Airway hyperresponsiveness and body mass index: the Child Health and Environment Cohort Study in Hesse, Germany.

Increased body mass index has been linked to wheezing, a diagnosis of asthma, and morbidity. We investigated the association between body mass index (BMI), breastfeeding, and airway hyperresponsiveness (AHR) in 536 German schoolchildren. We analyzed consecutive surveys in 1994-1995 and 1997, conducted as part of the Child Health and Environment Cohort Study in Hesse, Germany. The questionnaire included questions adapted from the German version of the International Study of Asthma and Allergy in Childhood (ISAAC). A bronchial challenge test using 4.5% hypertonic saline was conducted during the 1997 survey. AHR was defined as a fall in forced expiratory volume in 1 sec (FEV(1)) of > or = 15%. Of 536 children who participated in the 1997 survey (median age, 10.3 years), 82 (15%) tested positive for AHR. In a multivariate analysis, there was no association between AHR determined at age 10 years and the highest quintile of BMI compared to the lowest quintile at age 4 years (odds ratio (OR), 1.4; 95% confidence interval (CI), 0.5-3.6), 7-8 years (OR, 0.6; 95% CI, 0.1-2.5), or 10 years (OR, 1.1; 95% CI, 0.2-4.3). Breastfeeding for 12 weeks or longer protected against AHR (OR, 0.4; 95% CI, 0.2-0.9). However, when children in the highest quintile of BMI at age 4 years had been breastfed for 8 weeks or less, the prevalence of AHR at age 10 years was significantly increased (27.7%, P = 0.01). In conclusion, our results demonstrate a protective effect of breastfeeding against AHR, and reinforce the need to encourage breastfeeding. Although there was no association between BMI and AHR, our finding of an interactive effect of high BMI and short breastfeeding on AHR suggests a complex etiological pathway that needs to be further explored.

Effect of genistein on native epithelial tissue from normal individuals and CF patients and on ion channels expressed in Xenopus oocytes.

The flavonoid genistein has been shown to activate a Cl(-) conductance in various cell types expressing CFTR. We examined if similar effects can be observed when genistein is applied to native ex vivo tissues from human respiratory tract and rectum. We further compared the effects when genistein was applied to oocytes of Xenopus laevis expressing CFTR. In oocytes, both wtCFTR and DeltaF508-CFTR were activated by genistein while both cyclic AMP (K(v)LQT1) and Ca(2+) (SK4) activated K(+) channels were inhibited at high concentrations of genistein. Biopsies from nasal polyps and rectal mucosa were obtained from normal individuals (non-CF) and CF patients and in the presence of amiloride (10 micromol l(-1); mucosal side) the effects of genistein were assessed using a perfused Ussing chamber. In non-CF airway epithelia, genistein (50 micromol l(-1); mucosal side) increased lumen negative I(sc) but had no additional effects on tissues pre-stimulated with IBMX and forskolin (100 micromol l(-1) and 1 micromol l(-1); both sides). In non-CF rectal biopsies, in the presence of amiloride (10 micromol l(-1); mucosal side) and indomethacin (10 micromol l(-1); basolateral side), genistein increased lumen negative I(sc) and enabled cholinergic (carbachol; CCH, 100 micromol l(-1); basolateral side) stimulation of Cl(-) secretion indicating activation of luminal CFTR Cl(-) channels. However, after stimulation with IBMX/forskolin, genistein induced opposite effects and significantly inhibited CCH activated I(sc). In CF airway and intestinal tissues genistein failed to induce Cl(-) secretion. Thus, genistein is able to activate luminal CFTR Cl(-) conductance in non-CF tissues and mutant CFTR in oocytes. However, additional inhibitory effects on basolateral K(+) conductance and missing effects in native CF tissues do not support the use for pharmacological intervention in CF.

Assessing the effect of time-varying covariates in cross-sectional studies.

