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The Environmental Influences on Child Health Outcome (ECHO) program at the National Institutes of Health 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 program is to examine effects of a broad array of early environmental exposures on child health and development. The information includes longitudinal data and biospecimens from more than 100 000 children and family members from diverse settings across the United States ECHO investigators have published collaborative analyses showing associations of environmental exposures-primarily in the developmentally sensitive pre-, peri-, and postnatal 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 environmental epidemiology and to inform policies, practices, and programs to enhance child health. This article is part of a Special Collection on Environmental Epidemiology., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Investigators conducting human subject research have typically conveyed only clinically actionable results back to individual participants. Shifting scientific culture around viewing participants as partners in research, however, is prompting investigators to consider returning as much data or results as the participant would like, even if they are not clearly actionable. Expanding return of individual results may add value for individual participants and their communities, refine future research questions and methods, build trust, and enhance retention of participants. Yet, gaps remain in understanding the implications of these changes for groups of 'vulnerable' participants, including pregnant and pediatric participants. We present the findings of a National Institutes of Health workshop on returning individual research results, particularly as applicable to pregnant and pediatric participants. Research participants who were panelists at the workshop agreed that they desire to receive their results. Workshop findings and current literature indicate that participants have differing preferences for what results they receive. One way to address the limits of current practice is to develop flexible digital platforms that convey individual results along with researchers' availability to answer questions, and to provide as much information as possible about actionable steps to control environmental exposures associated with disease risk., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

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 23 0/7 -28 6/7 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., (Published by Elsevier Inc.)

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., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

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.

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.

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., (© 2015 Wiley Periodicals, Inc.)

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.

Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.

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.

In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.

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., (Copyright Thieme Medical Publishers.)

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 discussed as a companion paper 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., ((c) 2009 Wiley-Liss, Inc.)

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.

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.

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.

Asthma has been identified as a possible risk factor for Obstructive Sleep Apnea (OSA) in children. It is not known whether parent-reported asthma increases the likelihood of the diagnosis of OSA in snoring children. We hypothesized that snoring children with asthma are more likely to have OSA than snoring children without asthma. This study is a 1-year retrospective review of polysomnogram and questionnaire data collected on 236 patients referred to the University of Maryland Pediatric Sleep laboratory for evaluation of snoring. Of the 236 patients, 58% (137/236) were boys, and 79% (173/219 reporting race) were African-American (AA). The age at referral was 7.2 +/- 3.7 years (mean +/- S.D.). Mean body mass index (BMI) percentile was 73.4 +/- 32.3%, with 43.2% (54/125) >95th percentile. A history of asthma was reported by 31.4% (74/236); no subject was symptomatic on the night of the study. We found no increased risk for polysomnographically diagnosed OSA for asthmatics. To the contrary, by logistic regression analysis, a parent/guardian report of asthma decreased the odds of having OSA by 34% (p = 0.027), controlling for individual and socioeconomic factors and assessment results. Polysomnographic (PSG) differences between asthmatic and non-asthmatic children were found in only the arousal index (11.0 vs.9.3 +/- 6.5/h, p = 0.099) and total sleep time (337.1 +/- 64.3 vs. 347 +/- 65.2 min, p = 0.1) In a referral-based group of predominantly AA inner-city snoring children, asymptomatic asthma decreased the likelihood of OSA.

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

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.

Asthma causes pediatric morbidity throughout the US with substantial regional variability. Emergency department (ED) utilization data were studied to determine if geographic variability of pediatric asthma cases exists within a state. Records for non-neonatal Maryland children less than 18 years of age seen and discharged from Maryland EDs from April 1997 through March 2001 were analyzed. While Baltimore City had the highest rates of asthma visits, adjusted odds ratios identified the wealthiest suburban county to have a higher risk of an asthma ED visit. Children from rural counties, for the most part, had fewer ED asthma visits than children from urban and suburban counties.

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., (2006; 41:151-157. (c) 2005 Wiley-Liss, Inc.)

