Abstract An excess of atopic allergies has been found in patients with depression, and conversely, increased amounts of depressive symptoms have been reported in patients with atopic disorders. Thus far, however, the findings have mainly been based on clinical samples. In this thesis, the association between atopic disorders and depression was investigated at epidemiological level by using data from the Northern Finland 1966 Birth Cohort. An unselected cohort of 12058 liveborn children was followed prospectively from prenatal stages until 1997. During the 31-year follow-up, 6025 cohort members underwent skin prick tests. Data on lifetime depression diagnoses and atopic conditions were obtained from postal questionnaires and Finnish Hospital Discharge Registers, and the severity of the depressive symptoms was assessed with Hopkins Symptom Checklist-25. Information on the family histories of the atopic disorders was obtained from questionnaires of the 31-year follow-up. Females with positive skin prick test responses and self-reported histories of allergic symptoms exhibited a 2.7-fold probability of developing lifetime depression. The corresponding probability increased in line with the increased severity of depressive symptoms in atopic but not in non-atopic females, ranging from 3.0 to 4.7-fold. Among males, the atopy-depression association was seen only in the highest depression scores, the odds ratio being up to 6.3-fold. While the most severe, hospital-treated manifestations of both disorders were considered, atopic disorders increased the risk of depression 3-fold independently of the subject's gender and sociodemographic characteristics. When investigating the effect of familial atopy on a child's depression, maternal atopy increased the probability of lifetime depression nearly 2-fold in females, and over 4-fold, when a female cohort member's own atopy was also present. At epidemiological level, the presence of atopic conditions seemed to increase the probability of lifetime depression especially in females. Since both atopic disorders and depression are illnesses of major public health importance in Western countries, also the co-morbidity between these disorders should be seriously taken into account in clinical practice. Further investigations are called for in evaluating whether this association is specific to atopic disorders, since increased risks of depression have been noted in connection with many other physical diseases as well.

Introduction: Le traitement de la rhinite allergique (RA) est maintenant bien établi et la plupart des patients atteints par cette maladie y répondent. Néanmoins, il existe un pourcentage de patients qui ne sont pas contrôlés, malgré un traitement maximal, amenant au concept de SCUAD (Severe Chronic Upper Airway Disease), acronyme anglais pour "atteinte sévère et chronique des voies aériennes supérieures". En Chine, les données concernant la RA non contrôlée et le SCUAD sont insuffisantes. Le test de contrôle de la rhinite allergique (Allergic Rhinitis Control Test, ARCT) est un outil validé pour évaluer le contrôle de la RA et identifier la RA sévère. Néanmoins, l'ARIA (Allergic Rhinitis and its Impact on Asthma, acronyme anglais pour Rhinite Allergique et son Impact sur l'Asthme) n'offre pas de définition claire du contrôle de la RA et, du fait de l'absence de critères uniformes, le choix de la pharmacothérapie varie dans différentes régions et populations. Objectif: La première étude a eu pour objectif d'évaluer la prévalence et les caractéristiques des patients avec RA non contrôlée et SCUAD à Wuhan. A partir de cette étude préliminaire, une autre étude a été mise en oeuvre, pour évaluer le rôle de l'ARCT en tant qu'outil pour guider une pharmacothérapie par paliers, dans le but d'atteindre le contrôle de la RA. Méthode : Dans la première étude, tous les patients consultant pour une RA ont été évalues en prospectif par EVA et ARCT, et mis sous traitement selon le guide ARIA. Au bout de 15 jours (J15), une interview téléphonique a permis de ré-évaluer la RA au moyen d'une échelle numérique et de l'ARCT. La RA non contrôlée était définie par un score ARCT<20. Les patients souffrant de SCUAD étaient définis par un score ≥5 à J15. Dans la 2ème étude prospective, un traitement pharmacologique standard a été proposé aux patients souffrant de RA. Les paliers allaient du palier 1 (antihistaminique H1 à la demande) jusqu'au palier 5 (corticoïde oral). La RA était traitée et évaluée tous les 15 jours par ARCT. Si le score ARCT était ≥20, maintenu pendant 15 jours, le patient terminait l'étude. Si l'ARCT était <20, le patient recevait le prochain palier de traitement, selon une démarché prédéfinie, progressive, jusqu'au palier 5. Résultats: Au total, 252 patients ont été inclus dans la 1ère étude. La RA modérée/sévère était présente en 82,9% des patients, avec un impact sur le sommeil, travail, activités sociales et physique. Les patients avec RA non contrôlée à J15 étaient ceux avec un poids plus important (P=0,042), antécédents d'infections ORL ou de prise d'antibiotiques pour infections respiratoires dans les derniers 12 mois (62,3 vs. 45,6%, P=0,018), de tabagisme (P=0,024) et de dysosmie (P=0,005). Les patients avec SCUAD avaient plus fréquemment des antécédents d'infections ORL ou de prise d'antibiotiques pour infections respiratoires (P=0,014) et de dysosmie (P=0,003) et moins fréquemment de dermatite atopique (P=0,017). 