Background: Allergic sensitization is the most important risk factor for asthma and rhinitis among children, adolescents and young adults. Less is known about the incidence and remission of allergic sensitization, particularly in older adults. Furthermore, it is not clear if the earlier documented increase in prevalence of allergic sensitization continues. This thesis is focused on prevalence, incidence and remission of allergic sensitization to airborne allergens among adolescents and adults as well as on time trends in prevalence among adults. Furthermore, associated risk factors and the relation of allergic sensitization to asthma and rhinitis were assessed. Methods: In the study of children and adolescents, incidence, remission and prevalence of allergic sensitization were assessed in a cohort study of schoolchildren, aged 7-8 years (y) at baseline. In the studies of adults, incidence and remission of allergic sensitization were assessed in a randomly selected adult population sample in 1994 (n=664) aged 20-69 y, which was followed up in 2004 (n=555). Trends in prevalence of allergic sensitization were assessed by comparing two cross-sectional studies; the cohort from 1994 and another randomly selsected population sample examined in 2009 (n=737). The relation of allergic sensitization to asthma and rhinitis was determined in the adult cohort in 2009. Allergic sensitization was assessed by skin prick test (SPT) with ten common airborne allergens at ages 7-8, 11-12 and 19 y in the cohort of children and in the participants ≤ 60 y in the adult cohorts. Specific IgE to nine airborne allergens was analyzed in the adult cohorts in 2004 and 2009. Risk factors for allergic sensitization and variables defining respiratory disease and symptoms were assessed by questionnaires in the cohort of children and by structured interviews in the adult cohorts. Results: The 10-year cumulative incidence of allergic sensitization among the adults from 1994 to 2004 was 5%, while remission was 32%. In both adult cohorts, the prevalence of allergic sensitization was highest among young adults, aged 20-29 y, 55% and 61% and decreased significantly with increasing age. Among children and adolescents, both incidence and persistence of allergic sensitization were high, and the prevalence of allergic sensitization increased by age from 21% at age 7-8 y to 42% at age 19 y. Multisensitization at age 19 y was strongly associated with early onset of sensitization. The prevalence of sensitization to the major specific allergens birch, timothy, cat and dog as well as multisensitization (from 40% in 1994 to 56% in 2009, p=0.002) increased significantly from 1994 to 2009 among the adults. Sensitization to any allergen increased from 35% to 39%, however not significantly (p=0.13). A family history of allergic rhinitis was strongly and consistently associated with allergic sensitization in all ages. Male sex and urban living were significantly positively and birth order and furry animals at home in childhood were negatively associated with onset of sensitization before the age of 7-8 y, but not with onset of sensitization from 11-12y to 19 y. Young adult age and urban living were significant factors associated with allergic sensitization in adult age. Sensitization to any animal was significantly positively associated with current asthma (OR4.80 (95% CI 2.68-8.60)), whereas both sensitization to any pollen (OR 4.25 (2.55-7.06)) and any animal (OR 3.90 (95% CI 2.31-6.58)) were associated with current allergic rhinitis. The association between allergic sensitization and allergic rhinitis was strongest in young adult age and decreased with increasing age, while asthma was similarly associated with sensitization to any animal across all adult ages. Among asthmatics, the prevalence of allergic sensitization decreased with increasing age of asthma onset. Conclusion: Both incidence and persistence of allergic sensitization were high among children and adolescents explaining the increase in prevalence by increasing age. An inverse pattern with low incidence and high remission of allergic sensitization was seen among adults. The decrease in prevalence of allergic sensitization by increasing adult age might at least partly be explained by normal ageing and not only by an effect of year of birth (cohort effect). The significant increase in prevalence of sensitization to the specific allergens explained the significant increase in multisensitization over 15 years. A family history of allergy was the strongest and the only consistent risk factor for allergic sensitization in all ages. The prevalence of allergic sensitization decreased with increasing age of asthma onset among adult asthmatics.

