Exploring Definitions and Predictors of Severe Asthma Clinical Remission Post-Biologic in Adults.

RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

International severe asthma registry (ISAR): protocol for a global registry.

BACKGROUND: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. METHODS: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. CONCLUSIONS: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

Blood eosinophil count correlates with severity of respiratory failure in life-threatening asthma and predicts risk of subsequent exacerbations.

BACKGROUND: An elevated blood eosinophil count when asthma is stable predicts exacerbations and therapeutic response to corticosteroids or biologics targeting eosinophils. Few studies have examined the prognostic value of blood eosinophils measured at exacerbation. AIM: To elucidate the relationship between a spot blood eosinophil count-measured at the onset of a life-threatening asthma exacerbation-with indices of exacerbation severity and risk of subsequent exacerbations. METHODS: Real-world, retrospective review of all life-threatening asthma cases admitted at 4 public hospitals in Singapore between 2011-2015. We assessed the trends and correlations between blood eosinophil count on admission with arterial blood gas values, duration of mechanical ventilation, and risk of death, hypoxic ischemic encephalopathy or respiratory arrest. Risk of future exacerbations among survivors was modelled using Cox regression and survival curves. RESULTS: There were 376 index life-threatening exacerbations with median blood eosinophil count (5-95th percentiles) of 0.270 × 109 /L (0-1.410 × 109 /L). Arterial pH decreased and PCO2 increased with increasing eosinophil count. Duration of mechanical ventilation and risk of death, hypoxic ischaemic encephalopathy or respiratory arrest did not vary with eosinophils. Among 329 survivors who were followed-up over a median of 52 months, blood eosinophils ≥1.200 × 109 /L was associated with an increased hazard of emergency visits and/or admissions for asthma (hazard ratio 1.8, 95% confidence interval 1.1-2.9, P = .02). CONCLUSION: In this study of life-threatening asthma, we found that a spot blood eosinophil count correlates with severity of respiratory failure and predicts risk of subsequent exacerbations.

Treatable traits can be identified in a severe asthma registry and predict future exacerbations.

BACKGROUND AND OBJECTIVE: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. METHODS: The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. RESULTS: In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. CONCLUSION: Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

Exploring Definitions and Predictors of Response to Biologics for Severe Asthma.

BACKGROUND: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging. OBJECTIVE: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response. METHODS: This was a longitudinal cohort study using data from 21 countries, which shared data with the International Severe Asthma Registry. Changes in four asthma outcome domains were assessed in the 1-year period before and after biologic initiation in patients with a predefined level of prebiologic impairment. Responder cutoffs were 50% or greater reduction in exacerbation rate, 50% or greater reduction in long-term oral corticosteroid daily dose, improvement in one or more category in asthma control, and 100 mL or greater improvement in FEV1. Responders were defined using single and multiple domains. The association between prebiologic characteristics and postbiologic initiation response was examined by multivariable analysis. RESULTS: A total of 2,210 patients were included. Responder rate ranged from 80.7% (n = 566 of 701) for exacerbation response to 10.6% (n = 9 of 85) for a four-domain response. Many responders still exhibited significant impairment after biologic initiation: 46.7% (n = 206 of 441) of asthma control responders with uncontrolled asthma before the biologic still had incompletely controlled disease postbiologic initiation. Predictors of response were outcome-dependent. Lung function responders were more likely to have higher prebiologic FeNO (odds ratio = 1.20 for every 25-parts per billion increase), and shorter asthma duration (odds ratio = 0.81 for every 10-year increase in duration). Higher blood eosinophil count and the presence of type 2-related comorbidities were positively associated with higher odds of meeting long-term oral corticosteroid, control, and lung function responder criteria. CONCLUSIONS: Our findings underscore the multimodal nature of response, showing that many responders experience residual symptoms after biologic initiation and that predictors of response vary according to the outcome assessed.

A review of psychological dysfunction in asthma: affective, behavioral and cognitive factors.

BACKGROUND: The research on psychological dysfunction in asthma is extensive but heterogeneous. We undertook a narrative review about the effects of psychological dysfunction on asthma. METHODS: Electronic searches of MEDLINE, EMBASE, CINAHL and the Cochrane Library were conducted, supplemented by hand-searching bibliographies and seeking expert opinion. RESULTS: The impact of psychological factors on asthma can be classified according to dysfunction in the domains of affect, behavior and cognition. Affective or emotional disturbance may lead to poor asthma control by directly modulating disease activity. Maladaptive behaviors may occur in asthma patients. These include maladaptive breathing behaviors, such as impaired voluntary drive to breathe and dysfunctional breathing, as well as impaired asthma health behaviors, that is, a coordinated range of activities performed to maintain good disease control. Dysfunctional cognitions (thoughts and beliefs) about asthma and impaired cognitive processing of the perception of dyspnea are associated with poorly controlled disease and asthma deaths, respectively. The three domains of psychological dysfunction are often closely intertwined, leading to vicious circles. CONCLUSIONS: We have conceptualized psychological dysfunction in asthma using a framework consisting of affect, behavior and cognition. Their influences are intertwined and complex. Future research should focus on the formulation of a psychological assessment tool based on this framework and evaluating its efficacy in improving asthma outcomes.

