Immunopathogenesis and antifungal therapy for Severe Asthma with Fungal Sensitization and Allergic Bronchopulmonary Aspergillosis

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Abstract

Immunopathogenesis and antifungal therapy for Severe Asthma with Fungal Sensitization and Allergic Bronchopulmonary Aspergillosis, a Thesis submitted toThe University of Manchester for the Degree of Doctor of Philosophy (PhD) in the Faculty of Medical and Human Sciences, Dr Livingstone Chishimba, December 2015. Introduction: The Pathogenesis and treatment of Allergic bronchopulmonary aspergillosis (ABPA), severe asthma-non fungal sensitised (SANFS) and severe asthma with fungal sensitization (SAFS) is poorly understood. IL-17A, IgE and microbiome may be associated with pathogenesis of asthma, but their role in fungal-associated asthma is uncertain. Further, the efficacy of voriconazole, posaconazole and nebulised amphotericin B (NAB) in ABPA and SAFS has not been fully studied.Aims and objectives: The aim of this PhD thesis was to evaluate the role of IL-17A, IgE and lung microbiome in patients with SANFS, SAFS and ABPA. We also studied the efficacy and safety of NAB, voriconazole and posaconazole.Methods: Airway lymphocytes and peripheral blood mononuclear cells (PBMC) from patients with ABPA (n=16), SAFS (n=15), SANFS (n=11), mild asthma (MA) (n=6) and NH (n=11) were characterized by flow cytometric analysis (FACS) to determine the % of CD (+) IL-17A expressing cells. We also evaluated microbiome population using culture and PCR plus sequencing from BAL of these patients. In chapter 3, we analysed total and specific IgE in blood from adult cohorts of SAFS (n=34) and ABPA (n=48) using ImmunoCAP 100. In chapter 5 we studied the efficacy of voriconazole and posaconazole and in chapter 6; we studied the efficacy of NAB.Results: %CD4+IL-17A expressing cells were significantly higher in patients with severe asthma and correlated positively with serum neutrophil and presence of fungi in the airways. ABPA, SAFS and SANFS were similar but all were significantly higher than MA and NH. There were no differences in IL-17A expression between blood and the lung. Fungi were more frequently associated with severe asthma and low FEV1. Steroid treatment significantly increased airway fungal load. IgE against staphylococcal aureus (SE-IgE) correlated positively with FEV1 and OCS dose.Voriconazole and posaconazole improved asthma severity and radiological abnormalities. NAB was associated bronchospasm, but was extrely effective in the few patients (n=3) that took treatment for >12 months.These responders had unique characteristics.Conclusions: IL-17A, SE-IgE, and lung microbiome are associated with asthma severity. Steroid use in these patients may increase airway fungal load. Whereas voriconazole and posaconazole are efficacious, the use of NAB is associated with significant bronchospasm. SE-IgE –high asthma patients may be a distinct asthma phenotype. Larger studies are needed.

Keyword(s)

ABPA; Airway inflammation; Asthma phenotyping; Azole antifungals; Bonchoalveolar lavage (BAL); Fungal asthma; IgE; ImmunoCAP; Immunopathonegesis; Interleukin 17 (IL-17); Microbiome; Nebulised Amphotericin B; Severe asthma; Severe asthma with fungal sensitisation

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