Mario Barreto

8-Isoprostane in exhaled breath condensate and exercise-induced bronchoconstriction in asthmatic children and adolescents.

BACKGROUND Exercise-induced bronchoconstriction (EIB) in the asthmatic child is associated with persistent airway inflammation and poor disease control. EIB could arise partly from airway oxidative stress. Exhaled breath condensate (EBC) levels of 8-isoprostane (IsoP), which is a known marker of oxidative stress, might therefore be helpful for monitoring asthma noninvasively. METHODS We recruited 46 asthmatic children and adolescents 6 to 17 years of age (29 boys), all of whom underwent lung function testing, measurement of the fractional concentration of exhaled nitric oxide (FENO), and collection of EBCs for 8-IsoP measurement before and after exercise challenge. FENO was measured before exercise and 5 min and 20 min after exercise. Spirometry was repeated 1, 5, 10, 15, and 20 min after exercise. RESULTS Baseline 8-IsoP levels (but not baseline FENO levels) correlated with the fall in FEV(1) 5 min after exercise (r = - 0.47; p = 0.002). 8-IsoP levels measured after exercise remained unchanged from baseline levels; conversely, FENO levels decreased in parallel with the decline in FEV(1) at 5 min (r = 0.44; p = 0.002). The mean baseline 8-IsoP concentrations were higher in patients with EIB (n = 12) than in those without EIB (n = 34; 44.9 pg/mL [95% confidence interval (CI), 38.3 to 51.5] vs 32.3 pg/mL [95% CI, 27.6 to 37.0], respectively; p < 0.01). No difference was found in the mean baseline FENO between groups (with EIB group: 38.7 ppb; 95% CI, 24.5 to 61.1; without EIB group: 29.1 ppb; 95% CI, 22.0 to 38.4). CONCLUSIONS Increased 8-IsoP concentrations in EBC samples of asthmatic children and adolescents with EIB suggest a role for oxidative stress in bronchial hyperreactivity.

Exhaled nitric oxide in asthmatic and non-asthmatic children: Influence of type of allergen sensitization and exposure to tobacco smoke

Asthmatic bronchial inflammation is associated with increased nitric oxide concentrations in exhaled air (eNO). Recent data suggest that this effect arises from atopy. Our aim in this study was to find out whether atopy and sensitization to particular allergens influences eNO levels. A total of 213 subjects (41 asthmatics and 172 controls) (96 boys and 117 girls, 7.3–14 years of age) were studied. Parents completed a questionnaire that sought information on their childrens respiratory symptoms and exposure to tobacco smoke. Subjects underwent skin‐prick tests for the following common allergens: Dermatophagoides pteronyssinus (Dpt), cat fur, Aspergillus fumigatus, Alternaria tenuis, mixed grass, mixed tree pollen, Parietaria officinalis, egg, and cows milk. eNO was collected in 1‐l mylar bags (exhaled pressure 10 cmH2O, flow 58 ml/s) and analyzed by using chemiluminescence. Atopic and non‐atopic children without a history of chronic respiratory symptoms had a similar geometric mean eNO (atopics, n = 28, 11.2 p.p.b.; non‐atopics, n = 96, 10.0 p.p.b.; mean ratio 1.1, 95% confidence interval [CI]: 0.7–1.6). Conversely, atopic asthmatic subjects had significantly higher eNO values than non‐atopic asthmatic subjects (atopics, n = 25, 24.8 p.p.b.; non‐atopics, n = 16, 11.4 p.p.b.; mean ratio 2.2, 95% CI: 1.2–3.9, p= 0.000). In children with rhinitis alone (n = 15) and those with lower respiratory symptoms other than asthma (n = 33), eNO increased slightly, but not significantly, with atopy. eNO levels correlated significantly with Dpt wheal size (r = 0.51) as well with the wheal size for cat, mixed grass, and Parietaria officinalis (r = 0.30–0.29), and with the sum of all wheals (r = 0.47) (p= 0.000). Subjects sensitized only for Dpt (but not those subjects sensitized only for grass pollen or other allergens) showed significantly higher eNO levels than non‐atopic subjects (16.4 p.p.b. vs. 10.2 p.p.b., mean ratio 1.6, 95% CI: 1.1–2.3, p= 0.002). In asthmatic subjects, Dpt sensitization markedly increased eNO levels (Dpt‐sensitized subjects: 28.0 p.p.b.; Dpt‐unsensitized subjects: 12.2 p.p.b.; mean ratio 2.3, 95% CI: 1.5–3.5, p= 0.000). Non‐asthmatic Dpt‐sensitized subjects also had significantly higher eNO values than non‐asthmatic, non‐Dpt‐sensitized subjects (14.2 p.p.b. vs. 10.1 p.p.b.; mean ratio 1.4, 95% CI: 1.1–1.9, p= 0.008). No difference was found between eNO levels in asthmatic subjects and control subjects exposed or unexposed to tobacco smoke. In conclusion, eNO concentrations are high in atopic asthmatic children and particularly high in atopic asthmatics who are sensitized to house‐dust mite allergen.

