Confirmation of GPRA: a putative drug target for asthma.
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Anti-Asthmatic Agents↗
Biomedical subjects
Dirkje S Postma
Publications and source records attributed to Dirkje S Postma.
First study of infliximab treatment in patients with chronic obstructive pulmonary disease.
RATIONALE: Tumor necrosis factor-alpha is believed to be important in the induction and maintenance of airway inflammation in chronic obstructive pulmonary disease. OBJECTIVES: We aimed to evaluate the effect of the anti-tumor necrosis factor-alpha drug infliximab in patients with chronic obstructive pulmonary disease, with percentage of sputum neutrophils as the primary endpoint. METHODS: We performed an exploratory single-center, double-blind, placebo-controlled, randomized, phase 2 trial in which 22 current smokers with mild-to-moderate chronic obstructive pulmonary disease participated. Fourteen patients received three infusions of infliximab (5 mg/kg) at Weeks 0, 2, and 6, and eight patients received placebo infusions. Sputum samples, respiratory symptoms, quality of life, exhaled nitric oxide, lung function parameters, bronchial hyperresponsiveness, resting energy expenditure, and side effects were evaluated. MEASUREMENTS AND MAIN RESULTS: This study did not show a positive short-term effect of infliximab on airway inflammation, lung function, resting energy expenditure, or quality of life. Exhaled nitric oxide increased significantly at Day 2, Week 6, and Week 8 in patients receiving infliximab compared with those receiving placebo. Eight patients in the infliximab group (vs. none in the placebo group) reported increased coughing, but no serious adverse events or increase in respiratory infections were reported during 9 weeks of follow-up. CONCLUSIONS: In this short-term study, no clinically beneficial effects of infliximab were observed, and there were no significant safety issues. Definite conclusions concerning the effectiveness of infliximab treatment in chronic obstructive pulmonary disease await additional studies, including those with a larger number of patients with more advanced disease.
Antibodies, Monoclonal↗
Genomewide screen for pulmonary function in 200 families ascertained for asthma.
Changes in pulmonary function are important in determining asthma outcome. Genetic factors may influence airway obstruction in asthma. We performed a genomewide screen in 200 families of probands objectively diagnosed with asthma in the 1960s to identify chromosomal regions related to changes in pre- and postbronchodilator lung function (FEV1, VC, and FEV1%VC) and assess influences of early-life smoke exposure. Smoking (pack-years), age, sex, and height were covariates in variance component analyses. Significant evidence for linkage of pre- and postbronchodilator FEV1%VC was obtained for chromosome 2q32 (LOD,4.9, increasing to 6.03 with additional fine-mapping markers, and 3.2, respectively). Linkage existed for chromosome 5q for pre- and postbronchodilator VC (likelihood of disease [LOD], 1.8 and 2.6, respectively). Results for pre- and postbronchodilator FEV1 were less significant (LOD, 1.5 and 1.6, chromosomes 11p and 10q, respectively). Results were not affected by passive smoke exposure. There is significant evidence for linkage of FEV1%VC to chromosome 2q32 in families of probands with asthma, 35 cM proximal from linkage previously observed in families of probands with early-onset chronic obstructive pulmonary disease. Thus, there may be multiple genes on chromosome 2q that are important in determining presence and degree of airflow limitation in families ascertained for obstructive airway disease.
Adult↗
Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes.
Single-nucleotide polymorphisms of the beta(2)-adrenergic receptor gene and its 5' promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the beta(2)-adrenergic receptor (position 19 [Cys/Arg] of the 5' leader cistron and positions 16 [Arg/Gly] and 27 [Gln/Glu] of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well defined nonasthmatic, nonallergic subjects homozygous for the haplotype CysGlyGln, ArgGlyGlu, or CysArgGln were isolated. Desensitization of (-)-isoproterenol-induced cyclic adenosine monophosphate (cAMP) accumulation and beta(2)-adrenergic receptor sequestration and downregulation were measured in relation to beta(2)-adrenergic receptor-mediated inhibition of IFN-gamma and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the beta-agonist-induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of beta-agonist-induced cAMP response was not associated with haplotype-dependent beta(2)-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition, in lymphocytes of subjects with the CysGlyGln haplotype, of interleukin-5 production induced by treatment with antibodies to the T-cell receptor-CD3 complex and to costimulatory molecule CD28 (alphaCD3/alphaCD28). This is the first study demonstrating haplotype-related differences in agonist-induced beta(2)-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the beta(2)-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.
