Asthma symptoms and medication in the PIAMA birth cohort: evidence for under and overtreatment.

OBJECTIVE: Under and overtreatment of asthma may be a serious problem especially in young children, but the evidence is scarce and no longitudinal data are available. Our aim was to investigate whether inhaled medication use in young children was in agreement with asthma symptoms at the age of 2-8 yr. METHODS: Data were used from the 'Prevention and Incidence of Asthma and Mite Allergy' birth cohort, consisting of 3963 children born in the Netherlands. Between age 2 and 8 yr, children were followed up using annual postal questionnaires. Age-specific prevalences of asthma symptoms were assessed and compared with reported use of inhaled bronchodilators and/or corticosteroids. RESULTS: The proportion of current wheeze decreased with age. About a third of 'current wheezers' did not use any inhaled medication during the years in which symptoms were reported. At 8 yr, 30% of children with reported 'severe current asthma symptoms' were not using inhaled corticosteroids. On the other hand, up to 50% of children with inhaled corticosteroids for at least 2 yr did not report any wheezing during those 2 yr. CONCLUSION: The proportion of symptomatic children without appropriate treatment was substantial throughout childhood, even when parents reported prolonged or severe symptoms. Treatment of asymptomatic children with inhaled corticosteroids increased with age and accounted for up to a third of all inhaled steroid use at 8 yr. These findings suggest that under and overtreatment of asthma in children was common.

Uncontrolled asthma at age 8: the importance of parental perception towards medication.

BACKGROUND: Despite existing effective treatment options, asthma is uncontrolled in a considerable proportion of patients. The aim of this study was to identify determinants of uncontrolled asthma at age 8 in children participating in the PIAMA birth cohort study. METHODS: One hundred seventy children using inhaled corticosteroids in the previous 12 months at age 8 were included. Uncontrolled asthma was defined as: ≥3 items present in the past month: (1) day-time or (2) night-time asthma symptoms, (3) limitations in activities, (4) rescue medication use, (5) FEV(1) <0% predicted and (6) unscheduled physician visits because of asthma. Binomial regression was performed to study five groups of determinants representing asthma control: child and parental characteristics, environmental factors, therapy adherence and parental perception towards medication use (Beliefs about Medicines Questionnaire). RESULTS: Seventy seven children (45%) had uncontrolled asthma. Low maternal education (RR 1.6, 95% CI: 1.0-2.4) was associated with uncontrolled asthma. Parental necessity beliefs about medication use to maintain present and future health and parental concerns about potential adverse consequences of medication were also associated with uncontrolled asthma (RR 1.6, 95% CI: 1.1-2.2; and 1.6, 95% CI: 1.0-2.5, respectively). CONCLUSIONS: Environmental factors and therapy adherence were not associated with asthma control. In our cohort, uncontrolled asthma is associated with low maternal education and with strong parental beliefs about medication necessity and higher concern about potential side effects of medication.

Prediction of asthma in symptomatic preschool children using exhaled nitric oxide, Rint and specific IgE.

RATIONALE: For clinicians it remains very difficult to predict whether preschool children with symptoms suggestive of asthma will develop asthma in later childhood. OBJECTIVE: To investigate whether measurement of fraction of exhaled nitric oxide (FE(NO)), interrupter resistance (Rint) or specific immunoglobulin E (IgE) in 4-year-old children with suggestive symptoms can predict asthma symptoms up to age 8 years. METHODS: Children were recruited from the PIAMA birth cohort. All children with symptoms suggestive of asthma at age 3 or 4 years, who were invited for medical examination at age 4 (n=848), were eligible. Associations of FE(NO) (n=308), Rint (n=482) and specific IgE (n=380) at 4 years with wheezing and asthma at the ages of 5-8 years were assessed using repeated measurement analyses. The added predictive value of these objective tests was then investigated by including parameters for clinical history in the model. RESULTS: FE(NO) and specific IgE measured at 4 years were associated with wheezing and asthma at 8 years. Both tests also remained significant predictors after mutual adjustment and adjustment for clinical history: OR on wheezing at 8 years for FE(NO) ((10)log-scale, per IQR) 1.6 (95% CI 1.1 to 2.2) and for specific IgE 2.8 (95% CI 1.9 to 4.1). Rint was significantly associated with wheezing at age 6, but not at 7 and 8 years. CONCLUSIONS: In preschool children with symptoms suggestive of asthma, both FE(NO) and specific IgE measured at age 4, but not Rint, improved the prediction of asthma symptoms until the age of 8 years, independent of clinical history.

