2014 Progress Report: Endotoxin Exposure and Asthma in Children

EPA Grant Number: RD834515C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant RD834515
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Endotoxin Exposure and Asthma in Children
Investigators: Schwartz, David A.
Current Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Crooks, James L , Van Dyke, Michael V. , Forssen, Anna , Sordillo, Joanne , Rabinovitch, Nathan , Szefler, Stanley , Fingerlin, Tasha
Institution: National Jewish Health
Current Institution: National Jewish Health , Harvard T.H. Chan School of Public Health , National Jewish Medical and Research Center
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, 2014 through June 21,2015
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

We hypothesize that higher levels of endotoxin exposure cause persistent, problematic asthma and that key environmental (ozone and allergens) and genetic modifiers (endotoxin receptor polymorphisms) contribute to endotoxin susceptibility and pathological asthmatic responses. We are studying these endotoxin-induced airway conditions in children through three complementary clinical investigations.

First, we are capitalizing on an ancillary study of an NIH-­sponsored multi-­center cohort of children with asthma (Childhood Asthma Management Program), which has tracked asthma severity for more than a decade, to determine if endotoxin exposure, modified by genetics and environment, is associated with greater disease severity and persistence.

Second, we have planned a panel study of children with asthma to investigate whether endotoxin exposure, modified by environment, is associated with inflamed airways and elevated TLR expression on airway macrophages. Clinically, these inflammatory responses could drive poor asthma control and exacerbations.

Finally, we have taken advantage of a HUD-­sponsored inner-­city home intervention study to determine if a home environment intervention will reduce home endotoxin levels and improve asthma. This combination of studies is expected to provide an understanding of how endotoxin interacts with other potentially toxic exposures in the susceptible host to cause persistent, problematic asthma. These studies will help us to determine the levels of endotoxin exposure that are likely to be problematic for children with asthma, and to develop environmental educational and intervention programs to improve health outcomes.

Progress Summary:

As proposed, three complementary studies address the aims and hypotheses of Project 1: (1) Childhood Asthma Management Program (CAMP) ancillary study; (2) Denver Asthma Panel Study (DAPS); and (3) Housing and Urban Development (HUD) ancillary study. Based on our CEHC’s research experience, progress and findings so far, we sought to strengthen the accuracy and relevance of our exposure assessments in DAPS by adding personal wearable exposure monitoring and bedroom air stationary monitoring. After EPA approval in January 2014, we successfully added and completed our Endotoxin Personal Exposure Monitoring Study (EPEM) to enhance, operationalize and validate our personal exposure monitoring for the longitudinal DAPS. Until recently, the lab assay for endotoxin has utilized limulus amebocyte lysate, a reagent that cross-reacts with molds. Now, there is an endotoxin assay based on recombinant Factor C, which only binds endotoxin. To advance scientific understanding of pure endotoxin exposure (i.e., independent of mold) and asthma outcomes, we developed and validated a Standard Operating Procedure to measure endotoxin using the rFC assay and established quality control parameters.

(1) Our CAMP investigation is the first study, to our knowledge, to clearly distinguish household endotoxin from mold exposure in children with asthma. By using the endotoxin-specific rFC assay and separate mold exposure measures (i.e., mold plate counts), we evaluated the effects of household endotoxin and mold exposures on asthma severity. In fact, we found that higher endotoxin levels in baseline dust samples (n = 962) were associated with fewer prednisone days (an indicator of severe asthma exacerbations), while high mold correlations were found between log mold concentrations and endotoxin levels (unadjusted r = 0.17; p = < 0.0001). When the effects of endotoxin and mold exposures on prednisone days were assessed for each site (with both exposures in the model), endotoxin-associated reductions and mold-associated increases in prednisone days were found for 5 of the 8 CAMP sites (Baltimore, Denver, San Diego, St. Louis, and Toronto), consistent with the overall model.

