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1.  Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study 
BMJ : British Medical Journal  2001;322(7283):390-395.
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 ⩽1 episode of runny nose before the age of 1 year, those 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 ⩽3 infections).
Conclusion
Repeated viral infections other than lower respiratory tract infections early in life may reduce the risk of developing asthma up to school age.
PMCID: PMC26566  PMID: 11179155
2.  Progression of allergy and asthma through childhood to adolescence. 
Thorax  1996;51(Suppl 1):S3-S6.
The reduction in asthma symptoms and bronchial hyperresponsiveness in adolescence is not well understood. Nor can the differences in asthma prevalence and severity between the sexes, which reverse at puberty, be explained. It has been suggested that the improvement in asthma during adolescence may result from diminished clinical and immunological responsiveness directly related to hormonal changes and that the effect of age on the prevalence of asthma in each sex may relate to differences in hormonal status, potentially influencing airway size, inflammation, and smooth muscle and vascular functions. However, few comprehensive studies are available. In summary, all wheezing is not asthma. Non-asthmatic wheezing illnesses may in part be attributable to anatomical abnormalities of the lung (transient early wheezing, premature birth). Little is known about the genetic and environmental determinants of childhood asthma, and factors related to the development of atopic sensitisation, such as exposure to allergens, infectious diseases, or tobacco smoke early in life, and dietary habits may be important, whereas the relevance of air pollution remains to be established. Unfortunately, we still do not know how to prevent the manifestation of childhood asthma.
PMCID: PMC1129002  PMID: 8658385
3.  Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in children: a case-control study of three schools 
Thorax  1999;54(8):675-680.
BACKGROUND—The amount of allergen necessary to sensitise genetically "at risk" children is unclear. The relation between allergen exposure and asthma is also uncertain.
METHODS—To ensure a wide range of allergen exposures the data from case-control studies of asthma in children aged 12-14 years attending three schools in Los Alamos, New Mexico and Central Virginia were combined. Skin prick tests to indoor and outdoor allergens and bronchial hyperreactivity to histamine were assessed in children with and without symptoms of asthma. The concentration of mite, cat, and cockroach allergens in dust from the children's homes was used as a marker of exposure.
RESULTS—Three hundred and thirty two children (157 with asthmatic symptoms and 175 controls) were investigated. One hundred and eighty three were classified as atopic on the basis of allergen skin prick tests and 68 as asthmatic (symptoms plus bronchial responsiveness). The prevalence and degree of sensitisation to mite and cockroach, but not cat, was strongly associated in atopic children with increasing domestic concentrations of these allergens. Asthma was strongly associated with sensitisation to indoor allergens (p<10-6) and weakly to outdoor allergens (p = 0.026). There was an association between current asthma and the concentration of mite allergen amongst atopic children (p = 0.008) but not amongst those who were specifically mite sensitised (p = 0.16).
CONCLUSIONS—The domestic reservoir concentration of mite and cockroach, but not cat, allergen was closely related to the prevalence of sensitisation in atopic children. However, the prevalence of current asthma had a limited relationship to these allergen measurements, suggesting that other factors play a major part in determining which allergic individuals develop asthma.


PMCID: PMC1745561  PMID: 10413718
4.  The influence of sensitisation to pollens and moulds on seasonal variations in asthma attacks 
The European Respiratory Journal  2013;42(4):935-945.
No large study has described the seasonal variation in asthma attacks in population-based asthmatics in whom sensitisation to allergen has been measured.
2637 young adults with asthma living in 15 countries reported the months in which they usually had attacks of asthma and had skin-prick tests performed. Differences in seasonal patterns by sensitisation status were assessed using generalised estimating equations.
Most young adults with asthma reported periods of the year when their asthma attacks were more common (range: 47% in Sweden to 86% in Spain). Seasonal variation in asthma was not modified by sensitisation to house dust mite or cat allergens. Asthmatics sensitised to grass, birch and Alternaria allergens had different seasonal patterns to those not sensitised to each allergen, with some geographical variation. In southern Europe, those sensitised to grass allergens were more likely to report attacks occurred in spring or summer than in winter (OR March/April 2.60, 95% CI 1.70–3.97; OR May/June 4.43, 95% CI 2.34–8.39) and smaller later peaks were observed in northern Europe (OR May/June 1.25, 95% CI 0.60–2.64; OR July/August 1.66, 95% CI 0.89–3.10). Asthmatics reporting hay fever but who were not sensitised to grass showed no seasonal variations.
Seasonal variations in asthma attacks in young adults are common and are different depending on sensitisation to outdoor, but not indoor, allergens.
Seasonal variation in asthma attacks is associated with sensitisation to pollens and moulds, but not indoor allergens http://ow.ly/nsuRS
doi:10.1183/09031936.00097412
PMCID: PMC3787817  PMID: 23471350
5.  Early allergen exposure, skin prick responses, and atopic wheeze at age 5 in English children: a cohort study 
Thorax  2004;59(10):855-861.