Background A significant proportion of children are exposed to environmental tobacco smoke (ETS) throughout the world. This is mainly because of exposure to parental smoking. It is unknown to what extent the negative effects of ETS on respiratory symptoms track from childhood into adulthood. Methods TESAOD (Tucson Epidemiologic Study of Airway Obstructive Disease) is a large population-based prospective study that was initiated in 1972. Participants were followed prospectively with questionnaires and pulmonary function tests (PFTs) completed about every two years in 12 follow-up surveys up to 1996. Skin prick tests and blood samples for IgE measurements were collected at surveys 1, 6, and 11. We identified subjects who entered the study as children (<15 years old) and were followed to adulthood (>18 years) during the study follow-up. Based on questionnaire data, active asthma, wheeze, cough, and chronic cough (cough for three consecutive months) were coded as never (never reported in childhood or adulthood), incident (never reported in childhood, but ≥ one positive report in adulthood), remittent (≥ one positive report in childhood, but not in adulthood), and persistent (≥ one positive report both in childhood and adulthood). PFTs measurements included forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow at 25-75%. Parent information on smoking status was collected simultaneously at child visits. ETS exposure status was assessed as “ever” or “never” between birth and 15 years. Results Information on parental ETS exposure in childhood and outcomes in adulthood was available for 444 non-Hispanic white participants (51.4% male) with mean age at initial survey of 7.7 years. Total mean follow-up time was 19.0 years (8.8 years in adulthood). Between birth and 15 years, 53.4% of children were exposed to ETS. After adjusting for sex, age at enrollment, years of follow-up, and personal smoking status (assessed at age 15 and above), combined parental ETS exposure in childhood was significantly associated with persistent wheeze (RR(adj) 1.9, p=0.026), persistent cough (RR(adj) 5.9, p<0.001), and persistent (RR(adj) 3.7, p=0.030) and incident chronic cough (RR(adj) 2.3, p=0.040). Paternal ETS exposure in childhood was associated with persistent wheeze (RR(adj) 2.3, p=0.002), persistent cough (RR(adj) 3.9, p<0.001), persistent (RR(adj) 4.8, p=0.004) and incident chronic cough (RR(adj) 2.2, p=0.031), and persistent asthma (RR(adj) 2.3, p=0.016). Maternal ETS exposure was associated with persistent (RR(adj) 1.9, p=0.029) and incident cough (RR(adj) 2.5, p=0.006). Maternal ETS exposure was associated with an increased percent predicted FVC in adulthood (coefficient, 3.75; p=0.019). No other effects on lung function were seen. There were no effects of ETS exposure on total serum IgE or allergic sensitization. ETS exposure was associated with respiratory symptoms in adulthood among both never and current smokers. Conclusions ETS exposure in childhood has long term health effects on lung function and respiratory symptoms. These effects do not appear to be IgE-mediated. ETS exposure, especially paternal ETS exposure, seems to influence the persistence of respiratory symptoms from childhood to adulthood and to affect women more than men. These effects are independent of personal smoking and also seen in never smokers. Both smoking mothers and fathers should be targeted when attempting to reduce ETS exposure among children.