Asthma therapy during the first 8 years of life: a PIAMA cohort study.

OBJECTIVE: Many studies evaluated asthma medication use in children in a cross-sectional manner, yet little is known about longitudinal use patterns. This study describes the formation of a longitudinal data set on asthma medication use and shows first results regarding the prevalence and incidence of medication use. METHODS: The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) study is a prospective birth cohort study among 3963 Dutch children. Recruitment took place in 1996-1997. The data of the PIAMA birth cohort study were complemented with pharmacy data. Prescription information of family members was used to determine whether medication histories were complete from birth until age 8. The prevalence and incidence of asthma medication use was studied in children for whom complete medication histories were available. RESULTS: A first prescription for asthma medication was filled before age 8 by 280 (36%) children, with 88% starting therapy before age 5. Of all children who started therapy, 91.1% received short-acting beta(2)-agonists and 61.1% inhaled corticosteroids. CONCLUSION: The applied method of data collection rendered a data set including 777 children with complete medication histories for their first 8 years of life. This data set provides the opportunity to study longitudinal medication use patterns. First analyses show that asthma medication is initiated in a rather high percentage of children in this cohort and mainly at an age at which an asthma diagnosis cannot yet be firmly established.

High agreement between parental reported inhaled corticosteroid use and pharmacy prescription data.

PURPOSE: This study was conducted to assess the validity of parental reported use of inhaled corticosteroids (ICS) in children. METHODS: ICS users were identified within the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study and the PIAMA pharmacy sub-cohort which is nested within the PIAMA study. Complete medication histories were available for the first 8 years of life for children within the PIAMA pharmacy sub-cohort. Parental reported ICS use was measured by using data from questionnaires. ICS use in the pharmacy records was determined by using the Anatomical Therapeutic Chemical (ATC) codes. The proportion of overall agreement and kappa statistics with their corresponding 95% confidence intervals were calculated to quantify agreement between self-reported medication use and pharmacy prescription data. RESULTS: At all ages overall agreement was very high (>97%) and Cohen's kappa's ranged from 0.80 to 0.88 which also reflects excellent agreement between parental reported use of ICS and pharmacy prescription data. CONCLUSIONS: Our finding suggests that parental report of medication use is a reliable source of data to asses ICS use in children. The questionnaire-based medication data collected within the PIAMA study can be used to study asthma medication use in a large group of children.

Maternal food consumption during pregnancy and the longitudinal development of childhood asthma.

RATIONALE: Maternal diet during pregnancy has the potential to affect airway development and to promote T-helper-2-cell responses during fetal life. This might increase the risk of developing childhood asthma or allergy. OBJECTIVES: We investigated the influence of maternal food consumption during pregnancy on childhood asthma outcomes from 1 to 8 years of age. METHODS: A birth cohort study consisting of a baseline of 4,146 pregnant women (1,327 atopic and 2,819 nonatopic). These women were asked about their frequency of consumption of fruit, vegetables, fish, egg, milk, milk products, nuts, and nut products during the last month. Their children were followed until 8 years of age. Longitudinal analyses were conducted to assess associations between maternal diet during pregnancy and childhood asthma outcomes over 8 years. MEASUREMENTS AND MAIN RESULTS: Complete data were obtained for 2,832 children. There were no associations between maternal vegetable, fish, egg, milk or milk products, and nut consumption and longitudinal childhood outcomes. Daily consumption of nut products increased the risk of childhood wheeze (odds ratio [OR] daily versus rare consumption, 1.42; 95% confidence interval [95% CI], 1.06-1.89), dyspnea (OR, 1.58; 95% CI, 1.16-2.15), steroid use (OR, 1.62; 95% CI, 1.06-2.46), and asthma symptoms (OR, 1.47; 95% CI, 1.08-1.99). CONCLUSIONS: Results of this study indicate an increased risk of daily versus rare consumption of nut products during pregnancy on childhood asthma outcomes. These findings need to be replicated by other studies before dietary advice can be given to pregnant women.

