AZITHROMYCIN TO PREVENT RECURRENT WHEEZING FOLLOWING SEVERE RSV BRONCHIOLITIS

 描述（由申请方提供）：本项目的目的是确定在重度RSV毛细支气管炎期间使用大环内酯类阿奇霉素（AZM）是一种有效、简单、廉价和安全的干预措施，可显著降低RSV后复发性喘息的发生率，并可能代表预防RSV毛细支气管炎后哮喘的首个成功策略。哮喘是儿童期最常见的慢性疾病，长期发病率高。由于哮喘是不可治愈的，因此非常需要研究哮喘预防策略。早期RSV细支气管炎是反复喘息和哮喘的主要危险因素。最高风险发生在需要住院治疗的重度毛细支气管炎婴儿中：高达75%的住院婴儿会出现反复（≥3次）喘息发作，近50%的婴儿在7岁时被诊断为哮喘。因此，预防因RSV毛细支气管炎住院治疗后反复喘息可能会减少随后的哮喘诊断。常规哮喘治疗在减弱RSV后复发性喘息方面无效。因此，我们已经开始调查一个 预防RSV感染后喘息的创新方法：使用抗生素AZM，它对其他炎症性气道疾病具有有益作用。我们之前在40名因RSV细支气管炎住院的婴儿中进行的概念验证试验表明，AZM在随后的一年中将复发性喘息的发生率降低了约50%，并降低了气道炎症标志物。此外，我们的初步研究表明，AZM的有益作用也可能与其对气道微生物组的抗菌作用有关。根据我们以前的观察，我们建议调查以下2个领域：1。进行一项临床试验，评价在188例因RSV毛细支气管炎住院的婴儿中，与安慰剂相比，在常规毛细支气管炎治疗中添加AZM是否可减少学龄前儿童反复（≥3次）喘息发作的发生率。2.研究AZM如何随时间改变上呼吸道微生物群落结构;并确定这些变化是否与RSV后复发性喘息的发生率降低有关。该试验可能确定在严重RSV细支气管炎期间应用的第一种有效干预措施，其目的是预防RSV后复发性喘息，并最终预防哮喘。如果成功，这将通过降低与复发性喘息和哮喘相关的发病率和卫生保健利用率，对社会和卫生系统产生重大影响。该项目中的微生物组研究应该告诉我们AZM如何改变微生物组，以及这些变化如何与复发性喘息的发展相关。此外，这些发现可能为预防哮喘的微生物组导向疗法的发展提供信息。

 DESCRIPTION (provided by applicant): The goal of this project is to establish that use of the macrolide azithromycin (AZM) during severe RSV bronchiolitis is an effective, simple, inexpensive, and safe intervention that substantially reduces the occurrence of post-RSV recurrent wheezing and potentially represents the first successful strategy for the prevention of asthma following RSV bronchiolitis. Asthma is the most common chronic disease of childhood, resulting in significant long-term morbidity. As asthma is not curable, investigation of asthma prevention strategies is highly desirable. Early life RSV bronchiolitis is a major risk factor for recurrent wheezing and asthma. The highest risk is among infants with severe bronchiolitis requiring hospitalization: up to 75% of hospitalized infants experience recurrent (≥3) wheezing episodes and almost 50% are diagnosed with asthma by the age of 7 yrs. Therefore, prevention of recurrent wheeze following hospitalization for RSV bronchiolitis may reduce the subsequent diagnosis of asthma. Conventional asthma therapies are ineffective in attenuating post-RSV recurrent wheezing. Therefore, we have begun to investigate an innovative approach for the prevention of post-RSV wheeze: the utilization of the antibiotic AZM, which has beneficial effects in other inflammatory airway diseases. Our previous proof-of-concept trial in 40 infants hospitalized with RSV bronchiolitis has shown that AZM reduced the occurrence of recurrent wheeze during the subsequent year by approximately 50% and decreased markers of airway inflammation. Moreover, our preliminary studies have suggested that AZM's beneficial effects may also be related to its anti-bacterial effect on the airway microbiome. Based on our previous observations we propose to investigate the 2 following domains: 1. to perform a clinical trial evaluating if the addition of AZM, compared to placebo, to routine bronchiolitis care in 188 infants hospitalized with RSV bronchiolitis reduces the occurrence of recurrent (≥3) wheezing episodes during the preschool years. 2. To examine how AZM changes the upper airway microbiome community structure over time; and to determine if these changes are related to the reduction in the occurrence of post-RSV recurrent wheeze. This trial may identify the first effective intervention to apply during severe RSV bronchiolitis wth the goal of preventing post-RSV recurrent wheeze, and ultimately asthma. If successful, this would have significant impact on society and the health system through reductions in morbidity and health care utilization associated with recurrent wheeze and asthma. The microbiome studies in this project should inform us how the AZM modifies the microbiome, and how these changes relate to the development of recurrent wheeze. Moreover, these findings may inform the development of microbiome-directed therapies for asthma prevention.