Epithelial Cl(-) channels mediate Cl(-) and fluid secretion in the lung. In cystic fibrosis, aberrant Cl(-) secretion is one of the major causes for lung fluid imbalance. Regulation of Cl(-) channels is therefore an important issue in the lung. IFN-gamma regulates Na(+) and Cl(-) channels and fluid transport in the lung, but the mechanisms involved in these regulations are not clear. In expression studies, we found that IFN-gamma increased ClC-2 transcripts in Calu-3 cells. Studies of the promoter identified a minimal promoter which interacts with transcription factors Sp1 and Sp3. However, reporter gene assays showed that IFN-gamma did not activate the promoter. Instead, IFN-gamma significantly increased ClC-2 transcript stability. Using Ussing chamber experiments, we demonstrate that IFN-gamma activates a pH-regulated and Cd(2+)-sensitive short circuit current, characteristic properties of the ClC-2 Cl(-) channel. These data suggest that IFN-gamma activates ClC-2 channel activity in lung epithelial cells via mRNA stabilization.

Background: Cystic fibrosis (CF) lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs) in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease., Methods: The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%)., Results: PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene., Conclusions: CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity.

Background: General practitioners (GPs) have a central place in the management of asthma, particularly in the context of acute exacerbations., Aim: To evaluate the management of asthma exacerbations by GPs, and to investigate the ability of risk factors for near fatal asthma to predict the severity of asthma attacks in the community., Design of Study: A 1-month multicentre cross-sectional survey., Setting: One thousand and ninety-four GPs of the French Sentinel Network were contacted; 365 responded., Method: Asthma exacerbations were classified according to severity at presentation. Univariate and multivariate analyses were performed by logistic regression to identify those factors associated with severe exacerbations., Results: Exacerbations were described in 219 patients with asthma. Over half (54%) of exacerbations were severe. Peak expiratory flow was recorded during the consultation in 55% of patients who were more than 5 years old. beta(2) agonists were prescribed to 93% of patients, systemic corticosteroids to 71%, and antibiotics to 64%. Only 42% of patients had a written action plan for self-management of exacerbations. Risk factors for near fatal asthma, identified in 26% of patients, were not significantly associated with severe asthma exacerbations. Short duration of exacerbation before consultation (<3 hours) was associated with an increase in relative risk of severe exacerbation of 3.38, 95% confidence intervals (CIs) = 1.19 to 9.61, compared with duration of >3 hours., Conclusion: Risk factors for near fatal asthma identified in previous studies were not predictive of a severe exacerbation in general practice, with the exception of short duration of exacerbation before consultation. This suggests that new methods to predict risk in the outpatient settings should be developed.

Normal lung morphogenesis is dependent on chloride-driven fluid transport. The molecular identity of essential fetal lung chloride channel(s) has not been elucidated. CLC-2 is a chloride channel, which is expressed on the apical surface of the developing respiratory epithelium. CLC-2-like pH-dependent chloride secretion exists in fetal airway cells. We used a 14-day fetal rat lung submersion culture model to examine the role of CLC-2 in lung development. In this model, the excised fetal lung continues to grow, secrete fluid, and become progressively cystic in morphology (26). We inhibited CLC-2 expression in these explants, using antisense oligonucleotides, and found that lung cyst morphology was disrupted. In addition, transepithelial voltage (V(t)) of lung explants transfected with antisense CLC-2 was inhibited with V(t) = -1.5 +/- 0.2 mV (means + SE) compared with -3.7 +/- 0.3 mV (means + SE) for mock-transfected controls and -3.3 +/- 0.3 mV (means + SE) for nonsense oligodeoxynucleotide-transfected controls. This suggests that CLC-2 is important for fetal lung fluid production and that it may play a role in normal lung morphogenesis.

