Early age exposure to moisture damage and systemic inflammation at the age of 6 years.

Cross-sectional studies have shown that exposure to indoor moisture damage and mold may be associated with subclinical inflammation. Our aim was to determine whether early age exposure to moisture damage or mold is prospectively associated with subclinical systemic inflammation or with immune responsiveness in later childhood. Home inspections were performed in children's homes in the first year of life. At age 6 years, subclinical systemic inflammation was measured by serum C-reactive protein (CRP) and blood leukocytes and immune responsiveness by ex vivo production of interleukin 1-beta (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α) in whole blood cultures without stimulation or after 24 hours stimulation with phorbol 12-myristate 13-acetate and ionomycin (PI), lipopolysaccharide (LPS), or peptidoglycan (PPG) in 251-270 children. Moisture damage in child's main living areas in infancy was not significantly associated with elevated levels of CRP or leukocytes at 6 years. In contrast, there was some suggestion for an effect on immune responsiveness, as moisture damage with visible mold was positively associated with LPS-stimulated production of TNF-α and minor moisture damage was inversely associated with PI-stimulated IL-1ß. While early life exposure to mold damage may have some influence on later immune responsiveness, it does not seem to increase subclinical systemic inflammation in later life.

A switch in regulatory T cells through farm exposure during immune maturation in childhood.

BACKGROUND: Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the 'asthma-protective' farm effect via Tregs during childhood immune maturation. METHODS: Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+ CD25high FOXP3upper20% ). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents. RESULTS: Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96-132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001). CONCLUSIONS: Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical 'time window' for Treg-mediated asthma protection via environmental exposure before age 6 years.

STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years.

BACKGROUND: The transcription factor STAT6 is crucial for activation of the interleukin (IL)-4/IL-13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown. METHODS: STAT6 polymorphisms were genotyped in cord blood mononuclear cells by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene expression was assessed by real-time polymerase chain reaction (PCR) and cytokines by Multiplex. At age 3 years, atopic diseases were assessed by questionnaires. RESULTS: STAT6 rs324011 but not rs1059513 polymorphism was associated with significant or borderline significant decreased mRNA expression of Treg-associated genes (FOXP3, GITR, LAG3). Heterozygotes and minor allele homozygotes of rs324011 had low levels of tumor necrosis factor alpha (TNF-α) and increased interferon gamma (IFN-γ) (P ≤ 0.04), while heterozygotes and minor allele homozygotes of rs1059513 had increased TNF-α and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (P ≤ 0.05). In minor allele homozygotes of rs324011, expression of Treg-associated genes was strongly inverse correlated with IFN-γ (unstimulated, r = -0.7, P = 0.111; LpA stimulation, r = -0.8, P = 0.011), but not in heterozygotes or major allele homozygotes. Heterozygotes and minor allele homozygotes of rs324011 presented a lower risk of atopic dermatitis and obstructive bronchitis until age 3 years. CONCLUSIONS: Two STAT6 polymorphisms were associated with altered immune responses already at birth. STAT6 rs324011 was associated with lower neonatal Treg and increased Th1 response. Those neonates had a lower risk of atopic dermatitis and obstructive bronchitis until 3 years. Our data suggest a role for STAT6 polymorphisms in early immune regulation and implications on early atopic disease development.

Asthma and allergies: is the farming environment (still) protective in Poland? The GABRIEL Advanced Studies.

BACKGROUND: Evidence exists that a farming environment in childhood may provide protection against atopic respiratory disease. In the GABRIEL project based in Poland and Alpine regions of Germany, Austria and Switzerland, we aimed to assess whether a farming environment in childhood is protective against allergic diseases in Poland and whether specific exposures explain any protective effect. METHODS: In rural Poland, 23 331 families of schoolchildren completed a questionnaire enquiring into farming practices and allergic diseases (Phase I). A subsample (n = 2586) participated in Phase II involving a more detailed questionnaire on specific farm exposures with objective measures of atopy. RESULTS: Farming differed between Poland and the Alpine centres; in the latter, cattle farming was prevalent, whereas in Poland 18% of village farms kept ≥1 cow and 34% kept ≥1 pig. Polish children in villages had lower prevalences of asthma and hay fever than children from towns, and in the Phase II population, farm children had a reduced risk of atopy measured by IgE (aOR = 0.72, 95% CI 0.57, 0.91) and skin prick test (aOR = 0.65, 95% CI 0.50, 0.86). Early-life contact with grain was inversely related to the risk of atopy measured by IgE (aOR = 0.66, 95% CI 0.47, 0.92) and appeared to explain part of the farming effect. CONCLUSION: While farming in Poland differed from that in the Alpine areas as did the exposure-response associations, we found in communities engaged in small-scale, mixed farming, there was a protective farming effect against objective measures of atopy potentially related to contact with grain or associated farm activities.

