Airway "Resistotypes" and Clinical Outcomes in Bronchiectasis.

Rationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight a diverse pool of antimicrobial resistance genes: the "resistome," the clinical significance of which remains unclear. Methods: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts (n = 280), including the international multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study (n = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles, including increased macrolide and multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant "resistotypes," RT1 and RT2, the latter characterized by poor clinical outcomes, increased multidrug resistance, and P. aeruginosa. Successful targeted eradication in P. aeruginosa-colonized individuals mediated reversion from RT2 to RT1, a more clinically favorable resistome profile demonstrating reduced resistance gene diversity. Conclusions: The bronchiectasis resistome associates with clinical outcomes, geographic origin, and the underlying host microbiome. Bronchiectasis resistotypes link to clinical disease and are modifiable through targeted antimicrobial therapy.

Residential exposure to Aspergillus spp. is associated with exacerbations in COPD.

BACKGROUND: Sensitisation to Aspergillus fumigatus is linked to worse outcomes in patients with chronic obstructive pulmonary disease (COPD), however, its prevalence and clinical implications in domestic (residential) settings remains unknown. METHODS: Individuals with COPD (n=43) recruited in Singapore had their residences prospectively sampled and assessed by shotgun metagenomic sequencing including indoor air, outdoor air, and touch surfaces (total: 126 specimens). The abundance of environmental A. fumigatus and the occurrence of A. fumigatus (Asp f) allergens in the environment were determined and immunological responses to A. fumigatus allergens determined in association with clinical outcomes including exacerbation frequency. Findings were validated in 12 individuals (31 specimens) with COPD in Vancouver, Canada, a climatically different region. RESULTS: 157 metagenomes from 43 homes were assessed. Eleven and nine separate Aspergillus spp. were identified in Singapore and Vancouver respectively. Despite climatic, temperature, and humidity variation, A. fumigatus was detectable in the environment from both locations. The relative abundance of environmental A. fumigatus was significantly associated with exacerbation frequency in both Singapore (r=0.27, p=0.003) and Vancouver (r=0.49, p=0.01) and individuals with higher Asp f 3 sensitisation responses lived in homes with a greater abundance of environmental Asp f 3 allergens (p=0.037). Patients exposed and sensitised to Asp f 3 allergens demonstrated a higher rate of COPD exacerbations at 1-year follow-up (p=0.021). CONCLUSION: Environmental A. fumigatus exposure in the home environment including air and surfaces with resulting sensitisation carries pathogenic potential in individuals with COPD. Targeting domestic A. fumigatus abundance may reduce COPD exacerbations.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

Sensitisation to recombinant Aspergillus fumigatus allergens and clinical outcomes in COPD.

BACKGROUND: Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown. METHODS: A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non-Aspergillus allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes. RESULTS: Aspergillus fumigatus sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two "fungal sensitisation" groups. The first was characterised by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by Cladosporium sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) A. fumigatus allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within Aspergillus-sensitised COPD of patients with frequent exacerbations. CONCLUSION: Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude Aspergillus allergens.

Healthcare utilization and health-related quality of life of severe asthma patients in Singapore.

BACKGROUND: Notwithstanding unequivocal consensus on the disproportionate effect of severe asthma (SA) on asthma morbidity, healthcare utilization, quality of life, work impairment and socioeconomic burden, the burden of SA patients in Singapore has not been appraised. OBJECTIVES: To determine the burden of disease and extent of quality of life impairment in SA patients in Singapore. METHODS: A cross-sectional analysis of SA patients seen in Singapore General Hospital (2020-2021) to investigate emergency healthcare utilization, oral corticosteroid (OCS) burden and health-related quality of life (HRQoL) with primary endpoint EuroQoL-5 Dimension three-level (EQ-5D-3L) scores. The empirical measurement properties of the EQ-5D utility index in SA were comprehensively assessed through multivariate regression analyses. RESULTS: A total of 336 SA patients were recruited, 51.2% of SA patients had at least one acute healthcare resource utilization during the previous year, with 25.6% of patients having an emergency healthcare visit to the hospital. Overall mean (SD) EQ-5D-3L and EQ-5D-3L utility scores in SA patients were 6.22 (1.51) and 0.77 (0.30), respectively. EQ-5D utility scores were 0.14 lower in uncontrolled vs controlled asthma and 0.09 lower in the presence of severe exacerbation, whereas barely changed by maintenance OCS dose and airflow limitation. CONCLUSION: SA patients were found to have high disease burden, high healthcare resource utilization and OCS use, low biologics usage, poor HRQoL and utility in comparison with other chronic diseases.

The burden of systemic corticosteroid use in asthma management in Asia.

