Grantee Research Project Results
2015 Progress Report: Endotoxin Exposure and Asthma in Children
EPA Grant Number: R834515Center: Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Guo, Yanbing
Title: Endotoxin Exposure and Asthma in Children
Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Crooks, James L , Van Dyke, Michael V. , Faino, Anna , Sordillo, Joanne , Rabinovitch, Nathan , Szefler, Stanley , Fingerlin, Tasha
Current Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Murphy, Amy J , Strand, Mathew J. , Van Dyke, Michael V. , Martyny, John W. , Rabinovitch, Nathan
Institution: National Jewish Medical and Research Center , National Jewish Health , Harvard Medical School , Harvard University
Current Institution: National Jewish Health
EPA Project Officer: Hahn, Intaek
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
Project Period Covered by this Report: June 22, 2015 through June 21,2016
Project Amount: $1,897,209
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The goal is to determine the impact of ambient endotoxin and its interactions with other environmental exposures on asthma severity and exacerbations in children. Asthma exacerbations are one of the most common causes of urgent/emergent visits and hospitalizations for children. U.S. children living in urban, impoverished environments carry a disparate burden of severe asthma and exacerbations. Understanding how environmental exposures cause asthma exacerbations, especially in the urban poor environments where the problem is greatest, will bridge a significant knowledge gap. Understanding how other environmental exposures promote or cause toxic responses to endotoxin is central to the original scope of work. The research has generated new information about endotoxin exposure and has led us to improve our methods so that our research continues to have scientific and technical merit. Research experience, progress and findings, as well as prior experience with and recent advances in personal monitoring, suggested that we should strengthen the accuracy and relevance of the exposure assessments in our longitudinal Denver Asthma Panel Study (DAPS) by adding personal wearable exposure monitoring and bedroom air stationary monitoring. Our scope of work continues to address how endotoxin, both alone and in combination with other exposures such as ozone and allergens, contributes to asthma severity and exacerbations in children.
Progress Summary:
Researchers completed the Endotoxin Personal Exposure Monitoring (EPEM) pilot study to develop, enhance and operationalize personal exposure monitoring for DAPS, including: the wearable Micro-miniature Personal Exposure Monitor (MicroPEM™, RTI International) to measure PM10 and specific constituents, including black carbon (BC), brown carbon (BrC), and environmental tobacco smoke (ETS); Ogawa passive badge monitors to measure O3 and NO2; and Personal Environmental Monitor (PEM™, MSP Corp) for stationary air sampling in bedrooms. The DAPS protocol was developed to include these exposure monitoring enhancements, and received IRB approval and participant enrollment began in July 2014. Importantly, during the current funding period, DAPS study participant enrollment was completed. As planned, with 50 proposed study participants, we enrolled a total of 56 study participants to replace and anticipate study participant dropout and discontinuations. So far, 13 participants completed the study, with 87% retention, and the remainder are continuing in the study.
Preliminary analyses were performed to validate exposure monitoring methods using the first study visit data from these early DAPS enrollees and additional EPEM study participants with asthma meeting DAPS criteria (n = 25). Clinical measures of asthma severity (spirometry, exhaled nitric oxide, and Composite Asthma Severity Index (CASI)) were assessed concurrent with deployment of monitors.
The following summarizes the findings from these preliminary validation analyses:
- Wearing compliance was acceptable in 92% of study participants, from which we can conclude that our approach to achieve acceptable wearing compliance is effective.
- Comparing air pollutant exposures measured by personal versus stationary bedroom monitors, personal levels were significantly higher than stationary bedroom levels for PM10 (p = 0.025), BrC (p = 0.0005), and ETS (p < 0.0001); stationary bedroom levels for BrC and ETS were undetectable in 80% and 70% of participants, respectively. In contrast, stationary bedroom levels were significantly higher than personal levels for BC (p < 0.0001); personal BC levels were undetectable in 78% of participants. From this, we conclude that many respirable pollutants markedly differ in exposure levels measured with wearable versus stationary bedroom monitors.