Adult↗
A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population.
RATIONALE: A disintegrin and metalloprotease 33 (ADAM33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excessive decline of lung function in individuals with asthma. OBJECTIVES: To assess whether SNPs in ADAM33 are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD). METHODS: DNA was collected from subjects of the Vlagtwedde-Vlaardingen cohort participating in the last survey in 1989-1990 after a follow-up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. A total of 1,390 subjects from the cohort was genotyped for the following SNPs in ADAM33: F+1, Q-1, S_1, S_2, T_1, T_2, V_4, and ST+5. Differences in prevalence of SNPs were analyzed with chi(2) tests. Linear mixed effects models were used to analyze FEV(1) decline according to genotype. MEASUREMENTS AND MAIN RESULTS: In the whole population, mean adjusted decline was 18.7 and 12.7 ml/year in females and males, respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q-1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV(1) of, respectively, 4.9, 9.6, and 3.6 ml/year compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2, and T_2 in subjects with COPD. CONCLUSIONS: We demonstrated that SNPs in ADAM33 are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.
ADAM Proteins↗
Association of current smoking with airway inflammation in chronic obstructive pulmonary disease and asymptomatic smokers.
BACKGROUND: Inflammation in the airways and lung parenchyma underlies fixed airway obstruction in chronic obstructive pulmonary disease. The exact role of smoking as promoting factor of inflammation in chronic obstructive pulmonary disease is not clear, partly because studies often do not distinguish between current and ex-smokers. METHODS: We investigated airway inflammation in sputum and bronchial biopsies of 34 smokers with chronic obstructive pulmonary disease (9 Global initiative for Chronic Obstructive Lung Disease stage 0, 9 stage I, 10 stage II and 6 stage III) and 26 asymptomatic smokers, and its relationship with past and present smoking habits and airway obstruction. RESULTS: Neutrophil percentage, interleukin-8 and eosinophilic-cationic-protein levels in sputum were higher in chronic obstructive pulmonary disease (stage I-III) than asymptomatic smokers. Inflammatory cell numbers in bronchial biopsies were similar in both groups. Current smoking correlated positively with macrophages: in bronchial biopsies in both groups, and in sputum in chronic obstructive pulmonary disease. Pack-years smoking correlated positively with biopsy macrophages only in chronic obstructive pulmonary disease. CONCLUSION: Inflammatory effects of current smoking may mask the underlying ongoing inflammatory process pertinent to chronic obstructive pulmonary disease. This may have implications for future studies, which should avoid including mixed populations of smokers and ex-smokers.
Aged↗
Interleukin-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells.
Lung epithelial cells contribute to local inflammation by the production of pro-inflammatory mediators like interleukin (IL)-8 and IL-6. Although their production depends on gene transcription, previous studies showed that post-transcriptional mechanisms modulate IL-8 and IL-6 production. Human lung epithelial cells turn from normoresponsive into hyperresponsive IL-8- and IL-6-producing cells when their IL-8 and IL-6 mRNA degradation is reduced. We hypothesized that IL-17, a mediator predominantly released by memory T cells and present in airways of individuals with asthma, would modulate rather than induce IL-8 and IL-6 production by both human lung epithelial cells and fibroblasts. We show here for both cell types that IL-17 was a weak stimulus of IL-8 and IL-6 production, but markedly enhanced IL-8 and IL-6 responses to another stimulus, such as tumor necrosis factor-alpha. This modulatory effect of IL-17 was paralleled by a reduced IL-8 and IL-6 mRNA degradation, with no effect on IL-8 and IL-6 gene transcription. In conclusion, IL-17 particularly affects post-transcriptional regulation of IL-8 and IL-6 expression leading to enhanced IL-8 and IL-6 responses to secondary stimuli, and is only a weak proinflammatory stimulus by itself. This poses the interesting concept that by releasing IL-17 from memory T cells, the adaptive immune system instructs lung structural cells as part of the innate immune system to respond more vigorously.