255 patients ont été inclus dans la 2ème étude. Seulement 3,2% sont restés non contrôlés à la fin de l'étude. Les patients avec une RA modérée à sévère selon ARIA, RA persistante, impact modéré à sévère sur la qualité de vie, antécédents d'asthme, rhinorrhée et toux avaient toujours besoin d'un traitement associé, ainsi qu'un traitement prolongé pour atteindre le contrôle. Après ajustement sur chacune des variables, le seul facteur de risque restant significatif était la présence d'un asthme (il était moins probable que ces patients soient contrôlés par les premiers paliers de traitement). Conclusion: Les patients ayant une RA non-contrôlée ou atteints de SCUAD sont nombreux. L'EVA et l'ARCT sont des outils simples qui peuvent être utilisés dans l'évaluation globale de la sévérité et du contrôle de la RA. L'ARCT offre un critère objectif pour guider le traitement par paliers... / Background : The treatment of Allergic rhinitis (AR) is now well established and most patients respond well to the treatment. However, there are still some patients with uncontrolled AR despite optimal maximum treatment, leading to the concept of severe chronic upper airway disease (SCUAD). In China, there are insufficient epidemiological data regarding uncontrolled AR and SCUAD. Allergic Rhinitis Control Test (ARCT) has been validated for assessing AR control and to identify severe AR. However, Allergic Rhinitis and its Impact on Asthma (ARIA) still has no clear definition of AR control, and due to the absence of uniformed criteria, pharmacotherapy adjustment regimens varies in different areas and populations. ObjectiveThe first study aimed to assess the prevalence and the characteristics of patients with uncontrolled AR and SCUAD in Wuhan. On the basis of the preliminary study, a further study is designed to assess ARCT as a questionnaire driven stepwise pharmacological treatment to achieve AR control. Methods : In the first epidemiology study, all patients consulting for AR were prospectively assessed using VAS and ARCT and put on standardized treatment based on ARIA guidelines. After 15 days, they were reevaluated by a telephone interview using a numerical scale and ARCT. A score of ARCT <0 defined uncontrolled AR and a score ≥5 at day-15 defined SCUAD patients.In the second study, a standard pharmacotherapy regimen from step1 (oral second generation H1 antihistamine as needed) to step 5 (oral corticosteroid) was applied prospectively in a Chinese AR population. The AR patients were initiated with ARIA appropriate step treatment and assessed with ARCT every 15 days. If ARCT score was equal or above 20 and maintained for 15 days, the patient would finish the study; if ARCT score was strictly less than 20, the patient would receive higher step treatment according to a predefined open design up to step 5. Results: A total of 252 patients were included in the first study. Moderate/severe AR was diagnosed in 82.9% of the patients and they had an impact on sleep, work life, social activities and physical activities. Patients with uncontrolled ARat day-15 more frequently presented a higher weight (P=0.042), past history of ENT infection or antibiotics intake for respiratory infection in the last 12 months (P=0.018), smoking (P=0.024) and smell disturbance (P=0.005). Patients with SCUAD more frequently presented a past history of ENT infection or antibiotics intake for respiratory infection (P=0.014) and smell disturbance (P=0.003), while less commonly had atopic dermatitis (P=0.017). 255 patients were enrolled in the second study. Only 3.2% patients remained uncontrolled at the endpoint of the study. Patients with ARIA moderate/severe or persistent symptoms, moderate/severe impaired quality of life, asthma history, rhinorrhea and cough symptoms always needed up to step 4 and prolonged treatments to achieve disease control. After adjustment on each of the variables, the only factor that remained significant was asthma (less likely to be in a group controlled by the first steps’ therapies) .Conclusion: Uncontrolled AR and SCUAD patients are numerous. VAS and ARCT are simple and quantitative methods and self-completion questionnaire that can be used for a global evaluation of the severity and control of AR. ARCT offers an objective criterion for the stepwise pharmacotherapy of AR. Risk factor analysis did not reveal strong clinical characteristics that would help the physician to control AR better.