Alors que la rhinite a un fort impact sur la santé publique, chez l’adulte, il n’existe pas de définition standardisée de la rhinite dans les études épidémiologiques. De plus, les facteurs environnementaux de la rhinite sont mal connus et, en particulier, il existe très peu d'études sur les effets à long terme de la pollution atmosphérique sur la rhinite chez l'adulte. Pour combler ces lacunes, nous avons utilisé les données de deux études épidémiologiques multicentriques européennes ayant des données détaillées sur la santé respiratoire et d'exposition annuelle individuelle à la pollution atmosphérique. Nos résultats ont montré que pour mieux caractériser la rhinite, il faut considérer l’ensemble des caractéristiques des symptômes nasaux, les comorbidités et la sensibilisation allergique, et ne pas limiter la maladie à une question ou à un test de sensibilisation allergique. Nous n'avons trouvé aucune association entre la pollution atmosphérique à long terme et l'incidence de la rhinite, mais nous avons montré que l'exposition à long terme à la pollution était associée à une augmentation de la sévérité de la rhinite, soulignant le besoin de contrôler les niveaux de pollution atmosphérique. / Whereas rhinitis has an important public health impact, in adults there is no standardized definition of rhinitis in epidemiological studies. Furthermore, environmental factors of rhinitis are barely known, and in particular, there are very few studies on the effects of long-term exposure to air pollution on rhinitis in adults. To fill these gaps, we used data from two European multicentre epidemiological studies with extensive data on respiratory health and individual estimated exposures to long-term air pollution. Our findings showed that to better characterize rhinitis, one need to consider together all the characteristics of the nasal symptoms, the comorbidities and the allergic sensitization, and not to restrict the disease to one question or one allergic sensitization test. We found no association between long-term air pollution and incidence of rhinitis, but we showed that long-term exposure to air pollution is associated to an increased severity of rhinitis, emphasising that air pollution needs to be controlled.

Chronic respiratory diseases (CRDs) include chronic diseases involving the airways and other structures of the lung. In the current circumstance of Vietnam, people are exposed to numerous risk factors of CRD, such as heavy smoking, high frequency of pulmonary tuberculosis, chronic helminthiasis, allergic factors, migration and urbanization (the last associated with traffic-related pollution). The phenotype diagnoses should take into account the risk factors of each individual besides the clinical features, while the differential diagnoses mostly depend on the available techniques in each healthcare center. Our aim was to improve the differential diagnoses of the 3 most frequent CRDs: chronic obstructive pulmonary disease (COPD), asthma and COPD – asthma overlap syndrome (ACOS), in Vietnam. In the first part, we evaluated the prevalence of the allergen sensitization among patients with CRD, in regard to the urban and rural area in the South of Vietnam. House dust mites and cockroach droppings were the most frequent sensitizer. Compared with participants born in the urban setting, those born in the rural environment were less frequently sensitized and this protective effect disappeared in the case of migration from rural to urban areas. In the second part, we evaluated skin prick test as a method to screen dust mite sensitization in CRD in southern Vietnam. The data suggested that, in the present circumstance, skin prick test can be used to screen mite sensitization. In the third part, we evaluated the risk of mite sensitization in the native and migrant population, in regard to several environmental factors. Consistently with the hygiene hypothesis, compared to urban, exposure to high endotoxin concentration in rural was a protective factor against allergic sensitization. We reported for the first time that this effect was reversible among the migrants from rural to urban setting in association with lower endotoxin exposure. In the fourth part, we have defined asthma, COPD and ACOS based on clinical symptoms, cumulative smoking and airway expiratory flow with reversibility, on one side, and the age-related of the different phenotypes, on the other side. We hypothesized that the cumulative exposure to noxious particles should increase the age-related prevalence of COPD, while due to the immunosenescence process, the prevalence of IgE-mediated asthma should decrease with age, and ACOS prevalence being not related to age due to the combined mechanisms.  In conclusion, we showed in the South of Vietnam that:1) mites and cockroach allergens were the most frequent sensitizer in chronic respiratory diseases;2) the skin prick test to mite has been validated to screen mite sensitization;3) associated with a reduced level of endotoxin level, migration from rural to the urban setting was a risk factor of mite sensitization in chronic respiratory diseases;4) based on the clinical symptoms, spirometric values, and cumulative smoking, the diagnosis of asthma, COPD and ACOS have been made and their prevalence were 25, 42 and 33%, respectively. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