Impact of COVID-19 on perceived wellbeing, self-management and views of novel modalities of care among medically vulnerable patients in Singapore.

OBJECTIVES: This study aims to examine the impact of COVID-19 measures on wellbeing and self-management in medically vulnerable non-COVID patients and their views of novel modalities of care in Singapore. METHODS: Patients with cardiovascular disease (CVD), respiratory disease, chronic kidney disease, diabetes and cancer were recruited from the SingHealth cluster and national cohort of older adults. Data on demographics, chronic conditions and perceived wellbeing were collected using questionnaire. We performed multivariable regression to examine factors associated with perceived wellbeing. Qualitative interviews were conducted to elicit patient's experience and thematically analyzed. RESULTS: A total of 91 patients participated. Male patients compared with female patients perceived a lower impact of the pandemic on subjective wellbeing. Patients with CVD compared to those having conditions other than CVD perceived a lower impact. Impacts of the pandemic were primarily described in relation to emotional distress and interference in maintaining self-care. Hampering of physical activity featured prominently, but most did not seek alternative ways to maintain activity. Despite general willingness to try novel care modalities, lack of physical interaction and communication difficulties were perceived as main barriers. DISCUSSION: Findings underline the need to alleviate emotional distress and develop adaptive strategies to empower patients to maintain wellbeing and self-care.

Spillover Effects of COVID-19 on Essential Chronic Care and Ways to Foster Health System Resilience to Support Vulnerable Non-COVID Patients: A Multistakeholder Study.

OBJECTIVES: Little empirical research exists on how key stakeholders involved in the provision of care for chronic conditions and policy planning perceive the indirect or "spillover" effects of the COVID-19 on non-COVID patients. This study aims to explore stakeholder experiences and perspectives of the impact of COVID-19 on the provision of care for chronic conditions, evolving modalities of care, and stakeholder suggestions for improving health system resilience to prepare for future pandemics. DESIGN: Qualitative study design. SETTING AND PARTICIPANTS: This study was conducted during and after the COVID-19 lockdown period in Singapore. We recruited a purposive sample of 51 stakeholders involved in care of non-COVID patients and/or policy planning for chronic disease management. They included health care professionals (micro-level), hospital management officers (meso-level), and government officials (macro-level). METHODS: In-depth semi-structured interviews were conducted. All interviews were digitally recorded, transcribed verbatim, and thematically analyzed. RESULTS: Optimal provision of care for chronic diseases may be compromised through the following processes: lack of "direct" communication between colleagues on clinical cases resulting in rescheduling of patient visits; uncertainty in diagnostic decisions due to protocol revision and lab closure; and limited preparedness to handle non-COVID patients' emotional reactions. Although various digital innovations enhanced access to care, a digital divide exists due to uneven digital literacy and perceived data security risks, thereby hampering wider implementation. To build health system resilience, stakeholders suggested the need to integrate digital care into the information technology ecosystem, develop strategic public-private partnerships for chronic disease management, and give equal attention to the provision of holistic psychosocial and community support for vulnerable non-COVID patients. CONCLUSIONS AND IMPLICATIONS: Findings highlight that strategies to deliver quality chronic care for non-COVID patients in times of public health crisis should include innovative care practices and institutional reconfiguration within the broader health system context.

Impact of Air Pollution and Trans-Boundary Haze on Nation-Wide Emergency Department Visits and Hospital Admissions in Singapore.

INTRODUCTION: Air pollution is associated with adverse health outcomes. However, its impact on emergency health services is less well understood. We investigated the impact of air pollution on nation-wide emergency department (ED) visits and hospital admissions to public hospitals in Singapore. MATERIALS AND METHODS: Anonymised administrative and clinical data of all ED visits to public hospitals in Singapore from January 2010 to December 2015 were retrieved and analysed. Primary and secondary outcomes were defined as ED visits and hospital admissions, respectively. Conditional Poisson regression was used to model the effect of Pollutant Standards Index (PSI) on each outcome. Both outcomes were stratified according to subgroups defined a priori based on age, diagnosis, gender, patient acuity and time of day. RESULTS: There were 5,791,945 ED visits, of which 1,552,187 resulted in hospital admissions. No significant association between PSI and total ED visits (Relative risk [RR], 1.002; 99.2% confidence interval [CI], 0.995-1.008; P = 0.509) or hospital admissions (RR, 1.005; 99.2% CI, 0.996-1.014; P = 0.112) was found. However, for every 30-unit increase in PSI, significant increases in ED visits (RR, 1.023; 99.2% CI, 1.011-1.036; P = 1.24 × 10-6 ) and hospital admissions (RR, 1.027; 99.2% CI, 1.010-1.043; P = 2.02 × 10-5 ) for respiratory conditions were found. CONCLUSION: Increased PSI was not associated with increase in total ED visits and hospital admissions, but was associated with increased ED visits and hospital admissions for respiratory conditions in Singapore.