Résumé : PROBLÉMATIQUE: L’exposition résidentielle à l’humidité excessive ou aux moisissures est maintenant reconnue comme un facteur important influençant la santé respiratoire. Cette problématique a été peu étudiée chez les étudiants universitaires, bien que vulnérables par leur faible revenu et leur statut de locataire. OBJECTIFS: Cette maîtrise vise à décrire la prévalence (a) de l’exposition résidentielle à l’humidité excessive ou aux moisissures et (b) des maladies respiratoires chez les étudiants universitaires, ainsi qu’à (c) examiner l’association entre l’exposition résidentielle à l’humidité excessive ou aux moisissures et ces maladies. MÉTHODES: En 2014, une enquête électronique a été réalisée auprès de 2097 étudiants enregistrés à l’Université de Sherbrooke (Québec, Canada). Lorsque possible, des questions et des scores validés ont été utilisés pour estimer les prévalences des maladies respiratoires (rhinite allergique, asthme et infections respiratoires), de l’exposition résidentielle à l’humidité excessive ou aux moisissures et des covariables (ex. : revenu annuel familial, statut tabagique, atopie familiale, caractéristiques de l’étudiant). Les associations entre cette exposition et ces maladies ont d’abord été examinées par des tests de chi-carré en utilisant un seuil alpha de 0,05. Des régressions logistiques multivariées ont ensuite été utilisées pour déterminer les associations brutes et ajustée entre cette exposition et les maladies respiratoires. Les analyses descriptives ont été pondérées pour le sexe, l’âge et le campus d’étude. RÉSULTATS: L’exposition à l’humidité excessive ou aux moisissures était fréquente parmi les participants (36,0%; Intervalle de confiance (IC)95% : 33,9-38,1). Ceux-ci ont également été nombreux à rapporter une rhinite allergique (23,9%; IC95% :22,0-25,8), de l’asthme (32,6%; IC95% : 30,5-34,7) et des infections respiratoires (19,4%; IC95% :17,7-21,2) au cours de la dernière année. Après ajustement, les associations demeuraient significatives entre l’exposition à l’humidité excessive ou aux moisissures et la rhinite allergique (Rapport de cote (RC) : 1,30; IC95% : 1.05-1.60), l’asthme RC : 1,75; IC95% : 1,42-2,16), mais pas les infections respiratoires (RC : 1,07; IC95% : 0,85-1.35). CONCLUSIONS: La prévalence élevée de l’exposition résidentielle des étudiants universitaires à l’humidité excessive ou aux moisissures, de même que son association avec l’asthme et la rhinite allergique, mettent en lumière sa contribution potentielle à la forte prévalence des maladies respiratoires ayant une composante allergique dans cette population. Cette étude fournit un nouveau levier pour les organisations de santé publique et leurs partenaires afin d’adapter les stratégies préventives ciblant les logements insalubres, particulièrement chez les populations vulnérables. / Abstract : PROBLEMATIC: Indoor residential dampness and mold is now recognised as a major respiratory health determinant. University students are vulnerable to such exposure by their low income and high mobility, but few studies have assessed their exposure. OBJECTIVES: This project aims to describe prevalence of (a) residential dampness or mold exposure and (b) respiratory diseases in University students as well as to (c) examine the independent contribution of residential excessive dampness and mold to these diseases. METHODS: In 2014, an online survey was conducted among 2097 students registered at the University of Sherbrooke (Quebec, Canada). Validated questions, and scores when possible, were used to assess respiratory diseases (allergic rhinitis, asthma-like symptoms, respiratory infections), residential excessive dampness and mold, and covariates (e.g. family annual income, smoking status, parental atopy, student characteristics). Associations between exposure and diseases were first evaluated using bivariate analyses (khi-square tests) with an alpha value of 0.05. Using logistic regressions, the crude and adjusted relationships between residential excessive dampness or mold and respiratory diseases were examined. Results were weighted for sex, age and campus affiliation. RESULTS: Residential dampness or mold exposure was frequent (36.0%; 95%Confidence Interval (CI) : 33.9-38.1). Respondents also reported high prevalence of allergic rhinitis (32.6%; 95%CI : 30.5-34.7), asthma-like symptoms (23.9%; 95%CI : 22.0-25.8) and respiratory infections (19.4%; 95%CI : 17.7-21.2). After adjustment, associations with residential excessive dampness or mold were significant for allergic rhinitis (Odd Ratio(OR) : 1.30; 95%CI : 1.05-1.60) and asthma-like symptoms (OR : 1.75; 95%CI : 1.42-2.16), but not for respiratory infections (OR : 1.07; 95%CI : 0.85-1.35). CONCLUSIONS: High frequency of residential excessive dampness and mold, as well as its associations with asthma and allergic rhinitis highlight this exposure’s potential contribution to high atopy prevalence among university students. These results emphasize the importance for public health organizations to tackle poor housing, especially for vulnerable populations.

