The relationship of blood lead with immunoglobulin E, eosinophils, and asthma among children: NHANES 2005-2006.

Early life lead exposure may alter immune function and predispose a child to develop asthma. In an initial exploration of this hypothesis, we examined the association between blood lead, and serum immunoglobulin E (IgE), eosinophils, and asthma prevalence in a cross-sectional study of 1788 children from the National Health and Nutrition Examination Survey 2005-2006. Geometric mean blood lead, serum IgE, and percent eosinophils were 1.13 µg/dL (95% confidence interval (CI): 1.04, 1.22), 46.3 kU/L (95% CI: 40.3, 53.1), and 2.82 percent (95% CI 2.67, 2.98), respectively. Prevalence of asthma, atopic asthma, and atopy were 11.8% (95% CI: 9.5, 14.2), 8.1% (6.2, 9.9), and 44.4% (40.1, 48.7), respectively. Regression models controlled for season, age, sex, race/ethnicity, education, passive smoke exposure, and body mass index. Based on these models, there was an 11.1% (95% CI: 5.6, 16.9) increase in IgE and a 4.9% (95% CI: 2.3, 7.6) increase in eosinophils per 1 µg/dL increase in blood lead. In independent stratified analyses, lead was found to increase IgE and eosinophils among non-Hispanic whites, but not other children; and stronger associations were observed among children who lived with a smoker vs. not. Lead was not associated with asthma, atopic asthma, or general atopy. This study provides additional evidence of a cross-sectional association between lead with IgE and new evidence for eosinophils. This may be a mechanism for development of downstream allergic disease. The mechanisms that determine ultimate development of allergic disease are currently unknown, but are the focus of ongoing studies.

Assessment of Noise Exposure to Children: Considerations for the National Children's Study.

Evidence has been accruing to indicate that young children are vulnerable to noise in their physical environment. A literature review identified that, in addition to hearing loss, noise exposure is associated with negative birth outcomes, reduced cognitive function, inability to concentrate, increased psychosocial activation, nervousness, feeling of helplessness, and increased blood pressure in children. While increasing attention has been given to the health effects of noise in children, research about noise exposure is sparse and often the measure of exposure is simply proximity to a noise source. The U.S. National Children's Study (NCS) provides a unique opportunity to investigate noise exposures to pregnant women and children using a number of assessment modalities at different life stages. Measurement of noise levels in homes and other environments, personal dosimetry measurements made over a period of days, and questionnaires addressing sources of noise in the environment, annoyance to noise, perceived noise level, use of head phones and ear buds, noisy activity exposures, and occupational exposures, are planned for evaluation within the NCS Vanguard pilot study. We describe the NCS planned approach to addressing noise exposure assessment in study visits over a child's lifetime.

New models for large prospective studies: is there a risk of throwing out the baby with the bathwater?

Manolio et al. (Am J Epidemiol. 2012;175:859-866) proposed that large cohort studies adopt novel models using "temporary assessment centers" to enroll up to a million participants to answer research questions about rare diseases and "harmonize" clinical endpoints collected from administrative records. Extreme selection bias, we are told, will not harm internal validity, and "process expertise to maximize efficiency of high-throughput operations is as important as scientific rigor" (p. 861). In this article, we describe serious deficiencies in this model as applied to the United States. Key points include: 1) the need for more, not less, specification of disease endpoints; 2) the limited utility of data collected from existing administrative and clinical databases; and 3) the value of university-based centers in providing scientific expertise and achieving high recruitment and retention rates through community and healthcare provider engagement. Careful definition of sampling frames and high response rates are crucial to avoid bias and ensure inclusion of important subpopulations, especially the medically underserved. Prospective hypotheses are essential to refine study design, determine sample size, develop pertinent data collection protocols, and achieve alliances with participants and communities. It is premature to reject the strengths of large national cohort studies in favor of a new model for which evidence of efficiency is insufficient.

Activity change in response to bad air quality, National Health and Nutrition Examination Survey, 2007-2010.

