Prediction of the incidence and persistence of allergic rhinitis in adolescence: a prospective cohort study.

BACKGROUND: Predictive models have rarely been used in allergy research and practice. However, they might support physicians in advising patients. OBJECTIVE: The aim of this study was to create predictive models for the incidence and persistence of allergic rhinitis (AR) during adolescence. METHODS: A prospective population-based cohort study was conducted starting at age 9 to 11 years. Potential risk factors for atopic diseases obtained at baseline in 2810 subjects were used to create predictive logistic regression models for the incidence and persistence of physician-diagnosed AR with current symptoms at age 15 to 18 years. RESULTS: Positive skin prick test responses to outdoor allergens at baseline were the most important determinant for both the incidence and persistence of AR until follow-up. For the incidence of AR, positive skin prick test responses to indoor allergens, parental history of asthma, female sex, and not having been breast-fed exclusively for 2 or more months were additional statistically significant independent risk factors. Depending on the number of risk factors present, the probability of the incidence of AR increased from 2% (no risk factors present) to 72% (full model; 95% CI, 58% to 85%). The probability of persistence of AR ranged from 33% (no risk factors present) to 83% (full model; 95% CI, 70% to 97%). CONCLUSION: The course of AR over puberty can be predicted using risk factors that are easy to determine in childhood. Sensitization to outdoor allergens seems to play a much greater role for disease development than sensitization to indoor allergens. This might help pediatricians in advising patients.

Exhaled breath condensate nitrite--methodological problems of sample collection.

BACKGROUND: Exhaled breath condensate (EBC) analysis is a promising new method to monitor airway inflammation, however there are still multiple open methodological questions. The purpose of this study was therefore to investigate methodological influences on nitrite in EBC (surface contamination, flow dependency, storage time and inter- and within day variability). MATERIAL/METHODS: EBC samples of 10 healthy children, 10 healthy adults and 71 asthmatic children were collected and nitrite was analysed using the Griess reaction. Collector devices where either air-dried after disinfection or stored in distilled water till usage. Repeatability measurements were performed at three different times during one day and on five consecutive days. Flow dependency was analysed at 200 and 400 ml/s expiratory flow and storage stability was investigated at several time points within the first three hours after collection of the sample. In a preliminary study EBC nitrite was analysed in asthmatic children of different severity. RESULTS: Surface contamination appears to have a profound influence on nitrite levels and both within-day and inter-day variability is high. We found no flow dependency, and storage stability was satisfying although with considerable variety in several samples. There were no significant differences between the nitrite levels of the different asthmatic subgroups nor between the asthmatic children and the controls. CONCLUSIONS: These data indicate that EBC nitrite is a substance with a wide variety of influencing factors and different sources of origin. This has to be kept in mind when using exhaled nitrite as a biomarker for airway inflammation.

Exhaled breath condensate pH in infants and children with acute and recurrent wheezy bronchitis.

The analysis of exhaled breath condensate (EBC) is a promising new method to measure airway inflammation. So far only limited data exist about methodological issues of EBC sampling in infants and young children. We evaluated 18 children with acute wheezy bronchitis (median age 24.3 months (min-max: 4-89.9)), 54 children with recurrent wheezy bronchitis (median age 52.5 months (7.2-94.8)), and 32 healthy controls (median age 49.6 months (25.3-67.8)). EBC was sampled with a modified commercially available EBC-sampler, pH was measured after deaeration. EBC volume was significantly correlated to age (r = 0.56, P < 0.001). EBC pH was significantly decreased in all patients compared to the healthy controls (acute wheezy bronchitis 7.87 (7.16-8.19), P = 0.003, recurrent wheezy bronchitis 7.86 (6.95-8.39), P = 0.002, and healthy controls 8.04 (7.81-8.87), respectively). There were no significant differences of the EBC pH between the disease groups. When divided into different subgroups, an influence of inhaled steroid treatment was found with steroid-naive recurrent wheezers having significantly lower EBC pH levels compared to healthy controls (7.80 (6.95-8.37), P = 0.018), but not so steroid treated (7.94 (7.24-8.39), P = 0.055). Both, recurrent wheezers with or without a positive allergy test had significantly lower EBC pH compared to healthy controls (7.91 (6.95-8.37), P = 0.007 and 7.82 (7.32-8.39), P = 0.005, respectively). This study indicates that EBC can be collected with a modified commercially available EBC sampler in infants and young children. Further studies need to be performed to evaluate the relevance and meaning of pH differences of EBC in this age group.

Optical rhinometry: application on children and adolescents for nasal provocation tests.

