RESUMEN
This study evaluates the possible association between refractory ceramic fiber (RCF) exposure and all causes of death. Current and former employees (n = 1,119) hired from 1952 to 1999 at manufacturing facilities in New York (NY) state and Indiana were included. Work histories and quarterly plant-wide sampling from 1987 to 2015 provided cumulative fiber exposure (CFE) estimates. The full cohort was evaluated as well as individuals with lower and higher exposure, <45 and ≥45 fiber-months/cc. The Life-Table-Analysis-System was used for all standardized mortality rates (SMRs). Person-years at risk were accumulated from start of employment until 12/31/2019 or date of death. There was no significant association with all causes, all cancers, or lung cancer in any group. In the higher exposed, there was a significant elevation in both malignancies of the "urinary organs" (SMR = 3.59, 95% confidence interval [CI] 1.44, 7.40) and "bladder or other urinary site" (SMR = 4.04, 95% CI 1.10, 10.36), which persisted in comparison to regional mortality rates from NY state and Niagara County. However, six of the nine workers with urinary cancers were known smokers. In the lower exposed, there was a significant elevation in malignancies of the lymphatic and hematopoietic system (SMR = 2.54, 95% CI 1.27, 4.55) and leukemia (SMR = 4.21, 95% CI 1.69, 8.67). There was one pathologically unconfirmed mesothelioma death. A second employee currently living with a pathologically confirmed mesothelioma was identified, but the SMR was non-significant when both were included in the analyses. The association of these two mesothelioma cases with RCF exposure alone is unclear because of potential past exposure to asbestos.
Asunto(s)
Neoplasias Pulmonares , Mesotelioma , Neoplasias , Enfermedades Profesionales , Exposición Profesional , Cerámica , Estudios de Cohortes , Humanos , Neoplasias Pulmonares/mortalidad , Mesotelioma/mortalidad , Neoplasias/mortalidad , Enfermedades Profesionales/complicaciones , Enfermedades Profesionales/mortalidad , Exposición Profesional/efectos adversosRESUMEN
OBJECTIVE: We previously reported that children exposed to secondhand smoke (SHS) that carried variants in the NAT1 gene had over two-fold higher hair cotinine levels. Our objective was to determine if NAT1 polymorphisms confer increased risk for developing asthma in children exposed to SHS. METHODS: White participants in the Cincinnati Childhood Allergy and Air Pollution Study (n = 359) were genotyped for 10 NAT1 variants. Smoke exposure was defined by hair cotinine and parental report. Asthma was objectively assessed by spirometry and methacholine challenge. Findings were replicated in the Genomic Control Cohort (n = 638). RESULTS: Significant associations between 5 NAT1 variants and asthma were observed in the CCAAPS exposed group compared to none in the unexposed group. There was a significant interaction between NAT1 rs13253389 and rs4921581 with smoke exposure (p = 0.02, p = 0.01) and hair cotinine level (p = 0.048, p = 0.042). Children wildtype for rs4921581 had increasing asthma risk with increasing hair cotinine level, whereas those carrying the NAT1 minor allele had an increased risk of asthma regardless of cotinine level. In the GCC, 13 NAT1 variants were associated with asthma in the smoke-exposed group, compared to 0 in the unexposed group, demonstrating gene-level replication. CONCLUSIONS: Variation in the NAT1 gene modifies asthma risk in children exposed to secondhand-smoke. To our knowledge, this is the first report of a gene-environment interaction between NAT1 variants, smoke exposure, cotinine levels, and pediatric asthma. NAT1 genotype may have clinical utility as a biomarker of increased asthma risk in children exposed to smoke.