Air pollution contributes to poor respiratory and cardiovascular health. Susceptible individuals may be advised to mitigate effects of air pollution through actions such as reducing outdoor physical activity on days with high pollution. Our analysis identifies the extent to which susceptible individuals changed activities due to bad air quality. This cross-sectional study included 10,898 adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Participants reported if they did something differently when air quality was bad. Susceptible categories included respiratory conditions, cardiovascular conditions and older age (≥ 65 years). Analyses accounted for complex survey design; logistic regression models controlled for gender, race, education, smoking, and body mass index. 1305 individuals reported doing something differently (12.0%, 95% confidence interval (CI): 10.9, 13.1). This percentage was 14.2% (95% CI: 11.6, 16.8), 25.1% (95% CI: 21.7, 28.6), and 15.5% (95% CI: 12.2, 18.9) among older adults, those with a respiratory condition, and those with a cardiovascular condition, respectively. In adjusted regression models the following were significantly more likely to have changed activity compared to those who did not belong to any susceptible group: respiratory conditions (adjusted odds ratio (aOR): 2.61, 95% CI: 2.03, 3.35); respiratory and cardiovascular conditions (aOR: 4.36, 95% CI: 2.47, 7.69); respiratory conditions and older age (aOR: 3.83; 95% CI: 2.47, 5.96); or all three groups (aOR: 3.52; 95% CI: (2.33, 5.32). Having cardiovascular conditions alone was not statistically significant. Some individuals, especially those with a respiratory condition, reported changing activities due to poor air quality. However, efforts should continue to educate the public about air quality and health.

Teaching home environmental health to resident physicians.

Healthy Homes programs seek to integrate the evaluation and management of a multitude of health and safety risks in households. The education of physicians in the identification, evaluation, and management of these home health and safety issues continues to be deficient. Healthy Homes programs represent a unique opportunity to educate physicians in the home environment and stimulate ongoing, specific patient-physician discussions and more general learning about home environmental health. The Case Healthy Homes and Patients Program addresses these deficiencies in physician training while providing direct services to high-risk households. Pediatric and family practice resident physicians participate in healthy home inspections and interventions for their primary care patients and follow up on identified risks during health maintenance and acute illness visits.

Housing interventions and control of asthma-related indoor biologic agents: a review of the evidence.

Subject matter experts systematically reviewed evidence on the effectiveness of housing interventions that affect health outcomes, primarily asthma, associated with exposure to moisture, mold, and allergens. Three of the 11 interventions reviewed had sufficient evidence for implementation: multifaceted, in-home, tailored interventions for reducing asthma morbidity; integrated pest management to reduce cockroach allergen; and combined elimination of moisture intrusion and leaks and removal of moldy items to reduce mold and respiratory symptoms. Four interventions needed more field evaluation, 1 needed formative research, and 3 either had no evidence of effectiveness or were ineffective. The 3 interventions with sufficient evidence all applied multiple, integrated strategies. This evidence review shows that selected interventions that improve housing conditions will reduce morbidity from asthma and respiratory allergies.

Housing and allergens: a pooled analysis of nine US studies.