Background: Asthma in school children is rising, and indoor allergens are very common triggers of asthma attacks; however, the risk of the school environment on asthma has not been well studied., Objective: To determine the presence and the levels of common aeroallergens in schools, where asthma prevalence rates are high., Methods: Settled dust samples were collected from 12 Baltimore City public elementary schools, and they were analyzed for the following allergens: cockroaches (Bla g 1/2), dust mites (Der f 1/p 1), dog (Can f 1), cat (Fel d 1), and mouse (Mus m 1). School asthma prevalence rates were correlated with allergen levels, and association between allergen levels and other risk factors present in the schools' environment was examined., Results: The mean and range levels were 1.49 U/g (0 to 8) for Bla g 1/2; 0.38 microg/g (0 to 11.9) for the Der f 1/p 1; 1.44 microg/g (0.1 to 9.6) for Can f 1; 1.66 microg/g (0.2 to 12) for Fel d 1; and 6.24 microg/g (0.3 to 118.3) for Mus m 1. Dust mite, cat and dog allergens were significantly in rooms with carpet and/or area rugs, compared to rooms with bare floors (P < 0.05). Asthma prevalence rates varied from 11.8 to 20.8% between schools and positively correlation with the mean levels of Bla g 1/2 in the schools (P = 0.001)., Conclusions: Common allergens that are known to trigger asthma were detected in all school environments, where asthma prevalence rates were high. However, the overall allergen levels were low, indicating that other factors, including exposures in the homes of asthmatic patients, may have more relevance to sensitization and symptoms than school exposures.

Asthma hospitalization rates have increased in the United States since 1980. The exposure risk of many environmental factors, which contribute to respiratory disease, vary throughout the year. The objective of this study was to investigate the seasonal variation of pediatric asthma hospitalizations and predict hospitalization frequency. This was a longitudinal analysis of all pediatric asthma hospitalizations in the state of Maryland by age, gender, race, and residence using non-confidential discharge data sets from 1986 to 1999. Of the 631,422 pediatric hospitalizations in the state of Maryland during the years 1986-1999, 45,924 (7%) had a primary admission diagnosis of asthma. Frequency of hospitalization for asthma was lowest in the summer in all age groups, and highest in the fall. Seasonal variation in severe asthma episodes was least striking in children aged 15-18. This was in contrast to non-asthma admissions, which were highest in winter in preschool children, but relatively flat in school- and teenaged children. Using neural network modeling, weekly asthma hospitalizations could be predicted with an R2 between 0.71 and 0.8. Temporal trends in asthma hospitalizations were seen in each age group, gender, race, and location. The seasonal variability in asthma hospitalizations suggests that acute asthma is influenced by variables beyond socioeconomic factors and adherence to medical regimens. Strategies to combat exacerbations of asthma should take into consideration seasonal effects on a population. In addition, temporal trends examined over many years can be used to predict frequency of severe asthma episodes in a population.

Asthma is a chronic disease that affects millions of Americans. Evaluation and treatment guidelines have been developed by panels of experts for over 10 years. Management of the teen with asthma, however, creates special opportunities for the practitioner, because of the transition of adolescents from dependence on the family to an increased desire for independence. This article will review our current understanding of the special needs of the adolescent asthmatic, and make recommendations for improving disease control.

Chloride transport is critical to many functions of the lung. Molecular defects in the best-known chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), lead to impaired function of airway defensins, hydration of airway surface fluid, and mucociliary clearance leading to chronic lung disease, and premature death, but do not cause defects in lung development. We examined the expression of one member of the ClC family of volume- and voltage-regulated channels using the ribonuclease protection assay and Western blot analysis in rats. ClC-5 mRNA and protein are most strongly expressed in the fetal lung, and expression is maintained although downregulated postnatally. In addition, using immunocytochemistry, we find that ClC-5 is predominantly expressed along the luminal surface of the airway epithelium, suggesting that ClC-5 may participate in lung chloride secretion. Identifying candidate genes for critical ion transport functions is essential for understanding normal lung morphogenesis and the pathophysiology of several lung diseases. In addition, the manipulation of non-CFTR chloride channels may provide a viable approach for treating cystic fibrosis lung disease.