Additive effect of eosinophilia and atopy on exhaled nitric oxide levels in children with or without a history of respiratory symptoms.

Although atopy and blood eosinophilia both influence exhaled nitric oxide (eNO) measurements, no study has quantified their single or combined effect. We assessed the combined effect of atopy and blood eosinophilia on eNO in unselected schoolchildren. In 356 schoolchildren (boys/girls: 168/188) aged 9.0–11.5 yr, we determined eNO, total serum IgE, blood eosinophil counts and did skin prick tests (SPT) and spirometry. Parents completed a questionnaire on their childrens current or past respiratory symptoms. Atopy was defined by a SPT > 3 mm and eosinophilia by a blood cell count above the 80th percentile (>310 cells/ml). eNO levels were about twofold higher in atopic–eosinophilic subjects than in atopic subjects with low blood eosinophils [24.3 p.p.b. (parts per billion) vs. 14.1 p.p.b.] and than non‐atopic subjects with high or low blood eosinophils (24.3 p.p.b. vs. 12.2 p.p.b. and 10.9 p.p.b.) (p < 0.001 for both comparisons). The additive effect of atopy and high eosinophil count on eNO levels remained unchanged when subjects were analyzed separately by sex or by a positive history of wheeze (n = 60), respiratory symptoms other than wheeze (n = 107) or without respiratory symptoms (n = 189). The frequency of sensitization to Dermatophagoides (Dpt or Dpf) was similar in atopic children with and without eosinophilia (66.2% and 67.4%, respectively); eosinophilia significantly increased eNO levels in Dp‐sensitized children as well in children sensitized to other allergens. In a multiple linear regression analysis, eNO levels were mainly explained by the sum of positive SPT wheals and a high blood eosinophil count (t = 4.8 and 4.3, p = 0.000), but also by the presence of respiratory symptoms (especially wheeze) and male sex (t = 2.6 and 2.0, p = 0.009 and 0.045, respectively). Measuring eNO could be a simple, non‐invasive method for identifying subjects at risk of asthma in unselected school populations.

Lead neurotoxicity in children: is prenatal exposure more important than postnatal exposure?

Numerous studies indicate that low‐level lead poisoning causes mild mental retardation and low IQ scores in children. The general mean lead intake in the adult European population corresponds to a reassuring 14% (0.5–56%) of the tolerable daily intake: at this low level of exposure only few children (less than 10%) have blood lead levels (PbB) higher than 10μg/dl, previously considered the PbB of concern. In more recent years data now suggest that even when ‘the lifetime average blood lead concentration’ is below 10μg/dl an inverse association exists with intelligence quotient (IQ) scores. Two‐thirds (45–75%) of lead in blood, however, comes from long‐term tissue stores and this is especially true for newborn infants and pregnant women. Several data suggest that for lead the main toxic event is prenatal exposure: therefore we should focus our attention on maternal lead stores and whenever possible avoid their mobilization during pregnancy. In this regard we should design appropriate studies to confirm whether dietary supplementations can reduce bone resorption and lead mobilization during pregnancy. The hypothesis that the amount of maternal bone lead stores is the relevant parameter for predicting the level of neurotoxicity of this metal gives some optimism for the future: if we study children whose mothers never underwent high environmental pollution (born after the withdrawal of lead from gasoline) and hence have relatively low bone lead stores we could find that, at the population level, lead has little influence on children IQ scores

Skin reactivity to histamine and to allergens in unselected 9-year-old children living in Poland and Italy