In cross-sectional studies exposure and disease status of individuals are assessed at the same point in time, but sometimes information on prior exposure status is also gathered. Under such circumstances one approach to assessing the relationship between disease and exposure is using linear or logistic regression analysis, adjusting for exposure status at different points in time. It is shown that estimates for the effect of exposure at a certain point in time, adjusted for exposure at another point in time, are obtained from comparisons between groups with different patterns of exposure. Careful interpretation of the resulting estimates is necessary, taking into account a detailed consideration of possible exposure patterns. In addition, if changes in exposure are caused by the occurrence of the disease, then adjusting for multiple measurements of exposure can give misleading results. A regression analysis on dummy variables describing possible patterns of changes in exposure is proposed as an alternative approach. This approach facilitates interpretation of the resulting estimates. Furthermore, it can serve as a diagnostic tool to check for disease related changes in exposure. For this case transferring exposure change rates of healthy subjects to diseased subjects is suggested as an ad hoc method for assessing the hypothetical current relationship between exposure and disease.

Relationship between atopy and frequent bronchial response to exercise in school children.

The natural history of a bronchial response to exercise (BRE) was studied in a cohort of primary-school children, who were followed over a 2-year period. In 1,094 children, three free-running tests were performed in 1-year intervals. Children who responded in one of the tests were designated as "infrequent" responders (20.5%), whereas those responding at two or all three occasions were designated as "frequent" responders (7.4%). A frequent positive BRE was closely associated with atopy (defined as skin test positivity to 1 of 7 common aeroallergens) and respiratory symptom status. Compared to atopics without respiratory symptoms, an increased risk for a frequent positive BRE was seen for atopic children who were symptomatic during the whole study period [odds ratio (OR) 25.4; confidence interval (CI) 6.9-94.0], who had gained symptoms (OR, 11.0; CI, 2.8-43.2) or who had symptoms at the beginning of the study but had lost them during follow-up (OR, 4.6; CI, 1.0-20.6). A sensitization to dust mites (OR, 8.0; CI, 4.3-15.0) but not to animal dander (OR, 2.3; CI, 1.0-5.2) or pollen (OR, 0.7; CI, 0.3-1.6) was significantly related to a frequent positive BRE. Our findings support the notion that while "children grow out of asthma," they might maintain their bronchial hyperresponsiveness. Regarding specific sensitization, mite allergy seems to play the predominant role.

Relationship between exposure to dust mite allergen and bronchial response to exercise in schoolchildren sensitized to dust mites.

We assessed the relationship between the exposure to dust mite allergens and a bronchial response to exercise in 8-year-old schoolchildren. Dust was collected from the mattresses of 1,291 children and the concentration of mite allergens was estimated by a commercially available ELISA test using monoclonal antibodies (ALK, Copenhagen) against the major allergens of Dermatophagoides pteronyssinus (Der pt) and Dermatophagoides farinae (Der f). A positive bronchial response to exercise (decrease of peak expiratory flow > or = 15% after exercise) occurred in 21 (22.6%) of 101 children sensitized to mite allergens (wheal size > or = 4 mm) and in 51 (4.8%) of 1,070 nonsensitized children. In the highest exposure groups (> 10 micrograms allergen/g dust), 15% of children sensitized to Der f and 20% of children sensitized to Der pt were responsive to exercise. Corresponding figures for the lowest exposure groups (< 0.4 micrograms allergen/g dust) were 11 and 28%, respectively. This negative finding may indicate that measurement of allergen concentration in mattresses does not reflect true exposure or alternatively that at the age of 8 years high exposure to dust mite allergens does not affect bronchial response to exercise in sensitized children.

Effects of ambient ozone exposures during the spring and summer of 1994 on pulmonary function of schoolchildren.