[New spirometric reference values for children and adolescents in Germany considering height and non-linear age effects: the LUNOKID-study]. / Neue spirometrische Referenzwerte für Kinder und Jugendliche in Deutschland unter Berücksichtigung der Größe und nichtlinearer Alterseffekte: Die LUNOKID-Studie.

BACKGROUND: Comparing children's lung function with reference values is important for diagnosing respiratory diseases. The values by Zapletal et al., commonly used nowadays, are not appropriate for the current stage of children's development. We have now developed new reference values and a lower limit of normal (LLN) for children in Germany, divided into small-range age and height categories. MATERIAL AND METHODS: We examined 4- to 18-year-old children in 3 German communities under field conditions. 1943 children were healthy and had a visually acceptable lung function which also fulfilled international quality criteria. We used the regression model LMS, which was introduced by Stanojevic and Quanjer in this context. RESULTS: There were significant differences between the measured lung function and the predicted values according to Zapletal et al. The lung function did not only depend on the child's height, but also in a non-linear way on the age. The variation coefficient did not depend on age. CONCLUSIONS: To avoid diagnostic errors, the currently often used reference values according to Zapletal et al. should no longer be used. The non-linear dependence on age corresponds to the recently published results by Stanojevic and Quanjer.

TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy.

BACKGROUND: Toll-like receptor (TLR) polymorphisms have been associated with atopic diseases in children and adults. Development of atopic diseases may be modified by TLR-mediated signals that modulate T-regulatory cells (Tregs) early in life when maternal influences are still present and relevant. The aim of this study was to assess whether genetic TLR variants influence Tregs in neonates. METHODS: Twelve single nucleotide polymorphisms located in TLR1, TLR2, TLR4, TLR6, and TLR10 were genotyped in 200 cord blood samples (72 samples from atopic, 128 from nonatopic mothers). Cord blood mononuclear cells were cultured without or with stimulation [lipid A (LpA), peptidoglycan (Ppg), phytohemagglutinin, house dust mite]. mRNA expression of Treg marker genes [forkhead box protein P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3)], TLR2, Th1/Th2 cytokines, and tumor necrosis factor alpha (TNF-α) was measured. RESULTS: In children with the AA genotype of the TLR2 promoter variant rs4696480, gene expression of FOXP3 and Treg marker genes GITR and LAG3 as well as Th2 cytokines and TNF-α secretion was significantly increased in the presence of maternal atopy and Tregs decreased without maternal atopy. In carriers of the GG genotype for TLR2 rs1898830, gene expression of Treg marker genes was significantly decreased with and increased without maternal atopy. FOXP3 expression was also modified by TLR1 rs4833095 (P ≤ 0.03) and trendwise by TLR10 rs4129009 after LpA and Ppg stimulation. CONCLUSIONS: Genetic variations of TLR2, TLR1, and TLR10 affect Treg marker gene expression in cord blood. Gene-immunological interactions of the TLR pathway influence Tregs early in life, modulated by maternal atopy. This may be relevant for immune maturation in the development of atopic diseases in childhood.

Reliability of non-invasive cardiac output measurement in individuals with tetraplegia.

