How the Environmental influences on Child Health Outcome (ECHO) Cohort can spur discoveries in environmental epidemiology.

NIH's Environmental influences on Child Health Outcome (ECHO) program is an innovative, large, collaborative research initiative whose mission is to enhance the health of children for generations to come. The goal of the ECHO Cohort is to examine effects of a broad array of early environmental exposures on child health and development. It includes longitudinal data and biospecimens from over 100,000 children and family members from diverse settings across the U.S. ECHO investigators have published collaborative analyses showing associations of environmental exposures--primarily in the developmentally sensitive pre-, peri-, and post-natal periods--with preterm birth and childhood asthma, obesity, neurodevelopment, and positive health. Investigators have addressed health disparities, joint effects of environmental and social determinants, and effects of mixtures of chemicals. The ECHO Cohort is now entering its second 7-year cycle (2023-2030), which will add the preconception period to its current focus on prenatal through adolescence. Through a controlled access public use database, ECHO makes its deidentified data available to the general scientific community. ECHO Cohort data provide opportunities to fill major knowledge gaps in in environmental epidemiology, and to inform policies, practices, and programs to enhance child health.

Acute Responses to Diuretic Therapy in Extremely Low Gestational Age Newborns: Results from the Prematurity and Respiratory Outcomes Program Cohort Study.

OBJECTIVE: To determine if daily respiratory status improved more in extremely low gestational age (GA) premature infants after diuretic exposure compared with those not exposed in modern neonatal intensive care units. STUDY DESIGN: The Prematurity and Respiratory Outcomes Program (PROP) was a multicenter observational cohort study of 835 extremely premature infants, GAs of 230/7-286/7 weeks, enrolled in the first week of life from 13 US tertiary neonatal intensive care units. We analyzed the PROP study daily medication and respiratory support records of infants ≤34 weeks postmenstrual age. We determined whether there was a temporal association between the administration of diuretics and an acute change in respiratory status in premature infants in the neonatal intensive care unit, using an ordered categorical ranking of respiratory status. RESULTS: Infants in the diuretic exposed group of PROP were of lower mean GA and lower mean birth weight (P < .0001). Compared with infants unexposed to diuretics, the probability (adjusted for infant characteristics including GA, birth weight, sex, and respiratory status before receiving diuretics) that the exposed infants were on a higher level of respiratory support was significantly greater (OR, >1) for each day after the initial day of diuretic exposure. CONCLUSIONS: Our analysis did not support the ability of diuretics to substantially improve the extremely premature infant's respiratory status. Further study of both safety and efficacy of diuretics in this setting are warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01435187.

Adults born preterm: a review of general health and system-specific outcomes.

In this review of 126 publications, we report that an overwhelming majority of adults born at preterm gestations remain healthy and well. However, a small, but a significant fraction of them remain at higher risk for neurological, personality and behavioural abnormalities, cardio-pulmonary functional limitations, systemic hypertension and metabolic syndrome compared to their term-born counterparts. The magnitude of increased risk differed across organ systems and varied across reports. The risks were proportional to the degree of prematurity at birth and seemed to occur more frequently among preterm infants born in the final two decades of the 20th century and later. These findings have considerable public health and clinical practice relevance. CONCLUSION: Preterm birth needs to be considered a chronic condition, with a slight increase in the risk for long-term morbidities among adults born preterm. Therefore, obtaining a history of gestational age and weight at birth should be a routine part of care for patients of all age groups.

Cell therapy for lung diseases. Report from an NIH-NHLBI workshop, November 13-14, 2012.

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened the Cell Therapy for Lung Disease Working Group on November 13-14, 2012, to review and formulate recommendations for future research directions. The workshop brought together investigators studying basic mechanisms and the roles of cell therapy in preclinical models of lung injury and pulmonary vascular disease, with clinical trial experts in cell therapy for cardiovascular diseases and experts from the NHLBI Production Assistance for Cell Therapy program. The purpose of the workshop was to discuss the current status of basic investigations in lung cell therapy, to identify some of the scientific gaps in current knowledge regarding the potential roles and mechanisms of cell therapy in the treatment of lung diseases, and to develop recommendations to the NHLBI and the research community on scientific priorities and practical steps that would lead to first-in-human trials of lung cell therapy.

Improving outcomes for pulmonary vascular disease.