Asthma phenotypes in a multi-ethnic Asian cohort.

BACKGROUND: Identification of asthma phenotypes facilitates our understanding of asthma pathobiologies. Phenotypes observed in homogenous Asian cohorts have distinct differences from those described in Caucasian cohorts, suggesting that ethnicity may influence phenotypic expression. Phenotypic clusters in a multi-ethnic Southeast Asian cohort have not been described before, and direct comparisons of these clusters within a single study may reveal how ethnicity affects phenotypic expression. METHODS: Six hundred and thirty adult asthma patients from two healthcare institutions in Singapore were randomly assigned in a 2:1 fashion to a test and validation cohort. Latent class analysis was performed on both cohorts using age of asthma onset, sex, ethnicity, smoking status, body mass index, lung function, blood eosinophil count, asthma control test score, and exacerbation frequency as input variables. Phenotypic clusters between the test and validation cohorts were compared RESULTS: Three clusters were identified in both the test and validation cohorts, with corresponding clusters of each cohort sharing similar characteristics. Ethnic representation and asthma control were significantly different between clusters. Cluster one comprised Chinese females with late-onset asthma and the best asthma control. Cluster two comprised non-Chinese females with obesity and the worst asthma control. Cluster three was multi-ethnic with the greatest proportion of atopic patients. CONCLUSION: We identified three phenotypic clusters in our multi-ethnic Southeast Asian population, with distinct differences in ethnicity which may be attributable to inherent differences in baseline characteristics among ethnic groups.

Making Clinical Practice Guidelines Pragmatic: How Big Data and Real World Evidence Can Close the Gap.

Clinical practice guidelines (CPGs) have become ubiquitous in every field of medicine today but there has been limited success in implementation and improvement in health outcomes. Guidelines are largely based on the results of traditional randomised controlled trials (RCTs) which adopt a highly selective process to maximise the intervention's chance of demonstrating efficacy thus having high internal validity but lacking external validity. Therefore, guidelines based on these RCTs often suffer from a gap between trial efficacy and real world effectiveness and is one of the common reasons contributing to poor guideline adherence by physicians. "Real World Evidence" (RWE) can complement RCTs in CPG development. RWE-in the form of data from integrated electronic health records-represents the vast and varied collective experience of frontline doctors and patients. RWE has the potential to fill the gap in current guidelines by balancing information about whether a test or treatment works (efficacy) with data on how it works in real world practice (effectiveness). RWE can also advance the agenda of precision medicine in everyday practice by engaging frontline stakeholders in pragmatic biomarker studies. This will enable guideline developers to more precisely determine not only whether a clinical test or treatment is recommended, but for whom and when. Singapore is well positioned to ride the big data and RWE wave as we have the advantages of high digital interconnectivity, an integrated National Electronic Health Record (NEHR), and governmental support in the form of the Smart Nation initiative.

The emergence of Aspergillus species in chronic respiratory disease.

Chronic lung disease is recognized as an important risk factor for developing pulmonary aspergillosis. The development of specific aspergillus-associated syndromes depends on host immunity and underlying lung disease. In the setting of asthma, hypersensitivity to Aspergillus can lead to allergic bronchopulmonary aspergillosis (ABPA) or severe asthma with fungal sensitization (SAFS). Chronic use of systemic or inhaled corticosteroids coupled with recurrent antibiotic use for exacerbations prevalent in chronic obstructive pulmonary disease (COPD) predisposes to chronic pulmonary aspergillosis (CPA). Prior pulmonary tuberculosis is a risk factor for CPA, a syndrome with a wide range of presentations including a simple aspergilloma, chronic cavities, necrosis or fibrosis. Accumulating evidence suggests that the presence of or colonization by Aspergillus in the setting of chronic lung disease can worsen clinical course and outcomes even in the absence of overt pulmonary aspergillosis. We propose that understanding the complex interplay between host and fungi may provide key insights into the pathogenesis of Aspergillus-associated pulmonary syndromes in the setting of chronic lung disease, and provide novel therapeutic approaches to improve its identification and management.

Role of bronchoprovocation tests in identifying exercise-induced bronchoconstriction in a non-athletic population: a pilot study.