Asthma↗
Obtaining optimal control in mild asthma: theory and practice.
BACKGROUND: Studies have shown that asthma severity is easily under-estimated and as a result, patients may be under-treated with reduced asthma control. OBJECTIVE: This study, performed in the General Practice Research Database (GPRD), investigates asthma control in patients treated as intermittent asthmatics (short-acting beta agonist (SABA) alone), or persistent asthmatics (additional inhaled cortico-steroid (ICS), no other medication). METHODS: Patients (0-45 years) diagnosed with asthma between 1 January 1995 and 31 December 2001 taking > or =2 scripts for SABA (SABA only group) or > or =3 scripts for ICS (ICS group) in the first six months following diagnosis were selected. Factors associated with drug prescriptions were assessed. RESULTS: SABA script rates were 3.6 and 5.1 per year in the SABA and ICS group respectively, i.e. >1 dose/day. 10.5% of SABA group and 13.4% of ICS group used oral steroids. Within the SABA group, 37% were stepped up to ICS, the time to first ICS script being significantly associated with prior hospitalization (RR 2.26, CI 1.65-3.10) and atopy (RR 1.47, CI 1.33-1.63). A higher rate of oral steroid use was significantly associated with using ICS, being female, adult and smoking. Smokers and atopic individuals had increased risk of obtaining an earlier script for oral steroid (RR 1.32, CI 1.10-1.59 and RR 1.28, CI 1.10-1.49, respectively). CONCLUSIONS: Asthma control was sub-optimal in a substantial proportion of patients using relatively high doses of SABA, or SABA and ICS from the outset of asthma treatment in general practice. Being female, atopic, a smoker and prior hospitalization were all associated with lack of asthma control and could guide physicians in treatment prescribing.
Administration, Inhalation↗
Exposure to TARC alters beta2-adrenergic receptor signaling in human peripheral blood T lymphocytes.
The beta(2)-adrenergic receptor (beta(2)-AR) negatively regulates T cell activity through the activation of the G(s)/adenylyl cyclase/cAMP pathway. beta(2)-AR desensitization, which can be induced by its phosphorylation, may have important consequences for the regulation of T cell function in asthma. In the present study we demonstrate that the C-C chemokine thymus and activation-regulated chemokine (TARC) impairs the ability of beta(2)-agonist fenoterol to activate the cAMP downstream effector cAMP-responsive element binding protein (CREB) in freshly isolated human T cells. The TARC-induced activation of Src kinases resulted in membrane translocation of both G protein-coupled receptor kinase (GRK) 2 and beta-arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the beta(2)-AR as well as its association with GRK2 and beta-arrestin. Finally, in contrast to CREB, phosphorylation of Src and extracellular signal-regulated kinase was enhanced by fenoterol upon TARC pretreatment. In summary, we show for the first time that TARC exposure impairs beta(2)-AR function in T cells. Our data suggest that this is mediated by Src-dependent activation of GRK2, resulting in receptor phosphorylation, binding to beta-arrestin, and a switch from cAMP-dependent signaling to activation of the MAPK pathway. We propose that aberrant T cell control in the presence of endogenous beta-agonists promotes T cell-mediated inflammation in asthma.
Adrenergic beta-2 Receptor Agonists↗
Acute effects of cigarette smoking on inflammation in healthy intermittent smokers.
BACKGROUND: Chronic smoking is the main risk factor for chronic obstructive pulmonary disease. Knowledge on the response to the initial smoke exposures might enhance the understanding of changes due to chronic smoking, since repetitive acute smoke effects may cumulate and lead to irreversible lung damage. METHODS: We investigated acute effects of smoking on inflammation in 16 healthy intermittent smokers in an open randomised cross-over study. We compared effects of smoking of two cigarettes on inflammatory markers in exhaled air, induced sputum, blood and urine at 0, 1, 3, 6, 12, 24, 48, 96 and 192 hours and outcomes without smoking. All sputum and blood parameters were log transformed and analysed using a linear mixed effect model. RESULTS: Significant findings were: Smoking increased exhaled carbon monoxide between 0 and 1 hour, and induced a greater decrease in blood eosinophils and sputum lymphocytes between 0 and 3 hours compared to non-smoking. Compared to non-smoking, smoking induced a greater interleukin-8 release from stimulated blood cells between 0 and 3 hours, and a greater increase in sputum lymphocytes and neutrophils between 3 and 12 hours. CONCLUSION: We conclude that besides an increase in inflammation, as known from chronic smoking, there is also a suppressive effect of smoking two cigarettes on particular inflammatory parameters.