STUDY DESIGN: The study is conducted on the basis of comparative-repeated measures. OBJECTIVES: The objective of this study is to assess the reliability of non-invasive cardiac output (CO) measurements in individuals with tetraplegia (TP) at rest and during exercise using Innocor, and to test the hypothesis that CO measurements are less reliable in TP than in able-bodied (AB) individuals. SETTING: Ambulatory volunteers, Switzerland. METHODS: Nine male motor-complete TP (C5-C7) and nine pair-matched AB performed repeated CO measurements at rest and during submaximal arm-crank and wheelchair exercises in four different test sessions. Within- and between-day reliabilities were compared between TP and AB. RESULTS: Mean differences between measurements at rest (TP vs AB, within-day: 0.1±0.5 vs 0.2±0.6 l min(-1), between-day: -0.7±0.6 vs -0.1±0.8 l min(-1)), during arm-crank (TP vs AB, within-day: 0.1±0.9 vs 0.5±0.7 l min(-1), between-day: -0.3±1.1 vs 0.0±1.1 l min(-1)) and wheelchair exercises (TP vs AB, within-day: 0.3±1.2 vs -0.1±0.8 l min(-1), between-day: 0.1±1.1 vs 0.5±0.9 l min(-1)) were not significantly different between TP and AB (all P>0.05). Coefficients of variation in TP (within-day, rest: 6.8%, arm-crank: 9.6% and wheelchair: 10.8%; between-day, rest: 11.9%, arm-crank: 11.2% and wheelchair: 10.3%) and in AB (within-day, rest: 7.7%, arm crank: 6.8% and wheelchair: 6.0%; between-day, rest: 9.2%, arm crank: 8.5% and wheelchair: 8.0%) indicated acceptable reliability. CONCLUSION: In contrast to our hypothesis, we found non-invasive CO measurements using Innocor to be as reliable in TP as they are in AB. Consequently, Innocor can be recommended for repeated assessments of CO in TP within routine diagnostics or for evaluation of training progress.

Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence.

Childhood asthma is frequently perceived as a disease with uniform clinical pathways. This perception might be an oversimplification. The aim of the present study was to investigate the incidence and natural course of wheeze over the first 13 yrs of life and analyse the risk factors predicting wheeze at 11-13 yrs of age. The Multicentre Allergy Study, a German birth cohort, recruited 1,314 children in 1990. Physical examinations, interviews on atopic diseases, immunoglobulin (Ig)E and lung function tests were performed up to 13 yrs of age. Complete data on the course of wheeze were available for 441 children. It was found that incidence of wheezing declined with age. The first wheezing episode was reported by 29, 9 and 9% of participants at < or = 3 (early wheezers), 3-6 (late wheezers), and > 6 yrs (very late wheezers) of age, respectively. Wheezing at the age of 13 yrs was associated with parental atopy, and with IgE sensitisation to common allergens, elevated total IgE and exposure to high levels of indoor allergens in early life. All these associations were remarkably stronger among early wheezers than among early nonwheezers. In conclusion, the relevance of an early expression of atopy as a predictor of wheezing at age 13 yrs declines with increasing age of wheezing onset.

Variability of total serum immunoglobulin E levels from birth to the age of 10 years. A prospective evaluation in a large birth cohort (German Multicenter Allergy Study).

BACKGROUND: Many environmental factors influence the concentration of total serum IgE (tIgE); however, tIgE synthesis is believed to be under strong genetic influence. Multiple genetic studies on tIgE regulation have been performed. For these population-based studies tIgE was commonly determined at one time-point, assuming that tIgE phenotypes (adjusted for age and gender) are stable over time. OBJECTIVE: We assessed correlations of tIgE levels from birth to the age of 10 years in the birth cohort MAS (Multicenter Allergy Study; n=1314). MATERIALS AND METHODS: We determined cord-blood IgE levels, total and specific IgE at the age of 1, 2, 3, 5, 6, 7, and 10 years. Spearman correlation coefficients were calculated for tIgE at different time-points. All analyses were performed in the entire cohort, adjusted for gender, as well as in non-atopic children only. RESULTS: tIgE percentiles increased steadily from birth to the age of 10 years with higher values for boys than for girls at each time-point. tIgE values from birth to 3 years of age correlated poorly with tIgE levels at 10 years (r<0.5). However, good correlations (r>0.8) were observed for tIgE concentrations at 6, 7 and 10 years. The same results were observed when the analyses were limited to non-atopic children. CONCLUSION: In childhood, tIgE levels underlie remarkable variation over time even in the absence of atopy. For cross-sectional population-based genetic and epidemiologic studies, tIgE values of children <5 years should be interpreted with caution since these values correlate poorly with tIgE levels later in life.

Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood--report of the German Multicentre Allergy Study (MAS 90).

BACKGROUND: Controversial data have emerged regarding the question whether cat exposure in childhood favours or decreases the risk of sensitization and allergic airway disease. In a prospective birth-cohort study, we assessed the association between longitudinal cat allergen exposure, sensitization (immunoglobulin E, IgE), IgG antibody (ab) levels to cat and the development of asthma in children up to the age of 10 years. METHODS: Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 10 years were available for 750 children. Assessments included yearly measurements of specific serum IgE to cat and at age 6 and 18 months, 3, 4 and 10 years measurement of cat allergen Fel d 1 in house dust samples. Additionally, Fel d 1-specific IgG ab were determined in 378 serum samples of 207 children. Endotoxin exposure in mattress dust was measured in a subgroup of 153 children at age 10 years. From age 4 years on, International Study of Asthma and Allergy in Childhood (ISAAC) questionnaires were completed yearly in order to assess the prevalence of wheeze and asthma. RESULTS: Serum IgG-levels to cat showed a large variation, however, intraindividually values showed rather constant concentration over a longer time period. The IgG levels at school-age correlated with cat allergen exposure during the first 2 years of life. Specific IgE to cat was clearly associated with wheeze ever, current wheeze and bronchial hyperresponsiveness (BHR), this was also observed for children with specific IgE ab to cat (>0.35 kU/l) plus IgG levels above 125 U/ml. A large percentage of very highly exposed children showed high IgG but no IgE responses to cat, however, not all highly exposed children were found to be protected from sensitization. Children with IgG but without IgE ab to cat showed the lowest prevalence of wheeze ever and current wheeze despite high cat allergen exposure, however, this trend did not achieve significance. While homes of cat owners showed higher Fel d 1 concentrations than homes without cats, homes of cat owners were not found to have higher endotoxin levels in carpet dust samples than homes without cats. CONCLUSIONS: We could confirm that high cat allergen exposure in a cohort with lower community prevalence of cats is associated with higher serum IgG and IgE levels to cat in schoolchildren. Sensitization to cat allergen (IgE) is a risk factor for childhood asthma. While exposure to cat allergen during infancy is associated with sensitization (IgE), only in the very highly exposed children the likelihood of sensitization (IgE) is decreased and high IgG levels to cat without IgE were associated with low risk of wheeze. However, cat-specific IgG ab levels did not protect children with IgE-mediated sensitization from wheeze.

Transient early wheeze is not associated with impaired lung function in 7-yr-old children.

The aim of the present study was to analyse determinants of lung function in 7-yr-old children with different wheezing patterns (early, persistent and late onset) in a prospective cohort study. The German Multicentre Allergy Study (MAS) followed 1,314 children from birth onwards. Annual assessments included clinical check-ups, a structured interview and repeated measurement of specific immunoglobulins Ig(E) directed against food and inhalant allergens. At the age of 7 yrs, lung function was measured by body plethysmography in 800 children. Episodes of wheezing in the past 12 months ("current wheeze") were strongly associated with reduced lung function at age 7 yrs. Children with wheezing episodes only during the first 3 yrs of life showed a slight impairment in maximal expiratory flow when 50% of the forced vital capacity remains to be exhaled (98.9 +/- 24.2 versus 103.2 +/- 22.8% of the predicted value in children who never wheeze). Separate analysis of determinants of pulmonary function within these subgroups resulted in distinctly different patterns. Determinants of impaired lung function in the group of current wheezers were: time in years since first wheeze, a parental history of atopy, current sensitisation to indoor allergens, elevated cord blood IgE levels and a low ponderal index at birth. In the group of transient early wheezers, frequent lower respiratory tract infections early in life and maternal smoking during pregnancy were significant but weak determinants of impaired lung function. The present results indicate that determinants of pulmonary function in 7-yr-old children differ with respect to different wheezing phenotypes, demanding different therapeutic strategies. Although transient early wheezers were found to have normal-to-subnormal lung function, children with asthmatic symptoms (persistent and late-onset disease) at age 7 yrs already show significant impairment of expiratory flow volumes.