Los objetivos fueron conocer la incidencia atmosférica de polen en Santander y su repercusión sobre la población MÉTODOS: Método volumétrico de Hirst; influencia de la meteorología en el periodo de mayo a julio de 1998 a 2002, mediante medidas de asociación lineal entre variables meteorológicas diarias y los recuentos de polen diarios de gramíneas; pruebas cutáneas; relación entre las ventas mensuales de antihistamínicos en la ciudad y los recuentos mensuales de polen de gramíneas; y la relación entre los recuentos diarios y semanales de polen y variables meteorológicas y de contaminación con las asistencias a urgencias por rinoconjuntivitis y por asma en niños. Encuesta sobre síntomas de asma de la IUATLD y un cuestionario sobre 11 factores del interior. RESULTADOS: La media anual de polen total fue 8.604, el polen de familia poaceae supuso el mayoritario (28 %). La temperatura máxima fue la única variable explicativa de los recuentos de polen en su periodo. El 100% de los pacientes estaban sensibilizados a poaceae. Se encontró relación mensual de los recuentos de poaceae con las ventas de antihistamínicos (rs= 0,7; p<0,01) y relación diaria y semanal de dichos recuentos con las asistencias por rinoconjuntivitis en niños y adultos. Las asistencias a urgencias por asma en niños (2.396) y adultos (1.665) fueron más frecuentes de septiembre a diciembre. Se encontró relación durante el periodo de mayo a julio de los recuentos semanales de poaceae y de temperatura con las asistencias a urgencias en niños. La prevalencia de síntomas de asma en adultos fue de 15% (9,8 - 20,2). Mayor frecuencia de síntomas de asma entre quienes tenían un animal en casa : 41% frente a 14%; OR: 4,2 (1,9 - 9,2) y quienes habían vivido en Santander sus primeros 10 años de vida: 22% frente a 11%; OR: 2,9 (1,1 - 7,5). CONCLUSIONES: El polen de poaceae es el predominante en la atmósfera de Santander y el que sensibiliza a todos los polínicos. Se demostró una relación del mismo con la rinoconjuntivitis en niños y adultos, y en el asma bronquial en niños. Existe una elevada prevalencia de síntomas de asma en adultos de Santander, con probable implicación de factores de interior. / Objectives: To determine the atmospheric pollen counts in Santander and their effect on this population. METHODS: Hirst volumetric method; analysis of the effect of weather on the pollen counts from 1998 to 2002 by linear association measures; skin tests; association between antihistamine sales and pollen counts; association between daily and weekly pollen counts and weather and pollution variables and Emergency Room admittances caused by rhinitis-conjunctivitis and asthma in children. Survey about asthma symptoms (IUATLD) and indoor risks for asthma. RESULTS: Average annual pollen count was 8,604. Poaceae family predominated (28%). Maximum temperature was the only explanatory variable for pollen counts during its period. All the hay fever patients were sensitized to poaceae. We found a relationship between monthly pollen counts and monthly antihistamine sales (rs= 0.7; p<0.01) and daily and weekly association with admittances for rhinitis-conjunctivitis in children and adults. Admittances to E.R. caused by asthma in children (2396) and in adults (1665) were more frequent from september to december. During the period from may to july the asthma admittances of children were associated with weekly poaceae counts and weekly temperature. Prevalence of asthma symptoms in adults was 15% (9.8 - 20.2). Symptoms were more frequent among those with a pet: 41% vs 14%; OR: 4,2 (1.9-9.2) and among people who had lived in Santander during their first ten years of life: 22% vs 11%; OR: 2.9 (1.1-7.5). CONCLUSIONS: Poaceae pollen is the predominant in the atmosphere of Santander, all the hay fever patients are sensitised to it and there is a relationship between it and rhinitis-conjunctivitis in children and adults and between it and asthma in children. There is a high prevalence of symptoms of asthma in Santander; indoor factors are probably involved.