BACKGROUND: Housing conditions can contribute to allergen exposures that are linked to asthma, but little is known about which of those conditions are most likely to predict high levels of allergens in settled house dust. METHODS: We pooled allergen, housing condition, occupant behavior, demographic, and other data from nine asthma studies (n=950 homes in 6 US cities). Dust mite (Der f 1 or Der p 1), cockroach (Bla g 1 or Bla g 2), mouse (Mus m 1), cat (Fel d 1) and dog (Can f 1) allergens were measured in settled dust from kitchens or bedrooms, and concentrations were categorized according to previously published asthma symptom thresholds. We calculated odds ratios (OR) using logistic regression to identify those housing conditions and occupant behaviors that were associated with clinically significant allergen levels, after adjusting for numerous confounding variables. RESULTS: The adjusted results show that high cockroach allergen was associated with cracks or holes in walls (OR=2.1), high dust mite allergen was associated with mold odor (OR=2.5), housing built before 1951 (OR=2.1), and single-family home with slab on grade (OR=1.9); and mouse allergen was associated with rodent control or signs of rodents (OR=3.62) and inversely associated with presence of a cat (OR=0.20). Water leaks and below average housekeeping had unadjusted high odds ratios for high cockroach allergen. CONCLUSION: We have identified a number of housing conditions that are consistently associated with increased allergen dust concentrations. This study indicates that screening for housing-based asthma triggers should include presence of cats, dogs, cockroaches, or rodents; water leaks; mold or mold odor; holes or cracks in walls; and below average housekeeping. Single family houses that have basements or crawl spaces or are built before 1951 are also important predictors for increased allergens in housing.

Stachybotrys chartarum, trichothecene mycotoxins, and damp building-related illness: new insights into a public health enigma.

Damp building-related illnesses (DBRI) include a myriad of respiratory, immunologic, and neurologic symptoms that are sometimes etiologically linked to aberrant indoor growth of the toxic black mold, Stachybotrys chartarum. Although supportive evidence for such linkages is limited, there are exciting new findings about this enigmatic organism relative to its environmental dissemination, novel bioactive components, unique cellular targets, and molecular mechanisms of action which provide insight into the S. chartarum's potential to evoke allergic sensitization, inflammation, and cytotoxicity in the upper and lower respiratory tracts. Macrocyclic trichothecene mycotoxins, produced by one chemotype of this fungus, are potent translational inhibitors and stress kinase activators that appear to be a critical underlying cause for a number of adverse effects. Notably, these toxins form covalent protein adducts in vitro and in vivo and, furthermore, cause neurotoxicity and inflammation in the nose and brain of the mouse. A second S. chartarum chemotype has recently been shown to produce atranones-mycotoxins that can induce pulmonary inflammation. Other biologically active products of this fungus that might contribute to pathophysiologic effects include proteinases, hemolysins, beta-glucan, and spirocyclic drimanes. Solving the enigma of whether Stachybotrys inhalation indeed contributes to DBRI will require studies of the pathophysiologic effects of low dose chronic exposure to well-characterized, standardized preparations of S. chartarum spores and mycelial fragments, and, coexposures with other environmental cofactors. Such studies must be linked to improved assessments of human exposure to this fungus and its bioactive constituents in indoor air using both state-of-the-art sampling/analytical methods and relevant biomarkers.

Acute pulmonary hemorrhage during isoflurane anesthesia in two cats exposed to toxic black mold (Stachybotrys chartarum).

CASE DESCRIPTION: Acute pulmonary hemorrhage developed during isoflurane anesthesia in 2 Himalayan cats undergoing routine dental cleaning and prophylaxis. CLINICAL FINDINGS: The cats were siblings and lived together. In both cats, results of pre-operative physical examinations and laboratory testing were unremarkable. Blood pressure and oxygen saturation were within reference ranges throughout the dental procedure. Approximately 15 to 20 minutes after administration of isoflurane was begun, frothy blood was noticed within the endotracheal tube. Blood was suctioned from the endotracheal tube, and the cats were allowed to recover from anesthesia. TREATMENT AND OUTCOME: 1 cat initially responded to supportive care but developed a second episode of spontaneous pulmonary hemorrhage approximately 30 hours later and died. The other cat responded to supportive care and was discharged after 4 days, but its condition deteriorated, and the cat died 10 days later. Subsequently, it was discovered that the home was severely contaminated with mold as a result of storm damage that had occurred approximately 7 months previously. Retrospective analysis of banked serum from the cats revealed satratoxin G, a biomarker for Stachybotrys chartarum, commonly referred to as "toxic black mold." CLINICAL RELEVANCE: Findings highlight the potential risk of acute pulmonary hemorrhage in animals living in an environment contaminated with mold following flood damage.

