Uncontrolled and Severe Asthma: Novel Risk and Therapeutic Response Prediction, Maximising the Value of Future Interventions

This research program brings together a panel of experts across countries, including Singapore, to identify key themes and answer crucial research questions in this field. Together, these experts identified research priorities in the areas of inhaler device usage, biomarkers, and severe asthma.

Demographic and clinical characteristics of severe asthma patients worldwide

The International Severe Asthma Registry (ISAR) provides a platform to study severe asthma using patient records collected across the globe in a standardized fashion. Prior to the creation of ISAR, cross-comparison of severe asthma patients were hindered by variabilities in data collection and severe asthma definition across regional/national severe asthma registries. This project is the world’s first to describe and compare the demographic and clinical characteristics of the severe asthma population globally.

Lead Investigator: Prof David Price (Singapore)

Impact of exacerbation burden on lung function trajectory in a broad as well as severe asthma population

Severe asthma exacerbations have been reported to be associated with declining lung function. There is a need to examine this association in a real-life asthma population to devise early intervention plans. This project will examine the relationships between exacerbation burden and lung function trajectory using records from ISAR. This project will also explore the optimal time for therapeutic interventions to reduce lung function decline.

Lead Investigator: Prof Liam Heaney (United Kingdom)

Hidden severe asthma within the COPD/ACO population

Late-onset severe asthma is easily misdiagnosed as chronic obstructive pulmonary disorder (COPD) or asthma-COPD overlap syndrome (ACO). The distribution and characteristics of these hidden cases of severe asthma which could benefit from targeted biological therapies in a real-life COPD/ACO population are unknown. Thus, this project aims to estimate the prevalence of hidden severe asthma patients in a real-life COPD/ACO cohort and to compare the baseline characteristics of patients with severe asthma and those with ACO. This project also aims to evaluate the clinical response to biological treatment in hidden severe asthma patients within the COPD/ACO cohort.

Lead Investigator: Dr Chin Kook Rhee (South Korea)

Characterization of health disparities across countries in severe asthma

There exists a disparity in severe asthma mortality rates across countries. Whether this heterogeneity reflects patients’ accessibility to specialist care or the availability of novel asthma therapies. This project will describe inter-country disparities in asthma prevalence, asthma severity, treatment options, hospital resource utilization, morbidity and mortality.

Lead Investigator: to be confirmed

Characterization and comparison of eosinophilic and non-eosinophilic phenotypes of severe asthma

Severe asthma consists of multiple disease phenotype subsets, of which is a subset characterised by the presence of eosinophils, a type of cells responsible for allergic inflammation. Eosinophilic asthma comes with a heightened risk of attacks but is responsive to treatment with inhaled corticosteroid and biologics. A better understanding of this subset of severe asthma will enable better treatment guideline. This project aims to describe and compare the demographic and clinical features of the eosinophilic versus non-eosinophilic severe asthma phenotypes and to investigate the unique clusters of asthma phenotypes in the ISAR.

Lead Investigator: Prof David Price (Singapore)

Onset of asthma in severe asthma patients

The age of onset of asthma is a central factor in characterising the phenotypes of the disease, i.e. asthma with different age of onset shows differing clinical and pathological characteristics. This project will characterise the distribution of age of severe asthma onset and define a cut-off age which can distinguish between phenotype groups. Subsequently, we will describe and compare the demographic and clinical characteristics of early vs late-onset adult severe asthma.

Lead Investigator: Dr Enrico Heffler (Italy)

Assess the overlap of collected biomarkers in severe asthma

Biomarkers such as eosinophils, Immunoglobulin E and fraction exhaled nitric oxide are indicative of the underlying pathological processes that can identify the different phenotypical subsets of asthma. A better understanding of these phenotypes will pave the way for better disease prognosis prediction and personalised treatment. Biomarkers of asthma are known to overlap however the pattern of overlap in an international population of severe asthma patients is not known. In this project, we will assess the characteristics of biomarker overlap in severe asthma patient and the biomarkers’ independent and combined ability to inform about the phenotypes of severe asthma.

Lead Investigators: Dr Eve Denton & Dr Mark Hew (Australia)

Relationship between socioeconomic status and severe asthma outcome

Low socioeconomic status (SES) is often associated with general health problems, but the association between SES and poor asthma control is only poorly investigated. Thus, this project aims to elucidate the possible association between low SES and poor asthma control in severe asthma patients across the globe.