Cultural adaptation is associated with atopy and wheezing among children of Turkish origin living in Germany.

BACKGROUND: Turkish children have been found to suffer less from atopic diseases than their German peers. The underlying causes are unknown. OBJECTIVE: To evaluate rates of sensitization and atopic disease among children in Germany with German or Turkish ethnicity and different degrees of cultural adaptation. METHODS: This was a cross-sectional study. The setting was screening for school eligibility in an inner-city district of Berlin/Germany. The participants were preschool children born in Germany with double German or double Turkish parental citizenship. Cultural adaptation of Turkish children was assessed by the language parents used to communicate with their child: only Turkish (n = 60, group A); Turkish and German (n = 269, group B); and only German (n = 103, group C). Group D contained children from German parents (n = 383). The main outcome measures were specific sensitization to common aeroallergens (CAP-System, Pharmacia Phadiatop >or= 0.35 kU/L), and lifetime and 1-year prevalences of allergic disease symptoms (ISAAC questionnaire in German and Turkish, Mantel-Haenszel test for trend). RESULTS: Sensitization rates for groups A, B, C and D were 8.0%, 6.8%, 18.9% and 18.3%, respectively (P = 0.004). The corresponding prevalence rates for wheeze ever were 6.7%, 9.3%, 12.6% and 21.3% (P < 0.001), wheeze in the past year 3.3%, 3.7%, 9.7% and 10.2% (P = 0.001), itchy rash ever 3.3%, 6.3%, 8.7% and 13.7% (P < 0.001), itchy rash in the past year 1.7%, 3.7%, 4.9% and 9.5% (P < 0.001), respectively. No significant differences were found for hay fever symptoms. CONCLUSIONS: Higher cultural adaptation is correlated with higher rates of allergic sensitization and disease among children of Turkish origin living in Berlin. This correlation suggests that environmental rather than genetic differences are responsible for the differences observed.

The pattern of atopic sensitization is associated with the development of asthma in childhood.

BACKGROUND: Even though atopic sensitization has been shown to be strongly associated with childhood asthma, asthma eventually develops in only one third of atopic children. OBJECTIVE: The aim of this study was to prospectively investigate the pattern of atopic sensitization typically associated with the development of asthma in childhood. METHODS: The German Multicenter Allergy Study followed 1314 children from birth to the age of 7 years. Parental questionnaires on asthma and asthmatic symptoms were completed 6 times up to the age of 2 years and from then on yearly. Determination of specific IgE to 9 food and inhalant allergens was performed yearly, and at the age of 7 years, a bronchial histamine challenge was conducted. RESULTS: Onset of atopic sensitization in atopic children with current asthma at the age of 7 years was significantly earlier than in atopic children without current asthma (39.4% before age 1 year vs 21.0%, P =.015). Early atopic sensitization without any sensitization to inhalant allergens at the age of 7 years conferred no increased risk for asthma at this age. Only those children sensitized to any allergen early in life and sensitized to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio, 10.12; 95% CI, 3.81-26.88). However, even in this group of persistently sensitized children, the risk of being asthmatic at the age of 7 years was only increased if a positive parental history of asthma or atopy was present (odds ratio, 15.56; 95% CI, 5.78-41.83), with the effect being strongest for maternal asthma. CONCLUSION: Our results indicate that an underlying factor pertaining to asthma and maternal transmission may determine both a certain pattern of sensitization and the expression of asthma.

Puberty and prognosis of asthma and bronchial hyper-reactivity.