The role of fungal proteinases in pathophysiology of Stachybotrys chartarum.

The adverse health effects of Stachybotrys chartarum have often been linked to exposure to the trichothecene mycotoxins. Recent studies have shown that in addition to mycotoxins this fungus is capable of producing and secreting in vivo proteins such as hemolysins and proteinases. Spore extracts obtained from a high trichothecene producing isolate JS 58-17 exhibited a significantly lower proteolytic activity compared to the low trichothecene producer, JS 58-06. Growing isolates on rice or potato dextrose agar results in higher proteolytic activity of the spores compared to those grown on drywall. Proteinases in the spore extracts can hydrolyze gelatin and collagen I and IV. Analysis of zymograms shows the presence of several proteins with proteolytic activity in the spores of S. chartarum. Human tracheal epithelial cells exposed to spore extracts produced significantly higher levels of IL-6, IL-8, and TNF-alpha than control cells. This stimulation of cytokine production was completely abolished by Pefabloc, a serine protease inhibitor. Neutrophil numbers and proinflammatory cytokine (IL1-beta and TNF-alpha) concentrations were highly elevated in the lungs of 7 day old rat pups exposed intratracheally to 4 x 10(4) spores/gm body weight compared to control. No significant differences in those inflammatory indices in vivo were noted between the treatments with the high trichothecene producer, isolate JS 58-17 and JS 58-06, which does not produce macrocyclic trichothecenes. Immunohistochemistry revealed reduced collagen IV labeling in spore-induced lung granulomas in rat pups exposed to both isolates. These results suggest that proteinases from S. chartarum spores significantly contribute to lung inflammation and injury.

Mold and endotoxin levels in the aftermath of Hurricane Katrina: a pilot project of homes in New Orleans undergoing renovation.

BACKGROUND: After Hurricane Katrina, many New Orleans homes remained flooded for weeks, promoting heavy microbial growth. OBJECTIVES: A small demonstration project was conducted November 2005-January 2006 aiming to recommend safe remediation techniques and safe levels of worker protection, and to characterize airborne mold and endotoxin throughout cleanup. METHODS: Three houses with floodwater lines between 0.3 and 2 m underwent intervention, including disposal of damaged furnishings and drywall, cleaning surfaces, drying remaining structure, and treatment with a biostatic agent. We measured indoor and outdoor bioaerosols before, during, and after intervention. Samples were analyzed for fungi [culture, spore analysis, polymerase chain reaction (PCR)] and endotoxin. In one house, realtime particle counts were also assessed, and respirator-efficiency testing was performed to establish workplace protection factors (WPF). RESULTS: At baseline, culturable mold ranged from 22,000 to 515,000 colony-forming units/m3, spore counts ranged from 82,000 to 630,000 spores/m3, and endotoxin ranged from 17 to 139 endotoxin units/m3. Culture, spore analysis, and PCR indicated that Penicillium, Aspergillus, and Paecilomyces predominated. After intervention, levels of mold and endotoxin were generally lower (sometimes, orders of magnitude). The average WPF against fungal spores for elastomeric respirators was higher than for the N95 respirators. CONCLUSIONS: During baseline and intervention, mold and endotoxin levels were similar to those found in agricultural environments. We strongly recommend that those entering, cleaning, and repairing flood-damaged homes wear respirators at least as protective as elastomeric respirators. Recommendations based on this demonstration will benefit those involved in the current cleanup activities and will inform efforts to respond to future disasters.

Reduction in asthma morbidity in children as a result of home remediation aimed at moisture sources.