Background: For many years it has been assumed that the risk of childhood respiratory allergies is related to allergen exposures in early life. There are, however, few prospective data in support. We aimed to examine this relationship in a representative cohort of children born in Ashford, Kent (UK).
Methods: 625 children (94% of those eligible) were followed from birth to the age of 5.5 years at which time 552 underwent skin prick testing to extracts of house dust mite and cat fur allergens. Maternal reports of wheeze in the last year were collected by interview. These outcomes were related to individual domestic concentrations of Der p 1 and Fel d I allergens estimated from dust collection at the age of 8 weeks.
Results: 10% of children were sensitised to house dust mite or cat at age 5.5 years; 7% had atopic wheeze. No significant relationships between allergen exposure and either sensitisation or wheeze were found but, on examination, the exposure-response relationships for both allergens and for each outcome rose steeply at low levels of exposure and were attenuated at high levels of exposure. These patterns were modified by paternal atopy and by birth order.
Conclusions: There are no linear relationships between early allergen exposure and the induction of childhood respiratory allergy; rather, the risks of IgE sensitisation and asthma rise at very low levels of exposure and are attenuated thereafter. These patterns are influenced by parental atopy and birth order. These findings suggest important gene-environment interactions in the development of atopy and asthma and imply that reductions in domestic allergen exposure alone are unlikely to have a major impact in decreasing the incidence of these diseases in childhood.
doi:10.1136/thx.2003.019877
PMCID: PMC1746847  PMID: 15454651
6.  Risk factors for respiratory symptoms and atopic sensitisation in the Baltic area. 
Archives of Disease in Childhood  1995;72(6):487-493.
Recent studies have indicated that atopic sensitisation is uncommon while respiratory symptoms are common among schoolchildren in Eastern Europe. Risk factors for respiratory symptoms and atopic sensitisation were evaluated in a cross sectional study involving 2594 schoolchildren (10-12 years) from Sweden (n = 665), Poland (n = 410), and Estonia (n = 1519). The measurements included parental questionnaires and skin prick tests with eight standardised allergens. Multiple logistic analyses demonstrated that atopic heredity was a significant independent risk factor for respiratory symptoms and atopic sensitisation in all the countries. Current dampness and maternal smoking were related to respiratory symptoms whereas domestic crowding, male gender, and passive smoking during infancy were related to atopic sensitisation. Current maternal smoking had a strong dose response association with current coughing attacks (nocturnal cough > 4 weeks or exercise induced coughing attacks) but only in Eastern Europe. A strong inverse relationship was recorded between domestic crowding and sensitisation as the risk for sensitisation increased with decreasing number of persons per room in the household (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.43 to 0.77). Exposure to tobacco smoke at home during infancy was a risk factor for atopic sensitisation but only to animal dander and only in Eastern Europe (OR 1.41, 95% CI 1.03 to 1.93). In conclusion, there were small differences in the pattern of risk factors between Eastern and Western Europe. The only exception was environmental tobacco smoke being a risk factor only in Eastern Europe. The study also suggests that factors related to domestic crowding protect against atopic sensitisation in Estonia and Poland. A higher standard of living with less crowding may give rise to an increasing prevalence of atopic sensitisation also in Eastern Europe.
PMCID: PMC1511140  PMID: 7618931
7.  The presence of serum anti-Ascaris lumbricoides IgE antibodies and of Trichuris trichiura infection are risk factors for wheezing and/or atopy in preschool-aged Brazilian children 
Respiratory Research  2010;11(1):114.
Background
The elucidation of factors that trigger the development of transient wheezing in early childhood may be an important step toward understanding the pathogenesis of asthma and other allergic diseases later in life. Transient wheezing has been mainly attributed to viral infections, although sensitisation to aeroallergens and food allergens may occur at an early age. In developing countries, intestinal helminthic infections have also been associated with allergy or atopy-related disorders.
Objective
The aim of this study was to explore the association of Trichuris trichiura and Ascaris lumbricoides infections with wheezing and atopy in early childhood.
Study design
A cross-sectional study using a Portuguese-language ISAAC phase I questionnaire, adapted for preschool-aged children, nested in a cohort study of childhood diarrhoea, was conducted on 682 children. Two faecal samples per child were examined for the presence of intestinal helminthic infection. IgE antibodies against three allergenic preparations (Dermatophagoides pteronyssinus, Blomia tropicalis and common child food), as well as against A. lumbricoides antigens, were measured in a sub-sample of these children, whose parents allowed the procedure. Atopy was defined by the presence of levels of serum IgE antibodies ≥0.35 kU/L against at least one of the three tested allergenic preparations.