We also investigated the interaction of endotoxin with 48 SNPs in 11 Toll-Like Receptor (TLR) genes (TLR-1, -2, -3, -4, -5, -6, -9, -10, CD14, MyD88, LY96, ACAA1) on severe asthma exacerbations (i.e., at least one ER visit or hospitalization for asthma in the past year). This preliminary analysis was restricted to CAMP participants of Caucasian ethnicity: 517 CAMP Caucasian participants included 84 cases with at least one severe asthma exacerbation vs. 433 controls. For two SNPs (in TLR9 and MyD88), the presence of the dominant genotype and higher endotoxin levels increase the risk of severe asthma exacerbations. Because of these significant TLR gene-endotoxin interactions, we expanded our genotyping of genes downstream of the TLR receptor complex. We also performed a genome wide, pathway level analysis to develop a gene-by-environment model for endotoxin exposure and asthma exacerbations. Glycosphingolipid metabolism showed the most evidence for interaction with endotoxin exposure at the pathway level (FDR < 0.04) in models of asthma severity. Gene polymorphisms that contributed to glycosphingolipid pathway enrichment included interaction of endotoxin with polymorphisms in SPTLC2, ASAH1, GALC, ARSB, PPAP2B and SPTLC1. Other pathways and functional groupings that showed possible interactions with environmental endotoxin were monoamine G protein coupled receptors (including muscarinic receptors (CHRM3), histamine receptors (HRH1)) (FDR = 0.06), the nitric oxide synthase pathway (FDR = 0.08), and Fc Epsilon Receptor 1 signaling in mast cells (FDR = 0.15). Pathway level analysis identified functional groupings of genes that may interact with ambient endotoxin exposure to alter asthma severity in children. These gene-by-environment interactions would not have been detected in a conventional genome wide survey of individual SNP-level gene-by-environment associations.

Table 1. DAPS exposure assessment
Analyte Sampling Location Unit N % Detectable Mean SD Min Med Max
PM10 Personal μg/m3 19 100 34.83 13.24 13.89 33.80 60.69
Bedroom μg/m3 20 100 25.68 12.82 12.30 23.93 63.99
Denver μg/m3 22 100 18.96 12.34 1 16 75
ETS Personal μg/m3 19 100 1.23 0.99 0.17 0.97 3.48
Bedroom μg/m3 20 30 0.08 0.27 0.00 0.00 1.18
BrC Personal μg/m3 19 100 0.61 0.15 0.35 0.60 1.02
Bedroom μg/m3 20 20 0.11 0.28 0.00 0.00 1.11
BC Personal μg/m3 19 22 0.00 0.01 0.00 0.00 0.02
Bedroom μg/m3 20 100 0.82 0.26 0.17 0.84 1.20
NO2 Personal μg/m3 20 100 26.65 13.11 13.09 22.76 65.30
Bedroom μg/m3 21 100 27.40 22.74 11.93 20.45 118.90
Denver μg/m3 22 100 36.51 15.27 7.52 33.54 107.22
O3 Personal μg/m3 14 100 12.39 10.28 1.48 8.70 39.40
Outdoor μg/m3 14 100 63.62 8.09 54.18 60.92 79.95
Denver μg/m3 15 100 61.38 29.98 0 62.55 139.96
WC Personal % 22 100 74.3 17.4 36 73.9 108

Abbreviations: PM10=particulate matter <10μm, Denver=air monitoring station, ETS=environmental tobacco smoke, BrC=black carbon, NO2=nitrogen dioxide, O3=ozone, WC=wearing compliance, SD=standard deviation, Min=minimum, Max=maximum, Med=median.

Note: Personal data exclude subjects with poor data quality or WC less than 50%. Bedroom data exclude subjects with poor data quality.

(2) For DAPS, we strengthened the accuracy and relevance of our exposure assessments, by adding personal wearable exposure monitoring and bedroom air stationary monitoring. With EPA approval in January 2014, we successfully added and completed the Endotoxin Personal Exposure Monitoring study (EPEM) to develop, enhance and operationalize personal exposure monitoring methods for DAPS. The DAPS protocol was developed to include these exposure monitoring enhancements. We received IRB approval and participant enrollment began in July 2014. Currently, 15 study participants have been enrolled, and 13 have completed the study (87% retention). 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.

Exposure Samplers: The wearable Micro-miniature Personal Exposure Monitor (MicroPEM™, RTI International) and stationary Personal Environmental Monitor (PEM™, MSP Corp) samplers were used to measure particulate matter < 10 μm (PM10) via gravimetric analysis and real-time nephelometry as well as components of PM10, including black carbon (BC), brown carbon (BrC), and environmental tobacco smoke (ETS), via spectrophotometry. Ogawa™ passive badges (Ogawa USA) were used to measure O3 and NO2. Publically available Air Quality Index (AQI) data, from a Colorado Department of Public Health (CDPHE) air monitoring station in central Denver, were used for outdoor (ambient) comparisons of PM10, NO2, and O3. Table 1 presents summary statistics for exposure assessments.

