Chlorinated pool attendance, airway epithelium defects and the risks of allergic diseases in adolescents: Interrelationships revealed by circulating biomarkers.

It has been suggested that allergic diseases might be epithelial disorders driven by various environmental stressors but the epidemiological evidence supporting this concept is limited. In a cross-sectional study of 835 school adolescents (365 boys; mean age, 15.5 yr), we measured the serum concentrations of Club cell protein (CC16), surfactant-associated protein D (SP-D) and of total and aeroallergen-specific IgE. We used the serum CC16/SP-D concentration ratio as an index integrating changes in the permeability (SP-D) and secretory function (CC16) of the airway epithelium. In both sexes, early swimming in chlorinated pools emerged as the most consistent and strongest predictor of low CC16 and CC16/SP-D ratio in serum. Among girls, a low CC16/SP-D ratio was associated with increased odds (lowest vs. highest tertile) for pet sensitization (OR 2.97, 95% CI 1.19-8.22) and for hay fever in subjects sensitized to pollen (OR 4.12, 95% CI 1.28-14.4). Among boys, a low CC16/SP-D ratio was associated with increased odds for house-dust mite (HDM) sensitization (OR 2.01, 95% CI 1.11-3.73), for allergic rhinitis in subjects sensitized to HDM (OR 3.52, 95% CI 1.22-11.1) and for asthma in subjects sensitized to any aeroallergen (OR 3.38, 95% CI 1.17-11.0), HDM (OR 5.20, 95% CI 1.40-24.2) or pollen (OR 5.82, 95% CI 1.51-27.4). Odds for allergic sensitization or rhinitis also increased with increasing SP-D or decreasing CC16 in serum. Our findings support the hypothesis linking the development of allergic diseases to epithelial barrier defects due to host factors or environmental stressors such as early swimming in chlorinated pools.

Nasal epithelium integrity, environmental stressors, and allergic sensitization: a biomarker study in adolescents.

Changes in the airways epithelium caused by environmental insults might play a role in the development of allergic rhinitis. We measured albumin and Clara cell protein (CC16) in the nasal lavage fluid (NALF) from 474 adolescents (263 girls and 211 boys). The NALF CC16/albumin ratio, integrating the permeability and cellular integrity of the nasal epithelium, decreased mostly with time spent in chlorinated pools. In boys, a lower CC16/albumin ratio in NALF was associated with an increased risk of house dust mite sensitization. The results suggest that the CC16/albumin ratio in NALF can be used to detect nasal epithelium alterations linked to allergic sensitization.

Associations between proteins and heavy metals in urine at low environmental exposures: evidence of reverse causality.

Heavy metals can cause renal effects on vulnerable populations but it is uncertain whether these metals still pose health risks at the low exposure levels now prevailing in most industrialized countries. In a cross-sectional study performed on 736 adolescents, we assessed the associations between the concentrations of cadmium and lead in blood and urine and the urinary concentrations of albumin and of low-molecular-weight (LMW) proteins, retinol-binding protein (RBP) and ß(2)-microglobulin. Multiple regression analyses were tested using urinary markers normalized to urinary creatinine or specific gravity. Median metal concentrations were in blood (µg/L): lead, 15.1, cadmium, 0.18 and in urine (µg/g creatinine): cadmium, 0.09 and lead, 0.82. Multivariate analyses revealed significant associations in urine between RBP and cadmium as well as between ß(2)-microglobulin and lead whereas no associations were seen with metals in blood. These associations were completely abolished in subjects with increased urinary albumin, which may be explained by the competitive inhibition of LMW protein reabsorption by albumin. Given the evidence that cadmium and lead circulate mainly bound to LMW proteins, these associations observed at low exposure might simply reflect the interindividual variations in the renal uptake of proteins sharing the same affinity for tubular binding sites.

Respiratory effects associated with wood fuel use: a cross-sectional biomarker study among adolescents.