Results
Active T. trichiura infection but not A. lumbricoides infection was positively associated with wheezing in the total studied children population [adjusted OR = 2.60; CI = 1.54;4.38] and in the atopic children sub-population [adjusted OR = 3.07; CI = 1.00;9.43]. The association with atopy was also positive and statistically significant only in the brute analysis [OR = 2.13; CI = 1.03;4.40]. Anti-A. lumbricoides IgE antibodies, but not current A. lumbricoides infection, were positively associated with wheezing in atopic children [adjusted OR = 2.01; CI = 1.00;4.50] and in non-atopic children [adjusted OR = 3.07; CI = 1.13;8.35] and it was also associated with atopy [adjusted OR = 7.29; CI = 3.90; 13.4]. On the other hands, reports of wheezing were not significantly associated with atopy.
Conclusions
These data corroborate previous studies showing that wheezing is predominantly associated with infection in early childhood and shows that anti-A. lumbricoides IgE antibodies, but not active Ascaris infections, are associated with wheezing and atopy. Additionally, the data demonstrate that T. trichiura infection may play a role in the pathogenesis of atopic wheezing in early childhood.
doi:10.1186/1465-9921-11-114
PMCID: PMC2939601  PMID: 20731833
8.  Lung function at one month of age as a risk factor for infant respiratory symptoms in a high risk population 
Thorax  2002;57(5):388-392.
Background: Abnormal premorbid lung function is a risk factor for subsequent wheezing in children with one or no atopic parent. This study was undertaken to establish whether early lung function in high risk infants (both parents atopic) was a risk factor for respiratory symptoms in infancy and to examine the influence of maternal asthma, smoking, and allergen exposure during pregnancy on any association.
Methods: Infants were recruited from the NAC Manchester Asthma and Allergy Study cohort at birth. Partial forced expiratory flow volume technique under sedation was carried out to determine maximal flow at FRC (V'maxFRC). Children were followed prospectively and parents completed a standard respiratory questionnaire at one year of age.
Results: Sixty nine term infants (34 boys; 88% mothers non-smokers; no household pets) underwent respiratory function testing. Size adjusted V'maxFRC was significantly lower in infants who had recurrent wheeze during the first year of life (mean 1.3 ml/s/cm, 95% CI 0.99 to 1.60) than in those who did not (mean 2.03 ml/s/cm, 95% CI 1.71 to 2.36; p=0.01). V'maxFRC was also significantly lower in infants who had recurrent cough symptoms. In multivariate regression analysis, when adjusted for age at test, sex, maternal asthma, smoking and maternal mattress Der 1 levels, a lower size adjusted V'maxFRC score remained strongly associated with wheezing (OR 0.37, 95% CI 0.18 to 0.77, p=0.007). Maternal smoking also remained an independent risk factor (OR 29.85, 95% CI 2.46 to 362.5, p=0.008).
Conclusion: Significantly diminished lung function was present in high risk infants who subsequently wheezed and coughed. This was independent of maternal exposure to mite allergen, asthma, and smoking during pregnancy.
doi:10.1136/thorax.57.5.388
PMCID: PMC1746314  PMID: 11978912
9.  Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects 
Thorax  2005;60(1):17-21.
Background: The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed.
Methods: Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing.
Results: Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD20, geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p = 0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p = 0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens.
Conclusion: Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.
doi:10.1136/thx.2004.027839
PMCID: PMC1747172  PMID: 15618577
10.  Raised cord serum immunoglobulin E increases the risk of allergic sensitisation at ages 4 and 10 and asthma at age 10 
Thorax  2004;59(11):936-942.
Background: Evidence suggests that a raised level of cord serum IgE (CS-IgE) is a risk factor for allergic sensitisation. However, whether CS-IgE is a risk for asthma is controversial. A study was undertaken to investigate the association between CS-IgE levels and allergic sensitisation at 4 and 10 years of age and asthma at ages 1–2, 4 and 10.
Methods: CS-IgE was available for 1358 of 1456 children born between 1989 and 1990. The cohort was evaluated for allergic diseases at ages 1, 2, 4 and 10 years. Skin prick tests for six allergens were performed on 981 children at age 4 and 1036 at age 10. Asthma was defined based on a physician's diagnosis. Using logistic regression analysis, the risk of asthma and allergic sensitisation for raised levels of CS-IgE (⩾0.5 kU/l) was estimated.
Results: At ages 4 and 10 years 20.2% and 27.0% of children, respectively, had allergic sensitisation. The risk of allergic sensitisation was significantly associated with raised CS-IgE levels at ages 4 (OR 2.29) and 10 years (OR 1.73). The prevalence of asthma was 10.3% at age 1–2, 15.2% at age 4, and 12.8% at age 10. CS-IgE was not associated with asthma at age 1–2 and 4 but showed an increased relative risk at age 10 (OR 1.66, 95% CI 1.05 to 2.62). The association was stronger in children who did not develop allergic sensitisation at age 4 or 10 (OR 3.35, 95% CI 1.41 to 7.93).