The aim of this thesis was to identify risk factors for the onset of adult asthma. Other objectives were to study determinants of smoking habits and the association between sensitization and outcome of asthma. In 1990, a questionnaire was distributed to 12,732 individuals from three age groups (16, 30-39 and 60-69 years) in two counties of Sweden. In a second phase, 2538 subjects who had reported respiratory symptoms and 600 controls were invited to clinical investigations, 81% participated. At the follow-up in 2003 subjects of the remaining cohort (11,282) were re-invited. Analyses are based on the 67% (n=7563) who responded to both questionnaires 1990 and 2003. In 2003, 17.2% of the young adults, 11.4% of the middle-aged and 10.3% of the elderly reported having, or having had, asthma. A total of 791 subjects reported onset of asthma during the 13-year study period. Lifestyle factors such as smoking, obesity, hard physical training and a low consumption of fruit and fish were constant risk factors for onset of asthma after adjusting for socioeconomic group. A smoker’s risk of asthma onset was increased by 37%. The impact of risk factors differed between the age-groups. BMI had a significantly higher impact in the middle-aged and elderly. In subjects participating in the clinical investigations in 1990, sensitization to pets, were determinants of both persistent asthma and onset of asthma in 2003. The risk for persistent asthma was threefold. The risk for onset of asthma was more than doubled. Smoking at baseline in 1990 was the strongest determinant of being a smoker in 2003. Allergic sensitization and clinically verified asthma were not associated with smoking habits in 2003. No differences in changing smoking habits could be identified between smokers with or without asthma. In conclusion, modifiable lifestyle factors are important risk factors for adult onset asthma. The co-occurrence and interplay between asthma and cigarette smoking is still puzzling.

Allergic diseases are influenced by genetics and the environment. Maternal allergy appears to confer a higher risk for allergic sensitization than paternal allergy, suggesting an in utero influence. A decrease in particular infections or a lower exposure to microbial components during infancy is suggested to contribute to the high allergy prevalence in affluent societies. Toll-like receptors (TLR) 2 and 4 recognize peptidoglycan (PGN) and LPS respectively, are expressed on e.g. monocytes, and have been implicated in modulating the risk of IgE-sensitization. This thesis aimed to study the influence of maternal allergy and early microbial exposure on monocyte function and allergic sensitization during childhood. Blood samples from children participating in a prospective allergy cohort were used. Two-year old infants with allergic mothers had lower IL-6 production and reduced activation of the TLR-signalling intermediate p38-MAPK in response to PGN than children with non-allergic mothers. In 5-year old children, allergic disease and not maternal allergy influenced monocytic TLR2-regulation. Five-year olds who were seropositive for Epstein-Barr virus (EBV) at 2-years of age had a lower risk of persistent IgE-sensitization while EBV contraction after 2-years of age related to a higher risk of IgE-sensitization. Upon in vitro stimulation, NK cells from EBV+ 2-year olds produced lower IFN-g levels. EBV+ 2-year olds had also lower systemic IFN-g. In comparison to CD14++CD16- monocytes, CD14+CD16+ cells induced NK-cell IFN-g more potently in vitro, and EBV+ infants tended to have lower proportions of these CD14+CD16+ monocytes. This thesis highlights the importance of early-life microbial (EBV) exposure for a proper allergy-protective immunity. Also, maternal allergic heredity appears to influence monocytic microbial responses in early infancy. All these aspects relate to altered monocyte functionality, which suggest that they could have a role in allergic sensitization.