The use of wood as heating and cooking fuel can result in elevated levels of indoor air pollution, but to what extent this is related to respiratory diseases and allergies is still inconclusive. Here, we report a cross-sectional study among 744 school adolescents (median age 15 years) using as main outcomes respiratory symptoms and diseases, exhaled nitric oxide, total and aeroallergen-specific IgE in serum, and two epithelial biomarkers in nasal lavage fluid (NALF) or serum, that is, Clara cell protein (CC16) and surfactant-associated protein D (SPD). Information about the wood fuel use and potential confounders was collected via a personal interview of the adolescent and a questionnaire filled out by the parents. Two approaches were used to limit the possible influence of confounders, that is, multivariate analysis using the complete study population or pairwise analysis of matched sub-populations obtained using an automated procedure. Wood fuel use was associated with a decrease of CC16 and an increase of SPD in serum, which resulted in a decreased serum CC16/SPD ratio (median -9%, P = 0.001). No consistent differences were observed for the biomarkers measured in exhaled breath or NALF. Wood fuel use was also associated with increased odds for asthma [odds ratio (OR) 2.2, 95% CI: 1.1-4.4, P = 0.02], hay fever (OR = 2.4, 95% CI: 1.4-4.3, P = 0.002), and sensitization against pollen allergens (OR = 2.1, 95% CI: 1.3-3.4, P = 0.002). The risks of respiratory tract infections, self-reported symptoms, and sensitization against house-dust mite were not increased by wood fuel use. The increased risks of asthma, hay fever and aeroallergen sensitization, and the changes of lung-specific biomarkers consistently pointed towards respiratory effects associated with the use of wood fuel.

Impact of chlorinated swimming pool attendance on the respiratory health of adolescents.

OBJECTIVE: The goal was to estimate the burden of allergic diseases associated with chlorinated pool exposure among adolescents. METHODS: We examined 847 students, 13 to 18 years of age, who had attended outdoor or indoor chlorinated pools at various rates. Of them, 114 had attended mainly a copper-silver pool and served as a reference group. We measured total and aeroallergen-specific immunoglobulin E (IgE) levels in serum and screened for exercise-induced bronchoconstriction. Outcomes were respiratory symptoms, hay fever, allergic rhinitis, and asthma that had been diagnosed at any time (ever asthma) or was being treated with medication and/or was associated with exercise-induced bronchoconstriction (current asthma). RESULTS: Among adolescents with atopy with serum IgE levels of>30 kIU/L or aeroallergen-specific IgE, the odds ratios (ORs) for asthma symptoms and for ever or current asthma increased with the lifetime number of hours spent in chlorinated pools, reaching values of 7.1 to 14.9 when chlorinated pool attendance exceeded 1000 hours. Adolescents with atopy with chlorinated pool attendance of >100 hours had greater risk of hay fever (OR: 3.3-6.6), and those with attendance of >1000 hours had greater risk of allergic rhinitis (OR: 2.2-3.5). Such associations were not found among adolescents without atopy or with copper-silver pool attendance. The population attributable risks for chlorinated pool-related ever-diagnosed asthma, hay fever, and allergic rhinitis were 63.4%, 62.1%, and 35.0%, respectively. CONCLUSION: Chlorinated pool exposure exerts an adjuvant effect on atopy that seems to contribute significantly to the burden of asthma and respiratory allergies among adolescents.

Applicability of non-invasively collected matrices for human biomonitoring.

With its inclusion under Action 3 in the Environment and Health Action Plan 2004-2010 of the European Commission, human biomonitoring is currently receiving an increasing amount of attention from the scientific community as a tool to better quantify human exposure to, and health effects of, environmental stressors. Despite the policy support, however, there are still several issues that restrict the routine application of human biomonitoring data in environmental health impact assessment. One of the main issues is the obvious need to routinely collect human samples for large-scale surveys. Particularly the collection of invasive samples from susceptible populations may suffer from ethical and practical limitations. Children, pregnant women, elderly, or chronically-ill people are among those that would benefit the most from non-invasive, repeated or routine sampling. Therefore, the use of non-invasively collected matrices for human biomonitoring should be promoted as an ethically appropriate, cost-efficient and toxicologically relevant alternative for many biomarkers that are currently determined in invasively collected matrices. This review illustrates that several non-invasively collected matrices are widely used that can be an valuable addition to, or alternative for, invasively collected matrices such as peripheral blood sampling. Moreover, a well-informed choice of matrix can provide an added value for human biomonitoring, as different non-invasively collected matrices can offer opportunities to study additional aspects of exposure to and effects from environmental contaminants, such as repeated sampling, historical overview of exposure, mother-child transfer of substances, or monitoring of substances with short biological half-lives.

Infant swimming practice, pulmonary epithelium integrity, and the risk of allergic and respiratory diseases later in childhood.