Lipid transfer protein-linked hazelnut allergy in children from a non-Mediterranean birch-endemic area.

BACKGROUND: Hazelnut allergy in birch pollen-exposed areas is usually due to cross-reactivity (Cor a 1 and 2) and is usually mild in nature (oral allergy). In areas without birches, severe reactions are more prevalent and linked to sensitization to the lipid transfer protein (LTP) Cor a 8. OBJECTIVE: We sought to investigate whether sensitization to LTP plays a role in more severe (objective) hazelnut-induced symptoms in children from a birch-endemic area. METHODS: Sensitization to Cor a 8, Cor a 2, Cor a 1, and Bet v 1 was determined by means of RASTs and immunoblotting in hazelnut-sensitized children with (n = 8) and without (n = 18) objective reactions during double-blind, placebo-controlled food challenges. Additionally, samples from 191 hazelnut-sensitized nonchallenged children were analyzed. RESULTS: Children with objective reactions during double-blind, placebo-controlled food challenge had higher IgE titers to hazelnut (P < .001) and recognized more allergens on immunoblotting (P = .001) than those without such reactions. All children with objective symptoms were sensitized to Cor a 8 (0.51-23.3 IU/mL) compared with only 1 child without objective reactions (0.90 IU/mL). In a multivariate analysis only IgE against Cor a 8 remained as an independent risk factor (undefined odds ratio; P < .0001). In the group of nonchallenged children (n = 191), the prevalence of LTP sensitization was greater than 30%. Unexpectedly, sensitization to Cor a 1 was observed in children not sensitized to Bet v 1. CONCLUSION: Sensitization to hazelnut LTP is a risk factor for objective symptoms in children from a birch-endemic area.

Electromyographic monitoring of respiratory muscle activity in dyspneic infants and toddlers.

The aim of this study was to investigate whether the changes that occurred in the clinical asthma score (CAS) correlated with the changes in the respiratory electromyographic (EMG) activity over the days during admission to hospital in dyspneic infants and toddlers. Sixteen infants and toddlers (9 males) were studied during admission and 7 days after discharge. The CAS was used to assess the severity of dyspnea and consists of five items: respiration rate, wheezing, retractions, observed dyspnea, and inspiration-to-expiration ratio. Each item was scaled 0, 1, or 2, with a maximum score of 10. Electrical activity from the diaphragm (di) and intercostal muscles (int) was derived from surface electrodes. The logarithm of the EMG-Activity-Ratio (log EMGAR; ratio of mean peak-to-bottom EMG activity during admission to the hospital, to that at baseline, 7 days after discharge) was used as EMG parameter. For assessing the association between the repeated observations of the CAS and the EMG measurements we used the quantity r2 obtained with analysis of covariance. On the day of admission the patients had a mean CAS of 5.9 +/- 1.2. On the day of discharge the mean CAS decreased significantly to 2.1 +/- 1.6, indicating that the CAS returned to normal values. In line with this observation, a significant decrease in the log EMGARdi and log EMGARint was observed during the stay in the hospital. Over all subjects the correlation coefficient (r) of log EMGARdi versus CAS was 0.71, log EMGARint versus CAS was 0.67, and the mean log EMGAR versus CAS was 0.75 (p < 0.01, for all values). The correlation coefficients of subjects of < or = 1 year seemed to be lower than those of subjects of > 1 year of age (p < 0.01) and female subjects showed higher correlation coefficients than males. This study showed a moderate, but significant, relationship between the changes that occurred in the CAS and the changes in respiratory EMG activity during admission to hospital in dyspneic infants and toddlers. Moreover, the correlation coefficients of the combined leads of the intercostals and diaphragm (mean log EMGAR) were higher than those of the separate leads. The EMG measurements would extend diagnostic possibilities and would provide an objective measure to evaluate the clinical course of the disease and the efficacy of therapy in infants and toddlers with recurrent wheezing disorders.

