Ventilation inhomogeneity is a well recognised feature in older children and adults with asthma, even during asymptomatic periods. However, little is known about physiological changes in the airways, particularly small airways in preschool wheezers. This thesis investigated whether indices of ventilation inhomogeneity derived from multiple breath washout (MBW) were abnormal in asymptomatic preschool wheezers; whether MBW indices were more sensitive for detecting airways disease than specific airways resistance (sRaw); and whether there were differences in pulmonary function according to wheeze phenotype and atopic status. Preschool children (aged between 4-6 years) with recurrent wheeze, underwent pulmonary function assessments and were compared with age matched healthy controls. Fraction of exhaled nitric oxide (FeNO); MBW indices [lung clearance index (LCI), functional residual capacity (FRC), conductive (Scond) and acinar (Sacin) airways ventilation inhomogeneity] and sRaw were measured. Subgroup analysis was performed according to temporal wheeze phenotype of episodic (viral) and multi-trigger wheeze, and atopic status. FeNO and pulmonary function were compared in 72 healthy controls and 62 wheezers [episodic (n=28), multi-trigger (n=34; atopic (n=39), non-atopic (n=23)]. Group differences between healthy controls and wheezers were seen for FeNO, LCI, Scond and sRaw. FeNO was abnormal in 9/62 (15%), LCI in 16/62 (26%), Scond in 22/60 (37%) and sRaw in 12/62 (19%) wheezers. Multi-trigger wheezers had significantly higher LCI, Scond and sRaw than episodic wheezers. LCI was abnormal in 13/34 (38%), Scond in 21/34 (62%), and sRaw in 10/34 (29%) multi-trigger wheezers. In contrast, LCI was abnormal in 3/28 (11%) and Scond in 1/28 (3.5%), and sRaw in 2/28 (7%) episodic (viral) wheezers. There were no differences between atopic and non-atopic phenotypes. MBW indices in particular Scond detect airways disease in preschool wheezers more frequently than sRaw. Pulmonary function tests in particular Scond discriminate between episodic (viral) and multi-trigger wheezers, irrespective of atopic status providing physiological validation to clinical patterns of wheeze
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