Clinical trial NCT01607216: Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies
Official title: Prematurity and Respiratory Outcome Program: Single Center Study of Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Prematurity
Symptomatic Respiratory Disease
Bronchopulmonary Dysplasia
Keywords: Prematurity
Respiratory Illness
Lung Function
Lung Disease
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
name: University at Buffalo
First posted: 2012-05-30
Enrollment: 277
Sex: ALL
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Eligible subjects are limited to patients born at the Golisano Children's Hospital at the University of Rochester Medical Center and at Women's and Children's Hospital, University at Buffalo. All admissions to the participating Neonatal Intensive Care Units will be screened for eligibility.

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.

Eligibility criteria: 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

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

Primary outcomes:
measure: Symptomatic Respiratory Disease (SRD)
timeFrame: Assessed every three months until 1 year corrected gestational age
Secondary outcomes:
measure: Assessment of T lymphocyte numbers, subsets (CD4, CD8) and functional phenotype determined by flow cytometry.
timeFrame: Measured and compared at birth, at term corrected gestational age and at 1 year corrected gestational age
measure: Measure of severity of lung disease at 40 +/- 5 weeks corrected gestational age
timeFrame: From birth at premature gestational age to at 40 +/- 5 weeks corrected gestational age
measure: Statistical correlation of CD4 and CD8 lymphocyte function with severity and persistence of lung disease.
timeFrame: At at 40 +/- 5 weeks corrected gestational age and at one year of age
measure: Gene expression analysis of CD8 cells collected by FACS from preterm infants nearing discharge
timeFrame: At 40 +/- 5 weeks corrected gestational age
Other outcomes:
Locations:
city: Buffalo
country: United States
facility: Women and Children's Hospital of Buffalo
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
Study officials:
affiliation: University of Rochester
name: Gloria Pryhuber, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University at Buffalo
name: Rita Ryan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Thomas Mariani, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maitre NL, Ballard RA, Ellenberg JH, Davis SD, Greenberg JM, Hamvas A, Pryhuber GS; Prematurity and Respiratory Outcomes Program. Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach. J Perinatol. 2015 May;35(5):313-321. doi: 10.1038/jp.2015.19. Epub 2015 Mar 26.
citation: Pryhuber GS, Maitre NL, Ballard RA, Cifelli D, Davis SD, Ellenberg JH, Greenberg JM, Kemp J, Mariani TJ, Panitch H, Ren C, Shaw P, Taussig LM, Hamvas A; Prematurity and Respiratory Outcomes Program Investigators. Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States. BMC Pediatr. 2015 Apr 10;15:37. doi: 10.1186/s12887-015-0346-3.
citation: Scheible KM, Emo J, Yang H, Holden-Wiltse J, Straw A, Huyck H, Misra S, Topham DJ, Ryan RM, Reynolds AM, Mariani TJ, Pryhuber GS. Developmentally determined reduction in CD31 during gestation is associated with CD8+ T cell effector differentiation in preterm infants. Clin Immunol. 2015 Dec;161(2):65-74. doi: 10.1016/j.clim.2015.07.003. Epub 2015 Jul 29.
citation: Misra R, Shah S, Fowell D, Wang H, Scheible K, Misra S, Huyck H, Wyman C, Ryan RM, Reynolds AM, Mariani T, Katzman PJ, Pryhuber GS. Preterm cord blood CD4(+) T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4(+) T cells in bronchopulmonary dysplasia. Hum Immunol. 2015 May;76(5):329-338. doi: 10.1016/j.humimm.2015.03.007. Epub 2015 Mar 20.
citation: Grier A, Qiu X, Bandyopadhyay S, Holden-Wiltse J, Kessler HA, Gill AL, Hamilton B, Huyck H, Misra S, Mariani TJ, Ryan RM, Scholer L, Scheible KM, Lee YH, Caserta MT, Pryhuber GS, Gill SR. Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. Microbiome. 2017 Dec 11;5(1):158. doi: 10.1186/s40168-017-0377-0.
citation: Hoover J, Wambach J, Vachharajani A, Warner B, Carroll JL, Kemp JS. Postmenstrual age at discharge in premature infants with and without ventilatory pattern instability. J Perinatol. 2020 Jan;40(1):157-162. doi: 10.1038/s41372-019-0530-7. Epub 2019 Oct 14.