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Arilamina N-Acetiltransferasa/genética , Asma/epidemiología , Asma/genética , Cotinina/análisis , Isoenzimas/genética , Contaminación por Humo de Tabaco/análisis , Alelos , Niño , Preescolar , Exposición a Riesgos Ambientales , Femenino , Genotipo , Cabello/química , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple , Espirometría , Población BlancaRESUMEN
BACKGROUND: Asthma phenotypes are currently not amenable to primary prevention or early intervention because their natural history cannot be reliably predicted. Clinicians remain reliant on poorly predictive asthma outcome tools because of a lack of better alternatives. OBJECTIVE: We sought to develop a quantitative personalized tool to predict asthma development in young children. METHODS: Data from the Cincinnati Childhood Allergy and Air Pollution Study (n = 762) birth cohort were used to identify factors that predicted asthma development. The Pediatric Asthma Risk Score (PARS) was constructed by integrating demographic and clinical data. The sensitivity and specificity of PARS were compared with those of the Asthma Predictive Index (API) and replicated in the Isle of Wight birth cohort. RESULTS: PARS reliably predicted asthma development in the Cincinnati Childhood Allergy and Air Pollution Study (sensitivity = 0.68, specificity = 0.77). Although both the PARS and API predicted asthma in high-risk children, the PARS had improved ability to predict asthma in children with mild-to-moderate asthma risk. In addition to parental asthma, eczema, and wheezing apart from colds, variables that predicted asthma in the PARS included early wheezing (odds ratio [OR], 2.88; 95% CI, 1.52-5.37), sensitization to 2 or more food allergens and/or aeroallergens (OR, 2.44; 95% CI, 1.49-4.05), and African American race (OR, 2.04; 95% CI, 1.19-3.47). The PARS was replicated in the Isle of Wight birth cohort (sensitivity = 0.67, specificity = 0.79), demonstrating that it is a robust, valid, and generalizable asthma predictive tool. CONCLUSIONS: The PARS performed better than the API in children with mild-to-moderate asthma. This is significant because these children are the most common and most difficult to predict and might be the most amenable to prevention strategies.
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Asma/diagnóstico , Negro o Afroamericano , Hipersensibilidad a los Alimentos/epidemiología , Proyectos de Investigación , Asma/epidemiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Ruidos Respiratorios , Factores de Riesgo , Sensibilidad y Especificidad , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The "atopic march" has been considered a linear progression starting with eczema and culminating with development of asthma. Not all asthma cases, however, are preceded by eczema, and not all children with eczema go on to develop asthma. OBJECTIVE: The aim of this study was to explore the impact of allergic sensitization patterns on the association between early eczema and later childhood asthma. Given the numerous reported associations of the ciliary gene KIF3A with the atopic march, we also examined the impact of KIF3A risk allele rs12186803 on our analyses. METHODS: We studied 505 participants in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), a prospective birth cohort, with longitudinal eczema and asthma outcomes as well as prospective data regarding timing of sensitization to foods and aeroallergens. KIF3A genotypes were available on all children. RESULTS: Two high-risk groups were identified: one with and one without early eczema. The high-risk group with early eczema was more likely to be sensitized to food allergens, while the group without early eczema was more likely to be polysensitized to aeroallergens. The KIF3A rs12186803 risk allele interacted with food sensitization to increase asthma risk in children with eczema (P = 0.02). In children without eczema, asthma was associated with the interaction between rs12186803 and aeroallergen sensitization (P = 0.007). CONCLUSIONS & CLINICAL RELEVANCE: KIF3A interacted differentially with sensitization pattern to increase the risk of asthma in two high-risk groups of children with and without early eczema. Given the reported role of KIF3A in epithelial cell functioning, the results add evidence to the hypothesis that an impaired epithelial barrier is a key aspect in the development of allergic disease.
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Alelos , Asma/genética , Eccema/genética , Cinesinas/genética , Polimorfismo Genético , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Continuing use of analog film and digital chest radiography for screening and surveillance for pneumoconiosis and tuberculosis in lower and middle income countries raises questions of equivalence of disease detection. This study compared analog to digital images for intra-rater agreement across formats and prevalence of changes related to silicosis and tuberculosis among South African gold miners using the International Labour Organization classification system. METHODS: Miners with diverse radiological presentations of silicosis and tuberculosis were recruited. Digital and film chest images on each subject were classified by four expert readers. RESULTS: Readings of film and soft copy digital images showed no significant differences in prevalence of tuberculosis or silicosis, and intra-rater agreement across formats was fair to good. Hard copy images yielded higher prevalences. CONCLUSION: Film and digital soft copy images show consistent prevalence of findings, and generally fair to good intra-rater agreement for findings related to silicosis and tuberculosis.