Asthma and allergies are some of the most common illnesses worldwide that almost everybody will come in contact with. This thesis studied persons with allergic asthma, non-allergic asthma, allergic rhinitis and atopic dermatitis in a population-based sample. At an early stage, these illnesses were regarded as psychosomatic. Over time, as knowledge about asthma/allergy has increased more of a biomedical perspective was taken by the research field. In considering early documentations well as contemporary research, a psychobiosocial perspective was taken in this thesis when conducting the three studies. Thus, as psychological factors may affect the illness and be a result of the illness, it is important to incorporate these factors to better understand asthma and allergy. Study I examined the co- and multimorbidity in asthma/allergy with the environmental intolerances in the form of chemical and building-related intolerance. Study II investigated psychological distress in the four forms of asthma and allergy. Psychological distress was in this study defined as stress, burnout, anxiety, depression and environmental health worries. Study III examined usage of problem and emotion focused coping strategies and perceived social support from the surrounding in high and low asthma/allergy severity. All studies were performed using data from the Västerbotten Environmental Health Study, a questionnaire-based survey with focus on various environmental hypersensitivities and asthma and allergy. The result showed that the co- and multimorbidity with the environmental intolerances in asthma/allergy was larger than what was statistically excepted. Those with allergic asthma and atopic dermatitis experienced more stress, burnout and anxiety than those with non-allergic asthma, allergic rhinitis and non-asthma/allergy. Moreover, the most common way of coping with asthma and allergy was found to be strategies such as avoiding environments that are believed to affect health, and trying to accept the situation, independent of asthma/allergy severity. Finally, in general, those with asthma and allergy reported receiving most support from their partner, other family members and health care, and least support was perceived by those with low asthma/allergy severity.The findings suggest that co- and multimorbidity with environmental intolerances is relatively common in asthma and allergy, and should therefore be included in the clinical anamnesis for this patient group. The elevated level of distress in allergic asthma and atopic dermatitis evokes the question of use of therapies such as mindfulness maybe beneficial in certain afflicted persons. The results on coping and social support provide a foundation for further research regarding informing the asthma/allergy patient and family members about effective coping strategies and the importance of adequate social support. A metaperspective is taken in which interrelations between important variables in the thesis are discussed.

This study aimed to evaluate the clinical efficacy and systemic/mucosal antibody response changes after sublingual immunotherapy (SLIT) using Dermatophagoides pteronyssinus (Dpt) allergens with or without bacterial extracts in mite-allergic children. One-hundred and two patients presenting allergic rhinitis with or without asthma were selected for a randomized double-blind, placebo-controlled trial and distributed into three groups: DPT (Dpt allergen extract, n=34), DPT+MRB (Dpt allergen plus mixed respiratory bacterial extracts, n=36), and Placebo (n=32). Clinical evaluation and immunological analyses were carried out before and after 12 and 18 months of treatment, including rhinitis/asthma symptom and medication scores, skin prick test (SPT) to Dpt extract, and measurements of Dpt, Der p 1, Der p 2 specific IgE, IgG4, and IgG1 in serum and specific IgA in saliva and nasal lavage fluid. Clinical results showed a significant decline in rhinitis/asthma symptom scores in all groups, but medication use decreased only in DPT group after 12 months. SPT results showed no significant changes and SLIT was generally safe, with no severe systemic reactions. SLIT using Dpt allergen alone induced increased serum IgG4 levels to Dpt, Der p 1 and Der p 2, and increased serum IgG1 and salivary IgA levels to Dpt and Der p 1. SLIT using DPT+MRB was able to decrease IgE levels to Der p 2, to increase salivary IgA levels to Der p 1, but had no changes on specific IgG4 and IgG1 levels. In conclusion, clinical improvement was observed both in the SLIT group and the control, but only active SLIT was able to modulate the mucosal/systemic antibody responses. These findings support the role of specific