Lead Investigator: Prof Liam Heaney (United Kingdom)

OCS landscape: annual consumption, prevalence, outcomes and side-effects of long-term OCS users in severe asthma

Oral corticosteroid (OCS) represents a treatment option for severe asthma. Long-term treatment of OCS is however known to be associated with chronic diseases including osteoporosis, cataracts, diabetes and adrenal suppression. There is currently a gap of knowledge on the consumption habit of OCS, the clinical outcome and adverse events associated with OCS use in severe asthma patients. This project aims to describe the consumption of OCS within a global population of severe asthma patients and investigate the relationship between OCS exposure and onset of adverse events. The results of this project will improve treatment decisions for patients with severe asthma.

Lead Investigator: to be confirmed

Criteria for choosing and switching between similar biological treatment options in patients with atopic and non-atopic severe eosinophilic asthma

Treatment with biologics has shown promise as an efficacious and safe treatment option for severe asthma. Choosing the most suitable class of biologics personalised for each severe asthma phenotypes is important to achieve treatment success. Yet, data is limited to guide the initiation of biologics and the switching to a different class of biologics for treatment of severe asthma. Using an international severe asthma patient population database, this project aims to determine the criteria for starting on and switching biologic treatments based on the demographic and clinical characteristics as well as to investigate the long-term treatment outcomes in atopic and non-atopic severe eosinophilic asthmatics.

Lead Investigator: Prof George Christoff (Bulgaria)

Effectiveness across severe asthma biologic classes (Anti-IL-5 vs Anti IgE) in patients eligible for both

Severe asthma is heterogeneous, and depending on the underlying biological disease pathways, patients may be eligible to either anti-IL-5 or anti-IgE biologics treatment. Studies have demonstrated overlap in patients who are eligible for anti-IL-5 and anti-IgE biologics. Following-up from this finding, there is a need to compare the effectiveness of both classes of biologics in patients who are eligible for both classes of biologic treatments. This project will identify patients eligible to both anti-IL-5 and anti-IgE within an international severe asthma population and compare the clinical outcomes across patients receiving anti-IL-5 and patients receiving anti-IgE.

Lead Investigator: Prof David Price (Singapore)

Identify predictors (biomarkers) of response to biologics in severe asthma

Severe asthma consists of multiple disease subsets or phenotypes; thus, the usage of personalised medicine will be beneficial for effective patient management. Biomarkers have shown promise in predicting response towards medication. Using data of an international population of severe asthma patients within the International Severe Asthma Registry (ISAR), we aim to discover independent biomarker predictors of no, partial and high clinical response to biologics within a large population of severe asthma patients across multiple nations. This project will also evaluate the performance of baseline biomarkers in predicting response to biologics.

Lead Investigators: Dr Eve Denton & Dr Mark Hew (Australia)

Biologics in severe asthma: utilization patterns, causes for discontinuation and switching and adverse outcomes

Biologic therapy has been quickly integrated into the treatment regimen of severe asthma due to the safety and efficacy in treating severe asthma. Each class of biologics have different mechanisms of action, and thus selecting the best class for each patient is highly beneficial for the management of severe asthma. Currently, there is a lack of data and recommendation to inform the prescriber when effectiveness is sub-optimal, or how much can be gained by switching to a different biologic. There are also safety concerns around switching, particularly whether hypersensitivity to a given biologic increases the probability of experiencing a similar reaction with other classes of biologics. This study was initiated to describe the use of biologics in real-life patients with severe asthma, with respect to frequency, patterns and reason for discontinuation and switching to another biologic class.

Lead Investigator: Prof Andrew Menzies-Gow (United Kingdom)

Outcomes of switching between Anti-IL5 receptor α chain monoclonal antibody therapy and Anti-IL5 monoclonal antibody therapy in severe asthma

Severe asthma is a heterogeneous disease with multiple phenotypes, with differing responses to each class of medications, thus stressing the need for personalised medicine for severe asthma management. Biologics represent a novel group of treatment for asthma designed to target a specific biological target in the human body. As such, patients whose symptoms are not sufficiently controlled with one class of biologics may benefit from switching prescription to another class. This project will compare treatment effectiveness and safety concerns around switching between the two types of biologics and if hypersensitivity to a given biologic increases the probability of experiencing a similar reaction with the another.