To investigate the effect of natural exposure to ambient ozone over time, a follow-up study of school-aged children was performed in two small towns in southwestern Germany (Freudenstadt and Villingen) between March and October of 1994. Ozone half-hour mean concentrations were measured continuously and pulmonary function was tested in each child on four occasions (April, June, August, and September). To obtain an average short-term ozone effect, we first analyzed the data from the four time points separately and then constructed a model that included all information. During the study period the median (5th to 95th percentile) of all half-hour values of the ozone concentration was 101 micrograms/m3 or 50.6 ppb (45-179 micrograms/m3 or 22.5-89.8 ppb) in Freudenstadt and 64 micrograms/m3 or 32.1 ppb (1 to 140 micrograms/m3 or 0.5-70.1 ppb) in Villingen. To assess the effects of an individual ozone exposure we related the highest ozone concentration in the respective 24 hours before lung function testing to the results of the subconcentration in the respective 24 hours before lung function testing to the results of the subsequent pulmonary function tests. In the lung function test following the highest ozone exposure, the results of our cross-sectional linear regression analysis showed a significant negative correlation (P = 0.0181) between ozone exposure and forced vital capacity (FVC). In the longitudinal linear regression model we observed a negative statistical correlation between ozone exposure and lung function for the subpopulation living in the town with the high ozone levels (Freudenstadt). The association was more pronounced in boys than girls. For the children in Freudenstadt the decrement of FVC was -12.31 ml/10 micrograms/m3 ozone and the decrease in the forced expiratory volume in 1 second (FEV1) was -11.29 ml/10 micrograms/m3 ozone.

Pulmonary function in children of school age is related to the number of siblings in their family.

It has been suggested that the number of siblings in a family is a surrogate variable for exposure to early infections. Since there may be an association between early respiratory infections and impaired lung function in later life, the aim of this study was to elucidate the relationship between the number of siblings and pulmonary function. We analyzed pulmonary function data from 677 schoolchildren living in 431 nuclear families. Our results show that forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) expressed as a percentage of deviation from the predicted values (FVC%, FEV(1)%) increase significantly in line with the number of siblings in a family (FVC%: no sibling = reference, 1 sibling = +1.3%, 2 siblings = +1.9%, 3 siblings = +4.0%, 4 or more siblings = +5.1%; P-value for trend = 0.01; FEV(1)%: no sibling = reference, 1 sibling = +1.6%, 2 siblings = +2.0%, 3 siblings = +4.3%, 4 or more siblings = +6.5%; P-value for trend = 0.007). Pulmonary function values were no more strongly related to the number of older siblings than to the number of younger siblings (difference between the trend for older and younger siblings for FCV%: P = 0.7; FEV(1)%: P = 0.9). The association between pulmonary function and number of siblings can be explained neither by the child's atopic status, prevalence of asthma, or history of pneumonia, nor by former or current cigarette smoke exposure. This suggests that pulmonary function status of the child appears to be related to the number of siblings, and is unlikely to be explained solely by exposure to infections early in life. Our data therefore adds strength to the hypothesis that factors which cause the size of a sibship to influence a child's respiratory health have not yet been adequately explained.

Bronchial hyperresponsiveness to 4.5% hypertonic saline indicates a past history of asthma-like symptoms in children.

SUMMARY. To evaluate the importance of a past history of asthma-like symptoms over a period of 2 years and current bronchial hyperreactivity (BHR), 538 randomly selected schoolchildren, initially aged 7-8 years, were examined. At yearly intervals, three standardized questionnaires, including items from the ISAAC panel, were answered by parents. Following the last questionnaire, BHR to 4.5% hypertonic saline (HS) was recorded. In survey 1, lifetime prevalence of asthma was 4.9%. During the 12-month period, prevalence of wheeze and dyspnea ranged between 9.3 and 5.2% (Survey 1) and 5.9% and 4.4% (Survey 2). Among children with wheeze or dyspnea in Survey 3, BHR (defined as a fall of baseline FEV(1) > or = 15%) was significantly more frequent (50.0% and 60.7%, respectively) than among children without these symptoms (12.8%, P < 0.001, and 12.8%, P < 0.001, respectively). The negative predictive value of BHR to have neither wheeze nor dyspnea was about 88% and did not vary throughout the study (Survey 1, 87%; Survey 2, 88%; Survey 3, 88%). The relative risk of showing BHR was significantly increased in children with wheeze (survey 2, odds ratio (OR) 3.0 (95% confidence interval (CI) 1.0-8.7)) or dyspnea (Survey 1: OR 5.9 (95% CI 1.9-18.5), Survey 3: 5.2 (1.7-16.2), but not in children with dry cough or nocturnal cough (data not shown). Wheeze and dyspnea occurred repeatedly in the same individuals with BHR in a high percentage of children (83.3% and 76.5%, respectively). In conclusion, there is a strong association between recent and previous dyspnea and current BHR, and it indicates intraindividual persistence of symptom history.

