Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis

Cystic Fibrosis (CF) is a fatal, recessive genetic disorder characterized by progressive inflammation and lung damage. It is unclear whether current treatment strategies, which focus on detection and eradication of pathogenic microorganisms in the lung, are the best way to prevent the initiation of early inflammation and lung damage. This study asks how early acquisition of microbial flora occurs in infants with CF and healthy baby controls, and whether this process initiates or influences early inflammation and clinical disease progression in CF.

Study Overview

• Status: Active, not recruiting
• Conditions: Cystic Fibrosis

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Cystic Fibrosis Clinic, Yale New Haven Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 4 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Infants and children up to the age of 4 with Cystic Fibrosis, and age-matched controls without cystic fibrosis will be eligible for this study. Participants will be recruited from the Cystic Fibrosis clinic and Primary Care Clinic of the Yale New Haven Hospital.

Description

Cystic Fibrosis participants:

Inclusion Criteria:

• laboratory diagnosis of Cystic Fibrosis

Exclusion Criteria:

• Major organ system disease other than Cystic Fibrosis
• History of prematurity

Non Cystic Fibrosis control participants:

Inclusion Criteria:

• Proof of a negative newborn CF screening test

Exclusion Criteria:

• Major organ system disease
• History of prematurity

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cystic Fibrosis; Infants and toddlers with Cystic Fibrosis
Non-cystic fibrosis controls; Infants and toddlers without Cystic Fibrosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in the Average Unifrac Value in Fecal Microbiome & Metagenome Composition at 4 years	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	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in the Amounts of Calprotectin at 4 years	Fecal calprotectin will be measured by elisa	4 years
Change from Baseline in the Amounts of Short Chain Fatty Acids at 4 years	Fecal short chain fatty acids will be measured by gas chromatography	4 years

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Barbara I Kazmierczak, MD PhD, Yale University; Principal Investigator: Marie Egan, MD, Yale University

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): December 1, 2020
• Study Completion (Anticipated): October 1, 2023

Study Registration Dates

• First Submitted: August 6, 2012
• First Submitted That Met QC Criteria: August 6, 2012
• First Posted (Estimate): August 9, 2012

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: March 31, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Inflammation; Cystic Fibrosis
• Other Study ID Numbers: 1206010476

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No