Fungal infections in the lung are a major complication of cystic fibrosis (CF), contributing to pulmonary exacerbations, and accelerating lung function decline. Thirty percent of adult CF patients suffer from Aspergillus bronchitis (AB) and a further 17% have allergic bronchopulmonary aspergillosis (ABPA). Treatment often requires toxic and long-term antifungal agents and steroids, with triazole antifungal drug resistance rapidly emerging (currently 16% at the Royal Brompton Hopsital in CF). Cystic fibrosis-associated pulmonary aspergillosis (i.e. AB and ABPA) may lead to fatal invasive disease and is a contraindication to lung transplantation. New treatment approaches are urgently required to improve these unacceptably poor outcomes. Immunotherapies are currently revolutionizing clinical medicine, leading to dramatic improvements in mortality and outcome across a range of malignant diseases and auto-inflammatory conditions.
IMMUNOLOGICAL CLASSIFICATION OF CYSTIC FIBROSIS-ASSOCIATED PULMONARY ASPERGILLOSIS.
Individuals will be classified according to the novel immunologic classification of CFPA developed on the basis of fungal sputum cultures, Aspergillus IgG, sputum galactomannan, total IgE, and Aspergillus IgE. All baseline demographic and clinical data will be collected including CF genotype, chest imaging, lung function tests, body mass index, sputum culture results and antimicrobial usage, immunosuppressive treatments such as steroids, treatment with CFTR channel modulators, other allergen sensitizations and co-morbidities such as pancreatic, hepatic or renal dysfunction and diabetes mellitus.
In parallel, we will characterise peripheral blood mononuclear cell (PBMC) cytokine responses to A. fumigatus by multi-parameter Florescence Activated Cell Sorting. This will allow further immuno-stratification of our cohort, and will enable the identification of immuno-pathological endotypes associated with poor outcomes where therapeutic interventions should be focused.
This phenotyping strategy will enable systematic identification of immuno-biomarkers associated with disease mechanisms that could be targeted by re-purposing existing immuno-therapeutic approaches. We will also characterise the impact of other clinical variables (e.g. CF genotype and channel modulator therapy) on fungal disease severity and outcome.