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Pulmón/diagnóstico por imagen , Mineros , Intensificación de Imagen Radiográfica/métodos , Radiografía Torácica/métodos , Silicosis/diagnóstico por imagen , Tuberculosis Pulmonar/diagnóstico por imagen , Adulto , Infecciones por VIH/epidemiología , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Prevalencia , Silicosis/epidemiología , Sudáfrica/epidemiología , Tuberculosis Pulmonar/epidemiologíaRESUMEN
BACKGROUND: Allergic sensitization to fungi has been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. OBJECTIVE: We sought to determine the mechanism by which fungi affect asthma development and severity. METHODS: We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. RESULTS: We report that fungal exposure enhances allergen-driven TH2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with ß-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed TH2 and TH17 responses, including IL-13+IL-17+CD4+ double-producing effector T cells. Steroid resistance is dependent on fungus-induced TH17 responses because steroid sensitivity was restored in IL-17rc-/- mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A levels and asthma severity. CONCLUSION: Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Furthermore, our results provide a strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungus-exposed patients with difficult-to-treat asthma.
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Alérgenos/inmunología , Asma/inmunología , Hongos/inmunología , Células Th17/inmunología , Células Th2/inmunología , beta-Glucanos/inmunología , Contaminantes Atmosféricos/inmunología , Animales , Antiinflamatorios/uso terapéutico , Antígenos Dermatofagoides/inmunología , Asma/tratamiento farmacológico , Asma/epidemiología , Asma/patología , Niño , Preescolar , Dexametasona/uso terapéutico , Resistencia a Medicamentos/inmunología , Exposición a Riesgos Ambientales , Femenino , Glucocorticoides/uso terapéutico , Humanos , Lactante , Interleucina-17/sangre , Interleucina-17/inmunología , Lectinas Tipo C/genética , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Prevalencia , Receptores de Interleucina/genéticaRESUMEN
OBJECTIVES: Vermiculite ore containing Libby amphibole asbestos (LAA) was mined in Libby, MT, from the 1920s-1990. Recreational and residential areas in Libby were contaminated with LAA. This objective of this study was to characterize childhood exposure to LAA and investigate its association with respiratory health during young adulthood. METHODS: Young adults who resided in Libby prior to age 18 completed a health and activity questionnaire, pulmonary function testing, chest x-ray and HRCT scan. LAA exposure was estimated based on participant report of engaging in activities with potential LAA exposure. Quantitative LAA estimates for activities were derived from sampling data and literature reports. RESULTS: A total of 312 participants (mean age 25.1 years) were enrolled and reported respiratory symptoms in the past 12 months including pleuritic chest pain (23%), regular cough (17%), shortness of breath (18%), and wheezing or whistling in the chest (18%). Cumulative LAA exposure was significantly associated with shortness of breath (aOR = 1.12, 95% CI 1.01-1.25 per doubling of exposure). Engaging in recreational activities near Rainy Creek Road (near the former mine site) and the number of instances heating vermiculite ore to make it expand or pop were also significantly associated with respiratory symptoms. LAA exposure was not associated with pulmonary function or pleural or interstitial changes on either chest x-ray or HRCT. CONCLUSIONS: Pleural or interstitial changes on x-ray or HRCT were not observed among this cohort of young adults. However, childhood exposure to LAA was significantly associated with respiratory symptoms during young adulthood. Pleuritic chest pain, in particular, has been identified as an early symptom associated with LAA exposure and therefore warrants continued follow-up given findings of progressive disease in other LAA exposed populations.