OBJECTIVE: Irritant gases and aerosols contaminating the air of indoor swimming pools can affect the lung epithelium and increase asthma risk in children. We evaluated the impact of infant swimming practice on allergic status and respiratory health later in childhood. METHODS: Clara cell protein, surfactant-associated protein D, and total and aeroallergen-specific immunoglobulin E were measured in the serum of 341 schoolchildren aged 10 to 13 years, among whom 43 had followed an infant swimming program. Asthma was defined as doctor-diagnosed asthma and/or positive exercise-induced bronchoconstriction (15% decrease in postexercise forced expiratory volume). RESULTS: There were no significant differences between the infant swimming group and the other children regarding the levels of exhaled nitric oxide and total or aeroallergen-specific serum immunoglobulin E. Children who swam as infants showed, by contrast, a significant decrease of serum Clara cell protein and of the serum Clara cell protein/surfactant-associated protein D ratio integrating Clara cell damage and permeability changes of the lung epithelial barrier. These effects were associated with higher risks of asthma and of recurrent bronchitis. Passive exposure to tobacco alone had no effect on these outcomes but seemed to interact with infant swimming practice to increase the risk of asthma or of recurrent bronchitis. CONCLUSIONS: Our data suggest that infant swimming practice in chlorinated indoor swimming pools is associated with airways changes that, along with other factors, seem to predispose children to the development of asthma and recurrent bronchitis.

Increase of exhaled nitric oxide in children exposed to low levels of ambient ozone.

Ozone (O3) is known to induce lung function impairment and airways inflammation during episodes of photochemical smog. The aim of the present study was to assess the inflammatory effect of ambient O3 in healthy children using nitric oxide in exhaled air (eNO) as a noninvasive test. The study was performed on 6 groups of children (n = 11-15), aged 6.5 to 15 yr, who attended summer camps in rural areas of the south of Belgium in 2002. Ambient O3 concentrations continuously monitored in the camps ranged from 48 to 221 microg/m3 (1-h maximal concentration). Children remained outdoors during the experimental days, doing various recreational activities but no sports. Lung function tests (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) and eNO were measured twice in each child in the morning and in the evening. While lung function tests did not show any consistent pattern of decrease at these O3 levels, a highly significant increase in eNO was found in all subjects from an ambient 1-h O3 level of 167 microg/m3. A multivariate analysis did not reveal any influence of age, gender, height, weight, and body mass index (BMI) of the children. The threshold for this O3-induced increase in eNO estimated benchmark dose analysis was 135 microg/m3 for 1-h exposure and 110 microg/m3 for 8-h exposure. These observations suggest that ambient ozone produces early inflammatory changes in the airways of children at levels slightly below current air quality standards.

House cleaning with chlorine bleach and the risks of allergic and respiratory diseases in children.

Chlorine bleach or sodium hypochlorite can inactivate common indoor allergens. In this cross-sectional study we evaluated to what extent regular house cleaning with bleach can influence the risks of respiratory and allergic diseases in children. We studied a group of 234 schoolchildren aged 10-13 yr among whom 78 children were living in a house cleaned with bleach at least once per week. Children examination included a questionnaire, an exercise-induced bronchoconstriction test and the measurement of exhaled nitric oxide (NO) and of serum total and aeroallergen-specific immunoglobulin (Ig)E, Clara cell protein (CC16) and surfactant-associated protein D (SP-D). Children living in a house regularly cleaned with bleach were less likely to have asthma (OR, 0.10; CI, 0.02-0.51), eczema (OR, 0.22; CI, 0.06-0.79) and of being sensitized to indoor aeroallergens (OR, 0.53; CI, 0.27-1.02), especially house dust mite (OR, 0.43; CI, 0.19-0.99). These protective effects were independent of gender, ethnicity, previous respiratory infections, total serum IgE level and of family history of allergic diseases. They were however abolished by parental smoking, which also interacted with the use of bleach to increase the risk of recurrent bronchitis (OR, 2.03; CI, 1.12-3.66). House cleaning with bleach had effect neither on the sensitization to pollen allergens, nor on the levels of exhaled NO and of serum CC16 and SP-D. House cleaning with chlorine bleach appears to protect children from the risks of asthma and of sensitization to indoor allergens while increasing the risk of recurrent bronchitis through apparently an interaction with parental smoking. As chlorine bleach is one of the most effective cleaning agent to be found, these observations argue against the idea conveyed by the hygiene hypothesis that cleanliness per se increases the risk of asthma and allergy.

Chlorinated pool attendance, atopy, and the risk of asthma during childhood.

