COPD-overlap syndromes

ABSTRACT Introduction: Chronic obstructive pulmonary disease accounts for a large burden of lung disease. It can ‘overlap’ with other respiratory diseases including bronchiectasis, fibrosis and obstructive sleep apnea (OSA). While COPD alone confers morbidity and mortality, common features with contrasting clinical outcomes can occur in COPD ‘overlap syndromes’. Areas covered: Given the large degree of heterogeneity in COPD, individual variation to treatment is adopted based on its observed phenotype, which in turn overlaps with features of other respiratory disease states such as asthma. This is coined asthma-COPD overlap syndrome (‘ACOS’). Other examples of such overlapping clinical states include bronchiectasis-COPD (‘BCOS’), fibrosis-COPD (‘FCOS’) and OSA-COPD (‘OCOS’). The objective of this review is to highlight similarities and differences between the COPD-overlap syndromes in terms of risk factors, pathophysiology, diagnosis and potential treatment differences. Expert commentary: As a consequence of COPD overlap syndromes, a transition from the traditional ‘one size fits all’ treatment approach is necessary. Greater treatment stratification according to clinical phenotype using a precision medicine approach is now required. In this light, it is important to recognize and differentiate COPD overlap syndromes as distinct disease states compared to individual diseases such as asthma, COPD, fibrosis or bronchiectasis.

Fixed airways obstruction among patients with severe asthma: findings from the Singapore General Hospital-Severe Asthma Phenotype Study

BackgroundA subset of severe asthma patients has fixed airways obstruction, which is characterized by incomplete reversibility to bronchodilator challenge. We aimed to elucidate the factors associated with fixed airways obstruction in a cohort of patients with severe asthma in Singapore.Methods245 patients from the Singapore General Hospital-Severe Asthma Phenotype Study (SGH-SAPS) were screened. These patients fulfilled World Health Organization criteria for treatment-resistant severe asthma and were all on combination of high-dose inhaled corticosteroids and long-acting beta2 agonists. 76 patients had pre- and postbronchodilator lung function tests and were selected for analysis. They were divided into two groups based on postbronchodilator (Post BD) forced expiratory volume in one second, PostBDFEV1 % predicted: ≥70% (Non-Fixed Obs) andu2009<u200970% (Fixed Obs). We compared clinical and demographic parameters between the two groups.ResultsPatients in the Fixed Obs group were more frequently past or current smokers and had a higher pack-year smoking history. Overall, pack-year smoking history had a modest negative correlation with PostBDFEV1 % predicted. Atopy, allergen sensitization (type and numbers), comorbidities, symptoms, health care utilization and medication use did not differ between the two groups. The prebronchodilator FEV1 % predicted, FEV1/FVC and FVC % predicted were significantly lower in the Fixed Obs group. In addition, prebronchodilator FVC % predicted accounted for more variability than FEV1/FVC in predicting PostBDFEV1% predicted.ConclusionSmoking is associated with fixed airways obstruction in patients with treatment-resistant severe asthma in Singapore. Furthermore, our results suggest that both small and large airways obstruction contribute independently to fixed airways obstruction in severe asthma.

IMMUNOLOGICAL COROLLARY OF THE PULMONARY MYCOBIOME IN BRONCHIECTASIS: THE CAMEB STUDY

Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a “research priorities” consensus statement for bronchiectasis. Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S–28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes. The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus, Cryptococcus and Clavispora. Aspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus-associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations. The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus-associated disease should be considered even in apparently stable patients. The airway mycobiome in bronchiectasis is associated with clinically significant disease http://ow.ly/MCKj30knVrn

Precision medicine in united airways disease: A “treatable traits” approach

United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma‐allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a “treatable traits” approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.