<p>Allergic asthma is a chronic and complex disease of the airways characterized by dysregulated immune-inflammatory responses to aeroallergens and reversible airflow obstruction. The prevalence and economic burden of allergic asthma have increased substantially over the last five decades. Despite remarkable progress in our understanding of the immunobiology and pathophysiology of asthma, the ontogeny of the disease remains elusive. As a result, there is a lack of effective preventative strategies. Here, we used a murine model of allergic asthma to house dust mite (HDM), the most pervasive indoor aeroallergen worldwide to address issues pertaining to the development of allergic asthma. First, we provided a comprehensive computational view of the impact of dose and length of HDM exposure on both local and systemic allergic outcomes (Chapter 2). Parameters, such as thresholds of responsiveness, and non-linear relationships between allergen exposure, allergic sensitization and airway inflammation were identified. We, then, investigated molecular signatures implicated in the onset of allergic responses (Chapter 3). HDM exposure was associated with production of the epithelial-associated cytokines TSLP, IL-25 and IL-33. However, only IL-33 signaling was necessary for intact Th2 immunity to HDM, likely because of its superior ability to induce the critical co-stimulatory molecule OX40L on dendritic cells and expand innate lymphoid cells. Lastly, as individuals are most likely exposed to allergens concomitantly to other environmental immunogenic agents, we studied the impact of an initial immune perturbation on allergic responses to sub-threshold amounts of HDM (Chapter 4). We showed that transient expression of GM-CSF in the airway substantially lowers the threshold of allergen required to generate robust, HDM-specific Th2 immunity, likely through increasing IL-33 production from alveolar type II cells. These studies favor a paradigm whereby distinct molecular pathways can elicit type 2 immunity, intimating the need to classify asthma into distinct clinical subsets.</p> / Doctor of Philosophy (PhD)

A asma ocupacional é a forma mais comum de doença pulmonar relacionada ao trabalho e vários dos casos reportados estão correlacionados à exposição de proteases. A serino protease subtilisina foi bastante utilizada na década de 60 e foi a principal responsável pela alta incidência de asma na indústria de detergente. Este projeto visou a desenvolver um modelo murino de inflamação alérgica pulmonar à subtilisina e caracterizar os mecanismos principais envolvidos nessa resposta. A sensibilização e desafio com subtilisina induziu doença alérgica pulmonar, verificada pela eosinofilia às vias aéreas, produção de muco, IgE total, hiper reatividade brônquica e produção de citocinas tipo II no pulmão. Estas respostas foram dependentes da atividade enzimática da subtilisina, PAR-2, receptor de IL-33 ST2, IL-1R e da sinalização via MyD88. Em conjunto, nossos resultados estabelecem um novo modelo experimental de asma ocupacional induzida por subtilisina e fornece os principais mecanismos moleculares responsáveis pela inflamação alérgica. / Occupational asthma is the most common form of pulmonary disease related to work. Most of occupational asthma cases reported are strictly correlated with proteases exposure. Serine protease subtilisin was widely used in the detergent industry during the 60s, which resulted in increased incidence of occupational asthma. We aimed to develop and characterize a murine model of occupational asthma using subtilisin as allergen. Briefly, sensitization and challenge with subtilisin triggered lung allergic inflammation, as accessed by eosinophilic influx to the airways, mucus production, and increased levels of type II cytokines. Subtilisin induced total IgE and airway hyperactivity. Allergic responses to subtilisin were dependent on its serine protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, IL-1R, and Myd88 signaling. Together, these data establish a new murine model of occupational asthma induced by subtilisin and provide the main molecular mechanisms responsible for allergic inflammation.

A asma ocupacional é a forma mais comum de doença pulmonar relacionada ao trabalho e vários dos casos reportados estão correlacionados à exposição de proteases. A serino protease subtilisina foi bastante utilizada na década de 60 e foi a principal responsável pela alta incidência de asma na indústria de detergente. Este projeto visou a desenvolver um modelo murino de inflamação alérgica pulmonar à subtilisina e caracterizar os mecanismos principais envolvidos nessa resposta. A sensibilização e desafio com subtilisina induziu doença alérgica pulmonar, verificada pela eosinofilia às vias aéreas, produção de muco, IgE total, hiper reatividade brônquica e produção de citocinas tipo II no pulmão. Estas respostas foram dependentes da atividade enzimática da subtilisina, PAR-2, receptor de IL-33 ST2, IL-1R e da sinalização via MyD88. Em conjunto, nossos resultados estabelecem um novo modelo experimental de asma ocupacional induzida por subtilisina e fornece os principais mecanismos moleculares responsáveis pela inflamação alérgica. / Occupational asthma is the most common form of pulmonary disease related to work. Most of occupational asthma cases reported are strictly correlated with proteases exposure. Serine protease subtilisin was widely used in the detergent industry during the 60s, which resulted in increased incidence of occupational asthma. We aimed to develop and characterize a murine model of occupational asthma using subtilisin as allergen. Briefly, sensitization and challenge with subtilisin triggered lung allergic inflammation, as accessed by eosinophilic influx to the airways, mucus production, and increased levels of type II cytokines. Subtilisin induced total IgE and airway hyperactivity. Allergic responses to subtilisin were dependent on its serine protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, IL-1R, and Myd88 signaling. Together, these data establish a new murine model of occupational asthma induced by subtilisin and provide the main molecular mechanisms responsible for allergic inflammation.

