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    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
    (Massey University, 2024) Burmanje, Jeroen
    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.
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    Non-inflammatory mechanisms in asthma : a thesis with publications presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Public Health, Massey University, Wellington, New Zealand
    (Massey University, 2023-07-31) Ali, Hajar
    Until relatively recently asthma was considered to be an allergic disease characterised by airway inflammation. However, emerging evidence suggests that approximately 50% of asthmatics have no overt signs of inflammation. The pathophysiological mechanisms underlying disease in this group - non-eosinophilic asthma (NEA) - remain poorly understood. In 130 young-adults with generally well-controlled asthma and 79 non-asthmatics (aged 14-21 years), various non-invasive approaches were used to assess both inflammatory and non-inflammatory mechanisms in eosinophilic asthma (EA) and NEA. Studies focussed on: (i) neural mechanisms (including autonomic nervous system (ANS) activity, sensory nerve activity, and levels of neural mediators in induced sputum); and (ii) airway remodelling (measuring induced sputum levels of airway remodelling mediators), in different asthma phenotypes, whilst also taking into account clinical and inflammatory characteristics. In addition, the response to short acting β-agonist (SABA) and short acting muscarinic-antagonist (SAMA) treatment was compared between asthma phenotypes. Differences in some aspects of neural regulation were observed between EA, NEA, and non-asthmatics. In particular, airway sensory nerve reactivity was enhanced in NEA compared with non-asthmatics (p<0.05). Sensory nerve reactivity was also higher in NEA compared to EA, but this did not reach statistical significance (p=0.07). There was no evidence of an imbalance in ANS activity when comparing asthmatics and non-asthmatics, or EA and NEA. Increased levels of nociceptin were found in asthmatics and EA compared with non-asthmatics (P<0.05); nociceptin was positively associated with sputum eosinophils. Several inflammatory and remodelling mediators (including IL-1β, ECP, periostin, and VEGF-A) were elevated in EA but not NEA. There was no evidence of a differential response to SAMA between EA and NEA; however, a small subgroup of asthmatics responded better to SAMA. In conclusion, the studies described in this thesis suggest that sensory nerve reactivity may play an important role in the pathophysiology of NEA, but not EA, and may potentially represent a novel phenotype-specific treatable trait. Autonomic dysregulation does not appear to play a role in well-controlled asthma or specific asthma phenotypes. Findings suggest a potential involvement of nociceptin in asthma pathology, particularly in relation to airway eosinophilia. Finally, the identification of a small group of asthmatics who responded better to SAMA than SABA challenges current asthma treatment guidelines and suggests a need for a more personalised treatment approach. Further investigation of non-inflammatory mechanisms is warranted to improve understanding of other mechanisms underlying different asthma phenotypes, which will contribute to the identification of more specific treatable traits.