Impact of simulation training on performance and outcomes of endobronchial ultrasound-guided transbronchial needle aspiration performed by trainees in a tertiary academic hospital

BackgroundnEndobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic yield and low complication rate. Whilst it has been included in international guidelines for the diagnosis and staging of lung cancer, current results are mostly based on EBUS experts performing EBUS-TBNA in centres of excellence. The impact of simulation training on diagnostic yield, complications, scope damage and repair cost in a real-world teaching hospital is unclear.nnnMethodsnA review of our hospital EBUS-TBNA registry from August 2008 to December 2016 was performed. A positive diagnosis was defined as a confirmed histological or microbiological diagnosis based on EBUS sampling. Complications were classified as major or minor according to the British Thoracic Society guidelines. In addition, we assessed the cost of repairs for scope damage before and after simulation training was implemented. Using CUSUM analysis, the learning curves of individual trainees and the institution were plotted.nnnResultsnThere were 608 EBUS-TBNA procedures included in the study. The number of procedures performed by trainees who underwent conventional training was 331 and those who underwent simulation training performed 277 procedures. Diagnostic yield for trainees without simulation training was 88.2% vs. 84.5% for trainees with simulation training (P=0.179). There was no statistical difference in the diagnostic yield between the groups of trainees (OR: 0.781, 95% CI: 0.418-1.460, P=0.438) after adjusting for risk factors. There was an increase in overall complications from 13.6% to 16.6% (OR: 2.247, 95% CI: 1.297-3.891, P=0.004) after introduction of the simulation training, but a trend to decrease in major complications 3.6% to 0.7% (P=0.112). The cost for scope repairs for the trainees without simulation training was SGD 413.88 per procedure vs. SGD 182.79 per procedure for the trainees with simulation training, with the mean difference being SGD 231.09 per procedure (95% CI: 178.40-640.60, P=0.268). CUSUM analysis showed an increasing learning curve for the trainees with simulation training after an initial competency period.nnnConclusionsnThere was no statistical difference in diagnostic yield from EBUS-TBNA and cost of scope damage after simulation training was introduced into our training program. Interestingly, there was an increase in minor complications. CUSUM analysis can provide additional information on institutional learning curves. The value of simulation training in EBUS-TBNA remains uncertain.

A new therapeutic avenue for bronchiectasis: Dry powder inhaler of ciprofloxacin nanoplex exhibits superior ex vivo mucus permeability and antibacterial efficacy to its native ciprofloxacin counterpart

Graphical abstract Figure. No caption available. ABSTRACT Non‐cystic fibrosis bronchiectasis (NCFB) characterized by permanent bronchial dilatation and recurrent infections has been clinically managed by long‐term intermittent inhaled antibiotic therapy among other treatments. Herein we investigated dry powder inhaler (DPI) formulation of ciprofloxacin (CIP) nanoplex with mannitol/lactose as the excipient for NCFB therapy. The DPI of CIP nanoplex was evaluated against DPI of native CIP in terms of their (1) dissolution characteristics in artificial sputum medium, (2) ex vivo mucus permeability in sputum from NCFB and healthy individuals, (3) antibacterial efficacy in the presence of sputum against clinical Pseudomonas aeruginosa strains (planktonic and biofilm), and (4) cytotoxicity towards human lung epithelial cells. Despite their similarly fast dissolution rates in sputum, the DPI of CIP nanoplex exhibited superior mucus permeability to the native CIP (5–7 times higher) attributed to its built‐in ability to generate highly supersaturated CIP concentration in the sputum. The superior mucus permeability led to the CIP nanoplexs higher antibacterial efficacy (>3 log10 CFU/mL). The DPI of CIP nanoplex exhibited similar cytotoxicity towards the lung epithelial cells as the native CIP indicating its low risk of toxicity. These results established the promising potential of DPI of CIP nanoplex as a new therapeutic avenue for NCFB.

Utility of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Diagnosis of Intrathoracic Lymphadenopathy in Patients with Human Immunodeficiency Virus Infection

Objective. Intrathoracic lymphadenopathy (LAD) in patients with Human Immunodeficiency Virus (HIV) infection is common, with wide-ranging diagnoses, from benign to malignant causes. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) is a relatively new technology with established applications in lung cancer, sarcoidosis, and tuberculosis. We sought to find out whether the addition of EBUS-TBNA to the diagnostic algorithm for LAD in HIV patients will reduce the need for mediastinoscopy. Methods. Retrospective chart review of all EBUS-TBNA procedures performed in our centre from August 2008 to December 2012. Results. 513 patients had EBUS-TBNA performed during this period. We identified nine HIV-infected patients who had LAD of unknown cause and underwent EBUS-TBNA. The procedure reduced the need for mediastinoscopy in eight patients (89%). Conclusions. Potential mediastinoscopies can be avoided by utilising EBUS-TBNA in HIV patients with LAD.