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Asbestos Anfíboles/toxicidad , Exposición a Riesgos Ambientales , Pulmón/fisiopatología , Enfermedades Respiratorias/epidemiología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Pulmón/patología , Masculino , Minería , Montana/epidemiología , Pruebas de Función Respiratoria , Enfermedades Respiratorias/inducido químicamente , Adulto JovenRESUMEN
AIM: Report mortality (n = 1119), cancer incidence (n = 1207) and radiographic (n = 1451) findings from a 30-year investigation of current and former refractory ceramic fiber (RCF) workers. METHODS: Cause of death, health and work histories, radiographs and spirometry were collected. Mortality and cancer incidence were analyzed. Logistic regression analysis investigated the associations of latency and cumulative fiber exposure (CFE) on radiographic changes. RESULTS: The mortality study showed no increase in standardized mortality rates (SMR) for lung cancer, but urinary cancers were significantly elevated in the higher exposed group (SMR = 3.62, 95% CI: 1.33-7.88) and leukemia in the total cohort (SMR = 2.51, 95% CI: 1.08-4.94). One death attributed to mesothelioma was identified (SMR = 2.86, 95% CI: 0.07-15.93) in a worker reporting some asbestos exposure. The overall rate of pleural changes was 6.1%, attaining 21.4% in the highest CFE category for all subjects (adjusted odds ratio (aOR) = 6.9, 95% CI: 3.6-13.4), and 13.0% for those with no reported asbestos exposure (OR= 9.1, 95% CI: 2.5-33.6). Prevalence for recent hires (≥1985) was similar to the background. Interstitial changes were not elevated. Localized pleural thickening was associated with small decreases in spirometry results. CONCLUSION: Increases in leukemia and urinary cancer but not lung cancer mortality were found. One death attributed to mesothelioma was observed in a worker with self-reported asbestos exposure and a work history where occupational asbestos exposure may have occurred, rendering uncertainties in assigning causation. Radiographic analyses indicated RCF exposure alone is associated with increased pleural but not interstitial changes. Reductions in RCF exposure should continue. The mortality study is ongoing.
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Caolín/toxicidad , Fibras Minerales/toxicidad , Exposición Profesional , Enfermedades Respiratorias/etiología , Enfermedades Respiratorias/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/etiología , Oportunidad Relativa , Factores de Riesgo , Adulto JovenRESUMEN
RATIONALE: The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. OBJECTIVES: We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. METHODS: Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants' time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. MEASUREMENTS AND MAIN RESULTS: High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04-2.57 and aOR = 2.31; 95% CI, 1.28-4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01-2.88). CONCLUSIONS: Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development.
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Contaminantes Atmosféricos/efectos adversos , Contaminación del Aire/efectos adversos , Asma/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Ruidos Respiratorios/etiología , Emisiones de Vehículos , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood. OBJECTIVE: We sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children. METHODS: The effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes. RESULTS: DEP coexposure with HDM resulted in persistent TH2/TH17 CD127(+) effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased TH2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children. CONCLUSION: These findings suggest that DEP exposure results in accumulation of allergen-specific TH2/TH17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.
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Alérgenos/efectos adversos , Asma/inducido químicamente , Susceptibilidad a Enfermedades , Memoria Inmunológica , Material Particulado/efectos adversos , Animales , Animales Recién Nacidos , Asma/sangre , Asma/inmunología , Asma/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulina E/sangre , Lactante , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , Modelos Inmunológicos , Pyroglyphidae/química , Pyroglyphidae/inmunología , Bazo/inmunología , Bazo/patología , Células Th17/inmunología , Células Th17/patología , Células Th2/inmunología , Células Th2/patología , Emisiones de VehículosRESUMEN
BACKGROUND: Nasal eosinophils are a biomarker for allergic rhinitis (AR) and are associated with increased symptom severity. OBJECTIVE: To identify predictors of allergic eosinophilic rhinitis (AER) in early childhood in children at higher risk for chronic allergic respiratory disorders. METHODS: In the Cincinnati Childhood Allergy and Air Pollution Study, infants born to aeroallergen-sensitized and symptomatic parents were examined and underwent skin prick testing (SPT) annually to 15 aeroallergens from 1 to 4 years of age. Wheal circumferences were traced and scanned and areas were determined by computer planimetry. At 4 years, AER was defined as (1) at least 1 positive aeroallergen SPT result, (2) presence of sneezing and runny nose without a cold or influenza, and (3) nasal eosinophilia of at least 5%. Wheal areas at 1 to 3 years were analyzed for an association with AER compared with children without AR. RESULTS: At 4 years, 487 children completed rhinitis health histories, SPT, and nasal sampling. Ninety-nine children (22.8%) had AR. Thirty-eight children had AER (8.8% of total sample and 38.4% of AR sample, respectively). At 3 years, for every 1-mm(2) increase in Penicillium species (adjusted odds ratio 1.18, 95% confidence interval 1.06-1.32, P = .002) and maple (adjusted odds ratio 1.07, 95% confidence interval 1.01-1.13, P = .02), wheal area significantly increased the risk of AER at 4 years of age. CONCLUSION: Allergic eosinophilic rhinitis was identified in 8.8% of children at 4 years of age. Age 3 years was the earliest that aeroallergen SPT wheal areas were predictive of AER. Skin testing at 3 years identifies children at risk for an AR phenotype with nasal eosinophilia.