Conclusions: Raised cord serum IgE is a risk factor for allergic sensitisation at ages 4 and 10 years. This is the second study suggesting that CS-IgE is also a risk factor for asthma at age 10, probably related to the late onset of asthma. This association is not necessarily mediated by allergic sensitisation.
doi:10.1136/thx.2004.024224
PMCID: PMC1746882  PMID: 15516467
11.  Exhaled nitric oxide levels in non-allergic and allergic mono- or polysensitised children with asthma 
Thorax  2001;56(11):857-862.
BACKGROUND—Increased fractional exhaled NO concentrations (FENO) and blood/tissue eosinophilia are frequently reported in allergic children with mild asthma and are thought to reflect the intensity of the inflammation characterising the disease. The aim of this study was to investigate possible differences in FENO levels or in the intensity of the blood eosinophilia in allergic and non-allergic asthmatic children.
METHODS—112 children with stable, mild, intermittent asthma with a positive bronchial challenge to methacholine were consecutively enrolled in the study; 56 were skin prick test and RAST negative (non-sensitised) while 56 were sensitised to house dust mites (23 only to house dust mites (monosensitised) and 33 were sensitised to mites and at least another class of allergens (pollens, pet danders, or moulds)). Nineteen sex and age matched healthy children formed a control group.
RESULTS—Compared with non-allergic patients, allergic children had a significantly higher rate of blood eosinophilia (p=0.0001) with no differences between mono- and polysensitised individuals. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25-75% of vital capacity (FEF25-75%), and the degree of bronchial reactivity to methacholine were similar in non-atopic and atopic children, with no differences between mono- and polysensitised individuals. FENO levels measured by chemiluminescence analyser were higher in asthmatic children (15.9(14.3) ppb) than in the control group (7.6 (1.6) ppb, p=0.04) and higher in allergic patients (23.9 (2.1) ppb) than in non-allergic patients (7.9 (0.8) ppb, p=0.0001), but there were no differences between mono- and polysensitised individuals (p>0.1). Significant correlations between blood eosinophilia and FENO levels were seen only in allergic (r=0.35, p<0.01) and in polysensitised individuals (r=0.45, p<0.05).
CONCLUSIONS—In children with mild asthma, a similar degree of functional disease severity may be associated with a higher inflammatory component in allergic than in non-allergic subjects.


doi:10.1136/thorax.56.11.857
PMCID: PMC1745945  PMID: 11641510
12.  Environmental tobacco smoke, indoor allergens, and childhood asthma. 
Environmental Health Perspectives  2000;108(Suppl 4):643-651.
Both environmental tobacco smoke and indoor allergens can exacerbate already established childhood albeit primarily through quite disparate mechanisms. In infancy and childhood, environmental tobacco smoke (ETS) exposure is associated with measures of decreased flow in the airways, bronchial hyperresponsiveness, and increased respiratory infections, but the relationship between ETS and allergy is poorly understood. Indoor allergens from dust mite, cockroach, and cat can be associated with asthma exacerbation in children sensitized to the specific allergens. The precise role of either ETS or indoor allergens in the development of asthma is less well understood. The strong and consistent association between ETS and asthma development in young children may relate to both prenatal and postnatal influences on airway caliber or bronchial responsiveness. Dust mite allergen levels predict asthma in children sensitized to dust mite. The tendency to develop specific IgE antibodies to allergens (sensitization) is associated with and may be preceded by the development of a T-helper (Th)2 profile of cytokine release. The importance of either ETS or indoor allergens in the differentiation of T cells into a Th2-type profile of cytokine release or in the localization of immediate-type allergic responses to the lung is unknown. This article evaluates the strength of the evidence that ETS or indoor allergens influence asthma exacerbation and asthma development in children. We also selectively review data for the effectiveness of allergen reduction in reducing asthma symptoms and present a potential research agenda regarding these two broad areas of environmental exposure and their relationship to childhood asthma.
PMCID: PMC1637671  PMID: 10931782
13.  Specific Patterns of Allergic Sensitization in Early Childhood and Asthma & Rhinitis Risk 
BACKGROUND
Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk.
OBJECTIVE
To define relationships among established sensitization to particular aeroallergens, quantitative analyses of allergen-specific IgE levels, pet exposure and sensitization, and asthma and rhinitis risk.
METHODS
Children at high-risk for the development of asthma and allergic diseases were enrolled at birth into the Childhood Origins of ASThma (COAST) study. Allergen-specific IgE was assessed at ages 1, 3, 6, and 9 years by fluoroenzyme immunoassay (Unicap® 100, Pharmacia Diagnostics). Current asthma and rhinitis were diagnosed at age 6 and 8 years.