Association of allergy-related symptoms with sensitisation to common allergens in an adult European population.

BACKGROUND: Atopy is an important risk factor for asthma and allergic diseases. However, the relationship between atopy and allergic symptoms is not fully understood, and may not be the same for different allergy related symptoms and in differing environmental conditions. OBJECTIVE: To study the differences in the association of allergy-related symptoms and atopy, in an adult population from five European countries. METHODS: A prospective, multi-national study was conducted. Centres included Isle of Wight (UK), Vienna (Austria), Freiburg (Germany), Athens (Greece), and Kaunas (Lithuania). We used five questions derived from the ISAAC (International Study of Asthma and Allergy in Children) and other validated questionnaire, to evaluate the presence of allergic symptoms in a selected adult population. Atopy was assessed by SPT or IgE measurement to 3 core allergens (dust mite, cat and grass pollen) in all centres and 1-2 additional allergens relevant to each area (parietaria, olive, birch pollen, tree pollen mix, dog). RESULTS: Of 3985 subjects, 2478 (62%) responded positively to one or more core ISAAC questions. Sensitisation rate was high in Austria and UK and relatively low in Greece. Dust mite and cat were important allergens for asthma, odds ratio (OR): 2.24, 95% confidence interval (CI): 1.63-3.08 and OR: 2.31, CI: 1.69-3.14, respectively. Grass pollen was strongly associated with hay fever in all centres (OR: 3.62 CI: 2.81-4.66) and with birch pollen in Austria (OR: 3.57, CI: 2.09-6.09) and with parietaria in Greece (4.61 (2.99-7.12). In the comparative analysis, using UK as a reference, Lithuanians had a 10-20-fold reduced risk of asthma and hay fever, but were twice more likely to report chronic itching. The risk of dust mite allergy was 3- and 10-fold lower in Lithuania and Greece, respectively, whereas the risk of cat and grass pollen allergy was one and half times higher in Austria. CONCLUSION: The risk of allergic symptoms and sensitisation and their association vary widely in different European countries.

Infections and atopic disorders in childhood and organochlorine exposure.

The authors investigated whether organochlorine exposure is associated with prevalence of otitis media, pneumonia, pertussis, asthma, and increased immunoglobulin E levels in children. Organochlorine concentrations and histories of infection and atopic manifestation were available for 343 children, and immunoglobulin E levels were available for 340 children. The authors applied logistic and linear regressions and controlled for confounders. In general, the prevalence of infections in children was not related to organochlorine exposure. However, for the combined effect of dichlorodiphenyldichloroethene with polychlorinated biphenyls or hexachlorobenzene, a significantly increased relative risk (odds ratios = 3.70 and 2.38, respectively) was found for otitis media. Exposure to dichlorodiphenyldichloroethene resulted in a significantly higher odds ratio for asthma (odds ratio = 3.71; 95% confidence interval = 1.10, 12.56) and in immunoglobulin E concentrations above 200 kU/l (odds ratio = 2.28; 95% confidence interval = 1.20, 4.31). This is the first study in which dichlorodiphenyldichloroethene has been identified as a substantial risk factor for asthma and for increased immunoglobulin E blood levels.

Severe hypomyelination as the leading neuroradiological sign in a patient with fucosidosis.

Fucosidosis is a rare autosomal recessive lysosomal storage disease, resulting from a deficiency of alpha- L-fucosidase. We report on the clinical and MRI findings of a girl with this disorder. Developmental delay became obvious at an age between 6 and 12 months. Cranial MRI at 16 months revealed severe global hypomyelination of both supra- and infratentorial white matter but no involvement of basal ganglia or thalamus. No clinical signs typical for fucosidosis were present at this time, and psychomotor development still progressed slowly. Since the age of 2 years, progressive neurological deterioration occurred. The diagnosis was established by severely decreased activity of alpha- L-fucosidase in plasma and leukocytes and confirmed by the detection of compound heterozygosity for two missense mutations of the FUCA1 gene. A follow-up imaging at the age of 4 years showed progression of neuroradiological abnormalities, particularly progressive involvement of basal ganglia and thalami. The course of this patient and her MRI findings enlarge the clinical and neuroradiological spectrum of fucosidosis.