For most patients, asthma can be effectively managed using inhaled medications. However, patients who have severe and/or uncontrolled asthma, or who experience exacerbations, may require systemic corticosteroids (SCSs) to maintain asthma control. Although SCS are highly effective in this regard, even modest exposure to these medications can increase the risk for long-term, adverse health outcomes, such as type 2 diabetes, renal impairment, cardiovascular disease and overall mortality. Clinical and real-world data from studies investigating asthma severity, control and treatment practices around the globe have suggested that SCS are overused in asthma management, adding to the already substantial healthcare burden experienced by patients. Throughout Asia, although data on asthma severity, control and SCS usage are limited and vary widely among countries, available data strongly suggest a pattern of overuse consistent with the broader global trend. Coordinated changes at the patient, provider, institutional and policy levels, such as increasing disease awareness, promoting better adherence to treatment guidelines and increasing availability of safe and effective alternatives to SCS, are likely necessary to reduce the SCS burden for patients with asthma in Asia.

Development of a real-world database for asthma and COPD: The SingHealth-Duke-NUS-GSK COPD and Asthma Real-World Evidence (SDG-CARE) collaboration.

PURPOSE: The SingHealth-Duke-GlaxoSmithKline COPD and Asthma Real-world Evidence (SDG-CARE) collaboration was formed to accelerate the use of Singaporean real-world evidence in research and clinical care. A centerpiece of the collaboration was to develop a near real-time database from clinical and operational data sources to inform healthcare decision making and research studies on asthma and chronic obstructive pulmonary disease (COPD). METHODS: Our multidisciplinary team, including clinicians, epidemiologists, data scientists, medical informaticians and IT engineers, adopted the hybrid waterfall-agile project management methodology to develop the SingHealth COPD and Asthma Data Mart (SCDM). The SCDM was developed within the organizational data warehouse. It pulls and maps data from various information systems using extract, transform and load (ETL) pipelines. Robust user testing and data verification was also performed to ensure that the business requirements were met and that the ETL pipelines were valid. RESULTS: The SCDM includes 199 data elements relevant to asthma and COPD. Data verification was performed and found the SCDM to be reliable. As of December 31, 2019, the SCDM contained 36,407 unique patients with asthma and COPD across the spectrum from primary to tertiary care in our healthcare system. The database updates weekly to add new data of existing patients and to include new patients who fulfil the inclusion criteria. CONCLUSIONS: The SCDM was systematically developed and tested to support the use RWD for clinical and health services research in asthma and COPD. This can serve as a platform to provide research and operational insights to improve the care delivered to our patients.

Assessing the cost-effectiveness of mepolizumab as add-on therapy to standard of care for severe eosinophilic asthma in Singapore.

OBJECTIVE: To evaluate the cost-effectiveness of mepolizumab added to standard of care (SOC) compared with SOC alone among patients with severe uncontrolled eosinophilic asthma in the Singapore setting. METHODS: A Markov model with three health states (asthma on mepolizumab and SOC, asthma on SOC alone, and death) was developed from a healthcare system perspective over a lifetime horizon. During each 4-week cycle, patients in the non-death health states could experience asthma exacerbations requiring oral corticosteroid burst, emergency department visit, or hospitalization. Asthma-related mortality following an exacerbation or all-cause mortality could also occur at each cycle. The model was populated using local costs while utilities were derived from international literature. Transition probabilities were obtained from a mixture of Singapore-specific and internationally published data. RESULTS: The base-case analysis comparing mepolizumab plus SOC with SOC alone resulted in an incremental cost-effectiveness ratio (ICER) of SGD335 486 (USD238 195) per quality-adjusted life-year (QALY) gained. Sensitivity analysis demonstrated that the ICER was most sensitive to the price of mepolizumab, followed by the proportion of exacerbations which required hospital intensive care. Despite restricting mepolizumab use to patients with a higher baseline exacerbation rate (3 in the past year) in a scenario analysis, the ICER remained high at SGD238 876 (USD 169 602) per QALY gained. CONCLUSION: At its current price, mepolizumab is not considered a cost-effective use of healthcare resources in Singapore. Substantial price reductions for mepolizumab are required to improve its cost-effectiveness to an acceptable range. These results will be useful to inform national funding decisions.

A high-risk airway mycobiome is associated with frequent exacerbation and mortality in COPD.