Asunto(s)
Acer/inmunología , Eosinofilia/inmunología , Penicillium/inmunología , Rinitis Alérgica Perenne/diagnóstico , Rinitis Alérgica Perenne/inmunología , Alérgenos/inmunología , Biomarcadores , Preescolar , Eosinófilos/inmunología , Femenino , Humanos , Masculino , Mucosa Nasal/inmunología , Estudios Prospectivos , Pruebas CutáneasRESUMEN
BACKGROUND: No large, prospective, epidemiologic study has investigated the association between diesel exhaust particle (DEP) exposure and early aeroallergen sensitization and allergic rhinitis (AR) at 4 years of age. OBJECTIVE: To determine how exposure to traffic exhaust during infancy is associated with aeroallergen sensitization and AR at 4 years of age and the predictive utility of the wheal area at 1 to 3 years of age on AR at 4 years of age. METHODS: Infants born to aeroallergen sensitized parents were evaluated annually with skin prick tests to 15 aeroallergens with measurement of wheal areas. At 4 years of age, AR was defined as at least one positive aeroallergen skin prick test result and the presence of sneezing and a runny nose without a cold or flu. Infant (DEP) exposure was estimated using data from 27 air sampling monitors and a land use regression model. RESULTS: Complete data were available for 634 children at 4 years of age. Prevalence of AR increased annually from 6.9% to 21.9%. A positive trend was observed for high DEP exposure and aeroallergen sensitization at 2 and 3 years of age (odds ratio, 1.40; 95% confidence interval, 0.97-2.0) and (odds ratio, 1.35; 95% confidence interval, 0.98-1.85) but not with AR. At 2 years of age, every 1-mm(2) increase in the wheal area of timothy and Alternaria significantly increased the odds of AR at 4 years of age. At 3 years of age, every 1-mm(2) increase in the wheal area of fescue, dog, and Penicillium significantly increased the odds of AR at 4 years of age. CONCLUSION: DEP exposure enhances the risk of early aeroallergen sensitization. Aeroallergen wheal area at 2 and 3 years of age is associated with AR at 4 years of age.
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Contaminantes Atmosféricos/inmunología , Contaminación del Aire/efectos adversos , Alérgenos/inmunología , Rinitis Alérgica/epidemiología , Emisiones de Vehículos/toxicidad , Contaminantes Atmosféricos/efectos adversos , Alternaria/inmunología , Preescolar , Femenino , Humanos , Lactante , Exposición por Inhalación , Masculino , Padres , Penicillium/inmunología , Estudios Prospectivos , Pruebas Cutáneas , Encuestas y CuestionariosRESUMEN
The United States Environmental Protection Agency (EPA) developed a quantitative exposure-response model for the non-cancer effects of Libby Amphibole Asbestos (LAA) (EPA, 2014). The model is based on the prevalence of localized pleural thickening (LPT) in workers exposed to LAA at a workplace in Marysville, Ohio (Lockey et al., 1984; Rohs et al., 2008). Recently, Lockey et al. (2015a) published a follow-up study of surviving Marysville workers. The data from this study increases the number of cases of LPT and extends the observation period for a number of workers, thereby providing a strengthened data set to define and constrain the optimal exposure-response model for non-cancer effects from inhalation exposure to LAA. The new data were combined with the previous data to update the exposure-response modeling for LPT. The results indicate that a bivariate model using cumulative exposure and time since first exposure is appropriate, and the benchmark concentration is similar to the findings previously reported by EPA (2014). In addition, the data were also used to develop initial exposure-response models for diffuse pleural thickening (DPT) and small interstitial opacities (SIO).