The pool chlorine hypothesis postulates that the rise in childhood asthma in the developed world could result at least partly from the increasing exposure of children to toxic gases and aerosols contaminating the air of indoor chlorinated pools. To further assess this hypothesis, we explored the relationships between childhood asthma, atopy, and cumulated pool attendance (CPA). We studied 341 schoolchildren 10-13 years of age who attended at a variable rate the same public pool in Brussels (trichloramine in air, 0.3-0.5 mg/m3). Examination of the children included a questionnaire, an exercise-induced bronchoconstriction (EIB) test, and the measurement of exhaled nitric oxide (eNO) and total and aeroallergen-specific serum IgE. CPA by children (range, 0-1,818 hr) emerged among the most consistent predictors of asthma (doctor diagnosed or screened with the EIB test) and of elevated eNO, ranking immediately after atopy and family history of asthma or hay fever. Although the risk of elevated eNO increased with CPA [odds ratio (OR) = 1.30; 95% confidence interval (CI), 1.10-1.43] independently of total or specific serum IgE, the probability of developing asthma increased with CPA only in children with serum IgE > 100 kIU/L (OR for each 100-hr increase in CPA = 1.79; 95% CI, 1.07-2.72). All these effects were dose related and most strongly linked to pool attendance before 6-7 years of age. Use of indoor chlorinated pools especially by young children interacts with atopic status to promote the development of childhood asthma. These findings further support the hypothesis implicating pool chlorine in the rise of childhood asthma in industrialized countries.

Outcome value of Clara cell protein in serum of patients with acute respiratory distress syndrome.

OBJECTIVE: Injury to the alveolocapillary barrier characterizes ALI/ARDS; therefore determining levels of lung epithelium-specific small proteins in serum may help predict clinical outcomes. We examined whether serum Clara cell protein (CC-16) concentration is correlated with the outcome, mechanical ventilation duration, and incidence of nonpulmonary organ failure. DESIGN: Prospective multicenter observational study conducted by the Quebec Critical Care Network. MEASUREMENTS: Seventy-eight adult ARDS patients requiring mechanical ventilation were enrolled and 28-day mortality was the primary outcome. Ventilatory parameters were computed and blood was sampled daily. Clinical information collected included cause of death, duration of mechanical ventilation, number of ventilator-free days, and organ failures. RESULTS: Median serum levels of CC-16 were significantly higher in nonsurvivors than survivors on days 0-2 (19.93 microg/l, IQR 11.8-44.32, vs. 8.9, 5.66-26.38) and sustained up to day 14. CC-16 levels were correlated positively with the number of failing organs (rho 0.3623) and requirement for prolonged mechanical ventilation. Predictors of patient mortality included age, arterial carbon dioxide partial pressure, CC-16, and APACHE II score (odds ratios 1.35, 1.52, 1.37, 1.159, respectively). CONCLUSIONS: Higher initial CC-16 serum level is associated with increased risk of death, fewer ventilator-free days, and increased frequency of nonpulmonary multiple organ failure. CC-16 is a valuable biomarker of ARDS that may help predict outcome among ARDS patients with high-risk mortality.

Non-invasive biomarkers of pulmonary damage and inflammation: Application to children exposed to ozone and trichloramine.

To date, airways injury or inflammation caused by air pollutants has been evaluated mainly by analysis of bronchoalveolar lavage, an invasive technique totally unsuitable to children. The assessment of respiratory risks in this particularly vulnerable population has thus for a long time relied on spirometric tests and self-reported symptoms which are relatively late and inaccurate indicators of lung damage. Research in the field of biomarkers is now opening new perspectives with the development of non-invasive tests allowing to monitor inflammation and damage in the deep lung. Blood tests measuring lung-specific proteins (pneumoproteins) such as Clara cell protein (CC16) and surfactant-associated proteins (A, B or D) are now available to evaluate the permeability and/or the cellular integrity of the pulmonary epithelium. The application of these tests to children has recently led to the discovery of a lung epithelium hyperpermeability caused by trichloramine (nitrogen trichloride), an irritant gas contaminating the air of indoor-chlorinated pools. Serum CC16 can also serve to detect increases of airway permeability during short-term exposures to ambient ozone. Indicators measurable in exhaled air such as nitric oxide (NO) appear more useful to detect airway inflammation. By applying the exhaled NO test to children attending summer camps, we recently found that ambient ozone produces an acute inflammatory response in children from levels slightly lower than current air quality guidelines. In a study exploring the links between atopy, asthma, and exposure to chlorination products in indoor pools, we also found that the exhaled NO test can serve to detect the chronic airway inflammation associated with excessive exposure to trichloramine. Lung-specific proteins measurable in serum and markers in exhaled air represent sensitive tools that can be used to assess non-invasively the effects of air pollutants on the respiratory tract of children.