Contexte. Les premières années de vie apparaissent particulièrement propices au développement de la sensibilisation allergénique. Objectifs. Cette thèse vise à : i) décrire les profils de sensibilisation allergénique chez le nourrisson et l’enfant, ii) étudier l’association entre ces profils et la morbidité allergique et iii) identifier les facteurs de risque de cette sensibilisation. Méthodes. Dans le cadre du suivi de la cohorte prospective de naissances en population générale Pollution and Asthma Risk: an Infant Study (PARIS), la sensibilisation allergénique a été évaluée chez 1 860 nourrissons à 18 mois et 1 007 enfants à 8/9 ans par dosage des IgE spécifiques dirigées contre 16 et 19 allergènes, respectivement. Les informations concernant la santé et le cadre de vie des enfants ont été recueillies par questionnaires standardisés répétés. Des profils de sensibilisation et des profils de morbidité ont été identifiés par classification non supervisée et mis en relation par régression logistique multinomiale. Enfin, les facteurs associés à la sensibilisation allergénique chez le nourrisson ont été étudiés par régression logistique multivariée. Résultats. Dès 18 mois, 13,8% des enfants étaient sensibilisés et 6,2%, multi-sensibilisés. À 8/9 ans, ces prévalences étaient de 34,5% et 19,8%, respectivement. Les profils de sensibilisation identifiés chez le nourrisson (3) et dans l’enfance (5) différaient au regard de la morbidité allergique. L’analyse étiologique a permis de préciser le rôle des expositions précoces aux allergènes et aux microorganismes sur la sensibilisation allergénique. Conclusion. Cette thèse contribue à une meilleure compréhension de l’histoire naturelle de la sensibilisation allergénique, et ce, dès les premières années de vie. Cette connaissance est essentielle à la prévention des maladies allergiques qui en découlent. / Background. The first years of life appear to be critical for the development of allergic sensitization. Objectives. This thesis aims: i) to describe allergic sensitization profiles in infants and children, ii) to assess the link between these sensitization profiles and allergic morbidity, and iii) to identify risk factors for allergic sensitization. Methods. This work concerns children involved in the Pollution and Asthma Risk: an Infant Study (PARIS) population-based prospective birth cohort. Allergic sensitization was assessed in 1,860 18-month-old infants and 1,007 8/9-year-old children by specific IgE measurements towards 16 and 19 allergens, respectively. Lifelong health and living condition data were collected by repeated standardized questionnaires. Sensitization profiles and morbidity profiles were identified using unsupervised classification, and related to each other by multinomial logistic regression. Finally, risk factors for early allergic sensitization were assessed by multivariate logistic regression. Results. As soon as 18 months of age, 13.8% of children were sensitized and 6.2%, multi-sensitized. When 8/9 years old, corresponding prevalence was 34.5% and 19.8%, respectively. Sensitization profiles identified in infancy (3) and in childhood (5) differed in terms of allergic morbidity. Risk factor analysis allowed to clarify the role of early exposure to allergens and microorganisms on allergic sensitization. Conclusion. This thesis improves the natural history of allergic sensitization understanding, as soon as the first years of life. This knowledge is essential for subsequent disease preventing.