serum IgG4 and IgG1, in addition to salivary IgA, as probable blocking antibodies or biomarkers of tolerance that may be useful for monitoring the allergen specific immunotherapy. / Este estudo teve como objetivo avaliar a eficácia clínica e alterações da resposta de anticorpos sistêmicos e de mucosa após a imunoterapia sublingual (SLIT), utilizando alérgenos de Dermatophagoides pteronyssinus (Dpt), com ou sem extratos bacterianos em crianças alérgicas a ácaros. Cento e dois pacientes com rinite alérgica com ou sem asma foram selecionados para um estudo randomizado duplocego, controlado por placebo e distribuídos em três grupos: DPT (extrato alergênico de Dpt, n=34), DPT+MRB (extrato alergênico de Dpt associado com extrato de bactérias mistas do trato respiratório, n=36), e Placebo (n=32). Avaliação clínica e análises imunológicas foram realizadas antes do tratamento e após 12 e 18 meses, incluindo a pontuação de escores de sintomas e medicamentos de rinite/asma, teste cutâneo (SPT) ao extrato Dpt, e medidas de anticorpos específicos IgE, IgG4 e IgG1 para Dpt, Der p 1, Der p 2 no soro e IgA específicos na saliva e no lavado nasal. Os resultados clínicos mostraram uma redução significativa nos escores de sintomas de rinite/asma em todos os grupos, mas o uso de medicamentos diminuiu apenas no grupo DPT após 12 meses. Resultados de SPT não mostraram mudanças significativas e SLIT foi geralmente segura, sem reação sistêmica grave. SLIT usando somente alérgeno Dpt induziu aumento dos níveis de IgG4 para Dpt, Der p 1 e Der p 2 no soro, e aumentou os níveis de IgG1 no soro e salivares de IgA para Dpt e Der p 1. SLIT usando DPT+MRB foi capaz de diminuir os níveis de IgE para Der p 2, aumentar os níveis salivares de IgA para Der p 1, mas não tiveram alterações nos níveis de anticorpos específicos de IgG4 e IgG1. Em conclusão, foi observado melhora clínica tanto no grupo da SLIT como do controle, porém somente na SLIT com alérgeno foi capaz de modular as respostas de anticorpos sistêmicos e de mucosa. Estes achados reforçam o papel de anticorpos IgG4 e IgG1 séricos específicos, além de IgA salivar, como prováveis anticorpos bloqueadores ou biomarcadores de tolerância que podem ser úteis para monitoramento da imunoterapia alérgeno-específica. / Doutor em Imunologia e Parasitologia Aplicadas

Orientador: Ricardo de Lima Zollner / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T16:04:12Z (GMT). No. of bitstreams: 1 Vilella_LuizFelipeNoraRosa_M.pdf: 1382640 bytes, checksum: d0c8bc891d04399e182ad18470fe85b2 (MD5) Previous issue date: 2013 / Resumo: As vias aéreas superiores e inferiores constituem um sistema integrado, cuja interação é evidente na presença das doenças alérgicas, incluindo a rinite alérgica, que é co-morbidade relevante para o desenvolvimento da asma. Mecanismos já consolidados estão envolvidos, contudo o reflexo naso-brônquico, que consiste em um reflexo neural originado nas vias aéreas superiores causando impacto nas vias aéreas inferiores por meio da inflamação neurogênica foi sugerido em estudos experimentais. Evidências da presença deste reflexo em humanos baseiam-se em diferentes métodos que demonstraram prejuízo na função pulmonar após estimulação nasal, porém o monitoramento objetivo da permeabilidade nasal pela rinometria acústica associado ao estudo da função pulmonar por meio da espirometria, possibilita acessar respostas agudas nas vias aéreas após estimulação nasal, representando uma ferramenta promissora na investigação do reflexo naso-brônquico. Portanto, o objetivo deste estudo foi avaliar alterações na função pulmonar após provocação nasal, visando identificar o reflexo naso-brônquico na rinite alérgica isolada. 33 voluntários com rinite alérgica persistente moderada/grave (grupo experimento) e 10 saudáveis (grupo controle) foram submetidos a avaliação inicial e protocolo de investigação composto por espirometria e rinometria acústica basais, seguidas por teste de provocação nasal com concentrações crescentes de histamina; após aplicação de cada concentração a rinometria acústica era novamente realizada passados 1, 4, 8 e 12 minutos, sendo considerada provocação positiva após 20% de obstrução em AST-2, determinando o PN20; por fim, imediatamente nova espirometria era realizada. Ao comparar os dados de função pulmonar antes e após provocação nasal, foi observada diferença significativa no grupo rinite para VEF1 (p=0,002), CVF (p=0,005) e PFE (p=0,005), entretanto não houve variação significativa para nenhum dos parâmetros analisados no grupo controle. O reflexo naso-brônquico foi identificado a partir da variação do VEF1, após a provocação nasal no grupo controle (média acrescida de dois desvios