RESULTS
Sensitization to dog was strongly associated with increased asthma risk (p < 0.0001). Sensitization to perennial compared to seasonal allergens was more strongly associated with asthma risk, while sensitization to seasonal allergens was more closely associated with rhinitis risk. Increased levels of specific IgE to perennial allergens were associated with an increased asthma risk (p = 0.05), while any detectable level of IgE to seasonal allergens was associated with increased rhinitis risk (p = 0.0009). While dog and cat sensitization were both independently associated with increased asthma and rhinitis risk, dog exposure at birth was associated with a reduced risk of asthma, regardless of dog sensitization status during the first 6 years of life (p = 0.05).
CONCLUSIONS & CLINICAL RELEVANCE
Analyzing specific patterns of an individual’s allergic sensitization profile reveals additional relevant associations with asthma and rhinitis risk as opposed to the information gained from characterizing an individual as “atopic” by the presence of any demonstrable sensitization alone. Further, protective mechanisms of dog exposure with regards to asthma risk appear to be unrelated to the prevention of sensitization.
doi:10.1111/cea.12050
PMCID: PMC3557802  PMID: 23331564
asthma; rhinitis; children; IgE; allergic sensitization; pet exposure
14.  Maternal Influence in the Transmission of Asthma Susceptibility 
Asthma is one of the most common chronic diseases in children, with increasing morbidity and mortality. A genetic predisposition and exposure to allergens have been implicated as major risk factors for the development of asthma. However, increasing evidence indicates that the mother plays a crucial role in mediating the development of fetal-infant immune responses to inhaled allergens. The exact nature and mechanism of this maternal influence and how it might be associated with the development of allergic sensitization and asthma are not clear. Under normal conditions, the maternal environment during pregnancy promotes an initial Th2 skewed immune response in the offspring which transitions to a nonallergic Th1 type response after birth. However, the allergic mother’s influence may delay the normal transition to a nonallergic immune response to inhaled allergens in her children, thus increasing the risk for the development of allergic sensitization and/or asthma. Understanding the underlying mechanisms by which the maternal immune environment can influence the development of the fetal-infant immune response to inhaled allergens may lead to identifying new targets for the prevention of allergic sensitization and asthma.
doi:10.1016/j.pupt.2007.06.005
PMCID: PMC2478516  PMID: 17693106
in utero; postnatal; immune; development; allergy; lung
15.  Infant Origins of Childhood Asthma Associated with Specific Molds 
Background
The specific cause(s) of asthma development must be identified in order to prevent this disease.
Objective
Our hypothesis was that specific mold exposures are associated with childhood asthma development.
Methods
Infants were identified from birth certificates. Dust samples were collected from 289 homes when the infants were age eight months. Samples were analyzed for concentrations of 36 molds that comprise the Environmental Relative Moldiness Index (ERMI) and endotoxin, house dust mite, cat, dog, and cockroach allergens. Children were evaluated at age seven for asthma based on reported symptoms and objective measures of lung function. Host, environmental exposures and home characteristics evaluated included history of parental asthma, race, gender, upper and lower respiratory symptoms, season of birth, family income, cigarette smoke exposure, air conditioning, dehumidifier, carpeting, age of home, and visible mold at age one and child positive skin prick test (SPT) to aeroallergens and molds at age seven.
Results
Asthma was diagnosed in 24% of the children at age seven. A statistically significant increase in asthma risk at age seven was associated with high ERMI levels in the child’s home in infancy (adjusted risk ratio (aRR) for a 10-unit increase in ERMI = 1.8, 95% CI=1.5, 2.2). The summation of levels of three mold species, Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile was significantly associated with asthma (aRR = 2.2, 95% CI=1.8, 2.7).
Conclusion
In this birth cohort study, exposure during infancy to three mold species common to water-damaged buildings was associated with childhood asthma at age seven.
doi:10.1016/j.jaci.2012.05.030
PMCID: PMC3432137  PMID: 22789397
Asthma; molds; speciation; infants; Environmental Relative Moldiness Index
16.  432 Patterns of Sensitization to Common Food and inhalant Allergens and Allergic Symptoms in Preschool Children 
Background
The prevalence of sensitization to allergens and symptoms of allergic disease differ with regard to age, but the relationship is poorly understood. This study aimed to investigate the patterns of allergen sensitization and allergic symptoms with regard to age in early childhood.
Methods
A cross-sectional study was conducted on 629 children. Current allergic symptoms were assessed using the Korean-language ISAAC questionnaires adapted for preschool-aged children. The sensitization to five aero- and 3 food- allergens was evaluated by skin prick test.
