Thesis--Copenhagen. / Summary in Danish. Bibliography: p. [109]-120.

Thesis (doctoral)--Copenhagen.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Allergic drug reactions account for 6.5% of hospital admissions, prolonged hospitalization 15.1% of patients and are severe in 6.7% of patients. There are difficulties in understanding the immune mechanisms, diagnosis and treatment of patients. Therefore, such reactions are considered a Public Health problem. The objective of this study was to describe the cases of patients with suspected allergic hypersensitivity to drugs and to evaluate the response of individuals to skin tests. A total of 63 patients were included in the study. The experimental design was a cross-sectional observational study from June 2008 to October 2011. We applied a questionnaire to investigate the clinical and laboratory informations. Eight patients received other diagnosis and three died due to other reasons, so that 52 patients completed the study. Most patients were men (56.36%), non atopic, with a median age of 52 year. The drugs most commonly implicated were NSAIDs and the oral administration was the most commonly route used. It was documented 69 suspected reactions; most of them were considered as delayed hipersensitivity. Maculopapular rash and erythema multiforme were the most frequent manifestations. According to the severity of the reactions, most was considered moderate (72.46%). The patch test was performed in 22 patients for investigation of delayed reaction. Seven cases were positive (31.81%), DRESS (rash with eosinophilia and systemic symptoms) caused by captopril (+), contact eczema by rifamycin (+ +), lichenoid eruption by captopril (+), maculopapular rash + ampicillin and cephalexin to angioedema (+), two cases of fotoeczema one by captopril and another by AAS, both with positive results (+) and one case of Stevens-Johnson syndrome caused by phenytoin (++). For immediate hypersensitivity, 3 in 10 patients have shown positive results for prick test with AAS diluted to 1/1000. It was possible to confirm the liability of the drug reactions in 19 (27.53%), which demonstrated the importance of application of skin tests in the clinical investigation of allergic drug reactions. As for causality, 26 reactions were considered possible, 20 defined, 13 probable, 9 and a conditional reaction was considered not related to drugs. Given its importance, the performance of skin tests with these patients has opened perspectives on the possibility to incorporate this service in routine outpatient Dermatology HUWC. / As reaÃÃes alÃrgicas medicamentosas sÃo responsÃveis por 6,5% das admissÃes hospitalares, prolongam a hospitalizaÃÃo de 15,1% dos pacientes e sÃo graves em 6,7% dos pacientes. Hà dificuldades quanto à compreensÃo dos mecanismos imunolÃgicos, diagnÃstico e tratamento dos pacientes. Portanto, tais reaÃÃes sÃo consideradas um problema de saÃde pÃblica. O objetivo deste trabalho foi descrever os casos de pacientes com suspeita de hipersensibilidade alÃrgica a fÃrmacos e avaliar a resposta desses indivÃduos aos testes cutÃneos. Um total de 63 pacientes foram incluÃdos no trabalho, cujo delineamento experimental foi de um estudo observacional descritivo transversal realizado entre junho de 2008 e outubro de 2011. Utilizou-se um questionÃrio para investigaÃÃo das informaÃÃes clÃnico-laboratoriais. Oito pacientes receberam outro diagnÃstico e trÃs foram a Ãbito por outros motivos, de forma que 52 pacientes completaram o estudo. A maioria dos pacientes era homem (56,36%), nÃo atÃpicos, com mediana de idade de 52 anos. Os fÃrmacos mais implicados foram os AINES (anti-inflamatÃrios nÃo esteroidais) e a via oral foi a mais utilizada. Foram documentadas 69 reaÃÃes suspeitas, a maioria do tipo tardia. Exantema maculopapuloso e eritema multiforme foram as manifestaÃÃes mais freqÃentes entre as reaÃÃes tardias. Quanto à gravidade, a maioria foi considerada moderada (72,46%). O teste de contato foi realizado em 22 pacientes para investigaÃÃo de reaÃÃo tardia. Em sete casos, houve resultado positivo (31,81%), ou seja, DRESS (Rash com eosinofilia e sintomas sistÃmicos) causado por captopril (+), eczema de contato por rifamicina (++), erupÃÃo liquenÃide por captopril (+), exantema maculopapuloso + angiodema para cefalexina e ampicilina (+), dois casos de fotoeczema, um por captopril e outro por Ãcido acetilsalicÃlico (AAS), ambos com resultado (+) e um caso de sÃndrome de Steven-Johnson por fenitoÃna (++). Foram realizados dez testes de puntura e em trÃs pacientes houve positividade para AAS diluÃdo a 1/1000. Foi possÃvel confirmar a imputabilidade do fÃrmaco em 19 reaÃÃes (27,53%), o que demonstra a importÃncia da aplicaÃÃo dos testes cutÃneos na investigaÃÃo clÃnica das reaÃÃes alÃrgicas a medicamentos. Quando à causalidade, 26 reaÃÃes foram consideradas possÃveis, 20 definidas, 13 provÃveis, 9 condicionais e uma reaÃÃo foi considerada nÃo relacionada com fÃrmacos. Dada a sua importÃncia, a realizaÃÃo dos testes cutÃneos com esses pacientes abriu perspectivas sobre a possibilidade incorporar esse serviÃo na rotina do ambulatÃrio de Dermatologia do HUWC.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (doctoral)--Ludwig-Maximilians-Universität, Munich, Germany.