BACKGROUND: Studies on diagnostic tests for exercise-induced bronchoconstriction (EIB) have centered around the asthmatic and elite athletic population. Traditionally, the exercise challenge test (ET) was recommended to assess EIB. We aimed to compare the performance of surrogate testing, mainly the hypertonic saline (HS) test, and methacholine challenge test (MCT) versus ET in identifying EIB among non-athletic subjects. METHODS: We prospectively recruited subjects who did not have confirmed active asthma, but who reported exercise-induced dyspnoea. The participants underwent HS and ET on separate days within two weeks. MCT performed within one year were obtained retrospectively from medical records. The sensitivity, specificity, and accuracy of each diagnostic test were calculated using ET as the gold standard. RESULTS: We recruited 27 participants (mean age 20.6±2.5 years; 92.6% male). Five (18.5%) had a history of self-reported asthma prior to recruitment. Eleven participants (40.7%) had a positive ET test. The sensitivity, specificity and accuracy of HS in diagnosing EIB was 90.9%, 62.5% and 74.1%; while that of MCT was 88.9%, 83.3% and 85.7% respectively. Six subjects were positive to HS but had negative ET test. CONCLUSIONS: Both HS and MCT were found to be suitable alternatives to ET in screening for EIB in the non-athletic population in this pilot study. Further large scale studies are required to confirm this finding. These tests have the potential to replace ET for the diagnosis of EIB in centres without ET equipment or facilities.

Use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of granulomatous mediastinal lymphadenopathy.

INTRODUCTION: This study assessed the clinical utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of suspected granulomatous mediastinal lymphadenopathy. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent EBUS-TBNA for suspected granulomatous mediastinal lymphadenopathy at Singapore General Hospital between December 2008 and December 2011 inclusive. RESULTS: Over a period of 3 years, a total of 371 patients underwent EBUS-TBNA of whom 33 (9%) had the procedure performed for evaluation of suspected granulomatous mediastinal lymphadenopathy - 18 for suspected tuberculosis (TB) and non-tuberculous mycobacterial (NTM) lymphadenitis, and 15 for suspected sarcoidosis. EBUS-TBNA was diagnostic in 9 of the 13 patients with a final diagnosis of TB/NTM. EBUS-TBNA cultures were positive in 6 of them (46%), 1 showed acid-fast bacilli (AFB) although cultures were negative, and 2 had necrotising granulomatous inflammation from EBUS-TBNA biopsies and sputum cultures grew TB. EBUS-TBNA was diagnostic in 9 of the 14 patients with a final diagnosis of sarcoidosis through histology showing non-caseating granulomatous inflammation. The sensitivities of EBUS-TBNA for diagnosis of TB/NTM, sarcoidosis and overall granulomatous mediastinal lymphadenopathy were 69%, 64%, 64%; the negative predictive values were 56%, 17%, 33%; and accuracies were 78%, 67%, 70%, respectively. CONCLUSION: EBUS-TBNA can be useful in the diagnosis of suspected granulomatous mediastinal lymphadenopathy with sensitivities and accuracies of >60%.

The effects of oxygen therapy in patients presenting to an emergency department with exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To elucidate oxygen administration practices in the setting of acute exacerbations of chronic obstructive pulmonary disease (COPD) and compare these practices with those recommended in internationally accepted guidelines. DESIGN: Retrospective audit. PARTICIPANTS AND SETTING: 65 patients admitted to a Melbourne university teaching hospital via the emergency department (ED), identified through medical records by a discharge diagnosis (discharged between 1 June and 30 September 2005) of acute exacerbation of COPD (AECOPD). Those included had respiratory function test results consistent with British Thoracic Society guidelines for the diagnosis of COPD. MAIN OUTCOME MEASURES: Length of stay, need for high dependency unit (HDU) admission, use of non-invasive ventilation (NIV), and use of arterial blood gas (ABG) tests. RESULTS: Our audit showed that 95% of patients defined as retaining carbon dioxide received oxygen at a flow rate greater than 2 L/min. This process began in the ambulance and continued in the ED, often without monitoring of ABG levels. Length of stay was significantly longer (P = 0.029); need for NIV on admission greater (P = 0.0124); and rate of admission to the HDU higher (P = 0.0124) in patients who achieved a partial pressure of arterial oxygen (PaO(2)) >/= 74.5 mmHg compared with those with a PaO(2) < 74.5 mmHg. CONCLUSIONS: The vast majority of patients with AECOPD presenting to our university teaching hospital receive oxygen therapy outside of internationally accepted guidelines, often without monitoring of ABG levels. The use of high-flow oxygen may contribute to an increased length of stay, more frequent admission to HDU and greater use of NIV among patients who achieve a higher PaO(2).