padrões), logo 18,2% dos indivíduos com rinite apresentaram reflexo naso-brônquico (queda > 3% em VEF1). Além disso, para estes verificamos correlação positiva entre as alterações observadas em VEF1 e FEF25-75% (p=0,002 / r=0,97), sugerindo envolvimento das vias aéreas de pequeno calibre. Considerando as vias aéreas superiores, o protocolo proposto demonstrou respostas similares nos dois grupos, sem diferença significativa entre os mesmos para dose de histamina (p=0,98), tempo para atingir PN20 (p=0,97) e porcentagem de obstrução nasal (p=0,97). As alterações observadas na função pulmonar após provocação nasal sugerem a presença do reflexo naso-brônquico no paciente com rinite alérgica persistente moderada/grave. O protocolo proposto apresentou reprodutibilidade, sem intercorrências e, diante dos resultados obtidos, propomos que deva ser pensado na prática clinica com objetivo de aperfeiçoar o diagnóstico da presença do reflexo naso-brônquico, relevante para os pacientes com hiperreatividade brônquica / Abstract: Upper and lower airways consists an integrated system and their interaction becomes evident in allergic diseases, highlighting allergic rhinitis, which is co morbidity to asthma onset. Consolidated paths are involved in this crosstalk, however the nasobronchial reflex, that represents a neural reflex originated in upper airways that causes lower airways impairments was suggested in experimental studies. Evidences for the presence of this reflex in humans are based in different methods that have demonstrated impaired pulmonary function after nasal challenge, although, utilizing objective monitoring of nasal patency by acoustic rhinometry in association with pulmonary function evaluation provided by spirometry, it is possible to access acute airways responses after nasal provocations, representing to be promising tools in nasobronchial reflex investigation. Thus, the aim of this study was to evaluate changes in pulmonary function after nasal provocation, looking for nasobronchial reflex identification in subjects with isolated allergic rhinitis. 33 subjects with persistent moderate/severe allergic rhinitis and 10 healthy subjects underwent screening evaluation and investigation protocol consisting in baseline spirometric and acoustic rhinometry measurements, followed by histamine nasal provocation in increasing concentrations; after each histamine application, comparative acoustic rhinometry measurements were performed passed 1, 4, 8 and 12 minutes and positive provocation was considered after reached 20% of obstruction in MCA-2, determining the NPT20; finally, another spirometry was performed immediately NPT20 was reached. Comparing the pulmonary function before and after provocation in the rhinitis group, it was observed significant difference for FEV1 (p=0,002), FVC (p=0,005) and PEF (p=0,005), however in the same comparison for the control group no significant difference could be found for any of the analyzed parameters. Nasobronchial reflex was identified based on VEF1 percentage of variation after nasal provocation in control group (mean plus two standard deviations), 18,2% of rhinitis group presented nasobronchial reflex (> 3% fall in FEV1). Furthermore, for these ones we could verify positive correlation between VEF1 and FEF25-75% impairments (p=0,002/r=0,97), suggesting distal lower airways involvement. Considering upper airways, the proposed protocol demonstrated similar reactions in the two groups, with no significant differences between them for histamine dose (p=0,98), time to reach NPT20 (p=0,97) and percentage of nasal obstruction (p=0,97). Concluding, spirometric impairments showed here suggest the presence of nasobronchial reflex in patients with persistent moderate/severe allergic rhinitis. The proposed protocol proved to be reproducible, without intercurrences and, regarding results showed here, we propose that it should be thought in clinical practice, in order to improve the diagnosis of the presence of nasobronchial reflex, relevant to patients with bronchial hyperreactivity / Mestrado / Clinica Medica / Mestre em Clinica Medica