Thesis (doctoral)--Ludwig-Maximilians-Universität, Munich, Germany.

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18214号 / 薬博第804号 / 新制||薬||237(附属図書館) / 31072 / 京都大学大学院薬学研究科生命薬科学専攻 / (主査)教授 金子 周司, 教授 髙倉 喜信, 教授 竹島 浩 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Diss. (sammanfattning) Linköping : Univ. / Härtill 5 uppsatser.

HISTORICAL PERSPECTIVE: It has recently been shown that intensive prophylactic dietary and environmental control measures during early infancy may reduce the incidence and/or postpone the onset of atopic disease. In order to institute this prophylactic regime, early identification of the infants genetically "at risk" for atopic disease is essential, since sensitisation begins at birth, or even during intra-uterine life. European and Scandinavian studies have shown that a raised concentration of cord blood serum immunoglobulin E (CBsIgE) is an excellent predictive marker for the subsequent development of atopic disease. Other potential predictive atopic markers such as cord blood eosinophils, platelets and anti-cow's milk serum IgG have also been suggested as having possible predictive relevance for newborns in terms of the development of subsequent atopic disease. PROBLEM DEFINITION: Most of the work in this field has been done on Caucasian neonates, in Westernised, First World countries. In South Africa, it has been shown that the Black adult ethnic group has serum immunoglobulin E concentrations (sIgE) which are significantly higher than that found in the South African White adult ethnic group. Furthermore, it has been suggested that the elevated sIgE in the adult Blacks may be raised independently of allergic disease. It is, therefore, important to ascertain whether this elevation of sIgE in Black South African adults is evident already at birth in the cord blood sera of Black South African newborns. If so, it is imperative to ascertain whether any such elevation is reflective of a high genetic load for atopy in these Black newborns, and furthermore whether these Black newborns are consequently "high-risk" for the development of subsequent atopic disease, as has been previously reported in the literature for White newborns. Arising from an awareness of these specific South African problems, the following hypothesis was developed. HYPOTHESIS: The hypothesis states that: "Black South African newborns without an atopic family history (aFH) have significantly higher CBslgE values than similar White and Mixed newborns. An aFH does not influence the CBsIgE values in the Black newborns, as it does in the White and Mixed newborns. The CBsIgE values in Black newborns are not, furthermore, predictive for the development of subsequent atopy in infancy, as they are in the other ethnic groups". A description of the three South African ethnic groups considered in this study is provided in Section IV, (Pg. 74). AIMS OF THE STUDY: The aims of the study were three-fold: 1. To test the hypothesis. 2. To assess the relevance of alternative cord blood markers (eosinophils, platelets and anti-cow's milk serum IgG) as predictive atopic markers in each of the three ethnic groups. 3. To provide epidemiological information with regard to genetic and environmental influences on CBslgE, cord blood total eosinophil counts (CBTEC's) cord blood platelet counts (CBPlC's) and cord blood anti-cow's milk serum IgG concentrations (CBacmlgG).