Variability of peak expiratory flow rate in children: short and long term reproducibility.

BACKGROUND: Variability of peak expiratory flow (PEF) has been proposed as a surrogate for bronchial hyperresponsiveness. The normal range of variability of PEF for children has been reported and the test has been used to screen for asthma in population based studies. However, there is little information on the reproducibility of the method in epidemiological settings. METHODS: In a cohort study of primary school children the variability in PEF was recorded in two consecutive years for one week (first survey) and two weeks (second survey) using mini Wright peak flow meters. PEF was recorded twice daily (morning and evening) and average amplitude as a percentage of mean was calculated as a standard measure of PEF variability for each single week of PEF measurement. Children with PEF variability exceeding the 90% percentile of the distribution for the specific time period were regarded as having increased variability of PEF. RESULTS: Of 66 children with increased PEF variability in the first year, 13 (19.7%) had an abnormal test in the first week of the second year. Of 543 children with normal PEF variability in the first year, 44 (8.1%) had an abnormal test in the second study year (odds ratio 2.8, confidence interval (CI) 1.4 to 5.4). Of 646 children in the second survey 61 (9.4%) were abnormal during the first week and 68 (10.5%) had an increased PEF variability during the second week, but only 24 (3.7%) children had an increased PEF variability in both weeks. The sensitivity (specificity) for doctor-diagnosed asthma (12 month period prevalence) was 36.4% (91.0%) in the first week of the second survey. When measurements of both weeks of the second survey were used to calculate PEF variability there was little improvement in the sensitivity (38.1%) and specificity (91.5%), mainly because of decreased compliance in the second measurement week. CONCLUSIONS: In young children assessment of PEF variability in order to screen for asthma is of limited value because of the low reproducibility of the method.

Influence of skin prick test criteria on estimation of prevalence and incidence of allergic sensitization in children.

In a prospective cohort study on atopy in childhood, three skin prick tests (SPT) were performed in 1135 primary schoolchildren over a 2-year period. We studied the development of average sizes of allergen wheals in reactive children and of average sizes of histamine wheals in all children, and we investigated the influence of choice of SPT criterion on the prevalence and incidence of sensitization. A year-to-year increase of average allergen wheal sizes as well as of average histamine wheal sizes was observed. These increases seemed to be related to the natural growth of the children. Furthermore, an observer bias effect of the person who did the pricking on average wheal sizes was found. There were considerable differences in estimations of prevalences and incidences depending on the definition of SPT criterion. Estimations using a criterion based solely on the allergen wheal size were affected by variation of allergen wheal sizes caused by growth and observer effects. The ratio criterion was not influenced by observer effects, nor did it seem to be affected by aging effects. In conclusion, our data suggest that the ratio criterion, which relates the size of the allergen wheal to the size of the histamine wheal, is the most appropriate SPT criterion because it is not affected by growth of allergen wheals in childhood and it appears to compensate for possible observer bias.

The most common phenotypes of sensitization to inhalant allergens in childhood.

BACKGROUND: Atopic individuals are frequently sensitized to a limited number of certain allergens, although most of them are exposed to multiple inhalant allergens in daily life. OBJECTIVE: We investigated the hypothesis that observed common patterns of sensitization might occur with similar frequency within two independent study populations of school-children. METHODS: The results were derived from skin-prick tests conducted on two large samples of children (study 1: n = 583; study 2: n = 1099) examined with the same panel of six inhalant allergens. RESULTS: In order to ensure that the comparison was uniform, the younger subpopulation of study 1 (n = 147) was compared with the sample of study 2 (n = 374). The highest frequency for monosensitization was found for sensitization to Dermatophagoides pteronyssinus (study 1: 18.4%, study 2: 20.3%), followed by monosensitization to grass pollens (study 1: 12.2%; study 2: 8.8%). Using multiple logistic regression for each specific sensitization, a significantly increased relative risk of sensitization to hazel pollens (study 1 OR 5.9; study 2 OR: 24.3) appeared to be associated with sensitization to birch pollens. The same applied to dog dander (study 1 OR: 7.3; study 2 OR: 2.6), which showed an association with sensitization to cat dander. CONCLUSION: In summary, our data suggest that certain clusters of monosensitization and polysensitization to common inhalant allergens exist among a given population. This may well be a reflection of diversity in disposition to specific sensitization and/or antigen crossreactivity. From a practical point of view the data also might help in counselling parents of allergic children.