- Linear regression models were used to determine if respirable pollutant levels were associated with asthma severity outcomes, adjusting for age, race and gender. Multiple significant exposure-asthma severity correlations were observed:
- Personal BrC levels correlated with the airway inflammatory marker exhaled nitric oxide (Pearson r = 0.43; regression model p = 0.005). Stationary bedroom BrC levels did not correlate with asthma severity.
- Personal ETS levels inversely correlated with airflow (FEV1/FVC r = -0.45, p < 0.0001). Stationary bedroom ETS levels did not correlate with asthma severity.
- Personal NO2 levels correlated with asthma severity (CASI r = 0.63, p < 0.0001), and inversely correlated with airflow (FEV1 % predicted r = -0.44, p < 0.03; FEF25-75 % predicted r = -0.54, p < 0.003). Stationary bedroom NO2 levels also correlated with personal NO2 levels, asthma severity (CASI) and airflow (FEV1, FEV25-75 % predicted); however, the correlations with personal NO2 levels are modestly stronger.
In conclusion, these preliminary analyses have shown that personal monitors measure respirable pollutant exposures more accurately. As a result, the personal monitors can reveal correlations between asthma severity and air pollutant exposures that are missed by conventional stationary monitors.
Future Activities:
The coming, final year will include continuation of DAPS visits to completion of the DAPS study, and analyses and preparation of our findings for presentation and manuscript submissions. Findings from our DAPS-EPEM preliminary analyses were selected for presentation at the 2015 American Academy of Allergy, Asthma & Immunology Annual Meeting (Best of Environmental and Occupational Respiratory Diseases Interest Section) and the 2015 American Thoracic Society International Conference, and are being developed for publication. For the NIH-funded CAMP study, the Endotoxin Exposure Working Group completed its analyses, presented this work at the 2014 American Academy of Allergy, Asthma & Immunology Annual Meeting (Best of Environmental and Occupational Respiratory Diseases Interest Section), and is in the final stages of manuscript preparation for submission of their findings. We completed our collaborative investigation of endotoxin exposure and asthma outcomes in 150 inner city children in Baltimore (NIH-funded MAACS Study: PI E. Matsui) and a manuscript of our findings was published. We also completed a collaborative investigation of endotoxin exposure and early childhood wheezing phenotypes in a Denver inner city pre-school cohort (NIH-funded CAPS Study: PI M.D. Klinnert). This was presented in 2014 at a premier meeting, and it is in the final stages of manuscript preparation for submission. What we have learned from our CAMP, EPEM, MAACS, HUD and CAPS studies, and the other Projects and COTC in our CEHC, has informed and strengthened DAPS.
Journal Articles: 31 Displayed | Download in RIS Format
Other center views: | All 51 publications | 30 publications in selected types | All 30 journal articles |
---|
Type | Citation | ||
---|---|---|---|
|
Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray Jr PB, Pedersen BS, Schwartz DA, Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics 2016;204(1):327-336. |
R834515 (Final) |
Exit Exit |
|
Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies:the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. |
R834515 (Final) R835436 (2017) R836159 (2018) |
|
|
Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, Leng L, Montgomery RR, Shaw A, Schwartz DA, Bucala R. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with gram-negative bacteremia in older adults. Journal of Infectious Diseases 2014;209(5):764-768. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