Lead Investigator: to be confirmed

CRITical Inhaler mistaKes and Asthma controL (CRITIKAL) study

Improper use of inhaler device is a common and well-established reason for failure to achieve asthma control. Previously, however, there was no study which investigates the impact of each specific inhalation errors towards asthma outcome. The CRITIKAL project was thus initiated to answer the pertinent question of which inhaler technique errors represent the “critical” errors which were common and negatively impacts asthma outcomes.

Lead Investigator: Prof David Price (Singapore)

Hidden severe asthma patients in primary care vs. ISAR cohort

Patients with severe asthma have much to gain from referral to severe asthma services including a comprehensive review of diagnosis, triggers and treatable traits. However, only a minority of severe asthma patients received specialist care, the remaining are hidden within primary care. There is a need to improve the identification of undiagnosed patients with severe asthma within primary care who would benefit from an appropriate referral, and subsequently improve quality of life, reduce morbidity and/or mortality associated with severe asthma. This project will develop a criterion for identification of hidden severe asthma patients and compare the characteristics of the hidden patients to those managed in specialist care recorded in the ISAR.

Lead Investigator: Prof David Price (Singapore)

Easy Low Instruction Over Time (ELIOT): inhaler technique mastery and maintenance in healthcare professionals trained on different devices

Insufficient inhaler technique remains one of the most common causes of failure in achieving symptoms control in patients with asthma. Healthcare professionals (HCPs) are required to assess and train patients in the correct use of inhaler devices, yet it has been previously shown that many HCPs themselves lack the knowledge and skill on inhaler techniques to educate patients. As such, it is pertinent to correct this issue either through training of HCPs or by the introduction of newer, easier-to-use inhaler device models. Bringing together our internal expertise in real-life respiratory research and experts from different branches of specialities, this systematic, investigative and experimental project represents the world’s first attempt to assess the extent of training required for HCPs to master inhaler techniques.

Lead Investigator: Prof David Price (Singapore)

The evaluation of FeNO for predicting response to ICS in subjects with Non-Specific Respiratory Symptoms (NSRS)

Existing treatments for patients presenting with non-specific respiratory symptoms suggesting of asthma have a one-size-fits-all approach, often involving the prescription of inhaled corticosteroids (ICS). However, not all patients respond to ICS in the same manner, as such identification of patients most likely to respond to ICS would minimise inappropriate treatment and limit side-effects and unnecessary healthcare costs. FeNO (fraction exhaled nitric oxide) is easily measured in routine clinical visits and showed potential as a biomarker for ICS responsiveness in small clinical trials. However, current technology for the measurement of FeNO is expensive and there is a need for an affordable technology to measure FeNO in primary care. Therefore, the NSRS project was initiated to develop an affordable and reliable FeNO measurement technology which can be implemented as part of routine primary care in Singapore.

Lead Investigator: Prof David Price (Singapore)

Publications

Sinthia Bosnic-Anticevich, Christina Callan, Henry Chrystyn, Federico Lavorini, Vasilis Nikolaou, Vicky Kritikos, PN Richard Dekhuijzen, Nicolas Roche, Leif Bjermer, Cynthia Rand, Nicholas Zwar, David B Price. Inhaler technique mastery and maintenance in healthcare professionals trained on different devices. J Asthma 2018: 55(1): 79-88.
[PubMed] [Full Text]

David B. Price, Miguel Román-Rodríguez, R. Brett McQueen, Sinthia Bosnic-Anticevich, Victoria Carter, Kevin Gruffydd-Jones, John Haughney, Svein Henrichsen, Catherine Hutton, Antonio Infantino, Federico Lavorini, Lisa M. Law, Karin Lisspers, Alberto Papi, Dermot Ryan, Björn Ställberg, Thys van der Molen, Henry Chrystyn. Inhaler errors in the CRITIKAL study: type, frequency, and association with asthma outcomes. J Allergy Clin Immunol Pract 2017; 5(4): 1071-81.e9.
[PubMed] [Full Text]

David B Price, Roland Buhl, Adrian Chan, Daryl Freeman, Elizabeth Gardener, Clifford Godley, Kevin Gruffydd-Jones, Lorcan McGarvey, Ken Ohta, Dermot Ryan, Jörgen Syk, Ngiap Chuan Tan, TzeLee Tan, Mike Thomas, Sen Yang, Priyanka Raju Konduru, Marcus Ngantcha, Martina Stagno d’Alcontres, Therese S Lapperre. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2017.
[PubMed] [Full Text]

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