Exposure Monitor Deployment and Clinical Asthma Severity Assessments: Ogawa™ passive badges and PEM™ monitors were installed in participants’ bedrooms. Ogawa™ passive badges also were installed outside of the home during the summer visit. Each participant was fitted with a personal monitoring apparatus (MicroPEM™, Ogawa™ passive badges, and iTrack Micro™ GPS device). All devices were retrieved after approximately 72 hours. Spirometry, exhaled nitric oxide (eNO), and Composite Asthma Severity Index (CASI) were assessed concurrent with deployment of monitors and badges (Wildfire, et al. J Allergy Clin Immunol. 2012; PubMed PMID: 22244599).

Feasibility of Exposure Assessment Using Wearable Monitors in Children: Wearing compliance (WC) was calculated from MicroPEM™ accelerometry data and the personal exposure log. Statistical analyses included participants with greater than 50% (“acceptable”) wearing compliance based on thresholds used in prior studies (Lawless P, Thornburg J, et al. J Expo Sci Environ Epidemiol. 2012; PubMed PMID: 22377684). WC was acceptable in 91% of participants, with a median WC of 78% for those with acceptable WC.

Environmental Exposures are Detectable and Correlate with Clinical Assessments: Personal versus stationary exposures were analyzed with linear mixed models or Wilcoxon signed rank tests depending on the statistical distributions. Personal exposure levels were significantly higher than stationary bedroom levels for PM10 (p = 0.025), BrC (p = 0.0005), and ETS (p < 0.0001). In contrast, personal levels for BC were significantly lower than stationary bedroom levels (p < 0.0001). Linear regression models assessed how pollutant levels were associated with asthma severity, and were adjusted for age, race and gender, when applicable. Linear regression analyses revealed multiple significant exposure-asthma severity correlations (Table 2). Personal exposure-asthma severity correlations were stronger than stationary exposure-asthma severity correlations, suggesting that personal monitors provide more accurate measurements of environmental exposures.

Table 2. DAPS Phenotyping Assessments
  Pearson's r or n
n (%) p-vlaue1
CASI Score
Personal NO2

19

0.6337

<0.00001
Bedroom NO2 21 0.4207 0.0036  
FEV1 % predicted
Personal NO2

19

-0.4431

0.0312
Bedroom NO2 21 -0.4027 0.0438
FEF25-75 % predicted
Personal NO2

18

-0.5438

0.006
Bedroom NO2 20 -0.4684 0.0178
FEV1/FVC % predicted
Personal ETS

19

-0.4452

<0.0001
Bedroom ETS1 20 6 (30) *
eNO
Personal BrC

19

0.4281

0.0045
Bedroom BrC2 20 4 (20) *

1 P-value from linear regression model. CASI, FEVI/FVC and eNO adjusted for age, gender, and race. Models not run for bedroom ETS and BrC because of few values above LOD.

2 Bedroom ETS and BrC were dichotomized (O vs. >0), and reported as n (%) above O.

Abbreviations: BrC=brown carbon, NO2=nitrogen dioxide, ETS=environmental tobacco smoke, eNO=exhaled nitric oxide, FEV1=forced expiratory volume in 1 second, FVC=forced vital capacity, CASI=Composite Asthma Severity Index, FEF25-75=forced expiratory flow 25—75%

Future Activities:

The coming year will include continuation of DAPS visits, 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). 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 on this Report : 14 Displayed | Download in RIS Format

Other subproject views: All 23 publications 14 publications in selected types All 14 journal articles
Other center views: All 51 publications 30 publications in selected types All 30 journal articles
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Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2011)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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.). RD834515 (2013)
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  • Journal Article 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. RD834515 (2012)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • Journal Article 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. RD834515 (2013)
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  • 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, asthma triggers, asthma indices, airway inflammation, allergic response;, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Physiology, Allergens/Asthma, Health Effects, Biology, asthma, sensitive populations, asthma triggers, endotoxin, asthma indices, children, airway inflammation, allergic response

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011
  • 2012
  • 2013
  • 2015 Progress Report
  • Final

  • Main Center Abstract and Reports:

    RD834515    Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    RD834515C001 Endotoxin Exposure and Asthma in Children
    RD834515C002 Environmental Determinants of Early Host Response to RSV
    RD834515C003 Environmental Determinants of Host Defense