De Arras L, Seng A, Lackford B, Keikhaee MR, Bowerman B, Freedman JH, Schwartz DA, Alper S. An evolutionarily conserved innate immunity protein interaction network. Journal of Biological Chemistry 2013;288(3):1967-1978. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Gabehart K, Correll KA, Yang J, Collins ML, Loader JE, Leach S, White CW, Dakhama A. Transcriptome profiling of the newborn mouse lung response to acute ozone exposure. Toxicological Sciences 2014;138(1):175-190. |
R834515 (2011) R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C002 (2015) R834515C003 (2014) |
Exit Exit Exit |
|
Gabehart K, Correll KA, Loader JE, White CW, Dakhama A. The lung response to ozone is determined by age and is partially dependent on toll-like receptor 4. Respiratory Research 2015;16:117. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C002 (2015) R834515C003 (2014) |
Exit Exit Exit |
|
Gao Z, Dosman JA, Rennie DC, Schwartz DA, Yang IV, Beach J, Senthilselvan A. NOS3 polymorphism, lung function, and exposure in swine operations: results of 2 studies. Journal of Allergy and Clinical Immunology 2014;134(2):485-488. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Henao-Martinez AF, Agler AH, LaFlamme D, Schwartz DA, Yang IV. Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia. Infection, Genetics and Evolution 2013;16:386-391. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit |
|
Jing J, Yang IV, Hui L, Patel JA, Evans CM, Prikeris R, Kobzik L, O'Connor BP, Schwartz DA. Role of macrophage receptor with collagenous structure in innate immune tolerance. Journal of Immunology 2013;190(12):6360-6367. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Kelada SN, Wilson MS, Tavarez U, Kubalanza K, Borate B, Whitehead GS, Maruoka S, Roy MG, Olive M, Carpenter DE, Brass DM, Wynn TA, Cook DN, Evans CM, Schwartz DA, Collins FS. Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice. American Journal of Respiratory Cell and Molecular Biology 2011;45(4):817-824. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit |
|
Lai PS, Hofmann O, Baron RM, Cernadas M, Meng QR, Bresler HS, Brass DM, Yang IV, Schwartz DA, Christiani DC, Hide W. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. PLoS One 2013;8(5):e62910. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 2014;9(4):e93550 (10 pp.). |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Matsui EC, Hansel NN, Aloe C, Schiltz AM, Peng RD, Rabinovitch N, Ong MJ, Williams DL, Breysse PN, Diette GB, Liu AH. Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children. American Journal of Respiratory and Critical Care Medicine 2013;188(10):1210-1215. |
R834515 (2012) R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C001 (2015) R834515C002 (2014) R834515C003 (2014) R834510 (2014) |
Exit Exit Exit |
|
Oakes JL, O'Connor BP, Warg LA, Burton R, Hock A, Loader J, LaFlamme D, Jing J, Hui L, Schwartz DA, Yang IV. Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist. American Journal of Respiratory Cell and Molecular Biology 2013;48(1):27-34. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Szefler SJ, Dakhama A. New insights into asthma pathogenesis and treatment. Current Opinion in Immunology 2011;23(6):801-807. |
R834515 (2011) R834515 (Final) |
Exit |
|
Szefler SJ. Advancing asthma care: the glass is only half full! Journal of Allergy and Clinical Immunology 2011;128(3):485-494. |
R834515 (2011) R834515 (Final) |
Exit Exit Exit |
|
Szefler SJ. Advances in pediatric asthma in 2011: moving forward. Journal of Allergy and Clinical Immunology 2012;129(1):60-68. |
R834515 (2011) R834515 (Final) |
Exit Exit Exit |
|
Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012; 303(5):L391-L400.. |
R834515 (Final) |
Exit Exit |
|
Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, Schwartz DA. Novel regulators of the systemic response to lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology 2011;45(2):393-402. |
R834515 (2013) R834515 (2014) R834515 (2015) R834515 (Final) R834515C001 (2014) R834515C002 (2014) R834515C003 (2014) R834515C003 (2016) |
Exit Exit Exit |
|