Acute Disease↗
Elicitation of allergic asthma by immunoglobulin free light chains.
The observation that only 50% of patients with adult asthma manifest atopy indicates that other inflammatory mechanisms are likely involved in producing the characteristic features of this disorder; namely reversible airway obstruction, hyperresponsiveness, and pulmonary inflammation. Our recent discovery that antigen-specific Ig free light chains (LCs) mediate hypersensitivity-like responses suggests that these molecules may be of import in the pathophysiology of asthma. Using a murine experimental model of nonatopic asthma, we now have shown that an LC antagonist, the 9-mer peptide F991, can abrogate the development of airway obstruction, hyperresponsiveness, and pulmonary inflammation. Further, passive immunization with antigen-specific LCs and subsequent airway challenge can elicit a mast cell-dependent reaction leading to acute bronchoconstriction. These findings, and the demonstration that the concentration of free kappa LCs in the sera of patients with adult asthma were significantly increased (as compared with age-matched nonasthmatic individuals), provide previously undescribed insight into the pathogenesis of asthma. In addition, the ability to inhibit pharmacologically LC-induced mast cell activation provides a therapeutic means to prevent or ameliorate the adverse bronchopulmonary manifestations of this incapacitating disorder.
Animals↗
Polymorphisms in SPINK5 are not associated with asthma in a Dutch population.
BACKGROUND: Asthma and allergic phenotypes are complex genetic diseases with known linkage to chromosome 5q. This region has many candidate genes, including serine protease inhibitor Kazal type 5 (SPINK5), which has been associated with asthma and atopic dermatitis in family-based studies of children with atopic dermatitis. OBJECTIVE: We sought to investigate whether single nucleotide polymorphisms in SPINK5 are associated with asthma, atopic phenotypes, and atopic dermatitis. METHODS: We investigated whether single nucleotide polymorphisms in SPINK5 (ie, -785 A/G, Asn368Ser, and Lys420Glu) are associated with asthma, atopic phenotypes, and atopic dermatitis in 200 families ascertained by a proband with asthma (nonaffected spouses served as a matched control population) and an independent set of 252 trios with asthma. RESULTS: We found no association with asthma, atopic phenotypes, and atopic dermatitis after correction for multiple testing. CONCLUSION: The negative results in this study suggest that SPINK5 is not associated with asthma or atopic phenotypes in individuals ascertained by a proband with asthma. This is consistent with the finding that SPINK5 is not expressed in the lung. Because our patients were ascertained for asthma, a role of SPINK5 in atopic dermatitis cannot be excluded.
Adult↗
Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure.
BACKGROUND: Asthma is a common respiratory disease caused by the interaction of genetic susceptibility and exposure to various environmental factors. Passive smoke exposure, characterized by parental smoking, has been shown to be a risk factor for the development of atopy and asthma. OBJECTIVE: We sought to perform a genome-wide linkage screen for asthma and bronchial hyperresponsiveness (BHR) and to determine the influence of passive tobacco smoke exposure during childhood on the results of genetic linkage studies to investigate gene-environment interactions. METHODS: A genome-wide linkage screen for asthma and BHR was performed in 200 families ascertained through a parent with asthma. Analyses were performed separately for the entire sample and for the smoking-exposed and nonexposed families. RESULTS: For asthma and BHR, the strongest evidence for linkage was observed for chromosomes 3p and 5q. The families in which the children were exposed to passive smoking accounted for the evidence for linkage of BHR to 5q ( P < .001), but evidence for linkage to 3p was found in both sets of families. Similar results were observed for asthma. However, there was no observed difference in the frequency of asthma or BHR in the offspring from the smoke-exposed compared with the nonexposed families. CONCLUSION: The results from this study demonstrate that the influence of susceptibility genes for a common disease such as asthma might not be apparent unless there is the appropriate exposure to environmental stimuli, such as passive exposure to cigarette smoke. This approach should be useful for identification of asthma susceptibility genes.