Recognizing the importance of improving lung health through lung disease research, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts for the following purpose: (1) to review the current scientific knowledge underlying the basis for treatment of adults and children with pulmonary vascular diseases (PVDs); (2) to identify gaps, barriers, and emerging scientific opportunities in translational PVD research and the means to capitalize on these opportunities; (3) to prioritize new research directions that would be expected to affect the clinical course of PVDs; and (4) to make recommendations to the NHLBI on how to fill identified gaps in adult and pediatric PVD clinical research. Workshop participants reviewed experiences from previous PVD clinical trials and ongoing clinical research networks with other lung disorders, including acute respiratory distress syndrome, chronic obstructive lung disease, and idiopathic pulmonary fibrosis, as well. Bioinformatics experts discussed strategies for applying cutting-edge health information technology to clinical studies. Participants in the workshop considered approaches in the following broad concept areas: (1) improved phenotyping to identify potential subjects for appropriate PVD clinical studies; (2) identification of potential new end points for assessing key outcomes and developing better-designed PVD clinical trials; and (3) the establishment of priorities for specific clinical research needed to advance care of patients with various subsets of PVDs from childhood through adulthood. This report provides a summary of the objectives and recommendations to the NHLBI concentrating on clinical research efforts that are needed to better diagnose and treat PVDs.

National Heart, Lung, and Blood Institute perspective: lung progenitor and stem cells--gaps in knowledge and future opportunities.

Because the lung stem cell field is so new, there remain many unanswered questions that are being addressed regarding the identification, location, and role of exogenous and endogenous stem and progenitor cell populations in growth, regeneration, and repair of the lung. Advancing lung stem cell biology will require multidisciplinary teams and a long term effort to unravel the biologic processes of stem cells in the lung. While no clinical research in lung stem cell therapies are currently funded by NHLBI, the knowledge gained by understanding the basic biology of the lung stem cell populations will be needed to translate to diagnostic and therapeutic strategies in the future.

Respiratory causes of infant mortality: progress and challenges.

A marked reduction in infant mortality due to respiratory distress syndrome (RDS) has been reported in previous studies; however, deaths due to RDS are still more common in black infants than white infants. Because advances in respiratory care may have impacted non-RDS respiratory causes of infant mortality as well, the objective of this study was to determine if specific and total non-RDS respiratory causes of infant mortality have changed over time, and if health disparities exist. We analyzed and compared infant deaths due to RDS and other respiratory diseases from 1980 to 2005 in the United States and evaluated outcomes by race and gender. Infant mortality due to non-RDS causes declined more than twofold over this time frame, but not as dramatically as the fivefold decline in RDS deaths. Black compared with white infants had twice the mortality rate due to non-RDS respiratory causes. The most common non-RDS respiratory cause of infant mortality was due to congenital malformations of the respiratory tract, which did not change dramatically over the 25 years studied.

NHLBI training workshop report: the vanishing pediatric pulmonary investigator and recommendations for recovery.

The adequacy of the pipeline of advanced pulmonary fellows to supply appropriately trained and committed researchers to enter academic careers was the major topic of a recently held National Heart Lung and Blood Institute NHLBI Workshop: Respiratory Medicine-Related Research Training for Adult and Pediatric Fellows. The special challenges and opportunities for the academic pediatric pulmonary trainee were discussed as part of this workshop and are presented as a companion article to the report by the full workshop. Surveys were conducted of pediatric chairs of academic departments and pediatric pulmonary training directors in the United States to examine the current status and opportunities for the pediatric pulmonary trainee. Strategies for recruitment and retention of talented young trainees and junior faculty are proposed.

NHLBI workshop: respiratory medicine-related research training for adult and pediatric fellows.

The pulmonary physician-scientist has a special niche to generate basic research findings and apply them to a clinical disease and perhaps impact its medical care. The availability of new high throughput-based scientific technologies in the "omics era" has made this an opportune time for physician scientists to prepare and embark on an academic career in respiratory disease research. However, maintaining an adequate flow through the research pipeline of physician-scientist investigators studying respiratory system diseases is currently a challenge. There may not be a sufficient workforce emerging to capitalize on current research opportunities. The National Heart, Lung, and Blood Institute (NHLBI) organized a workshop to assess ways to attract and properly train advanced fellows to pursue research careers in adult and pediatric lung diseases. Participants included representatives from the various pulmonary training programs, respiratory-related professional societies, and NHLBI staff. Deliberation centered on present barriers that might affect interest in pursuing research training, devising better incentives to attract more trainees, and how current research support offered by the NHLBI and the Professional Societies (in partnership with Industry and Patient Support groups) might be better coordinated and optimized to ensure a continued pipeline of pulmonary investigators. Major recommendations offered are: (1) Attract trainees to pulmonary/critical care medicine-based research careers by increasing research exposure and opportunities for high school, college, and medical students. (2) Increase awareness of the outstanding physician-scientist role models in the lung community for trainees. (3) Facilitate mechanisms by which the lung community (NHLBI, professional societies, and partners) can better support and bridge senior fellows as they transition from Institutional Training Grants (T32) to Career Series (K) awards in their early faculty career development.

Elevated ambient air zinc increases pediatric asthma morbidity.

