Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis
|Study Design:||Observational Model: Case Control
Time Perspective: Prospective
|Official Title:||Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis|
- Change from Baseline in the Average Unifrac Value in Fecal Microbiome & Metagenome Composition at 4 years [ Time Frame: 4 years ] [ Designated as safety issue: No ]High throughput sequencing will be used to identify microbial taxa and microbial genes present in feces, and to determine how these change over a period of 4 years
- Change from Baseline in the Amounts of Calprotectin at 4 years [ Time Frame: 4 years ] [ Designated as safety issue: No ]
- Change from Baseline in the Amounts of Short Chain Fatty Acids at 4 years [ Time Frame: 4 years ] [ Designated as safety issue: No ]
- Change from Baseline in the Amounts of Nitric Oxide at 4 years [ Time Frame: 4 years ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples Without DNA
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||December 2020|
|Estimated Primary Completion Date:||December 2020 (Final data collection date for primary outcome measure)|
Infants and toddlers with Cystic Fibrosis
Non-cystic fibrosis controls
Infants and toddlers without Cystic Fibrosis
Cystic Fibrosis is the most common lethal genetic disorder in Caucasian populations. Mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) affect its ability to act as a chloride channel. The recent development of a transgenic pig model of CF has demonstrated that newborn CF lungs, free of bacteria and inflammation at birth, become colonized with a mixed microbial flora that likely initiates early inflammatory changes which precede clinically apparent deterioration in lung function.
Because chronic infection and inflammation play central roles in CF disease progression and exacerbations, many clinicians and researchers have focused on identifying pathogens associated with CF infection and inflammation. Recent studies outside the area of CF, however, have clearly demonstrated that "non-pathogens", such as the commensal flora carried by all humans at multiple mucosal sites, engage the host's innate and adaptive immune systems constantly. This interaction between "microbiome" and host genome is responsible for appropriate development and function of protective inflammatory and immune responses.
We hypothesize that acquisition of a commensal flora by newborns with CF may play a critical role in initiating pathogenic inflammatory responses that subsequently lead to lung damage. The acquired commensal flora may initially be identical to that of a non-CF infant, but may be altered by the direct or indirect effects of CFTR mutation on the mucosal environment. Such an altered flora is likely to encode different metabolic and regulatory functions, and may directly influence host inflammatory responses. If so, a novel therapeutic opportunity may exist to modulate this commensal flora, or to manipulate its immunomodulatory functions in a way that interrupts the insidious cycle of inflammation and damage that characterizes CF.
We propose to test our hypothesis in three specific aims: (1) Describe the acquisition and evolution of gut and respiratory tract microbiomes in CF infants and non-CF controls; (2) Determine the relationship between the microbiota and markers of inflammation in these two cohorts; and (3) Determine whether early declines in lung function are associated with inflammatory biomarkers or microbiome composition/function. This study is novel in its focus on a rarely studied population, at a time when interventions might significantly impact progression of this lethal disease and preserve pulmonary function. Its innovation lies in applying state of the art technologies and methods to samples that can be collected simply and non-invasively, thus increasing the likelihood that the findings of this study can be translated into clinical practice.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01661491
|Contact: Marie Egan, MD||(203) firstname.lastname@example.org|
|Contact: Barbara Kazmierczak, MD, PhD||(203) email@example.com|
|United States, Connecticut|
|Cystic Fibrosis Clinic, Yale New Haven Hospital||Recruiting|
|New Haven, Connecticut, United States, 06520|
|Contact: Marie Egan, MD 203-785-2480|
|Primary Care Clinic, Yale New Haven Hospital||Not yet recruiting|
|New Haven, Connecticut, United States, 06520|
|Principal Investigator:||Barbara I Kazmierczak, MD PhD||Yale University|
|Principal Investigator:||Marie Egan, MD||Yale University|