Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

Completed

• Conditions: Symptomatic Respiratory Disease; Prematurity; Bronchopulmonary Dysplasia

• Registration Number: NCT01607216
• Lead Sponsor: University of Rochester

Brief Summary

This is an observational study that proposes to collect clinical, physiological, cellular and molecular information in an attempt to identify a set of factors that may predict the risk for persistent lung disease in babies born prematurely.

Detailed Description

Approximately 550,000 babies born prematurely each year in the United States suffer from birth at a time in development when the respiratory tract and immune system would normally be protected and maintained in a naïve state. This project is a component of the NIH Prematurity and Respiratory Outcomes Program (PROP) whose goals are the identification of disease mechanisms and biomarkers to stratify premature infants, at the time of discharge, for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC) project will investigate prematurity-dependent alterations in cellular innate and adaptive immune systems resulting in increased susceptibility to respiratory infections and environmental irritants, and leading to respiratory morbidity in the first year of life. Prior studies have established developmental (maturity) and disease-related changes in circulating and pulmonary lymphocyte populations but a comprehensive assessment of their relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by premature birth in such a way as to reduce resistance to viral infections and to promote cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the time of discharge from the hospital and at twelve months corrected age. The lymphocytic phenotype will be analyzed particularly in the context of gestational age and maternal-fetal stressors capable of modulating oxidative stress (oxygen exposure, infection and environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular phenotype of isolated CD8 lymphocytes, a cell type preferentially recruited to the lungs of premature infants and capable of contributing to disease pathogenesis, by genome-wide expression profiling, in order to uncover novel disease pathways and define a gene expression signature associated with disease risk. Finally, we propose to build a statistical model, using cellular and molecular phenotypes and additional clinical variables, for stratifying risk of lung morbidity within the first year of life.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2011-08
• Study First Submitted: 2012-03-14
• Study First Submitted QC: 2012-05-24
• Study First Posted: 2012-05-30
• Primary Completion: 2015-07
• Study Completion: 2015-07
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-07
• Last Update Posted: 2020-01-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 277

Inclusion Criteria

1. Premature infants born at gestational age 24 0/7 to 35 6/7 week and admitted to the Neonatal Intensive Care Unit or normal newborn nursery at URMC or UB
2. Healthy term infants 37 0/7 to 41 6/7 recruited from the birthing centers or Ob/Gyn floors (3-1200 at URMC) prior to discharge
3. Infants who are less than or equal to 7 days old

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Exclusion Criteria

1. The infant is not considered to be viable (therapies limited due to futility decision made by clinical care team)
2. Congenital heart disease (not including PDA and hemodynamically insignificant VSD or ASD)
3. Structural abnormalities of the upper airway, lungs or chest wall
4. Other congenital malformations or syndromes that adversely affect life expectancy or cardio-pulmonary development
5. Family is unlikely to be available for long-term follow-up as determined by the site investigators dependent on the distance of the infant's residence from the follow-up center and/or family plans to move out of the region
6. Family does not speak or understand English

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Symptomatic Respiratory Disease (SRD)	Assessed every three months until 1 year corrected gestational age	The primary goal of the PROP studies (single center and multicenter protocols) is to identify biomarkers (biochemical, physiological and genetic) and clinical variables that are associated with and thus potentially predictive of pulmonary status in preterm infants up to 1 year corrected age. We propose a composite primary outcome of SRD that is based on serial parental reports of respiratory symptoms, medications, hospitalizations and dependence on technology during the first year of life.

Secondary Outcome Measures

Name	Time	Method
Gene expression analysis of CD8 cells collected by FACS from preterm infants nearing discharge	At 40 +/- 5 weeks corrected gestational age	Patterns of gene expression identified in isolated and sorted CD8 T cells from preterm infants just prior to discharge from the neonatal intensive care unit will be identified and compared to the severity and persistence of symptomatic respiratory disease (SRD) over the first year of life.
Measure of severity of lung disease at 40 +/- 5 weeks corrected gestational age	From birth at premature gestational age to at 40 +/- 5 weeks corrected gestational age	Severity of lung disease will be assessed by length of time on mechanical ventilation, length of time on oxygen, oxygen requirement at 36 weeks corrected gestational age, need for pulmonary medications at determined at hospital discharge, or at 40 +/- 5 weeks corrected gestational age.
Assessment of T lymphocyte numbers, subsets (CD4, CD8) and functional phenotype determined by flow cytometry.	Measured and compared at birth, at term corrected gestational age and at 1 year corrected gestational age	Assessment of T lymphocyte numbers, subsets (CD4, CD8) and functional phenotype including characteristics of effector and memory function, and intracellular cytokine production in response to in vitro T cell receptor nonspecific and specific stimulation
Statistical correlation of CD4 and CD8 lymphocyte function with severity and persistence of lung disease.	At at 40 +/- 5 weeks corrected gestational age and at one year of age	The severity of lung disease prior to first hospital discharge and the persistence and severity of SRD in the first year of life will be compared with the T cell lymphocyte phenotypes at birth, at hospital discharge and at one year of life. Specifically, at minimum, the ability of T lymphocytes at rest and after stimulation to produce interferon gamma at the test time points will be compared with the history of lung disease. The intent is to identify biomarkers and to suggest immune-mediated mechanisms for lung disease in preterm infants

Trial Locations

Locations (2)

University of Rochester Medical Center; 🇺🇸 Rochester, New York, United States

Women and Children's Hospital of Buffalo; 🇺🇸 Buffalo, New York, United States