Xenon MRI assessment of response to cystic fibrosis therapies

描述（由申请人提供）：美国胸科学会最近发表了治疗囊性纤维化（CF）加重的新临床指南。这些基于证据的建议的例子包括不进行协同作用测试来对抗多重耐药感染，以及每天只使用一剂氨基糖苷类抗生素，这被发现与三剂同样有效。然而，对于评估的10种疗法中的6种，根本没有足够的数据来提出建议。这六项包括住院与门诊治疗;同时使用静脉和吸入抗生素;用于治疗铜绿假单胞菌的抗生素数量;持续输注倍他内酰胺类抗生素;以及抗生素治疗的持续时间。这种情况清楚地表明，需要新的工具来评估CF治疗的反应，特别是对于那些涉及抗生素和CF急性加重的治疗。 超极化气体MRI已被证明可有效评估儿童和成人囊性纤维化患者的局部气流损伤。迄今为止，所有儿童超极化气体MRI研究都采用超极化氦-3，因为所需的基础设施更广泛。由于超极化氙-129（HSV 4）在血液和组织中的溶解度以及伴随的副作用（包括短暂的欣快、烦躁和/或麻木），认为其不太适合儿童。然而，最先进的偏振基础设施提供了高达50%的受阻偏振，允许适度剂量的临床成像。此外，从诊断的角度来看，氙在组织和血液中的溶解度正是使其能够询问肺组织炎症的性质，这可以作为囊性纤维化恶化中抗生素反应的重要生物标志物。我们的合作最近展示了在单次屏气中同时采集氙气相和氙溶解相图像。在我们的一个“健康”志愿者中，我们发现一个以前未诊断的炎性结节在溶解相图像上非常明显。这一结果表明，该技术可能对炎症敏感。由于炎症是CF的主要治疗靶点，因此该技术可能非常适合检测CF患者对治疗的反应。 我们建议利用HSP 70同步气体和溶解相MRI以及新的双核结构-功能通气成像方案，在单次屏气内采集质子和HSP 70图像，以监测囊性纤维化加重的治疗反应。将招募5名因囊性纤维化加重而入院的患者，包括至少2名儿童。患者将在治疗开始时和治疗开始后三周进行成像。数据将被纳入CF的成像生物标志物中，并与其他指标（如肺活量测定和患者自我评估）进行比较。 公共卫生相关性：新的治疗方法正在进行3期临床试验，这些试验针对囊性纤维化（CF）的潜在异常，并恢复CF中异常的细胞膜氯离子通道的功能。由于这些治疗对不同的CF基因型有不同的作用，因此迫切需要开发一种评估治疗效果的技术，特别是对幼儿，以便在肺损伤不可逆之前开始有效的治疗。超极化氙（HSP 70）MRI是一种不依赖电离辐射的肺功能成像新模式，其安全性的提高对儿童尤为重要。这项拟议的研究是确定HSP 70 MRI是否可以成为CF的有用结局指标的重要一步，这可能对该患者人群产生巨大的临床影响。

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.