HHe-3 MR is a non-invasive imaging method which maps and quantifies regions of ventilation heterogeneity (VH) in the lung. VH is an important feature of asthma, but little is known as to how VH informs patient phenotypes. Purpose: To determine if VH indicators quantified by HHe-3 MRI predict phenotypic characteristics and map to regions of inflammation in children with problematic wheeze/asthma. Methods. Sixty children with poorly-controlled asthma underwent HHe-3 MRI, including 22 with

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... lveolar lavage (BAL). The HHe-3 signal intensity defined four ventilation compartments. The nonventilated and hypoventilated compartments divided by the total lung volume defined a VH index (VHI %). Results: Children with VHI % in the upper quartile had significantly greater airflow limitation, bronchodilator responsiveness, blood eosinophils, expired nitric oxide (FeNO), and BAL eosinophilic/ neutrophilic granulocyte patterns compared to children with VHI % in the lower quartile. Lavage return from hypoventilated bronchial segments had greater eosinophil % than from ventilated segments. Conclusion: In children with asthma, greater VHI % as measured by HHe-3 MRI identifies a severe phenotype with higher type 2 inflammatory markers, and maps to regions of lung eosinophilia. Listed on ClinicalTrials.gov (NCT02577497). Abbreviations BAL bronchoalveolar lavage CT computerized tomography FeNO Fraction expired nitric oxide FEV 1 forced expired volume in one second FEV 1 /FVC forced expired volume in one second/forced vital capacity FVC forced vital capacity HHe-3 hyperpolarized helium-3 GINA Global Initiative for Asthma ICS inhaled corticosteroids LABA long-acting beta agonists MCID Minimal clinically important difference 1 Posted on Authorea 28 Aug , MD: Study design, senior clinician-investigator, protocol development aind implementation, recruitment, clinical oversight, data analysis. Jaime Mata, PhD: Oversight of hyperpolarized gas preparation and administration, technical leadership in administering gas and imaging sequence protocols, day to day involvement in study conduct and participant safety. King Qing, PhD: Study design, technical co-leadership in administering gas, oversight of imaging sequence protocols, day to day involvement in study conduct and participant safety. Nicholas J. Tustison, PhD: on-line image analysis, invented platform for quantifiyng lung volume compartments based on on He-3 signal intensity. John P. Mugler III PhD: Senior investigator for image development, sequencing, and process, oversight of day to day image acquistion and quality. Craig H. Meyer, PhD: development of spiral pulse sequences and image reconstruction. Y. Michael Shim, MD: Medical leadership of hyperpolarized noble gas research program, developed quality and safety standards, input on study design. Kristin Wavell: Lead study coordinator, responsible for study adaptation, identification and intervention into episodes of poor asthma control and exacerbations, central role in data acquisition and secure storage, regulatory official. Talissa Altes MD: Senior investigator, critical input into study design and implementation.