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Asbestos Anfíboles/efectos adversos , Exposición por Inhalación/efectos adversos , Enfermedades Pulmonares/inducido químicamente , Modelos Biológicos , Modelos Estadísticos , Enfermedades Profesionales/inducido químicamente , Exposición Profesional/efectos adversos , Salud Laboral , Pleura/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benchmarking , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Enfermedades Pulmonares/patología , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/patología , Ohio , Pleura/patología , Medición de Riesgo , Factores de Tiempo , Incertidumbre , Adulto JovenRESUMEN
BACKGROUND: Epithelial genes have previously been associated with asthma but only explain a small fraction of heritability. In part, this might be due to epistasis, which is often not considered. OBJECTIVE: We sought to determine independent and epistatic associations between filaggrin (FLG), serine protease inhibitor Kazal-type 5 (SPINK5), and thymic stromal lymphopoietin (TSLP) gene variants and childhood asthma. METHODS: Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5, and TSLP in asthmatic, allergic, and nonallergic nonasthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository. Associations with asthma were also assessed in 6 replication populations. RESULTS: We observed independent associations of variants in SPINK5 (P = .003) and TSLP (P = .006) with childhood asthma; a SPINK5 single nucleotide polymorphism was replicated. In subjects with 1 or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated with a significant increase in asthma (67% vs 53%, P = .0017). In contrast, the presence or absence of TSLP minor alleles did not affect asthma risk in subjects without the SPINK5 risk alleles. The SPINK5 and TSLP epistasis was replicated in a black population (P = .036) who did not display independent association with variants in these genes. CONCLUSIONS: Our results support epistasis between SPINK5 and TSLP, which contributes to childhood asthma. These findings emphasize the importance of using biology to inform analyses to identify genetic susceptibility to complex diseases. The results from our study have clinical relevance and support that the therapeutic effects of anti-TSLP therapy in asthmatic patients might be dependent on SPINK5 genotype.
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Asma/genética , Citocinas/genética , Epistasis Genética , Proteínas de Filamentos Intermediarios/genética , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Adolescente , Población Negra , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Proteínas Filagrina , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo Genético , Inhibidor de Serinpeptidasas Tipo Kazal-5 , Población Blanca , Linfopoyetina del Estroma TímicoAsunto(s)
Asma/etiología , Susceptibilidad a Enfermedades , Eccema/complicaciones , Variación Genética , Cinesinas/genética , Rinitis Alérgica/complicaciones , Factores de Edad , Niño , Eccema/genética , Estudios de Asociación Genética , Humanos , Desequilibrio de Ligamiento , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Rinitis Alérgica/genéticaRESUMEN
BACKGROUND: The specific cause or causes of asthma development must be identified to prevent this disease. OBJECTIVE: Our hypothesis was that specific mold exposures are associated with childhood asthma development. METHODS: Infants were identified from birth certificates. Dust samples were collected from 289 homes when the infants were 8 months of age. Samples were analyzed for concentrations of 36 molds that comprise the Environmental Relative Moldiness Index (ERMI) and endotoxin, house dust mite, cat, dog, and cockroach allergens. Children were evaluated at age 7 years for asthma based on reported symptoms and objective measures of lung function. Host, environmental exposure, and home characteristics evaluated included a history of parental asthma, race, sex, upper and lower respiratory tract symptoms, season of birth, family income, cigarette smoke exposure, air conditioning, use of a dehumidifier, presence of carpeting, age of home, and visible mold at age 1 year and child's positive skin prick test response to aeroallergens and molds at age 7 years. RESULTS: Asthma was diagnosed in 24% of the children at age 7 years. A statistically significant increase in asthma risk at age 7 years was associated with high ERMI values in the child's home in infancy (adjusted relative risk for a 10-unit increase in ERMI value, 1.8; 95% CI, 1.5-2.2). The summation of levels of 3 mold species, Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile, was significantly associated with asthma (adjusted relative risk, 2.2; 95% CI, 1.8-2.7). CONCLUSION: In this birth cohort study exposure during infancy to 3 mold species common to water-damaged buildings was associated with childhood asthma at age 7 years.
