Pathophysiological mechanisms in asthma phenotypes : an international multicentre study : a thesis presented in partial fulfilment of the requirements for the degree of Master of Health Science in Bioscience at Massey University, Wellington, New Zealand

Abstract

Background: Differences in asthma prevalence have been reported in high-, medium- and low-income countries. While different asthma phenotypes may be involved, little is known about the underlying mechanisms or if they vary between countries. Aims: To assess in high-income (New Zealand, UK) and medium- to low-income (Brazil, Uganda, Ecuador) countries, whether: 1) levels of sputum inflammatory, remodelling, or neural mediators differ between asthma phenotypes within countries; and 2) levels of sputum inflammatory, remodelling, or neural mediators differ between specific asthma phenotypes between countries. Methods: Questionnaires and clinical assessments (including skin prick test, spirometry, and sputum induction) were conducted in 527 asthmatics and 191 non asthmatics aged 8 – 27 years (Brazil: 91 and 11, Ecuador: 55 and 11, Uganda: 68 and 16, New Zealand: 204 and 103, United Kingdom: 50 and 22, respectively). Asthma subgroups (eosinophilic and non-eosinophilic asthma) and inflammatory phenotypes (eosinophilic, neutrophilic, paucigranulocytic, and mixed granulocytic asthma) were identified based on ≥2.5% eosinophils and/or ≥61% neutrophils in sputum. Twenty sputum mediators were analysed using Luminex MAGPIX or ELISA. Results: Sputum levels of eosinophil-associated mediators (ECP, PGD-2, periostin) were higher in eosinophil-associated asthma groups, and neutrophil-associated mediators (IL-1β, IL-6, IL-8, NE) were higher in neutrophil associated asthma groups, irrespective of country. Nociceptin was increased in EA compared to other phenotypes in 4/5 countries (e.g. UK EA vs NA (562.9 vs 67.2 ng/mL, p<0.05). Sputum mediator levels varied significantly between specific phenotypes when comparing countries, but in PGA (the most prevalent phenotype overall (49.5%)), there was no evidence of increased inflammatory, neural, or remodelling mediators. Conclusions: Similar associations between specific mediators and asthma phenotypes were found across countries, suggesting common underlying mechanisms. Mediator levels in the same phenotypes varied across countries, which may be due to methodological variations or differences in environmental exposures. While PGA is very common across all countries studied, the underlying pathophysiology remains unknown.