Xenon MRI assessment of response to cystic fibrosis therapies

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DESCRIPTION (provided by applicant): New clinical guidelines for the treatment of exacerbations in cystic fibrosis (CF) were recently published by the American Thoracic Society. Examples of these evidence-based recommendations include not performing synergy testing to combat multi-drug-resistant infections, and using only one daily dose of aminoglycoside antibiotics, which was found equally effective as three. However for six of ten therapies evaluated, there simply was not enough data to make recommendations. These six included inpatient versus outpatient care; simultaneous use of intravenous and inhaled antibiotics; number of antibiotics used to treat pseudomonas aeruginosa; continuous infusion of betalactam antibiotics; and duration of antibiotic treatment. This situation clearly indicates that new tools are needed for evaluating response to therapy in CF, particularly for those involving antibiotics and the treatment of CF exacerbations. Hyperpolarized-gas MRI has been shown to be effective for assessing regional airflow impairment of cystic fibrosis in pediatric and adult patients. To date all hyperpolarized-gas MRI studies in children have employed hyperpolarized helium-3 due to wider access to the required infrastructure. Hyperpolarized xenon-129 (HXe) has been perceived as less appropriate for children due to its solubility in blood and tissues, and concomitant side effects including brief euphoria, dysphoria, and/or numbness. However, state-of-the-art polarization infrastructure is providing HXe polarizations as high as 50%, allowing clinical imaging with modest doses. Furthermore from a diagnostic perspective, the solubility of xenon in tissue and blood is precisely the property that makes it able to interrogate lung tissue inflammation, which may serve as an important biomarker for antibiotic response in cystic fibrosis exacerbations. Our collaboration recently demonstrated simultaneous acquisition of xenon gas-phase and xenon dissolved-phase images in a single breath hold. In one of our "healthy" volunteers, we discovered a previously undiagnosed inflammatory nodule was highly conspicuous on the dissolved phase images. This result suggests that this technique may be sensitive to inflammation. Since inflammation is a primary treatment target in CF, this technique may be well suited to detect response to treatment in patients with CF. We propose to utilize HXe simultaneous gas- and dissolved-phase MRI together with a new dual-nucleus structure-function ventilation imaging protocol, acquiring both proton and HXe images within a single breath hold, to monitor therapeutic response in cystic fibrosis exacerbations. Five patients admitted for a cystic fibrosis exacerbation will be recruited, including at least two children. Patients will be imaged upon initiation of treatment and three weeks after therapy commences. Data will be incorporated into an imaging biomarker for CF and compared with other metrics such as spirometry and patient self-assessments. PUBLIC HEALTH RELEVANCE: New treatments are in Phase 3 clinical trials that target the underlying abnormality in cystic fibrosis (CF) and restore the function of the cell membrane chloride channel that is abnormal in CF. Because these treatments work differently for different CF genotypes, there is a pressing need to develop a technique for the assessment of treatment efficacy, particularly for young children, so that effective treatment can be initiated before lung damage is irreversible. Hyperpolarized xenon (HXe) MRI is a new modality for imaging lung function that does not rely on ionizing radiation, an improvement in safety that is particularly important for children. The proposed study is a vital step toward determining whether HXe MRI could be a useful outcome measure in CF, something that could have tremendous clinical impact in this patient population.