Background: Clinical pathways for asthma are tools that have the potential to improve compliance with nationally recognized management guidelines, but their effect on patient outcomes has not been documented., Objectives: To determine the effect of an asthma clinical pathway on patients' length of stay, use of nebulized beta-agonist therapy while hospitalized, and use of acute care clinics for 2 weeks after discharge., Design/methods: The study was a randomized, controlled trial. Patients between the ages of 2 and 18 years admitted with an asthma exacerbation and not under the care of an asthma specialist were eligible for the study. Patients were randomized either to a conventional ward (control group) or to a ward using the clinical pathway (intervention group). For 2 weeks after discharge, we collected data to determine whether patients visited a health care provider for worsening asthma., Results: One hundred ten patients (26%) were enrolled. Control and intervention groups had similar demographic and asthma severity profiles. The intervention group had an average length of stay 13 hours shorter than did the control group. In addition, at every dosing interval, the intervention group received less nebulized beta-agonist therapy. There were no deaths in either group., Conclusion: A clinical pathway for inpatient asthma decreased the length of stay and beta-agonist medication use with no adverse outcomes or increased acute-care encounters through 2 weeks after discharge.

Objective: To evaluate the accuracy of the pulse oximeter to detect hypoxemia in patients with sickle cell disease in an ambulatory care setting., Study Design: Simultaneous measurements of PaO(2), arterial oxygen saturation by co-oximetry (criterion standard), and pulse oximetry were performed in 21 children with sickle cell disease during 22 outpatient visits. The bias and precision of the pulse oximeter compared with measured arterial oxygen saturation by co-oximetry were determined. The sensitivity, specificity, and positive and negative predictive values of the pulse oximeter to detect hypoxemia (PaO(2) <70 mm Hg) were also calculated., Results: The mean difference between pulse oximetry and measured oxygen saturation (bias) was 5.0% and the SD (precision) was 5.3. Twenty-one patients had a PaO(2) greater than 70 mm Hg; 7 of these (33%) were predicted to be hypoxic by pulse oximetry with values less than 93%, for a specificity to detect normoxia of 67%., Conclusion: Making treatment decisions based on pulse oximetry data alone in patients with sickle cell disease who are not acutely ill may be inappropriate.

The fetal lung actively transports chloride across the airway epithelium. ClC-2, a pH-activated chloride channel, is highly expressed in the fetal lung and is located on the apical surface of the developing respiratory epithelium. Our goal was to determine whether acidic pH could stimulate chloride secretion in fetal rat distal lung epithelial cells mounted in Ussing chambers. A series of acidic solutions stimulated equivalent short-circuit current (I(eq)) from a baseline of 28 +/- 4.8 (pH 7.4) to 70 +/- 5 (pH 6.2), 114 +/- 12.8 (pH 5.0), and 164 +/- 19.2 (pH 3.8) microA/cm(2). These changes in I(eq) were inhibited by 1 mM cadmium chloride and did not result in large changes in [(3)H]mannitol paracellular flux. Immunofluorescent detection by confocal microscopy revealed that ClC-2 is expressed along the luminal surface of polarized fetal distal lung epithelial cells. These data suggest that the acidic environment of the fetal lung fluid could activate chloride channels contributing to fetal lung fluid production and that the changes in I(eq) seen in these Ussing studies may be due to stimulation of ClC-2.

Mutations in the chloride channel, ClC-5, have been described in several inherited diseases that result in the formation of kidney stones. To determine whether ClC-5 is also involved in calcium homeostasis, we investigated whether ClC-5 mRNA and protein expression are modulated in rats deficient in 1alpha,25(OH)(2) vitamin D(3) with and without thyroparathyroidectomy. Parathyroid hormone (PTH) was replaced in some animals. Vitamin D-deficient, thyroparathyrodectomized rats had lower serum and higher urinary calcium concentrations compared with control animals as well as lower serum PTH and calcitonin concentrations. ClC-5 mRNA and protein levels in the cortex decrease in vitamin D-deficient, thyroparathyroidectomized rats compared with both control and vitamin D-deficient animals. ClC-5 mRNA and protein expression increase near to control levels in vitamin D-deficient, thyroparathyroidectomized rats injected with PTH. No significant changes in ClC-5 mRNA and protein expression in the medulla were detected in any experimental group. Our results suggest that PTH modulates the expression of ClC-5 in the kidney cortex and that neither 1alpha,25(OH)(2) vitamin D(3) nor PTH regulates ClC-5 expression in the medulla. The pattern of expression of ClC-5 varies with urinary calcium. Animals with higher urinary calcium concentrations have lower levels of ClC-5 mRNA and protein expression, suggesting that the ClC-5 chloride channel plays a role in calcium reabsorption.

