Prematurity, Respiratory Outcomes, Immune System, and Microbiome Study (PRISM)

Public health importance: Babies born preterm, approximately 1 out of every 9 live births in the United States, have significant respiratory morbidity over the first two years of life, exacerbated by respiratory viral infections. Many (<50%) return to pediatricians, emergency rooms and pulmonologists with symptoms of respiratory dysfunction (SRD): intermittent or chronic wheezing, poor growth and an excess of upper and lower respiratory tract infections (LRTI). SRD correlate inversely with gestational age and weight at birth and is more common in those with chronic lung disease of prematurity, yet its incidence and severity varies widely among both the prematurely born and those born at term. There is evidence from clinical studies and animal models that risks of LRTI and recurrent wheezing is influenced by gut and respiratory flora and by T cell responses to infection. Information gained from this study will be used to identify characteristics, risk factors and potential mechanisms for early and persistent lung disease in children born at term and born preterm. This Clinical Research Study will investigate the relationships between sequential respiratory viral infections, patterns of intestinal and respiratory bacterial colonization, and adaptive cellular immune phenotypes which are associated with increased susceptibility to respiratory infections and long term respiratory morbidity in preterm and full term infants. We hypothesize that the timing and acquisition of specific viral infections and bacterial species are directly related to respiratory morbidity in the first year of life as defined by SRD and by measures of pulmonary function. We hypothesize that cellular and molecular immuno-maturity are altered due to factors presented by premature birth in such a way as to promote chronic inflammatory and cytotoxic damage to the lung, with subsequent enhanced, damaging responses to infectious agents and environmental irritants. Our preliminary studies demonstrate both feasibility and expertise in mutiparameter immunophenotyping of small volume peripheral blood samples obtained from premature infants including gene expression arrays of flow cytometry sorted cells. We will use new technologies for known viral identification, as well as high-throughput metagenome sequencing of RNA and DNA virus like particles (VLP) to be used for viral discovery in infant respiratory sample and use of high-throughput pyrosequencing (454T) of bacterial 16S rRNA to determine shifts in bacterial community structure, occurring in pre-term (PT) as compared to full term (FT) infants, over the first year of life. Finally, we present statistical approaches to stratify disease risk predictors using multivariate logistic regression modeling approaches. We propose to evaluate T cell phenotypic and functional profiles relative to viral and predominant bacterial exposures according to highly complementary, but independent, Specific Objectives. Objective 1: To determine if viral respiratory infections and patterns of respiratory and gut bacterial community structure (microbiome) in prematurely born babies predict the rate and degree of immunologic maturation, and pulmonary dysfunction, measured from birth to 36 weeks corrected gestational age (CGA). Objective 2: To determine the relationship between respiratory viral infections and disease severity up to one year CGA, and the lymphocyte (Lc) phenotypes documented at term gestation (birth for term infants and 36 wks/NICU discharge in preterm infants) and at one year CGA. Three secondary outcomes of this objective will be to a) relate the quantity, type and severity of viral infections with pulmonary function at one and three years of life, b) relate the viral community structure to severity of viral infections and c) to seek evidence of modulation of viral susceptibility by bacterial respiratory and gut community structure (microbiome). The relationship of colonization with known and non-identified bacterial species in both the respiratory tract and the gut will be evaluated. Flow cytometry data corresponding to this study can be found within Immport study SDY1302. Positive and negative controls for microbiome samples are uploaded under SRA bioproject PRJNA474485. Microbiome samples corresponding to PRISM2 are distinguished from PRISM1 via "_PRISM2" appended to the sample name. Within the positive and negative controls, PRISM1 controls are uploaded as bam files and PRISM2 controls are uploaded as paired fastq. Samples ending in -08 correspond to TLDA qPCR results for a given sample. There is a column for each pathogen tested and a column to indicate where that pathogen was bacteria or virus.]]>
Inclusion Criteria for Preterm Cohort: Signed Informed Consent from parent(s) or legal guardian(s) Preterm infants born at gestational age 23 0/7 to 35 6/7 weeks Preterm infants admitted to the URMC NICU or Normal Newborn Nursery Infants less than or equal to 7 days old Attending physician agreement Inclusion Criteria for Full Term Cohort: Healthy term infants 37 0/7 to 41 6/7 weeks gestation Recruited prior to delivery, or from the birthing centers and labor and delivery floor Infants less than or equal to 7 days old Signed Informed Consent from parent(s) or legal guardian(s) Exclusion Criteria: Considered to be non-viable (decision by clinical care team to limit life-saving therapies) Known congenital heart disease, not including patent ductus arteriosus (PDA), hemodynamically insignificant ventricular septal defect (VSD) or atrial septal defect (ASD) Known structural abnormalities of the upper airway, lungs, or chest wall Known other congenital malformations or syndromes that adversely affect life expectancy or cardiopulmonary development (i.e., neuromuscular disease, trisomy 21). Known to be born to women who are human immunodeficiency virus (HIV) positive (HIV testing is not required prior to study entry but is available for most mothers-to-be and is performed on all newborns in NY state). Known congenital or acquired immune deficiency Family is unlikely to be available for long-term follow-up. No legal guardian who speaks and reads English. Specifically for the term Infants, as healthy infants, no NICU admission prior to consent. Any infant with a diagnosis of hypertension, hyperthyroidism, seizures, arrhythmias, or sensitivity to sympathomimetic amines will be excluded from the BDR assessment. Any infant with hypersensitivity to any of components of albuterol sulfate will be excluded from the BDR assessment. An infant or child with such history may remain eligible for the remainder of the study if they qualify by other inclusion and exclusion criteria. ]]>
Enrollment: 267 Study Start Date: March 2013 Study Completion Date: ongoing ]]>