Background. Seasonal allergic rhinitis (SAR) is a chronic disease affecting about 23% of the European population with increasing prevalence rates. Beside classical symptoms (i.e. sneezing, nasal congestion), patients frequently complain about subjective impairments in cognitive functioning during periods of acute allergic inflammation. However, objective evidence for such deficits or the role of potential modulators and underlying mechanisms is limited. The present study aimed to investigate the effect of SAR on attention-related cognitive processes. In addition, relationships between attention performance, sleep and mood disturbances as well as specific disease characteristics as potential modulators of this link were explored. Method. SAR patients (n = 41) and non-allergic healthy controls (n = 42) completed a set of attention tasks during a symptomatic allergy period and during a non-symptomatic period. Influences of sleep, mood, total immunoglobulin E (IgE) levels and individual allergy characteristics on cognitive performance were evaluated. Results. Compared to healthy controls, SAR patients had a slower processing speed during both symptomatic and nonsymptomatic allergy periods. Additionally, they showed a more flexible adjustment in attention control, which may serve as a compensatory strategy. Reduction in processing speed was positively associated with total IgE levels whereas flexible adjustment of attention was linked with anxious mood. No association was found between SAR-related attention deficits and allergy characteristics or sleep. Conclusions. SAR represents a state that is crucially linked to impairments in information processing and changes in attentional control adjustments. These cognitive alterations are more likely to be influenced by mood and basal inflammatory processes than sleep impairments or subjective symptom severity.

Seasonal allergic rhinitis (SAR) is a disease caused by allergens from both environmental and genetic factors. Some researchers have studied the SAR based on traditional genetic methodologies. As technology develops, a new technique called single-cell RNA sequencing (scRNA-seq) is developed, which can generate high-dimension data. We apply two machine learning (ML) algorithms, random forest (RF) and partial least squares discriminant analysis (PLS-DA), for cell source classification and gene selection based on the SAR scRNA-seq time-series data from three allergic patients and four healthy controls denoised by single-cell variational inference (scVI). We additionally propose a new fitting method consisting of bootstrap and cubic smoothing splines to fit the averaged gene expressions per cell from different populations. To sum up, we find that both RF and PLS-DA could provide high classification accuracy, and RF is more preferable, considering its stable performance and strong gene-selection ability. Based on our analysis, there are 10 genes having discriminatory power to classify cells of allergic patients and healthy controls at any timepoints. Although there is no literature founded to show the direct connections between such 10 genes and SAR, the potential associations are indirectly confirmed by some studies. It shows a possibility that we can alarm allergic patients before a disease outbreak based on their genetic information. Meanwhile, our experiment results indicate that ML algorithms may discover something between genes and SAR compared with traditional techniques, which needs to be analyzed in genetics in the future.

Objective: Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) are of high importance in otorhinolaryngology. Some of their symptoms are related to changes in the nasal trigeminal sensitivity. The aim of this study was to compare nasal trigeminal sensitivity in patients with AR, CRSwNP, and healthy controls (HC). - Methods: A total of 75 individuals participated (age 19–78 years; 34 AR, 10 CRSwNP and 31 HC). Olfactory function was determined using the extended Sniffin’ Sticks test battery. Trigeminal sensitivity was assessed with CO₂ detection thresholds.Trigeminal negative mucosal potentials (NMP) and EEG-derived event-related potentials (ERP) were recorded in response to selective olfactory (phenylethyl alcohol) and trigeminal (CO₂) stimuli using high-precision air-dilution olfactometry. - Results: In comparison to HC, AR patients had lower CO₂ thresholds, also reflected in shorter peak latencies in NMP and trigeminal ERP measurements. CRSwNP patients had a decreased sensitivity for trigeminal stimuli, also reflected in prolonged trigeminal ERP latencies, and reduced olfactory function compared to HC. - Conclusion: AR patients seemed to be more sensitive to trigeminal stimuli than CRSwNP patients. Importantly, the differences could be shown on psychophysical and electrophysiological levels. The changes in trigeminal sensitivity appear to be present already at the level of the respiratory epithelium. The differences between the two groups may depend on the specific inflammatory changes accompanying each disorder, the degree of inflammatory activity, or duration of the inflammatory disorder. However, because the sample sizes are relatively small, these results need to be confirmed in the future studies with larger groups.