Yang IV, Tomfohr J, Singh J, Foss CM, Marshall HE, Que LG, McElvania-Tekippe E, Florence S, Sundy JS, Schwartz DA. The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. American Journal of Respiratory and Critical Care Medicine 2012;185(6):620-627. |
R834515 (Final) |
Exit Exit Exit |
|
Julian CG, Yang IV, Browne VA, Vargas E, Rodriguez C, Pedersen BS, Moore LG, Schwartz DA. Inhibition of peroxisome proliferator-activated receptor gamma: a potential link between chronic maternal hypoxia and impaired fetal growth. FASEB Journal 2014;28(3):1268-1279. |
R834515 (Final) |
Exit |
|
Kelada SN, Carpenter DE, Aylor DL, Chines P, Rutledge H, Chesler EJ, Churchill GA, Pardo-Manuel de Villena F, Schwartz DA, Collins FS. Integrative genetic analysis of allergic inflammation in the murine lung. American Journal of Respiratory Cell and Molecular Biology 2014;51(3):436-445. |
R834515 (Final) |
Exit Exit |
|
Liang L, Willis-Owen SAG, Laprise C, Wong KCC, Davies GA, Hudson TJ, Binia A, Hopkin JM, Yang IV, Grundberg E, Busche S, Hudson M, Ronnblom L, Pastinen TM, Schwartz DA, Lathrop GM, Moffatt MF, Cookson W. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 2015;520(7549):670-674. |
R834515 (Final) |
Exit |
|
Eyring KR, Pedersen BS, Yang IV, Schwartz DA. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome. PloS one 2015;10(12):e0144087 (10 pp.). |
R834515 (Final) |
Exit Exit |
|
Julian CG, Pedersen BS, Salmon CS, Yang IV, Gonzales M, Vargas E, Moore LG, Schwartz DA. Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy. Clinical and Translational Science 2015;8(6):740-745. |
R834515 (Final) |
Exit Exit |
|
Yang IV, Pedersen BS, Liu A, O’Connor GT, Teach SJ, Kattan M, Misiak RT, Gruchalla R, Steinbach SF, Szefler SJ, Gill MA, Calatroni A, David G, Hennessy CE, Davidson EJ, Zhang W, Gergen P, Togias A, Busse WW, Schwartz DA. DNA methylation and childhood asthma in the inner city. Journal of Allergy and Clinical Immunology 2015;136(1):69-80. |
R834515 (Final) |
Exit Exit Exit |
|
Lai PS, Liang L, Cibas ES, Liu AH, Gold DR, Baccarelli A, Phipatanakul W. Alternate methods of nasal epithelial cell sampling for airway genomic studies. Journal of Allergy and Clinical Immunology 2015;136(4):1120-1123.e4. |
R834515 (Final) |
Exit Exit |
|
Yang IV, Richards A, Davidson EJ, Stevens AD, Kolakowski CA, Martin RJ, Schwartz DA. The nasal methylome: a key to understanding allergic asthma. American Journal of Respiratory and Critical Care Medicine 2017;195(6):829-831. |
R834515 (Final) |
Exit Exit Exit |
|
Yang IV, Pedersen BS, Liu AH, O'Connor GT, Pillai D, Kattan M, Misiak RT, Gruchalla R, Szefler SJ, Khurana Hershey GK, Kercsmar C, Richards A, Stevens AD, Kolakowski CA, Makhija M, Sorkness CA, Krouse RZ, Visness C, Davidson EJ, Hennessy CE, Martin RJ, Togias A, Busse WW, Schwartz DA. The nasal methylome and childhood atopic asthma. Journal of Allergy and Clinical Immunology 2017;139(5):1478-1488. |
R834515 (Final) |
Exit Exit Exit |
Supplemental Keywords:
Endotoxin, exposure, children, asthma, risk, health effects, susceptibility, sensitive populations, genetic pre-disposition, genetic polymorphism, indoor air, dose-response, ozone, remediation, human health, scientific discipline, health, health effects, biology, health risk assessment, children's health, allergens/asthma, asthma indices, intervention, RFA, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Children's Health, Biology, asthma, asthma triggers, sensitive populations, endotoxin, asthma indices, airway inflammation, children, allergic responseRelevant Websites:
Research Programs & Departments | National Jewish Health ExitProgress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834515C001 Endotoxin Exposure and Asthma in Children
R834515C002 Environmental Determinants of Early Host Response to RSV
R834515C003 Environmental Determinants of Host Defense
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2014 Progress Report
- 2013 Progress Report
- 2012 Progress Report
- 2011 Progress Report
- 2010 Progress Report
- Original Abstract
30 journal articles for this center