Adult↗
Effect of low-dose ciclesonide on allergen-induced responses in subjects with mild allergic asthma.
BACKGROUND: Inhalation of allergens by sensitized patients with asthma induces reversible airway obstruction, airway hyperresponsiveness, and eosinophilic airway inflammation. Attenuation of allergen-induced bronchoconstriction and inflammation has been used to examine the efficacy of therapeutic agents such as inhaled corticosteroids in asthma. Ciclesonide, a nonhalogenated inhaled corticosteroid being developed for the treatment of persistent asthma, remains inactive until cleaved by esterases in the lung. OBJECTIVE: This study examined the effect of low doses of inhaled ciclesonide, 40 microg and 80 microg, on allergen-induced bronchoconstriction, serum eosinophil cationic protein, and eosinophilic airway inflammation. METHODS: Twenty-one nonsmokers with mild atopic asthma completed a multicenter, randomized, 3-way crossover study comparing the effects of 7-day treatment of ciclesonide or placebo. Allergen-induced responses, including the early and late fall in FEV1, peripheral blood eosinophils, serum eosinophil cationic protein levels, and eosinophils in induced sputum were measured. RESULTS: Ciclesonide 80 microg attenuated the early and late asthmatic responses, including the change in FEV1, serum eosinophil cationic protein, and sputum eosinophils measured at 24 hours postchallenge (P < .025). Ciclesonide 40 microg attenuated the late asthmatic responses and sputum eosinophils measured at 24 hours postchallenge (P < .025), with no effect on the early allergen-induced bronchoconstriction, 24-hour FEV1, or serum eosinophil cationic protein levels (P < .025). CONCLUSION: With the exception of 24-hour postchallenge peripheral blood eosinophils, a low dose of ciclesonide, 80 microg, was effective in blocking all allergen-induced responses measured.
Adult↗
Recognition of asthma in adolescents and young adults: which objective measure is best?
BACKGROUND: Objective assessment of airway function is important in epidemiologic studies of asthma to facilitate comparison between studies. Airway hyperresponsiveness (AHR), peak expiratory flow (PEF) variability, and bronchodilator reversibility (BR) are widely used as markers of airway lability in such studies. Data from a survey of a population sample of adolescents and young adults (n = 609; 288 males), aged 13-23 years, were analyzed to investigate whether AHR, PEF variability, and BR can be used interchangeably as markers of asthma in an epidemiological setting. METHODS: Case history, including self-reported and doctor-diagnosed asthma, smoking habits, and use of asthma medication, was obtained by interview and questionnaire. Lung function, airway responsiveness (positive test: PC20 FEV1 < 16 mg/mL histamine), PEF variability (positive test: amplitude percentage mean > 20%), BR (positive test: deltaFEV1 [(FEV1max - FEV1min)/FEV1max) 100] > 10%), blood eosinophil count, and skin prick test reactivity were measured by using standard techniques. RESULTS: The prevalence of a positive test was AHR 16.4%, PEFpos 13.3%, and BRpos 7.2%, respectively; 73.5% of the sample had three negative tests. Among the 74 participants with current self-reported asthma (12.2%), 34 subjects (46%) had more than one positive test. Using AHR as the only objective marker of asthma identified 93% of the participants with current asthma, whereas PEF and BR identified 45% and 10%, respectively. Confining the analysis to participants with only one positive test revealed that 61% of the subjects with isolated AHR had current asthma, whereas none of the subjects with isolated BRpos had asthma, and only one participant with isolated PEFpos had current asthma. Degree of histamine responsiveness was closer associated with other asthma-related factors, including self-reported asthma, use of asthma medication, and level of lung function, than PEF variability and bronchodilator responsiveness. CONCLUSIONS: Airway responsiveness to histamine, diurnal peak-flow variability, and bronchodilator reversibility cannot be used interchangeably as objective markers of asthma in epidemiologic studies. On the basis of the present findings, airway hyperresponsiveness to a nonspecific bronchoconstrictor is recommended as the objective marker of asthma-related airway lability.
Adolescent↗
Different modulation of decorin production by lung fibroblasts from patients with mild and severe emphysema.