OBJECTIVE: Home dampness and the presence of mold and allergens have been associated with asthma morbidity. We examined changes in asthma morbidity in children as a result of home remediation aimed at moisture sources. DESIGN: In this prospective, randomized controlled trial, symptomatic, asthmatic children (n = 62), 2-17 years of age, living in a home with indoor mold, received an asthma intervention including an action plan, education, and individualized problem solving. The remediation group also received household repairs, including reduction of water infiltration, removal of water-damaged building materials, and heating/ventilation/air-conditioning alterations. The control group received only home cleaning information. We measured children's total and allergen-specific serum immuno-globulin E, peripheral blood eosinophil counts, and urinary cotinine. Environmental dust samples were analyzed for dust mite, cockroach, rodent urinary protein, endotoxin, and fungi. The follow-up period was 1 year. RESULTS: Children in both groups showed improvement in asthma symptomatic days during the preremediation portion of the study. The remediation group had a significant decrease in symptom days (p = 0.003, as randomized; p = 0.004, intent to treat) after remodeling, whereas these parameters in the control group did not significantly change. In the postremediation period, the remediation group had a lower rate of exacerbations compared with control asthmatics (as treated: 1 of 29 vs. 11 of 33, respectively, p = 0. 003; intent to treat: 28.1% and 10.0%, respectively, p = 0.11). CONCLUSION: Construction remediation aimed at the root cause of moisture sources and combined with a medical/behavioral intervention significantly reduces symptom days and health care use for asthmatic children who live in homes with a documented mold problem.

Mycotoxin adducts on human serum albumin: biomarkers of exposure to Stachybotrys chartarum.

OBJECTIVE: Despite the growing body of evidence showing adverse health effects from inhalation exposure to the trichothecene-producing mold Stachybotrys chartarum, controversy remains. Currently, there are no reliable assays suitable for clinical diagnosis of exposure. We hypothesized that satratoxin G (SG) -albumin adducts may serve as biomarkers of exposure to this fungus. DESIGN: We studied the formation of adducts of SG with serum albumin in vitro using Western blots and mass spectrometry (MS) and searched for similar adducts formed in vivo using human and animal serum. RESULTS: Samples of purified human serum albumin that had been incubated with increasing concentrations of SG showed concentration-dependent albumin bands in Western blots developed with anti-SG antibodies. MS analysis found that as many as 10 toxin molecules can be bound in vitro to one albumin molecule. The sequencing of albumin-adduct tryptic peptides and the analysis of pronase/aminopeptidase digests demonstrated that lysyl, cysteinyl, and histidyl residues are involved in the formation of these adducts. Serum samples from three patients with documented exposure to S. chartarum similarly revealed lysine-, cysteine-, and histidine-SG adducts after exhaustive digestion, affinity column enrichment, and MS analysis. These adducts were also found in the sera from rats exposed to the spores of S. chartarum in contrast to control human subjects and control animals. CONCLUSIONS: These data document the occurrence of SG-albumin adducts in both in vitro experiments and in vivo human and animal exposures to S. chartarum. RELEVANCE TO CLINICAL PRACTICE: SG-amino acid adducts may serve as reliable dosimeter biomarkers for detection of exposure to S. chartarum.

Specific molds associated with asthma in water-damaged homes.

OBJECTIVE: We sought to determine if specific molds were found in significantly higher concentrations in the water-damaged homes of asthmatic children compared with homes with no visible water damage. METHODS: The mold concentrations in the dust in asthmatic children's bedrooms in water-damaged homes (N = 60) and control homes (N = 22) were measured by mold-specific quantitative polymerase chain reaction. RESULTS: Two molds, Scopulariopsis brevicaulis and Trichoderma viride, had significantly (P < 0.05) higher concentrations in asthmatics' homes compared with control homes and three other molds (Penicillium crustosum group, Stachybotrys chartarum, and Wallemia sebi) had P values <0.1. CONCLUSIONS: A relative moldiness index was developed to predict the likely development of asthma in water-damaged homes in Cleveland.

Acute inflammatory responses to Stachybotrys chartarum in the lungs of infant rats: time course and possible mechanisms.