Background: This thesis focuses on the incidence and remission of reported food hypersensitivity in schoolchildren followed from 8 to 12 -years of age and the prevalence of hypersensitivity to milk, egg, cod and wheat among 12-year olds investigated by reported data, clinical investigation and double-blind placebo-controlled food challenges and biomarkers. Methods: The studies are mainly based on a population based cohort recruited in 2006 from three municipalities in Northern Sweden. All children in first and second grade, aged 7-8 years, were invited to a parental questionnaire study and 2585 (96% of invited) participated. The children in two of the municipalities were also invited to a skin prick test with airborne allergens. At age 11-12 years, there was a follow-up of the cohort using the same methods, with the addition of a child interview and assessment of body mass index (BMI). At the follow-up, children who reported milk hypersensitivity were invited to structured interviews and children reporting complete elimination of milk, egg, cod or wheat due to perceived hypersensitivity were invited to a clinical examination and blood sampling. According to test results, the children were categorized into different food hypersensitivity phenotypes according to preset criteria. Children categorized as current food allergy were then invited to further evaluation with a double-blind placebo-controlled food-challenge using newly developed recipes. Before their use, the recipes were successfully validated regarding detectable sensorial differences between the active and placebo substances in a separate cohort of healthy schoolchildren (n=275). Before and after the challenge series blood samples were collected for analyses of cytokine mRNA expression in peripheral blood mononuclear cells including hallmark cytokines for the humoral allergy-promoting T helper (Th) 2 response, cellular cytotoxicity-promoting Th1 response, inflammatory-, and T regulatory responses. Fecal inflammatory biomarkers were also analyzed before and after the challenge series. Results: Reported food hypersensitivity increased from 21% at age 7-8 years to 26% at 11-12 years. There was a high incidence (15%) as well as a high remission (33%) of reported food hypersensitivity. Risk factors associated with incidence and remission were different for milk hypersensitivity and hypersensitivity to foods other than milk. The agreement between reported symptoms to milk, egg, cod, wheat, soy and peanut and sensitization to the culprit food was poor. At 11 to 12-years of age the prevalence of reported allergy to milk, egg, cod or wheat was 4.8% while the allergy prevalence according to clinical evaluation was 1.4%. This figure was further halved when evaluated with double-blind placebo-controlled food challenges. The majority of children with reported allergy to milk, egg, cod and wheat were categorized as other food hypersensitivity phenotypes, the most common being probable lactose intolerance (40%) and outgrown food allergy (19%). Even though reported milk hypersensitivity among the 11-12 year olds was 14.5%, only 3% were categorized as current milk allergy. Current and outgrown milk allergy was associated with other atopic disorders and a lower BMI (OR 0.8, 95% CI 0.80-0.98). Before the challenge series, the mRNA expression of the cytokines IL-13 and IL-10 were higher among children with a positive compared to a negative challenge outcome. Conclusion: Reported food hypersensitivity was common among school children in Northern Sweden and increased from 7-8 years to 11-12 years of age, and both the incidence and remission of reported hypersensitivity was high. There was an 8-fold difference in the prevalence of allergy to milk, egg, cod or wheat when reported data was assessed by clinical examinations and double-blind placebo-controlled food challenges. Allergy to milk, egg, cod and wheat was an uncommon cause of complete avoidance of these foods due to perceived hypersensitivity. Some of the analyzed biomarkers might serve as prognostic markers for symptomatic, IgE-mediated food allergy but need further validation. / Bakgrund: Födoämnesöverkänslighet håller på att bli ett stort och kostsamt hälsoproblem i västvärlden. Prevalensen av rapporterad födoämnes-överkänslighet bland barn ökar, men det är fortfarande oklart om detta avspeglar en sann ökning i populationen. Det finns en stor spridning mellan uppmätta prevalenstal i olika studier och i de få studier där man följt upp rapporterade data med objektiva metoder ses en hög överrapportering. Data saknas om reell prevalens av födoämnesöverkänslighet bland skolbarn i Sverige. Befintliga prevalensdata baseras på rapporterad födoämnes-överkänslighet och studier saknas där angiven födoämnesöverkänslighet i en barnpopulationskohort validerats med objektiva metoder. Även om dubbelblinda provokationer räknas som ”gold standard” används i praktiken endast sjukhistoria, pricktest och analys av specifikt Immunoglubulin E (IgE) samt öppna provokationer för diagnostik. Metoderna har flera felkällor och mer tillförlitlig diagnostisk behövs, särskilt vid sena och svårtolkade symtom. Korrekt diagnos är särskilt viktig när baslivsmedel har eliminerats