Optical rhinometry is a new method that allows the direct, real time measurement of changes in swelling of the nasal mucosa by external measurement. The measurement is carried out with monochromatic near-infrared light. The change of intensity of the swelling is displayed and recorded. Different preceding studies on adults already showed the reliability and absence of side effects of the measuring method. With the help of a prototype of an optical rhinometer specially developed for children, 65 measurements were performed on a total of 13 children and adolescents having one-sided nasal provocation tests with histamine and allergens, negative provocation tests with control solution and decongestion with xylometazoline. The nasal provocation tests were implemented by optical rhinometry while simultaneously using the established method of active anterior rhinomanometry. We found significant differences between positive and negative provocation tests in both methods (p < 0.01). Decongestion was different from all other groups in both methods (p < 0.01). No clear connection could be made between the percentage increase of rhinometric extinction and the percentage increase of obstruction measured by anterior rhinomanometry. The evaluation of the nasal provocation test via continuous direct measurement of swelling of the nasal mucosa membrane seems feasible in children. Data which so far could not be measured, such as the beginning of swelling and the time of the maximum state of swelling, might increase the diagnostic validity of provocation tests.

Assessing bronchial responsiveness to hypertonic saline using the stepwise protocol of Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC II).

Measurement of bronchial responsiveness to hypertonic saline was applied in 22 study centers worldwide as part of Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC Phase Two). Because the amount of inhaled saline was difficult to standardize during the stepwise protocol with inhalation periods of increasing duration, we evaluated different statistical procedures based on inhalation time in relation to wheeze and current asthma. Data on random samples on 9 to 11-year-old children (n = 1,418) from two German centers were analyzed. The following statistical approaches were evaluated: (1) bronchial hyperreactivity (BHR) defined dichotomously as a fall in FEV1 (forced expiratory volume in 1 s) >or=15%; (2) PT15: the provocation time causing BHR using survival-analyses methods; (3) time-response-slope (continuous) of the individual FEV1-courses calculated by a linear model after comparing different mathematical models. The sensitivity and specificity of BHR versus current asthma were 47% and 87%, respectively. Analyses of the provocation time indicated an increased risk (adjusted hazard-ratio: 4.3; 95% CI: 2.8-6.5) for a fall in FEV1 >or= 15% among children with current asthma in comparison to those without. The time-response-slope differed markedly between children with and without wheeze and current asthma (P < 0.0001). BHR is meaningful and relatively easy to use, but has low sensitivity. Time-response-slopes utilize the available information from the stepwise protocol better than BHR and survival-analysis based on PT15. Response parameters based on inhalation time discriminate well between children with and without asthma and will be compared in the analyses of ISAAC Phase Two data.

Adolescents' jobs and the course of dermatitis symptoms throughout puberty.

OBJECTIVES: This study evaluated the course of dermatitis symptoms throughout puberty taking into account occupational exposures in a population-based study. METHODS: Participants enrolled in the ISAAC-II (International Study of Asthma and Allergies in Childhood) study in Munich and Dresden in 1995 and 1996 were sent a postal questionnaire in 2002 (age at follow-up 16 to 18 years). The questionnaire included items on atopic diseases, jobs, including holiday jobs and vocational training, and potential confounders. The most recent of the adolescents' jobs held for at least 8 hours a week, and for at least 1 month, were coded according to the ISCO-88 system. RESULTS: Overall, data of 3785 adolescents were included in the analyses. The incidence of dermatitis symptoms during puberty among those without such symptoms at baseline was 7%. Altogether 31% of the participants reported an employment history. Those already employed were more likely to report a new onset of dermatitis symptoms. Jobs associated with a new onset of symptoms were work in the health care sector, vocational training in bakeries, and cleaning. The first 9 months of exposure were particularly relevant for new cases of dermatitis symptoms (odds ratio 3.7, 95% confidence interval 1.5-9.6). CONCLUSIONS: Early occupational exposure is associated with the development of symptoms of dermatitis. The types of skin alterations need to be assessed in the next stage of the study.

G-Protein-coupled receptor polymorphisms are associated with asthma in a large German population.