BACKGROUND: Recent studies indicate that the composition of fine particulate matter [PM

Risk areas for pediatric acute care: asthma differs from upper and lower respiratory illness.

OBJECTIVE: To determine if emergency department utilization for pediatric respiratory illness varies across small geographic jurisdictions within a large urban city. DESIGN: A retrospective analysis of Maryland Health Services Cost Review Commission Emergency Department discharge data. SETTING/PATIENTS: All non-neonatal, Baltimore City residents <18 years old with valid diagnoses admitted and discharged from emergency departments (ED) in the state of Maryland from April 1, 1997 to December 31, 2000 (n=245,339). MAIN OUTCOME MEASURES: Crude and adjusted ED visit rates for asthma, upper and lower respiratory illnesses (per 1000 population). To evaluate the effect of geography on pediatric ED visit rates, odds of an asthma ED visit, URI, or LRI vs. non-respiratory ED visit were compared across regions of the city. RESULTS: We determined that residential areas with high ED utilization rates for upper and lower respiratory illnesses, as well as non-respiratory illnesses correlate with regions of high ED utilization for asthma, even after adjusting for race, gender and age of the population. The regions with high odds ratios that an ED visit was for asthma were different from those with high ORs for URI and LRI after also controlling for poverty. CONCLUSIONS: This suggests that poverty accounts for high utilization of the ED in urban settings, but suggests that environmental exposures that increase the risk of ED care for asthma differ from those that lead to URI and LRI.

Acidic pH hyperpolarizes nasal potential difference.

Nasal potential difference (NPD) has served as a non-invasive diagnostic method for cystic fibrosis (CF) a disease of chloride channel expression and function in secretory epithelia. Investigators have also used NPD to demonstrate ion transport abnormalities in newborns with respiratory distress. Standard perfusates for diagnostic NPD studies include the use of amiloride, replacement of chloride with gluconate, cAMP agonists, and nucleotides such as ATP. The pH of these perfusates may also be relevant to NPD studies as we have previously shown that the respiratory epithelia in mammals express CLC-2, which is a pH sensitive chloride channel. We hypothesized that acidic pH might activate chloride secretion in vivo if CLC-2 is present in human respiratory epithelia. Our objective was to determine the effect of acidic pH on NPD measurements and the frequency of expression of CLC-2 in normal subjects. Healthy adults were recruited and CLC-2 protein expression was detected in 20 of 29 primary nasal epithelial cell cultures. Acidic pH stimulated NPD responses in 33% of subjects. These findings suggest that pH sensitive alternative pathways are available for modulation in human respiratory epithelia and that NPD protocols should standardize pH of perfusates.

Prenatal and Perinatal Determinants of Lung Health and Disease in Early Life: A National Heart, Lung, and Blood Institute Workshop Report.

Human lung growth and development begins with preconception exposures and continues through conception and childhood into early adulthood. Numerous environmental exposures (both positive and negative) can affect lung health and disease throughout life. Infant lung health correlates with adult lung function, but significant knowledge gaps exist regarding the influence of preconception, perinatal, and postnatal exposures on general lung health throughout life. On October 1 and 2, 2015, the National Heart, Lung, and Blood Institute convened a group of extramural investigators to develop their recommendations for the direction(s) for future research in prenatal and perinatal determinants of lung health and disease in early life and to identify opportunities for scientific advancement. They identified that future investigations will need not only to examine abnormal lung development, but also to use developing technology and resources to better define normal and/or enhanced lung health. Birth cohort studies offer key opportunities to capture the important influence of preconception and obstetric risk factors on lung health, development, and disease. These studies should include well-characterized obstetrical data and comprehensive plans for prospective follow-up. The importance of continued basic science, translational, and animal studies for providing mechanisms to explain causality using new methods cannot be overemphasized. Multidisciplinary approaches involving obstetricians, neonatologists, pediatric and adult pulmonologists, and basic scientists should be encouraged to design and conduct comprehensive and impactful research on the early stages of normal and abnormal human lung growth that influence adult outcome.

Accelerating Scientific Advancement for Pediatric Rare Lung Disease Research. Report from a National Institutes of Health-NHLBI Workshop, September 3 and 4, 2015.

Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD.

NHLBI viewpoint: Lung health and disease prevention research starting in childhood.

Lung health begins in utero when the complex structure of the airway, alveolar, and vascular structures are formed. To really impact the United States and global burden of chronic lung diseases in both adults and children, we must understand normal and abnormal development, the outcomes of disrupted development, and the effects of in utero and postnatal exposures on lung health. With increasing recognition of early life origins of adult diseases,(1) it is important to know what early events and interventions can alter the trajectory of lung development, growth, and decline to help promote lung health and reduce chronic lung disease.