Two common polymorphisms in the coding part of the CD43 gene are not associated with atopy.

BACKGROUND: Recently linkage and association of the chromosomal region 16p12-11 with enhanced IgE responsiveness have been shown. The gene coding for CD43 (sialophorin) has been localized to this region. Sialophorin represents a major sialoglycoprotein on the surface of human lymphocytes, monocytes and granulocytes. It is supposed to play an important role in human mast cell, T- and B-cell regulation and activation and has been described in connection with immunodeficiency diseases such as the Wiskott-Aldrich syndrome. Therefore, it can be designated as a candidate gene for atopy. METHODS: Using SSCP analysis and direct genomic sequencing, polymorphisms in the CD43 gene have been looked for and their association with atopy has been tested in a population of 260 largely atopic children and young adults. RESULTS: Three common polymorphisms in the coding part of the CD43 gene were found. Two of them are leading to amino acid exchanges, one from argine to cysteine at amino acid position 337 of the mature gene product and one from leucine to phenylalanine at amino acid position 341. Subsequent association studies revealed no obvious influence of R337C or L341F on IgE regulation (p = 0.47 and 0.43), neither in a cognate nor in an uncognate fashion. CONCLUSION: We conclude that CD43 polymorphisms are unlikely to account for the observed linkage effect at 16p12-11. Whether the polymorphisms R337C and L341F adjacent to phosphorylation sites in the intracellular region of the protein alter the normal functioning of CD43 remains to be elucidated.

Characterization of the membrane-bound and a soluble form of human IL-4 receptor alpha produced by alternative splicing.

IL-4 plays a major role in IgE production. Its signal is conferred to effector cells through binding to the alpha chain of the membrane-bound human IL-4 receptor (huIL-4Ralpha). Here we present the genomic structure and organization of huIL-4Ralpha. The promotor region shows binding sites for several transcription factors involved in inflammatory processes. HuIL-4Ralpha has been shown to be organized differently to that of mouse IL-4Ralpha. A soluble form of huIL-4Ralpha is produced by alternative splicing of the huIL-4Ralpha gene (shuIL-4Ralpha/splice). Expression of the corresponding mRNA coding for the extracellular part of the receptor and an additional three amino acids is also shown. A second form of huIL-4Ralpha, i.e. shuIL-4Ralpha/prot, is produced by limited proteolysis of the receptor (shedding) and is already known. These results reveal a complex pattern for the regulation of the IL-4 pathway at the receptor level. The patterns of expression of all three receptor proteins as well as their individual meaning in the context of inflammation still have to be elucidated.

Common polymorphisms and alternative splicing in the ILT3 gene are not associated with atopy.

Recently, a linkage of the chromosomal region 19q13.4 with bronchial asthma has been demonstrated. This region harbours the so-called leucocyte receptor cluster with the gene for immunoglobulin-like-transcript 3 (ILT3) as a member. ILT3 represents an inhibitory receptor bearing three immunoreceptor tyrosine inhibitory motifs (ITIM). The protein mediates downregulation of cell activation through recruitment of different SH2-containing protein tyrosine phosphatases. With regard to the negative immunoregulatory function particularly on B-cells, ILT3 represents a candidate gene for atopy and asthma. The aim of this study was to screen for common polymorphisms in the gene coding for ILT3 and to test for association with the atopic phenotype. Using single-stranded conformal polymorphism-analysis and direct genomic sequencing seven polymorphisms, three mutations, a common deletion of 7 bp in the third intron and evidence for further alternative splicing of the ILT3 gene were found. Although no association was found with atopy phenotypes, it might prove useful to test for association with bronchial asthma.