RATIONALE: Recently, a new asthma susceptibility gene, GPRA (G-protein-related receptor for asthma), has been identified by positional cloning. Initial association studies in a Finnish and Canadian population suggested an association with asthma and elevated serum IgE levels. OBJECTIVE: In a large, nested case-control study, associations between GPRA polymorphisms, asthma, and serum IgE levels were analyzed. METHODS: Using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) technology, 1,872 German children aged 9 to 11 years (including 624 children with asthma and/or bronchial hyperresponsiveness) were genotyped for seven polymorphisms in the GPRA gene. MEASUREMENTS: Hardy-Weinberg equilibrium was assessed, and association studies with single nucleotide polymorphisms (SNPs) and haplotypes were performed. MAIN RESULTS: SNP 546333 increased the risk for asthma (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.04-1.88; p = 0.025) and concomitant asthma and bronchial hyperresponsiveness (BHR; OR, 2.38; 95% CI, 1.22-4.66; p = 0.009). Also, SNP 585883 was associated with asthma (OR, 1.34; 95% CI, 1.04-1.72; p = 0.022) and asthma in combination with BHR (OR, 2.71; 95% CI, 1.45-5.09; p = 0.001). Furthermore, SNP 585883 was associated with elevated serum IgE levels (OR, 1.63; 95% CI, 1.10-2.42; p = 0.015). Haplotype combinations of risk alleles increased the OR for asthma to 1.83 (95% CI, 1.08-3.08; p = 0.024) and for asthma and concomitant BHR to OR 3.51 (95% CI, 1.08-11.37; p = 0.036). CONCLUSIONS: These results indicate that GPRA polymorphisms increase the susceptibility for asthma and BHR, and to a lesser degree for the elevation of serum IgE, in a German population, confirming initial observations in other white populations.

Mucoepidermoid carcinoma as an unusual cause for recurrent respiratory infections in a child.

Recurrent respiratory infections in a 9-year-old girl prompted a chest radiograph and a CT scan, which showed a right middle lobe consolidation. Bronchoscopy revealed a tumor that totally obstructed the middle lobe. Open lung biopsy revealed a low-grade mucoepidermoid carcinoma. Middle and lower right lung lobectomy was performed, followed by an uneventful recovery. Cytogenetic investigation of tumor cells exhibited the translocation t(11;19). This case shows that further diagnostic modalities such as CT scanning should be performed early in children with recurrent lower respiratory tract infections who have suspicious radiographic findings such as persistent atelectasis or recurrent unifocal infiltration. Bronchial mucoepidermoid carcinoma is infrequent, and molecular investigations might shed additional light on the prognosis.

NOD1 variation, immunoglobulin E and asthma.

Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protect against asthma through unknown mechanisms. The innate immune system is able to identify microbial components through a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid (iE-DAP). The NOD1 gene is on chromosome 7p14, in a region that has been genetically linked to asthma. We carried out a systematic search for polymorphism in the gene. We found an insertion-deletion polymorphism (ND(1)+32656) near the beginning of intron IX that accounted for approximately 7% of the variation in IgE in two panels of families (P<0.0005 in each). Allele*2 (the insertion) was associated with high IgE levels. The same allele was strongly associated with asthma in an independent study of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.4-28.3, dominant model]. Differential binding of the two ND(1)+32656 alleles was observed to a protein from nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND(1)+32656*1) was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognition of specific bacterial products affects the presence of childhood asthma.

Predictors of health care utilization of children with asthma in the community.

The aim of this study was to assess the pattern of use of health care services among children with asthma symptoms within the community, and assess groups at increased risk of emergency department (ED) visits or hospital admissions (HA). Using International Study of Asthma and Allergies in Childhood phase II protocol, information about asthma management and utilization of health care services was collected by parental questionnaire in a community-based random sample of 5-7- and 9-11-year-old children (n = 11,094) in Dresden and Munich. Only 11.2% of children with current wheeze did not utilize any health care facility or consultation for their asthma symptoms in the 12 months prior to survey, while 86.2%, 12.3%, and 3.6% had at least one asthma related physician's consultation, ED visits, or HA, respectively. Predictors of ED visits and HA among current wheezers were: younger age, male gender, speech-limiting wheeze, level of exposure to environmental tobacco smoke. In addition, children of low socioeconomic status were more likely to have ED visits because of their asthma. Childhood asthma is a major public health problem in Germany leading to substantial morbidity and utilization of health care services. Exposure to tobacco smoke comes out as the major modifiable risk factor related to asthma morbidity in children.

Pseudomonas aeruginosa and Burkholderia cepacia cannot be detected by PCR in the breath condensate of patients with cystic fibrosis.

The collection of sputum for microbiological examination in young cystic fibrosis patients can be very difficult. However, a knowledge of bacterial flora colonizing the patient's airways is of paramount importance for proper antimicrobial therapy. It is also known that cystic fibrosis patients colonized by Pseudomonas species have a poorer prognosis than Pseudomonas-negative patients. Noninvasive ways of diagnosing airway inflammation that require only minimal cooperation of the patient might yield new possibilities for early detection of airway colonisation. The breath condensate method as a noninvasive diagnostic technique seems especially appropriate for use in children. Therefore, the aim of this study was to evaluate whether the breath condensate method could be used for detection of Pseudomonas species in children with cystic fibrosis. In total, 32 breath condensate and seven sputum samples were obtained from 13 cystic fibrosis patients with Pseudomonas aeruginosa- or Burkholderia cepacia-positive sputum culture (20 samples were obtained during forced expiration). PCR for combined detection of Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia was performed. PCR results of all breath condensate samples were negative for Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or Burkholderia cepacia, while all sputum sample results were positive. A minimum DNA quantity of 10 fg could be detected in dilution series of the positive control group. We conclude that the breath condensate method cannot be used as a tool for detection of Pseudomonas species.

Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations.

BACKGROUND: Early exposure to microbial matter such as LPS may influence the development of asthma and allergies by activation of innate immunity pathways as indicated by studies in farming environments. Recently, polymorphisms in caspase recruitment domain containing protein 15 (CARD15), an intracellular LPS receptor protein, have been associated with Crohn's disease. Because these polymorphisms lead to changes in LPS recognition, they may affect the development of asthma and allergies. OBJECTIVE: We genotyped a large population of German schoolchildren (N = 1872) from East and West Germany for 3 functional relevant CARD15 polymorphisms for their role in the development of asthma and allergy. METHODS: By use of parental questionnaires, skin prick testing, pulmonary function tests, bronchial challenge tests, and measurements of serum IgE levels, children were phenotyped for the presence of atopic diseases. Genotyping was performed with PCR-based restriction enzyme assays. To assess associations between atopic phenotypes and genotypes standard statistical procedures were applied. RESULTS: Children with the polymorphic allele C2722 had a more than 3-fold risk to develop allergic rhinitis (P <.001) and an almost 2-fold risk for atopic dermatitis (P <.05). Furthermore, the T2104 allele was associated with an almost 2-fold risk for allergic rhinitis (P <.05). When a C insertion at position 3020 was present, the risk of atopy increased by 50% (P <.05) and serum IgE levels were elevated (P <.01). CONCLUSION: The shared genetic background between Crohn's disease and atopy may indicate that an impaired recognition of microbial exposures results in an insufficient downregulation of excessive immune responses, giving rise to either T(H)2 dominated allergies or T(H)1 related Crohn's disease.

[Validation and subjective reports of exposure to traffic by traffic count, NO2 dispersion modeling and measuring NO2 emissions]. / Validierung von subjektiven Angaben zur Verkehrsexposition durch Verkehrszählungen, NO2-Ausbreitungsmodellierungen und NO2-Imissionsmessungen.

OBJECTIVES: The validity of self-reports of traffic density on street of residence in cities has not been evaluated extensively yet. METHODS: This study compared traffic self-reports with exposure estimates based on traffic counts and emission measurements. RESULTS: Self-reports correlated well with traffic count data but less well with data from measurements of background emission. CONCLUSIONS: As traffic counts primarily represent direct exposure to road traffic and emission concentrations primarily represent city background exposure to traffic-related pollutants, self-reports reflect direct traffic exposure more strongly than background exposure.

Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis.

BACKGROUND: Specific immunotherapy (SIT) and treatment with monoclonal anti-IgE antibody have complementary modes of action. OBJECTIVE: The purpose of this study was to determine whether combined therapy could provide better efficacy than either treatment alone. METHODS: We conducted a randomized, double-blinded trial to assess the efficacy and safety of subcutaneously administered anti-IgE (omalizumab) or placebo in children and adolescents with seasonal allergic rhinitis in both a birch pollen season and a grass pollen season (sequential seasons together lasting an average of 84 days). There were 4 treatment arms. Each subject was started on SIT-birch or SIT-grass, and anti-IgE or placebo was started before and maintained during the anticipated pollen seasons (a total of 24 weeks). The primary efficacy variable was symptom load, the sum of daily symptom severity score plus rescue medication use. RESULTS: A total of 221 subjects (intent-to-treat population) aged 6 to 17 years were analyzed for efficacy. Combination therapy reduced symptom load over the 2 pollen seasons by 48% (P <.001) over SIT alone. When analyzed separately by season, the 2 groups receiving unrelated SIT were considered placebo controls. In the grass season, symptom loads were as follows: unrelated (birch) SIT + placebo, 0.89 (reference value); unrelated (birch) SIT + anti-IgE, 0.49 (-45%); SIT-grass + placebo, 0.61 (-32%); SIT-grass + anti-IgE, 0.26 (-71%). CONCLUSION: Anti-IgE therapy conferred a protective effect independent of the type of allergen. Additional clinical benefit was demonstrated in both pollen seasons, whether there was coverage by SIT or not. This combination might prove useful for the treatment of allergic rhinitis, particularly for polysensitized patients.