Sinusitis in Children and the Nasopharyngeal Microbiome

描述（由申请人提供）：儿童急性细菌性鼻窦炎是初级保健医生最常见的临床问题之一。鼻窦炎的诊断导致超过18亿美元花费在12岁以下的儿童身上，并且在美国每年有超过2000万的抗生素处方。同样重要的是，过度治疗在很大程度上导致了抗生素耐药性的发展，这已经成为自前抗生素时代以来有效治疗的最严重障碍之一。尽管急性细菌性鼻窦炎的频率和重要性，其发病率和身份的前驱诱发病毒感染从未报道。 本研究的目的是确定儿童急性细菌性鼻窦炎的负担，并使用最先进的分子技术来确定鼻咽微生物组和先前的急性病毒感染对儿童急性细菌性鼻窦炎发展的作用。为了实现这些目标，我们建议进行一项系统的纵向研究，鼻咽部的环境，否则健康的儿童获得病毒性上呼吸道感染（URI）。将确定引起49至84个月儿童URI的特定病毒因子，并在基线时和病毒URI发作后2至3天内使用高分辨率、非培养方法以及常规微生物学技术表征鼻咽微生物组（关于鼻窦病原体和鼻咽微生物群）。将对儿童进行前瞻性随访，以确定哪些受试者发生急性细菌性鼻窦炎，哪些受试者的URI自发消退。我们的总体假设是，鼻咽微生物组是维持正常上呼吸道生理的主要因素，并强烈影响发生鼻窦炎和其他呼吸道细菌感染的风险。通过识别某些人口统计特征（例如，年龄、性别、兄弟姐妹、参加日托等）、鼻咽微生物组的特征（特异性鼻窦病原体和鼻腔微生物群的多样性、均匀性和相对丰度）以及先前的病毒感染，我们将确定急性细菌性鼻窦炎发展的风险因素。最终，这些信息将帮助我们将治疗重点放在那些最有可能发展为急性细菌性鼻窦炎的人身上，从而限制抗生素的使用。检查健康和病毒感染后鼻咽微生物组的细菌多样性将提供关于呼吸道的几种继发性细菌感染的关键见解，其中存在先行病毒感染（急性中耳炎，急性细菌性肺炎和急性细菌性鼻窦炎）。最后，确定呼吸道病毒引起鼻咽微生物组变化的机制将导致新的预防和治疗措施，这些措施可能在细菌感染演变之前很久就开始了。

DESCRIPTION (provided by applicant): Acute bacterial sinusitis in children is one of the most common clinical problems presenting to the primary care practitioner. A diagnosis of sinusitis results in over $1.8 billion spent on children < 12 years of age and is responsible for over 20 million antibiotic prescriptions per year in the US. Equally important, overtreatment contributes in large part to the development of antimicrobial resistance which has become one of the most serious obstacles to effective therapy since the pre-antibiotic era. Despite the frequency and importance of acute bacterial sinusitis, its incidence and the identity of the antecedent predisposing viral infections has never been reported. The goals of this study are to determine the burden of acute bacterial sinusitis in children and use state-of- the-art molecular techniques to determine the role of the nasopharyngeal microbiome and antecedent acute viral infections on the development of acute bacterial sinusitis in children. To accomplish these goals, we propose to conduct a systematic longitudinal study of the nasopharyngeal environment of otherwise healthy children who acquire viral upper respiratory infections (URIs). The specific viral agents that cause URIs in children 49 to 84 months of age will be identified and the nasopharyngeal microbiome will be characterized (regarding sinopathogens and commensal microbiota) using high-resolution, culture-independent methods as well as conventional microbiologic techniques at baseline and again within 2 to 3 days of onset of the viral URI. Children will be followed prospectively to determine which subjects develop acute bacterial sinusitis and which resolve their URI spontaneously. It is our overall hypothesis that the nasopharyngeal microbiome is a major factor in the maintenance of normal upper respiratory tract physiology and strongly influences the risk of developing sinusitis and other bacterial infections of the respiratory tract. By identifying certain demographic features (e.g., age, gender, siblings, attendance at daycare, etc), the characteristics of the nasopharyngeal microbiome (diversity, evenness and relative abundance of specific sinopathogens and commensal microbiota) and the antecedent viral infection, we will determine risk factors for the development of acute bacterial sinusitis. Ultimately, this information will help us to focus treatment on those at highest risk to develop acute bacterial sinusitis thereby limiting exposure to antimicrobials. Examining the bacterial diversity of the nasopharyngeal microbiome in health and after viral infection will provide critical insights with regard to several secondary bacterial infections of the respiratory tract in which there is an antecedent viral infection (acute otitis media, acute bacterial pneumonia and acute bacterial sinusitis). Finally, defining the mechanisms by which respiratory viruses cause changes in the nasopharyngeal microbiome will lead to new preventative and therapeutic measures which may be instituted long before the bacterial infection evolves.