Results
The prevalence of current asthma decreased (20.5%/8.2%), current rhinitis increased (36.1%/56.1%) with increasing age from 3 to 6 years, while no change in the prevalence of current eczema (16.9%/15.3%). Similarly, as age increased, sensitization rates to inhalant allergens increased (21%/33%), those to food allergens decreased (10%/2%). The prevalence of polysensitized children increased (8%/22%), monosensitized children decreased (18%/11%) with age, but atopic state did not change with age (27%/33%). The agreement rate between sensitization to dust mite and atopic state increased with age, showing a rate of 93% at 6 years (P = 0.05). The presence of atopic dermatitis in the first 2 years of life (aOR = 4.1, 2.2–7.6, P < 0.001) and polysensitization (aOR = 3.0, 1.4–5.0, P < 0.005) were significant risk factors for current rhinoconjunctivitis. In contrast, monosensitization was a risk factor for current asthma (aOR = 2.1, 1.1–4.1, P < 0.024) and current eczema (aOR = 2.1, 1.0–4.3, P < 0.042).
Conclusions
These data showed that the type and numbers of sensitization and allergic symptoms changed with age in early childhood. Polysensitization may play an important role in allergic march.
doi:10.1097/01.WOX.0000412195.01618.97
PMCID: PMC3512891
17.  Smoking and occupational allergy in workers in a platinum refinery. 
BMJ : British Medical Journal  1989;299(6705):939-942.
OBJECTIVE--To test the hypothesis that smoking increases the risk of sensitisation by occupational allergens. DESIGN--Historical prospective cohort study. SETTING--Platinum refinery. SUBJECTS--91 Workers (86 men) who started work between 1 January 1973 and 31 December 1974 and whose smoking habit and atopic state (on skin prick testing with common allergens) had been noted at joining. MAIN OUTCOME MEASURES--Results of skin prick tests with platinum salts carried out routinely every three to six months and records of any respiratory symptoms noted by the refinery's occupational health service. Follow up was until 1980 or until leaving refinery work, whichever was earlier. RESULTS--57 Workers smoked and 29 were atopic; 22 developed a positive result on skin testing with platinum salts and 49 developed symptoms, including all 22 whose skin test result was positive. Smoking was the only significant predictor of a positive result on skin testing with platinum salts and its effect was greater than that of atopy; the estimated relative risks (95% confidence interval) when both were included in the regression model were: smokers versus non-smokers 5.05 (1.68 to 15.2) and atopic versus non-atopic 2.29 (0.88 to 5.99). Number of cigarettes smoked per day was the only significant predictor of respiratory symptoms. CONCLUSION--Smokers are at increased risk of sensitisation by platinum salts.
PMCID: PMC1837835  PMID: 2508944
18.  Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma 
Disease Models & Mechanisms  2013;6(4):993-1000.
SUMMARY
Development of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but could involve epigenetic changes. To investigate this, we employed a recently developed mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or downregulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNAs exhibited marked up- or downregulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNAs included genes involved in immune or inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-γ, the latter increasing following chronic challenge. We conclude that, in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T-cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation might play a role in the development of childhood asthma.
doi:10.1242/dmm.011247
PMCID: PMC3701218  PMID: 23611895
19.  THE RELATIONSHIP BETWEEN MATERNAL ADIPOSITY AND INFANT WEIGHT GAIN AND CHILDHOOD WHEEZE AND ATOPY 
Thorax  2013;68(4):372-379.
Background
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Methods
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Results
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Discussion
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
doi:10.1136/thoraxjnl-2012-202556
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
20.  Cohort study of peanut and tree nut sensitisation by age of 4 years. 
BMJ : British Medical Journal  1996;313(7056):514-517.
OBJECTIVE: To determine the prevalence of sensitisation to peanuts and tree nuts in all children born during one year in one geographical area. DESIGN: Birth cohort study with structured review at ages 1, 2, and 4 years. SETTING: All children born on the Isle of Wight between January 1989 and February 1990. SUBJECTS: Of 1456 children originally included, 1218 were reviewed at age 4 years. Of these, 1981 had skin prick tests. MAIN OUTCOME MEASURES: Positive skin test results, clinical atopic disease, and risk factors for the development of atopy. RESULTS: 15 of 1218 (1.2%) children were sensitised to peanuts or tree nuts (13 to peanuts). Six had had allergic reactions to peanuts (0.5% of the population), one to hazelnuts, and one to cashew nuts; three had had anaphylactic reactions. Seven children had positive skin test results or detectable IgE to peanuts without clinical symptoms. Two children who reacted to peanut in infancy had lost their sensitivity by 4 years. Family history of atopy, allergy to egg (odds ratio 9.9, 95% confidence interval 2.1 to 47.9, and eczema (7.3, 2.1 to 26.1) were important predictors for peanut allergy. CONCLUSIONS: IgE mediated allergy to peanuts is common in early childhood. In many the allergy persists but a minority may develop tolerance.