Stachybotrys chartarum has been linked to building-related respiratory problems including pulmonary hemorrhage in infants. The macrocyclic trichothecenes produced by S. chartarum have been the primary focus of many investigations. However, in addition to trichothecenes this fungus is capable of producing other secondary metabolites and a number of protein factors. This study examines the effects of intact, autoclaved, and ethanol-extracted spores on the lungs of infant rats as an approach to differentiate between secondary metabolites and protein factors. Seven-day-old infant rats were exposed intratracheally to 1 x 10(5) spores/g body weight (toxic strain JS58-17) and sacrificed at various times up to 72 h. The inflammatory response was measured by morphometric analysis of the lungs and determination of inflammatory cells and cytokine concentrations in bronchoalveolar lavage (BAL) fluid. Alveolar space was greatly reduced in animals exposed to fungal spores compared to phosphate buffered saline (PBS)-treated controls. The largest effects were observed in pups treated with intact spores where alveolar space 24 h after treatment was 42.1% compared to 56.8% for autoclaved spores, 51.1% for ethanol-extracted spores, and 60.6% for PBS-treated controls. The effects of different spore preparations on inflammatory cells, cytokine, and protein concentrations in the BAL fluid can be ranked as intact > autoclaved > extracted. Tumor necrosis factor alfa (TNF-alpha), interleukin 1-beta (IL-1beta), and neutrophils were the most sensitive indicators of inflammation. The difference between autoclaved (100% trichothecene toxicity, denatured/enzymatically inactive proteins) and intact (100% trichothecene activity, unaltered/released proteins) spores indicates the involvement of fungal proteins in the inflammatory response to S. chartarum and sheds new light on the clinical importance of "nontoxic" strains.

Quantitative polymerase chain reaction analysis of fungi in dust from homes of infants who developed idiopathic pulmonary hemorrhaging.

Fungal concentrations were measured in the dust of 6 homes in Cleveland, Ohio, where an infant developed pulmonary hemorrhage (pulmonary hemorrhage homes [PHH]) and 26 reference homes (RH) with no known fungal contamination. Quantitative polymerase chain reaction assays for 82 species (or assay groups) were used to identify and quantify fungal concentrations. The ratios of the geometric means of PHH to RH were >1 for 26 species (group I). However, the same ratios were <1 for 10 species (group II). Probit analysis of the sum of the logs of the concentrations of these 2 groups resulted in a 95% probability range for separating PHH from RH homes. The same 82 fungal species were also tested for hemolysin production on sheep's blood agar (incubated at 37 degree C). Hemolysins were more commonly produced by group I species (42%) compared with group II species (10%).

Localization of satratoxin-G in Stachybotrys chartarum spores and spore-impacted mouse lung using immunocytochemistry.

Satratoxin-G (SG) is the major macrocyclic trichothecene mycotoxin produced by Stachybotrys chartarum (atra) and has been implicated as a cause of a number of animal and human health problems including pulmonary hemorrhage in infants. However, there is little understanding where this toxin is localized in the spores and mycelial fragments of this species or in the lung impacted by SG-sequestered spores. The purpose of this study was to evaluate the distribution of SG in S. chartarum spores and mycelium in culture, and spore-impacted mouse lung in vivo, using immunocytochemistry. SG was localized predominately in S. chartarum spores with moderate labelling of the phialide-apex walls. Labelling was primarily along the outer plasmalemma surface and in the inner wall layer. Only modest labelling was observed in hyphae. Toxin localization at these sites supports the position that spores contain the highest satratoxin concentrations and that the toxin is constitutively produced. In impacted mouse lung, highest SG labelling was detected in lysosomes, along the inside of the nuclear membrane in nuclear heterochromatin and RER within alveolar macrophages. Alveolar type II cells also showed modest labelling of the nuclear heterochromatin and RER. There was no evidence that the toxin accumulated in the neutrophils, fibroblasts, or other cells associated with the granulomas surrounding spores or mycelial fragments. These observations indicate that SG displays a high degree of cellular specificity with respect to its uptake in mouse lung. They further indicate that the alveolar macrophages play an important role in the sequestration and immobilization of low concentrations of the toxin.