INTRODUCTION: The chronic obstructive pulmonary disease (COPD) bacteriome associates with disease severity, exacerbations and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain. METHODS: We report the largest multicentre evaluation of the COPD airway mycobiome to date, including participants from Asia (Singapore and Malaysia) and the UK (Scotland) when stable (n=337) and during exacerbations (n=66) as well as nondiseased (healthy) controls (n=47). Longitudinal mycobiome analysis was performed during and following COPD exacerbations (n=34), and examined in terms of exacerbation frequency, 2-year mortality and occurrence of serum specific IgE (sIgE) against selected fungi. RESULTS: A distinct mycobiome profile is observed in COPD compared with controls as evidenced by increased α-diversity (Shannon index; p<0.001). Significant airway mycobiome differences, including greater interfungal interaction (by co-occurrence), characterise very frequent COPD exacerbators (three or more exacerbations per year) (permutational multivariate ANOVA; adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups: one with increased symptoms (COPD Assessment Test score) and Saccharomyces dominance, and another with very frequent exacerbations and higher mortality characterised by Aspergillus, Curvularia and Penicillium with a concomitant increase in serum sIgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher 2-year mortality. CONCLUSION: The airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality.

Impact of psychological impairment on quality of life and work impairment in severe asthma.

BACKGROUND: Psychological impairment, such as anxiety and depression, is common in severe asthma. However, the impact of psychological impairment on asthma-specific quality of life (ASQOL) and work impairment has not been assessed within Southeast-Asia. Furthermore, previous ASQOL questionnaires contained items overlapping with asthma control, making it challenging to isolate the relationship between psychological impairment with ASQOL and asthma control, respectively. OBJECTIVE: To evaluate the relationship between psychological impairment with ASQOL and work impairment in severe asthma. METHODS: This is a cross-sectional study of severe asthma at Singapore General Hospital. We assessed ASQOL, psychological impairment, work impairment and asthma control using validated questionnaires. An ASQOL questionnaire not containing items evaluating asthma symptoms was selected to reduce overlap with asthma control. Medical records were used to obtain other asthma characteristics and healthcare utilization patterns. RESULTS: Amongst 111 patients, 37% had psychological impairment based on Hospital Anxiety and Depression Scale. Poorer ASQOL was associated with anxiety (p = .013) after controlling for demographic characteristics, asthma control and comorbidities. Anxiety symptoms were associated with greater health concerns while depression symptoms were associated with sleep difficulty and physical limitations. Having depressive symptoms was associated with an additional 16% impairment of total work hours (p = .038). Psychological impairment was not associated with spirometry results or healthcare utilization. Ethnicity significantly predicted both ASQOL and work impairment. CONCLUSIONS: In severe asthma, patients with psychological impairment have poorer ASQOL and greater work impairment than those without psychological impairment. There is an urgent need to mitigate this problem.

Managing asthma in the COVID-19 pandemic and current recommendations from professional bodies: a review.

OBJECTIVE: To provide a summary of the management of asthma in the current COVID-19 pandemic by examining and comparing the recommendations from various professional bodies. DATA SOURCES AND STUDY SELECTION: Websites of known respiratory professional bodies were searched for COVID-19 guidance related to asthma. Subject matter experts were also consulted for useful resources. Resources that were targeted at healthcare professionals were included, while those targeting patients and the general public were excluded. RESULTS: There is currently little data to suggest that asthma protects from or increases the risk of COVID-19, nor is there any data to support strong recommendations for or against specific asthma treatments. Physicians should continue to manage asthma according to existing accepted asthma guidelines and recommendations. All prescribed medications, especially inhaled corticosteroids, should be continued, and, where indicated, oral corticosteroids and biologic therapies should still be used. Nebulizers and spirometry should be avoided where possible to reduce the risk of viral transmission. A detailed history should be taken to differentiate asthma exacerbations from COVID-19. CONCLUSION: Understanding similarities and differences among the recommendations of the various professional bodies will aid in medical decision-making in managing asthma in the COVID-19 pandemic. Health professionals should also consider the individual needs, preferences and values of their patients and the unique characteristics of their local healthcare systems.

Dysfunctional Bronchial Cilia Are a Feature of Chronic Obstructive Pulmonary Disease (COPD).

Impaired mucociliary clearance may increase COPD exacerbation risk. We aimed to compare bronchial ciliary function and epithelial ultrastructure of COPD patients to healthy controls and explore its relationship to exacerbator phenotypes (frequent [FE] and infrequent [IFE] exacerbator). In this cross-sectional study, 16 COPD patients and 12 controls underwent bronchial brushings. Ciliary beat frequency (CBF) and dyskinesia index (DI; % of dyskinetic cilia) were assessed using digital high-speed video microscopy, and epithelial ultrastructure using transmission electron microscopy (TEM). Bronchial epithelium in COPD showed lower CBF and higher DI, compared to controls (median [IQR] CBF: 6.8 (6.1-7.2) Hz vs 8.5 (7.7-8.9) Hz, p<0.001 and DI: 73.8 (60.7-89.8) % vs 14.5 (11.2-16.9) %, p<0.001, respectively). This was true for FE and IFE phenotypes of COPD, which were similar in terms of bronchial CBF or DI. Subgroup analyses demonstrated lower CBF and higher DI in FE and IFE COPD phenotypes compared to controls, irrespective of smoking status. TEM showed more loss of cilia, extrusion of cells, cytoplasmic blebs and dead cells in COPD patients versus controls. Profound dysfunction of bronchial cilia is a feature of COPD irrespective of exacerbation phenotype and smoking status, which is likely to contribute to poor mucus clearance in COPD.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1963695 .