PMCID: PMC2351897  PMID: 8789974
21.  Does maternal smoking during pregnancy predict the smoking patterns of young adult offspring? A birth cohort study 
Tobacco Control  2006;15(6):452-457.
Objective
To examine the association between maternal smoking during pregnancy and the development of smoking behaviour patterns among young adult offspring.
Method
Data were from the Mater‐University of Queensland Study of Pregnancy (MUSP), a birth cohort of 7223 mothers and children enrolled in Brisbane, Australia, in 1981. The development of smoking behaviours (early or late onset, or combination of onset and prevalence patterns) among offspring at age 21 years with different patterns of maternal smoking (never smoked, smoked before or after pregnancy but not during pregnancy, or smoked during pregnancy) were compared. Maternal smoking information was derived from the prospectively collected data from the beginning of pregnancy until the child was 14 years of age. Analyses were restricted to the 3058 mothers and children whose smoking status was reported.
Results
The proportion of young adults who smoked regularly, either with early onset or late onset, was greater among those whose mothers had smoked during pregnancy compared with those whose mothers had never smoked. The smoking patterns among those adolescent offspring whose mothers stopped smoking during pregnancy, but who then smoked at other times during the child's life, were similar to those whose mothers had never smoked. This association was robust to adjustment for a variety of potential covariates.
Conclusions
The findings provide some evidence for a direct effect of maternal smoking in utero on the development of smoking behaviour patterns of offspring and provide yet another incentive to persuade pregnant women not to smoke.
doi:10.1136/tc.2006.016790
PMCID: PMC2563674  PMID: 17130374
22.  Socioeconomic predictors of high allergen levels in homes in the greater Boston area. 
Environmental Health Perspectives  2000;108(4):301-307.
In the United States, childhood asthma morbidity and prevalence rates are the highest in less affluent urban minority communities. More than 80% of childhood asthmatics are allergic to one or more inhalant allergens. We evaluated whether socioeconomic status was associated with a differential in the levels and types of indoor home allergens. Dust samples for an ELISA allergen assay were collected from the homes of 499 families as part of a metropolitan Boston, Massachusetts, longitudinal birth cohort study of home allergens and asthma in children with a parental history of asthma or allergy. The proportion of homes with maximum home allergen levels in the highest category was 42% for dust mite allergen (> or = 10 microg/g Der p 1 or Der f 1), 13% for cockroach allergen (> or = 2 U/g Bla g 1 or Bla g 2), 26% for cat allergen (> or = 8 microg/g Fel d 1), and 20% for dog allergen (> or = 10 microg/g Can f 1). Homes in the high-poverty area (> 20% of the population below the poverty level) were more likely to have high cockroach allergen levels than homes in the low-poverty area [51 vs. 3%; OR, 33; 95% confidence interval (CI), 12-90], but less likely to have high levels of dust mite allergen (16 vs. 53%; OR, 0.2; CI, 0.1-0.4). Lower family income, less maternal education, and race/ethnicity (black or Hispanic vs. white) were also associated with a lower risk of high dust mite levels and a greater risk of high cockroach allergen levels. Within a single U.S. metropolitan area we found marked between-community differences in the types of allergens present in the home, but not necessarily in the overall burden of allergen exposure.
Images
PMCID: PMC1638021  PMID: 10753087
23.  Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children 
Thorax  2005;61(5):376-382.
Background
Asthma exacerbation is the most common cause of hospital admission in children. A study was undertaken to investigate the importance of allergen exposure in sensitised individuals in combination with viral infections and other potentially modifiable risk factors precipitating asthma hospital admission in children.
Methods
Eighty four children aged 3–17 years admitted to hospital over a 1 year period with an acute asthma exacerbation (AA) were matched for age and sex with two control groups: stable asthmatics (SA) and children admitted to hospital with non‐respiratory conditions (IC). Risk factors were assessed by questionnaires and determination of allergen sensitisation, home allergen exposure, pollen exposure, and respiratory virus infection.
Results
Several non‐modifiable factors (atopy, duration of asthma) were associated with increased risk. Among the modifiable factors, pet ownership, housing characteristics, and parental smoking did not differ between the groups. Regular inhaled corticosteroid treatment was significantly less common in the AA group than in the SA group (OR 0.2, 95% CI 0.1 to 0.6; p = 0.002). A significantly higher proportion of the AA group were virus infected (44%) and sensitised and highly exposed to sensitising allergen (76%) compared with the SA (18% and 48%) and IC groups (17% and 28%; both p<0.001). In a multiple conditional logistic regression (AA v SA), allergen sensitisation and exposure or virus detection alone were no longer independently associated with hospital admission. However, the combination of virus detection and sensitisation with high allergen exposure substantially increased the risk of admission to hospital (OR 19.4, 95% CI 3.7 to 101.5, p<0.001).