It is a commonly held view that pediatric asthma frequently abates during puberty. However, little data are available that associate the stage of puberty with the prognosis of asthma and bronchial hyper-reactivity (BHR). In this study, 155 children with active asthma at 10 years of age (60 girls [38.70%], 95 boys [61.3%]) were followed-up until they reached 14 years of age. The stage of puberty was assessed by parental questionnaire; in addition, serum 3-alpha-androstanediolglucuronide, as an endocrinological marker for peripheral androgen status, was measured in 107 subjects. Persistence of asthma was determined via questionnaire, lung function testing, and bronchial provocation (hyperventilation of cold, dry air). At 14 years of age, 73.3% of girls were reported to have had menarche and 40.8% of boys a voice change, and only 35.5% of the subjects had experienced acute asthma symptoms during the last 12 months, with an almost unchanged gender ratio (19 girls [34.5%], 36 boys [65.5%]) vs. that recorded at 10 years of age. The level of androstanediolglucuronide was higher in the children who reported puberty (mean+/-SD): 3.03+/-2.13 nmol/l vs. 1.89+/-1.26 nmol/l, p = 0.003. No statistically significant relationship was found between the reported signs of late puberty and loss of asthma or BHR. Likewise, no significant association was found between asthma persistence and the level of androstanediolglucuronide (2.39+/-1.75 nmol/l vs. 2.44+/-1.82 nmol/l, p = 0.84), or BHR and the level of androstanediolglucuronide (3.02+/-1.97 nmol/l vs. 2.28+/-1.67 nmol/l, p = 0.13), at 14 years of age, in girls or boys. At 14 years of age, no change in the gender ratio of children with active asthma had occurred. These results may indicate that the change in gender predominance of asthma through the second decade of life is not caused by increased loss of established asthma in boys between 10 and 14 years of age.

Polymorphisms in the bradykinin B2 receptor gene and childhood asthma.

Bradykinin has been suggested as one of the key mediators of bronchial asthma. Polymorphisms with a potential functional relevance have been described in the B2 bradykinin receptor gene. Study of these polymorphisms in 77 children with asthma and 73 controls revealed no association. However, when comparing the asthmatics according to their age at onset (before and after age 4), the exon 1 allele BE1-2G was significantly associated with late-onset asthma (p<0.05). Since BE1-2G has previously been shown to lead to a higher transcription rate of the B2 receptor, this result warrants further investigation of the role of bradykinin in conferring susceptibility to pediatric asthma.

Histamine challenges discriminate between symptomatic and asymptomatic children. MAS-Study Group. Multicentre Allergy Study.

The aims of this study were to investigate a threshold value for bronchial responsiveness in children aged 7 yrs, which discriminates between symptomatic and asymptomatic children, and to identify determinants of this responsiveness. Titrated bronchial histamine challenges using the reservoir method were performed in 645 children aged 7 yrs, from the birth cohort Multicentre Allergy Study (MAS). When defining a reference population of healthy children within the MAS cohort, the 95th percentile of the provocative concentration causing a 20% fall in forced expired volume in one second PC20 among these asymptomatic study subjects amounted to 0.60 mg x mL(-1). This resulted in a specificity of 93.0% and a sensitivity of 45.9%, for discriminating between "current wheezers" and "non-current wheezers". Determinants of airway responsiveness at this age were pulmonary function, sensitization to indoor allergens, total immunoglobulin E and current wheeze. The results indicate that a very low cut-off provocative concentration causing a 20% fall in forced expired volume in one second (<1.0 mg x mL(-1)) defines airway hyperresponsiveness in children aged 7 yrs using the reservoir method. Provocation protocols for histamine challenges in this age group should therefore start with concentrations markedly below 1.0 mg x mL(-1).

Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.

OBJECTIVE: To investigate the association between early childhood infections and subsequent development of asthma. DESIGN: Longitudinal birth cohort study. SETTING: Five children's hospitals in five German cities. PARTICIPANTS: 1314 children born in 1990 followed from birth to the age of 7 years. MAIN OUTCOME MEASURES: Asthma and asthmatic symptoms assessed longitudinally by parental questionnaires; atopic sensitisation assessed longitudinally by determination of IgE concentrations to various allergens; bronchial hyperreactivity assessed by bronchial histamine challenge at age 7 years. RESULTS: Compared with children with /=2 episodes were less likely to have a doctor's diagnosis of asthma at 7 years old (odds ratio 0.52 (95% confidence interval 0.29 to 0.92)) or to have wheeze at 7 years old (0.60 (0.38 to 0.94)), and were less likely to be atopic before the age of 5 years. Similarly, having >/=1 viral infection of the herpes type in the first 3 years of life was inversely associated with asthma at age 7 (odds ratio 0.48 (0.26 to 0.89)). Repeated lower respiratory tract infections in the first 3 years of life showed a positive association with wheeze up to the age of 7 years (odds ratio 3.37 (1.92 to 5.92) for >/=4 infections v