eftersom kostrestriktionerna riskerar att leda till negativa konsekvenser för livskvalitet och intag av viktiga näringsämnen. Syfte: Studierna i denna avhandling fokuserade på incidens och remission av födoämnesöverkänslighet bland skolbarn i Norrbotten, som följdes från 7-8 år till 11-12 års ålder, och på prevalens av överkänslighet mot mjölk, ägg, fisk och vete bland 12-åringar, undersökt med rapporterade data, klinisk undersökning samt dubbelblinda placebokontrollerade födoämnes-provokationer och biomarkörer. Metod: Den huvudsakliga delen av det här projektet är baserat på en populations-baserad kohort som rekryterades 2006 från 3 kommuner i norra Sverige. Föräldrar till alla barn i klass 1 och 2 (7-8 år) bjöds in till ett frågeformulär, som besvarades av 96% (n=2585) av de inbjudna. Barnen från två av kommunerna, Luleå och Kiruna, bjöds också in till ett pricktest med 10 vanliga luftburna allergen och 90% (n=1700) av de inbjudna deltog. År 2010, när barnen var 11-12 år, gjordes en studieuppföljning med samma metoder och med ytterligare tillägg av en intervju med barnet och bestämning av body mass index (BMI). Studiedeltagandet i enkäter och pricktest var lika högt vid uppföljningen som vid studiestart. Vid studieuppföljningen bjöds barn med rapporterad mjölköverkänslighet in till en strukturerad intervju och barn som helt undvek mjölk, ägg, fisk eller vete på grund av upplevd överkänslighet, bjöds in till klinisk undersökning och provtagning. Baserat på testresultaten kategoriserades barnen i olika fenotyper av födoämnesöverkänslighet utifrån förutbestämda kriterier. Barn som bedömdes ha en aktuell födoämnesallergi bjöds därefter in till vidare utredning med dubbelblind placebokontrollerad födoämnes-provokation. De recept som användes vid de dubbelblinda provokationerna hade dessförinnan validerats avseende detekterbara smak- och konsistens-skillnader mellan aktiv- och placebosubstans i en separat kohort av friska skolbarn (n=275). Före och efter den dubbelblinda provokationen samlades blodprover in för analys av cytokin mRNA-uttryck i mononukleära celler. Analyserna inkluderade cytokiner kännetecknande för humoralt allergidrivande T-hjälpar 2 (Th2) svar, cellulärt cytotoxiskt drivande Th1 svar samt inflammatoriskt- och T-reglerande svar. Vidare insamlades avföringsprover för analys av inflammatoriska biomarkörer före och efter genomgången provokationsserie. Resultat: Prevalensen av föräldrarapporterad födoämnesöverkänslighet ökade från 21% vid 7-8 år till nästan 26% vid 11-12 års ålder. Incidensen av rapporterad födoämnesöverkänslighet var hög (15%), liksom remissionen (33%). Riskfaktorer associerade med incidens och remission var olika för mjölk-överkänslighet och överkänslighet mot andra födoämnen. Vi såg också en bristande samstämmighet mellan föräldrarapporterad överkänslighet mot mjölk, ägg, fisk, vete, soja och jordnöt och IgE-sensibilisering mot det aktuella födoämnet. Vid 11-12 års ålder var prevalensen av rapporterad allergi mot mjölk, ägg, fisk eller vete 4.8%, medan prevalensen baserad på klinisk undersökning och provtagning var 1.4%. Prevalenssiffran halverades ytterligare när kliniskt bedömd födoämnesallergi validerades med dubbelblinda placebo-kontrollerade födoämnesprovokationer. Majoriteten av barnen med rapporterad allergi mot mjölk, ägg, fisk eller vete klassificerades som andra fenotyper av födoämnesöverkänslighet, varav de vanligast förekommande var möjlig laktosintolerans (40%) och utläkt födoämnesallergi (19%). Även om förekomsten av rapporterad mjölköverkänslighet bland 11-12 åringarna var så hög som 14.5%, kategoriserades bara 3% av dessa som en aktuell mjölkallergi. Mjölkallergi, aktuell eller utläkt, var associerat med andra atopirelaterade tillstånd och ett lägre BMI (OR 0.82, 95% CI 0.80-0.98) jämfört med barn som inte undvek mjölkprodukter. Före den dubbelblinda provokationsserien var mRNA-uttrycket av den Th2-relaterade cytokinen IL-13 och den regulatoriska cytokinen IL-10 högre bland barn med provokationspåvisad födoämnesallergi jämfört med barn med en negativ födoämnesprovokation. Såväl före som efter provokationsserien kunde högre nivåer av inflammationsmarkörerna eosinofil-deriverat neurotoxin (EDN) och kalprotektin uppmätas i avföringsprover från barn med positivt provokationsutfall jämfört med barn med negativ födoämnesprovokation. Skillnaderna i uppmätta nivåer av biomarkörer i faeces uppnådde dock inte statistisk signifikans. Slutsats: Rapporterad födoämnesöverkänslighet var vanligt förekommande bland skolbarn i Norrbotten och ökade från 7-8 år till 11-12 års ålder. Incidensen av rapporterad födoämnesöverkänslighet var hög, liksom remissionen. Prevalensen av rapporterad allergi mot mjölk, ägg, fisk eller vete var 8 gånger högre än den prevalens som kunde påvisas med dubbelblind placebokontrollerad födoämnesprovokation. Allergi mot mjölk, ägg, fisk och vete var en ovanlig orsak till att barn helt undvek dessa födoämnen på grund av upplevd överkänslighet. Några av de biomarkörer som analyserades innan provokationsserierna visade lovande resultat som möjliga, framtida prognostiska markörer för symptomatisk, IgE-medierad födoämnesallergi. Dessa resultat behöver dock valideras med ytterligare studier.