Conclusions
Natural virus infection and real life allergen exposure in allergic asthmatic children increase the risk of hospital admission. Strategies for preventing exacerbations will need to address these factors.
doi:10.1136/thx.2005.042523
PMCID: PMC2111190  PMID: 16384881
asthma; inhaled allergens; viruses; atopy; children; hospitalisation
24.  Effect of cyclosporin A on the allergen-induced late asthmatic reaction 
Thorax  1997;52(5):447-452.
BACKGROUND: The allergen-induced late asthmatic reaction (LAR) is associated with mucosal inflammation involving several cell types including activated T lymphocytes and eosinophils. In contrast, the early asthmatic reaction (EAR) is considered to results from rapid allergen-induced release of bronchoconstrictor mediators from IgE sensitised mast cells. Cyclosporin A has efficacy in chronic severe corticosteroid-dependent asthma and is believed to act principally by inhibiting cytokine mRNA transcription in T lymphocytes. However, it has effects on other cell types in vitro, including the inhibition of exocytosis/degranulation events in mast cells. It was therefore hypothesised that cyclosporin A would attenuate both the EAR and LAR in subjects with mild asthma. METHODS: Twelve sensitised atopic asthmatic subjects with documented dual asthmatic responses were studied in a double blind, placebo controlled, crossover trial. On two separate study visits subjects received two oral doses of either cyclosporin A or matched placebo before inhaled allergen challenges. The forced expiratory volume in one second (FEV1) was measured half hourly for eight hours and blood eosinophil counts were analysed three, six, and 24 hours after the challenge. Treatment effects on blood eosinophil counts as well as the EAR and LAR, respectively defined as the areas under the curve (AUC) of FEV1 changes from baseline between 0-1 and 4-8 hours after challenge, were compared by non-parametric crossover analysis. RESULTS: Cyclosporin A reduced both the LAR (median AUC -41.9 1.h (interquartile range -82.7 to -12.4) for cyclosporin A and -84.5 1.h (-248.9 to -39.1) for placebo; p = 0.007) and the late increase in blood eosinophils (median 0.2 x 10(9)/1 (0.15 to 0.4) for cyclosporin A and 0.4 x 10(9)/1 (0.25 to 0.55) for placebo; p = 0.024) but had no effect on the EAR. The reduction of the LAR by cyclosporin A correlated significantly with prechallenge blood concentrations of cyclosporin A (r = 0.6, p = 0.028). CONCLUSIONS: These data are consistent with the concept that cyclosporin A has anti-inflammatory actions in asthma resulting from inhibition of mRNA transcription of eosinophil-active cytokines, predominantly in T lymphocytes. Cyclosporin A, possibly in its inhaled form, or other agents which prevent cytokine gene transcription may therefore have potential in ameliorating the inflammatory component of asthma. 



PMCID: PMC1758561  PMID: 9176537
25.  Sensitization profile in differential diagnosis: Allergic asthma vs. chronic (nonspecific) cough syndrome 
Background
In the subgroup of children with chronic cough, distinguishing children with allergic asthma from those with non-specific respiratory symptoms is difficult. We have focused on determination of diagnostic efficiency of serum total IgE, sIgE, and skin prick test in differentiation of asthmatic children from children with nonspecific respiratory symptoms.
Material/Methods
A total of 131 children with median age of 7.5 years were enrolled in study and divided into 2 groups; children with allergic asthma (N=71) and children with chronic cough (N=60). Participants underwent the standard allergological examination, including skin prick test and measurement of total IgE, and following 3 allergen-specific IgE antibodies against aeroallergens: Dermatophagoides pteronyssinus, Ambrosia artemisiifolia, and Phleum pratense.
Results
The percentage of patients with elevated level of total and sIgE was higher in children with allergic asthma than in children with chronic cough syndrome (P=0.0001). In children with asthma, sIgE had a better diagnostic value than total IgE. The best diagnostic efficiency of cut-off values for sIgE was shown for Der p sIgE. Skin prick test to all allergens had 78.82% sensitivity and 91.3% specificity in differentiating the 2 tested groups. The highest sensitivity and specificity in skin prick test was proved for Dermatophagoides pteronyssinus.
Conclusions
The sensitization profile consisting of total IgE, sIgE levels, and SPT clearly distinguishes children with allergic asthma from children with chronic nonspecific cough, but still with overlap. Therefore, diagnosis should always be confirmed by a thorough allergy investigation.
doi:10.12659/MSM.883925
PMCID: PMC3673807  PMID: 23715171
asthma; chronic cough; total IgE level; allergen-specific IgE level; diagnostic efficiency

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