Mannose-binding lectin and upper respiratory tract infections in children and adolescents: a review.

OBJECTIVE: To review the literature on mannose-binding lectin (MBL) polymorphisms and susceptibility for upper respiratory tract infection (URI) in children and adolescents. DATA SOURCES: We searched PubMed from 1966 and EMBASE from 1974 to July 2005, using the terms respiratory tract infection, respiratory infection, upper respiratory infection, MBL, and mannose-binding lectin. STUDY SELECTION: Initially, 110 studies were identified. Two reviewers independently screened identified titles and abstracts. Potentially relevant studies were obtained and the full text examined. Inclusion criteria were human subjects, 18 years or younger, URI, and MBL polymorphisms. Seven of the initially identified studies met the inclusion criteria. DATA EXTRACTION: Information was gathered for each study on study design, population, possible confounders, and outcomes measured. DATA SYNTHESIS: Because there was significant heterogeneity between the identified studies, we had to describe the identified studies separately. The largest case-control studies (n = 3) as well as the cohort study (n = 1) suggest an association between MBL polymorphisms and URI, especially in young children. Results of the smaller studies (n = 3) are inconsistent. CONCLUSIONS: The association between MBL polymorphisms and URI in children remains controversial. Large prospective cohort studies with regular documentation of URI and possible confounders such as atopy and environmental factors are required to establish the role of MBL polymorphisms in susceptibility for URI.

Influence of the macrophage bacterial resistance gene, Nramp1 (Slc11a1), on the induction of allergic asthma in the mouse.

Based on the hygiene hypothesis that lack of early childhood bacterial infections would favor development of allergic disease, we hypothesize that genes controlling antibacterial resistance may be important as well. We, therefore, studied whether Nramp1 alleles that determine resistance (Nramp1r) or susceptibility (Nramp1s) to intracellular bacteria at the macrophage level affect sensitivity to induction of allergic asthma. Nramp1s and congenic Nramp1r mice were sensitized with ovalbumin/alum on days 0 and 14 and challenged with ovalbumin or saline aerosols on days 42, 45, and 48. On day 49, airway responsiveness was assessed, blood was withdrawn, and lung lavage was performed. We demonstrated that ovalbumin sensitization and challenge of Nramp1s and Nramp1r mice caused comparable airway hyperreactivity and airway eosinophilia and a similar increase in serum levels of ovalbumin-specific IgG1 and IgG2a. Ovalbumin challenge, however, induced significantly lower serum levels of total and ovalbumin-specific IgE and significantly lower mast cell degranulation in Nramp1r mice as compared with Nramp1s mice. In addition, ovalbumin challenge of Nramp1r mice led to significantly less release of Th2 cytokines into the airways. Results show that Nramp1 can affect the development of allergy but not the development of airway hyperresponsiveness in the mouse.

Therapeutic treatment with heat-killed Mycobacterium vaccae (SRL172) in a mild and severe mouse model for allergic asthma.

The hypothesis that a lack of early childhood bacterial infections would favor the development of allergic disease suggests that bacteria can be used as a potential treatment for allergic asthma. Therefore, in this study, we investigated the therapeutic potential of heat-killed Mycobacterium vaccae in two mouse models of allergic asthma. For this purpose, mice were sensitized i.p. with ovalbumin/alum (severe model) or ovalbumin alone (mild model) and challenged on days 77, 80 and 83 by inhalation of either ovalbumin or saline aerosols. Treatment of mice with M. vaccae (s.c. 10(7) or 10(8) colony-forming units) on days 56 and 63, however, did not reduce airway hyperresponsiveness and eosinophilia, IgE and interleukin-5 production 24 h after ovalbumin challenge in either mouse model. We therefore conclude that treatment of sensitized mice with M. vaccae before allergen exposure is not able to reduce the allergic and asthma-like response in a mild and a severe model of allergic asthma.