Several studies have shown a higher prevalence of positive skin‐prick tests to airborne allergens in Western than in Eastern European countries. We have recently reported that skin histamine reactivity significantly increased in Italy over the past 15 years. Population differences in skin histamine reactivity could, at least in part, explain the reported differences in positive allergen skin tests. To test this hypothesis we compared histamine skin reactivity and the prevalence of allergen positive skin‐prick tests in a sample of Italian and Polish schoolchildren. A total of 336 unselected 9‐year‐old‐schoolchildren (198 in Italy and 138 in Poland) underwent skin‐prick tests with three different histamine concentrations (10, 1 and 0.2 mg/ml) and with a panel of common airborne allergens according to the ISAAC protocol, phase two. Mean wheals elicited by skin‐prick tests with the three serial concentrations of histamine were significantly larger (p < 0.001) and shifted more toward higher values (p < 0.001) in Italian than in Polish children. The differences were greater for the intermediate histamine concentration tested (1 mg/ml) than for the highest concentration (10 mg/ml). Skin‐prick tests for airborne allergens were more frequently positive in Italian children: wheals ≥ 3 mm induced by any allergen [odds ratio (OR) 1.69; confidence interval (CI) 0.98–2.92] by Dermatophagoides pteronyssinus (OR 1.92; CI 0.97–3.80) and by D. farinae (OR 3.15; CI 1.16–8.63). Labeling as positive allergen wheal reactions half the size of the 10 mg/ml histamine wheal or larger reduced but did not abolish the Italian–Polish differences. The significantly higher skin histamine reactivity observed in Italian children could help to explain why allergen skin‐test reactions differ in the East and West European populations. Moreover, differences in nonallergen‐specific factors among populations should be considered in the interpretation of skin test results (e.g. cut‐off points). To obtain meaningful results, epidemiological studies of allergies should include serial histamine dilutions.

Factors attributable to the level of exhaled nitric oxide in asthmatic children.

BackgroundAsthma is a heterogeneous disease with variable symptoms especially in children. Exhaled nitric oxide (FeNO) has proved to be a marker of inflammation in the airways and has become a substantial part of clinical management of asthmatic children due to its potential to predict possible exacerbation and adjust the dose of inhalant corticosteroids.ObjectivesWe analyzed potential factors that contribute to the variability of nitric oxide in various clinical and laboratory conditions.Materials and methodsStudy population consisted of 222 asthmatic children and 27 healthy control subjects. All children underwent a panel of tests: fractioned exhaled nitric oxide, exhaled carbon monoxide, asthma control test scoring, blood sampling, skin prick tests, and basic spirometry.ResultsFeNO and other investigated parameters widely changed according to clinical or laboratory characteristics of the tested children. Asthmatics showed increased levels of FeNO, exhaled carbon monoxide, total serum IgE, and higher eosinophilia. Boys had higher FeNO levels than girls. We found a significant positive correlation between FeNO levels and the percentage of blood eosinophils, %predicted of forced vital capacity, total serum IgE levels, and increasing age.ConclusionsVarious phenotypes of childrens asthma are characterized by specific pattern of the results of clinical and laboratory tests. FeNO correlates with total serum IgE, blood eosinophilia, age, and some spirometric parameters with different strength. Therefore, the coexistence of atopy, concomitant allergic rhinitis/rhinoconjunctivitis, and some other parameters should be considered in critical evaluation of FeNO in the management of asthmatic children.

Association of asthma with extra-respiratory symptoms in schoolchildren: Two cross-sectional studies 6 years apart

Epidemiological information on symptoms affecting extra‐respiratory organs and apparatuses in asthmatic children is scarce. The aim of this study therefore was to evaluate, at a population level, if and what extra‐respiratory symptoms are associated with asthma. Two questionnaire‐based, cross‐sectional surveys were carried out on 1,262 students (651 males; mean age 9.57 years, age‐range 6–14 years) in 1992 and on 1,210 students (639 males; mean age 9.02 years, age‐range 6–14 years) in 1998, from two elementary and two junior high schools in Rome, Italy. Questionnaires included queries about asthma and its risk factors and extra‐respiratory symptoms (headache, restlessness, sleep disturbances, urticaria, itching, and abdominal pain). Of responders, 11.9% (279/2,342) had a history of asthma. After adjustment for gender, family history of atopic disease, low birth weight, early respiratory problems, and damp house, asthma was significantly associated with recurrent abdominal pain (odds ratio [OR] 1.90; 95% confidence interval [CI]: 1.04, 3.16), itching (OR 3.15; 95% CI: 1.75, 5.68), and urticaria (OR 2.52; 95% CI: 1.02, 6.20). Asthma was reported by 10.2% (201/1,962) of children unaffected by this triad, by 20.1% (56/279; OR 2.20) with one of the symptoms, and by 31.6% (12/38; OR 4.04) with two or more symptoms. An emerging characteristic of pediatric asthma in our setting appears to be its association with certain extra‐respiratory symptoms (abdominal pain, itching, and urticaria). A global, internistic approach to asthmatic children is increasingly required both in the clinical setting and in future epidemiological studies.

