Therapeutic outcomes in allergic bronchopulmonary aspergillosis (ABPA)

Background Allergic bronchopulmonary aspergillosis (ABPA) is the most common form of pulmonary aspergillosis, affecting up to 4.8 million patients worldwide [9].

Despite significant population heterogeneity, treatment strategies are suboptimal because the model of care is currently a one-size-fits-all model; all patients will be treated with corticosteroids to quickly control the symptoms, and itraconazole will be given as the first line antifungal.

However, there are risks associated with these treatments [10, 11] and the efficacy of alternatives such as newer and higher activity triazole antifungals, or the place of biologic therapies like anti-IL5 antagonists has not been thoroughly investigated.

My retrospective studies in an asthmatic population with ABPA (undergoing peer review) suggest that posaconazole is superior to corticosteroids and itraconazole in the treatment of ABPA, using FEV1 as a key outcome measure. This appears to be related to a reduction in serum Aspergillus IgG, a key marker of airway fungal burden.

Significantly, existing quality of life and symptom tools used in ABPA trials are not disease specific, are complex and have not been consistently responsive.

We need a better understanding of therapies that can control disease rapidly, patients' unique characteristics that can influence outcome, and the correlation of patient symptom scores with lung physiology, so that treatment can be optimised for the patient in a precision medicine model.

Hypothesis: Therapies that reduce airway fungal burden lead to improved FEV1, and better patient symptom scores Research Aim To undertake an observational study of treatment outcomes in ABPA Objectives 1. To undertake a systematic review and network analysis (NMA) to evaluate the evidence for current therapies in ABPA 2.

To conduct a retrospective multi-hospital electronic health record-based clinical informatics analysis to determine the impact of treatments on patient outcome 3.

To qualitatively assess the validity, reliability and responsiveness of patient reported outcomes, and assess correlations with measurable observations in a prospective single-centre feasibility study Methods and Timelines Study 1: Months 1-9: A systematic review incorporating a NMA assessing the comparative effectiveness of available therapies Study 2: Months 10-20 - conventional statistics and machine learning to generate predictive models of outcome - test hypothesis that medication that reduces airway fungal burden consequently leads to an improvement in lung function Study 3: Months 6 and 8-24 - Assess feasibility for future randomized control trials - Conduct a qualitative study with semi structured interviews for patient reported outcome measure (PROM) development, and ascertain content validity, reliability and responsiveness Evaluation: Months 25-28 - Conduct a mixed methods assessment of the relationship between subjective PROMs and measurable observations.

Implementation: Months 29-34: Explore strategies for implementation of new findings/guideline development into a clinical pathway e.g. using a Quality Improvement approach Anticipated impact and dissemination This work will be co-produced with patients The findings of this study will be shared at national and international conferences, as well as in high-impact journals, professional network meetings, and patient and public engagement cafes.

Identification of a more effective treatment for ABPA will result in improved treatment outcomes and will reduce NHS cost pressures.