Airflow limitation in asthmatic children assessed with a non-invasive EMG technique.

The aim of the study was to investigate the association between electromyography (EMG) of the diaphragm and intercostal muscles and the forced expiratory volume in 1 s (FEV(1)) at different levels of histamine-induced airflow limitation, and the response to salbutamol. Moreover, we assessed the reproducibility of the EMG measurements on 2 different occasions during different levels of airflow limitation in asthmatic school children. Fourteen children with asthma performed 2 histamine challenges with a 24-h time interval and 1 child performed 1 histamine challenge. The EMG signals were derived from surface electrodes. The logarithm of the EMG-activity-ratio (log EMGAR; mean peak-bottom ratio of respiratory muscle activity) was used as EMG parameter. The log EMGAR of the diaphragm (di) and the log EMGAR of the intercostal muscles (int) associated well with the histamine-induced fall in FEV(1) at 5% steps from the baseline value. After administration of salbutamol log EMGARdi and log EMGARint returned to baseline mean peak-bottom values (for all leads P<0.001). The EMGARdi and EMGARint values were reproducible at different levels of airflow limitation. This study showed that EMGARdi and EMGARint as a parameter for a change in electrical activity of the diaphragm and intercostal muscles associated well with FEV(1), was reversible after salbutamol and was reproducible at different levels of histamine-induced airflow limitation in asthmatic school children.

Recognition of self-heat shock protein 60 by T cells from patients with atopic dermatitis.

Heat shock protein 60 (hsp60) is a highly conserved stress protein and target of self-reactive T cells in various inflammatory diseases. Not much is known about a possible role in atopic disease. As atopic diseases are considered to be the result of a disturbance in the balance between T helper cells type 2 and regulatory T cells, it is of interest to know whether hsp60 acts as a bystander antigen in atopic disease. Our aim was to investigate whether hsp60 is involved in the chronicity of inflammation of atopic dermatitis (AD). We studied the expression of hsp60 in skin tissue of adults with AD by immunohistochemistry. Peripheral blood mononuclear cells (PBMC) of children with AD were cultured with hsp60 and proliferative responses, cytokine secretion, surface markers, and functional assays were compared to responses of PBMC of healthy controls (HC). Hsp60 was detected more in lesional skin of AD patients compared to nonlesional skin. Furthermore, PBMC of children with AD proliferated more strongly in response to hsp60 compared to HC. hsp60-reactive T cells of atopic children produced high levels of IFNγ and low levels of IL-10. In vitro activation with hsp60 leads to the induction of CD4(+)CD25(bright) T cells expressing FOXP3 in both HC as well as in atopic children. However, despite their regulatory phenotype, hsp60-induced CD4(+)CD25(bright)CD127(-)FOXP3(+) T cells of AD patients were incapable of suppressing effector T cells in vitro. hsp60 is recognized by proinflammatory (IFNγ high, IL-10 low) T cells in atopic patients and is more present in lesional AD skin. This suggests that hsp60-specific T cell responses contribute to local inflammation in AD.

Plasma IL-25 is elevated in a subgroup of patients with clinical reactivity to peanut.

BACKGROUND: One of the IL-17 family members, IL-25, has been implicated with the initiation and amplification of Th2 responses in animal models and has been associated with airway hyper-reactivity. The involvement of IL-25 and also IL-17 in food allergic disease remains to be investigated. FINDINGS: In this study thirty children suspected of peanut allergic disease underwent a double-blind placebo controlled food challenge (DBPCFC) and IL-25 and IL-17 plasma levels were determined before and after challenge. IL-25 was highly elevated only in subgroup of children with a positive DBPCFC outcome. Plasma IL-25 was absent in children with a negative DBPCFC outcome and in healthy controls. CONCLUSIONS: This study shows that IL-25, an IL-17 family member, is highly elevated only in children with a clinical response to peanut. This suggests a role for IL-25 in the pathogenesis of peanut allergy and elevated plasma IL-25 may be a sign of a severe atopic phenotype.