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Asma/etiología , Hongos/inmunología , Niño , Estudios de Cohortes , Exposición a Riesgos Ambientales , Humanos , LactanteRESUMEN
Secondhand smoke is associated with a myriad of adverse health outcomes. Therefore, it is essential for clinicians to ask precise questions about exposures, particularly for children. We present 4 questions that incorporate several locations of exposure and provide a more comprehensive account of children's smoke exposures than maternal smoking alone.
Asunto(s)
Efectos Tardíos de la Exposición Prenatal/epidemiología , Encuestas y Cuestionarios/normas , Contaminación por Humo de Tabaco/efectos adversos , Preescolar , Cotinina/análisis , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Ontario/epidemiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Pronóstico , Radioinmunoensayo , Factores Socioeconómicos , Factores de TiempoRESUMEN
BACKGROUND: Contradictory findings on the differential effects of second-hand smoke (SHS) on lung function in girls and boys may result from masked relationships between host and environmental factors. Allergic sensitization may augment the relationship between SHS and decreased lung function, although its role in relation to the inconsistent gender differences in children has not been elucidated. HYPOTHESIS: We hypothesize that there will be differences between boys and girls related to early-life allergic sensitization and exposure to SHS on pulmonary function later in childhood. METHODS: Participants in this study (n = 486) were drawn from the Cincinnati Childhood Allergy and Air Pollution (CCAAPS) birth cohort study consisting of 46% girls. Allergic sensitization was assessed by skin prick test (SPT) to 15 aeroallergens at ages 2, 4, and 7, while pulmonary function and asthma diagnosis occurred at age 7. SHS exposure was measured by hair cotinine at ages 2 and/or 4. Gender differences of SHS exposure on pulmonary function among children with positive SPTs at ages 2, 4, and 7 as well as first- and higher-order interactions were examined by multiple linear regression. Interactions significant in the multivariate models were also examined via stratification. Comparisons within and between stratified groups were assessed by examining the slope of the parameter estimates/beta coefficients and associated p-values and confidence intervals. RESULTS: Increased cotinine levels were significantly associated with decreases in FEV(1) (-0.03 l, p < 0.05), peak expiratory flow (-0.07 l/s, p < 0.05), and FEF (25-75%) (-0.06 l/s, p < 0.01). The interaction between cotinine and sensitization at age 2 was borderline significant (p = 0.10) in the FEF(25-75%) model and showed an exposure response effect according to the number of positive SPTs at age 2; zero (-0.06 l/s, p < 0.01), one (-0.09 l/s, p < 0.05), or two or more positive SPTs (-0.30 l/s, p < 0.01). Despite increased polysensitization among boys, the association between cotinine and FEF(25-75%) among girls, with two or more positive SPTs at age 2, showed the greatest deficits in FEF(25-75%) (-0.34 l/s vs. -0.05 l/s and -0.06 l/s for non-sensitized girls and boys, respectively. Girls with two or more positive SPTs showed a twofold greater decrease in FEF(25-5%) (-0.34 l/s; 95% CI: -0.55, -0.13) compared to boys with the same degree of allergic sensitization (-0.18 l/s; 95% CI: -0.41, 0.06), although this difference was not statistically significant. CONCLUSIONS: Reductions in lung function were observed among children exposed to SHS, and the number of aeroallergen-positive SPTs at age 2 modifies this relationship. Girls experiencing early childhood allergic sensitization and high SHS exposure are at greater risk of decreased lung function later in childhood compared to non-sensitized girls and boys and demonstrate greater deficits compared to boys with similar degrees of sensitization.