Mechanisms responsible for regulation of pulmonary epithelial chloride-channel expression in the perinatal period are under investigation to better understand normal lung development and airway disease pathogenesis. The ClC-2 epithelial chloride channel is regulated by changes in pH and volume and is most abundant in lung during fetal development. In this study, we identify and sequence the ClC-2 promoter, which is GC rich and lacks a TATA box. By construction of a series of promoter-luciferase constructs, a 67-bp GC box-containing sequence in the promoter is shown to be critical to ClC-2 expression in primary and immortalized fetal lung epithelial cells. Electrophoretic mobility shift assays and antibody supershifts demonstrate that the Sp1 and Sp3 transcription factors are expressed in fetal lung nuclei and interact with the GC box sequences in the promoter. Immunoblotting techniques demonstrate that Sp1 and Sp3 are perinatally downregulated in the lung with the same temporal sequence as ClC-2 downregulation. This work suggests that Sp1 and Sp3 activate ClC-2 gene transcription and that reduction in Sp1 and Sp3 at birth explains perinatal downregulation of ClC-2 in the lung.

Keratinocyte growth factor (KGF) is mitogenic for epithelial cells and induces cystic dilation of fetal lung explants through cystic fibrosis transmembrane conductance regulator-independent chloride channels. One candidate fetal lung chloride channel that is highly expressed on the apical surface of the respiratory epithelium and markedly downregulated after birth is CLC-2. We hypothesized that KGF regulates CLC-2 expression in the fetal lung. Primary fetal rat distal lung epithelial cell monolayers were grown in medium containing 10 ng/ml KGF for 48 h. CLC-2 protein was increased by Western blot analysis of whole-cell lysates in KGF-treated cultures. Similarly, KGF stimulated CLC-2 messenger RNA (mRNA) by Northern blot analysis. This enhanced expression was dose-dependent and maximal at 48 h with 10 ng/ml KGF. Promoter-reporter gene experiments demonstrated that KGF did not stimulate gene transcription. By inhibition of new mRNA synthesis with actinomycin D, evidence was obtained that KGF stabilizes CLC-2 mRNA. We speculate that KGF may positively influence pulmonary chloride and fluid secretion by a secondary pathway affecting CLC-2 degradation.

Cystic fibrosis (CF) is a lethal inherited disease that results from abnormal chloride conduction in epithelial tissues. ClC-2 chloride channels are expressed in epithelia affected by CF and may provide a key "alternative" target for pharmacotherapy of this disease. To explore this possibility, the expression level of ClC-2 channels was genetically manipulated in airway epithelial cells derived from a cystic fibrosis patient (IB3-1). Whole-cell patch-clamp analysis of cells overexpressing ClC-2 identified hyperpolarization-activated Cl- currents (HACCs) that displayed time- and voltage-dependent activation, and an inwardly rectifying steady-state current-voltage relationship. Reduction of extracellular pH to 5.0 caused significant increases in HACCs in overexpressing cells, and the appearance of robust currents in parental IB3-1 cells. IB3-1 cells stably transfected with the antisense ClC-2 cDNA showed reduced expression of ClC-2 compared with parental cells by Western blotting, and a significant reduction in the magnitude of pH-dependent HACCs. To determine whether changes in extracellular pH alone could initiate chloride transport via ClC-2 channels, we performed 36Cl- efflux studies on overexpressing cells and cells with endogenous expression of ClC-2. Acidic extracellular pH increased 36Cl- efflux rates in both cell types, although the ClC-2 overexpressing cells had significantly greater chloride conduction and a longer duration of efflux than the parental cells. Compounds that exploit the pH mechanism of activating endogenous ClC-2 channels may provide a pharmacologic option for increasing chloride conductance in the airways of CF patients.