Diffusing capacity for carbon monoxide in children with type 1 diabetes

Aims/hypothesisFew data are available on lung dysfunction in children with diabetes. We studied the association of pulmonary function variables (flows, volumes and alveolar capillary diffusion) with disease-related variables in children with type 1 diabetes mellitus.MethodsWe studied 39 children with type 1 diabetes (mean age 10.9±2.6 years, disease duration 3.6±2.4 years, insulin·kg−1·day−1 0.77±0.31) and 30 healthy control children (mean age 10.4±3.0 years). Pulmonary function tests included spirometry, N2 wash-out and the single-breath diffusing capacity for carbon monoxide (DLCO) corrected for the alveolar volume (DLCO/VA). Glycaemic control was assessed on the basis of HbA1c, with HbA1c values of 8% or less considered to indicate good glycaemic control, and HbA1c values of 8% or more considered to indicate poor control.ResultsChildren with poor glycaemic control had comparable percentage values for predicted flows and volumes but lower DLCO/VA values than children with good glycaemic control and healthy control children (86.7±12.6 vs 99.8±18.4 and 102.0±15.7; p<0.05). The predicted DLCO/VA percentages correlated with HbA1c levels (r=−0.39, p=0.013). A multiple regression analysis (stepwise model) controlling for HbA1c levels and other disease-related variables (age of disease onset, disease duration, daily insulin dose/kg, sex) identified HbA1c levels as the sole predictor of DLCO/VA in percent.Conclusions/interpretationIn children with type 1 diabetes, the diffusing capacity diminishes early in childhood and is associated with poor metabolic control. Although low DLCO/VA levels in these children probably reflect pulmonary microangiopathy induced by type 1 diabetes, other factors presumably influencing CO diffusion capacity measurements (e.g. a left shift in HbA1c resulting in high O2 binding and low CO binding) could explain the apparent capillary and alveolar basal membrane dysfunction.

Changes over 13 years in skin reactivity to histamine in cohorts of children aged 9–13 years

Background: Several studies report substantial differences in the prevalence of skin test reactivity to allergens in children from adjacent geographic areas; others report an increased prevalence over time. To find out whether these differences depend on variations in skin reactivity to histamine, we determined the time trend of histamine wheal sizes in successive cohorts of unselected children living in the same area (Viterbo, Italy).

The Prevalence of Atopy in Asthmatic Children Correlates Strictly with the Prevalence of Atopy among Nonasthmatic Children

Background: Because asthma preferentially burdens persons with atopy, atopy is simplistically considered a primary ‘cause’ of asthma. Yet at the population level, the percentage of asthma cases ‘attributable’ to atopy ranges from less than 10% to more than 60%. Seeking to understand the rationale for the variability of atopy-attributable cases of asthma, we systematically reviewed the results of our own previous epidemiological studies and several studies conducted by others in children. Methods: From each of the 37 random pediatric populations selected by a Medline search combining the key words ‘IgE or skin tests or hypersensitivity, immediate’ with ‘epidemiological studies, cross-sectional, case-control, prevalence, longitudinal, epidemiology of asthma’ (12 from our previous pediatric surveys and a further 25 reported from 19 studies in children), we extracted the population prevalence of asthma and atopy among asthmatic subjects and among the nonasthmatic part of the population. Results: No correlation was found between the prevalence of asthma (range 1.8–44.1%) and atopy (range 5.8–63.9%) in these 37 populations of children (r = 0.052, p = 0.761). Nevertheless, the prevalence of atopy among asthmatics strictly correlated with the prevalence of atopy in nonasthmatics (r = 0.900, p< 0.001, slope 1.364). Conclusion: The prevalence of asthma and atopy varies worldwide and at various time points and independently undergoes the influence of powerful environmental factors. The almost perfect correlation we found between atopy in asthmatics and atopy in the nonasthmatic part of the childhood population shows that the prevalence of atopy in asthma depends on environmental factors that simultaneously induce atopy in asthmatic and nonasthmatic subjects.