We have previously reported diminished immunohistochemical staining of decorin in lung tissue from patients with severe emphysema. The aim of this study is to investigate whether this diminished staining is due to a quantitative abnormal production of decorin by pulmonary fibroblasts in vitro. Therefore, we measured decorin (Western blot), collagen type I (ELISA), and fibronectin (ELISA) production by fibroblasts obtained from lung tissue of patients with severe and mild emphysema at basal culture conditions and after modulation with transforming growth factor-beta1, basic fibroblast growth factor, and interferon-gamma. Decorin production at basal culture conditions was significantly higher in fibroblast cultures from patients with severe emphysema compared to fibroblasts from mild emphysema. After stimulation with transforming growth factor-beta1 and basic fibroblast growth factor, decorin production was significantly more reduced in fibroblast cultures from patients with severe emphysema whereas collagen type I and fibronectin production were not affected. We conclude that decorin production by lung fibroblasts of patients with severe emphysema is dysregulated after modulation with cytokines known to be important in smoking associated inflammation. This dysregulation of decorin production may contribute to the impaired lung tissue repair, present in patients with emphysema, since these alterations in the extracellular matrix may cause diminished cytokine binding and neutralization.
Adult↗
Airway cellular response to two different immunosuppressive regimens in lung transplant recipients.
A number of new immunosuppressive drugs have become available in transplant medicine. We investigated the effects of two different immunosuppressive protocols on bronchoalveolar lavage fluid cellular characteristics in 34 lung transplant recipients who were treated with anti-thymocyte globulin induction therapy, cyclosporine, azathioprine (AZA), and prednisolone (regimen I), compared with 17 recipients receiving basiliximab induction, tacrolimus, AZA, and prednisolone (regimen II). We performed bronchoalveolar lavages between 15 and 40 d post-transplantation, in stable clinical condition and no acute rejection, cytomegalovirus, and/or respiratory tract infection. The regimen II treatment was associated with a significantly lower percentage lavage fluid lymphocytes than with regimen I. The CD4/CD8 ratio was significantly higher with regimen II than with regimen I: 1.56 (range 0.41-2.16) and 0.33 (0.04-0.95) respectively; p < 0.001, mainly because of a lower percentage CD8(+) cells with regimen II: 25% (12-51) vs. regimen I: 60% (34-77); p < 0.001. The percentage CD4(+) CD25(+) cells appeared lower with regimen II: 21% (10-88) vs. regimen I: 50% (0-87); p = 0.04. Overall survival was similar between the groups, whereas a beneficial trend in freedom of bronchiolitis obliterans syndrome was observed with regimen II. Airway lymphocyte subtypes are affected by the immunosuppressive protocol used. This observation should be taken into account when studying transplant recipients, and may contribute to our understanding of alloreactive airway disease.
Adult↗
The effect of prenatal exposure on total IgE at birth and sensitization at twelve months and four years of age: The PIAMA study.
There is increasing evidence that the development of the fetal immune system can be influenced by environmental exposure in utero. We investigated whether prenatal exposure is associated with a high neonatal total IgE level and sensitization at the age of 1 and 4 yr. Data from 1027 infants were collected in a Dutch birth cohort study (PIAMA study). Total IgE was measured in heel prick blood collected in the first week of life. Sensitization was defined as a specific IgE level in serum of > or =0.35 IU/ml against house dust mite, cat, dog, milk or egg. Logistic regression analysis was performed to study independent relationships between risk factors and a high neonatal total IgE (> or =0.50 IU/ml) or sensitization. A high neonatal total IgE was found in 12.2% of boys and 6.2% of girls. A dog at home during pregnancy was negatively associated with a high neonatal total IgE [odds ratio (95% CI) 0.5 (0.2-1.0)]. A cat at home [OR 0.6 (0.4-1.0) and maternal smoking (OR 0.4 (0.2-1.0)] were negatively associated with sensitization at 12 months, but not at 4 yr. The presence of older siblings, season of birth, birth weight, mode of delivery, gestational age and maternal age were not associated with a high neonatal total IgE or sensitization. The higher total IgE level and prevalence of sensitization at 4 yr in boys compared with girls was only present in children from allergic mothers. Our results suggest a short-lasting protective effect of prenatal exposure to pets on total IgE at birth and early sensitization.
Age Factors↗