Environmental fungal sensitisation associates with poorer clinical outcomes in COPD.

INTRODUCTION: Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis; however, clinical relevance in COPD remains unclear. METHODS: Patients with stable COPD (n=446) and nondiseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assessed outdoor and indoor environmental allergen exposure in COPD. We identified key fungi in outdoor air and developed specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of 11 COPD patients and linked to clinical outcome. RESULTS: High frequencies of sensitisation to a broad range of allergens occur in COPD. Fungal sensitisation associates with frequent exacerbations, and unsupervised clustering reveals a "highly sensitised fungal predominant" subgroup demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD and promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function, illustrating the importance of environmental exposures on clinical outcomes in COPD. CONCLUSION: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD.

Coronavirus disease 2019 (COVID-19): an evidence map of medical literature.

BACKGROUND: Since the beginning of the COVID-19 outbreak in December 2019, a substantial body of COVID-19 medical literature has been generated. As of June 2020, gaps and longitudinal trends in the COVID-19 medical literature remain unidentified, despite potential benefits for research prioritisation and policy setting in both the COVID-19 pandemic and future large-scale public health crises. METHODS: In this paper, we searched PubMed and Embase for medical literature on COVID-19 between 1 January and 24 March 2020. We characterised the growth of the early COVID-19 medical literature using evidence maps and bibliometric analyses to elicit cross-sectional and longitudinal trends and systematically identify gaps. RESULTS: The early COVID-19 medical literature originated primarily from Asia and focused mainly on clinical features and diagnosis of the disease. Many areas of potential research remain underexplored, such as mental health, the use of novel technologies and artificial intelligence, pathophysiology of COVID-19 within different body systems, and indirect effects of COVID-19 on the care of non-COVID-19 patients. Few articles involved research collaboration at the international level (24.7%). The median submission-to-publication duration was 8 days (interquartile range: 4-16). CONCLUSIONS: Although in its early phase, COVID-19 research has generated a large volume of publications. However, there are still knowledge gaps yet to be filled and areas for improvement for the global research community. Our analysis of early COVID-19 research may be valuable in informing research prioritisation and policy planning both in the current COVID-19 pandemic and similar global health crises.

Distinct "Immunoallertypes" of Disease and High Frequencies of Sensitization in Non-Cystic Fibrosis Bronchiectasis.

RATIONALE: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear. OBJECTIVES: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis. METHODS: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined. MEASUREMENTS AND MAIN RESULTS: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome. CONCLUSIONS: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.

Comparison of exacerbation phenotypes among patients with severe asthma.

Background: Exacerbation phenotypes among patients with severe asthma have been largely characterized during stable periods. Little is known about severe asthma patients during exacerbation periods. Objective: To compare persistently frequent exacerbators (PFE), non-persistently frequent exacerbators (NPFE), and infrequent exacerbators (IFE) among patients with severe asthma during stable and exacerbation periods. Methods: Patients with severe asthma who were admitted for asthma exacerbations from 2011 to 2017 and on follow up at Singapore General Hospital were recruited and categorized as PFEs (two or more exacerbations per year over 2 consecutive years), NPFEs (two or more exacerbations in 1 year only), or IFEs (fewer than two exacerbations per year over 2 consecutive years). Demographic, clinical, and laboratory data were collected at baseline and during exacerbation periods. Results: The participants were categorized as the following: 20 PFEs, 36 NPFEs, and 57 IFEs, with no significant demographic differences. The participants as PFEs (versus NPFEs and IFEs) were characterized by having a higher prevalence of psychiatric disorders (25% versus 8% versus 5%; p = 0.046), more comorbidities (7 versus 4 versus 2; p < 0.001), and a higher steroid burden per year (1150 versus 456 versus 350 mg; p < 0.001). The participants who were PFEs (versus IFEs) had a higher total immunoglobulin E (IgE) level (625 versus 232 IU/mL; p = 0.046) and longer duration of admission stay (3 versus 2 days; p = 0.009). All three groups had higher blood neutrophil counts during exacerbation periods than during stable periods (p = 0.008 versus p < 0.001 versus p = 0.004). Conclusion: The participants categorized as PFEs were characterized by comorbidities, higher steroid burden, IgE levels, and longer hospital stays. Exacerbations in the participants with severe asthma, regardless of exacerbation phenotype, were characterized by neutrophilia. These findings provided insights into potential therapeutic strategies to reduce exacerbations in patients with 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 ClavisporaAspergillus 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.