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

Described for the first time approximately 30 years ago, exercise-induced anaphylaxis is a rare disorder characterized by development of a severe allergic response occurring after mild-to-strenuous physical activity. This disorder is especially important to recognize with the recent increase in physical activity and health fitness fads. A number of predisposing factors (eg, prior ingestion of particular food groups) linked to exercise-induced anaphylaxis has been outlined over the years. Mechanisms govern big the condition are still being unveiled, and it is likely that one mechanism involves mast cell degranulation and inflammatory mediator generation resulting from the biochemical effects of exercise, sometimes in the presence of an ingested allergen such that wheat or shell fish. Clinical manifestations usually occur after around 10 minutes of exercise, and follow a specific sequence, starting with pruritis and widespread urticarial lesions, evolving into a more typical anaphylactic picture with respiratory distress and vascular collapse. Fatality is exceedingly rare, with only one documented casein the literature. There is an overlap of symptoms with other syndromes (such as systemic mastocytosis and cholinergic urticaria), and these should be remembered when establishing a differential. Treatment of exercise-induced anaphylaxis consists of immediate stabilization geared toward the anaphylactic response with epinephrine and antihistamines. The patient needs to be educated on preventive measures and equipped with an epinephrine autoinjector in the event of an emergency. Exercise-induced anaphylaxis remains a potentially serious disorder, and the health care provider should be aware of its clinical features and effective management strategies.

<p>The work in this thesis encompasses (a) the development of a robust analytical method suitable for the comprehensive analysis of polar and non-polar metabolites in a single analysis and (b) the application of this method to the study of the metabolites involved in peanut allergy. During the course of this work the methods for the analysis of large metabolite data sets evolved significantly and the approaches used in this work evolved in parallel to the literature. This work constitutes the first comprehensive metabolomic investigation of an allergy response.</p> <p>Hypersensitivity or allergy to peanuts is an increasingly problematic health concern around the world involving approximately 1-2% of children in North America. There are no useful clinical biomarkers for this allergy. Comprehensive metabolomics holds vast potential for the discovery of metabolites and metabolite pathways that may be involved during the development of peanut allergy and during peanut-induced anaphylaxis. The comprehensive study of metabolites involved in peanut allergy presented a significant challenge since no single analytical technique is capable of analysis of all metabolites within a single analytical run.</p> <p>The thesis begins with development of a tandem column liquid chromatography-electrospray ionization-mass spectrometry method which allowed the separation and analysis of both polar and non-polar metabolites in a single analysis. This tandem column technique was also shown to significantly reduce the amount of ion suppression observed compared to the ion suppression observed when using either column independently.</p> <p>This methodology was applied to the comprehensive metabolomics analysis of blood serum samples obtained from mice which were (a) being sensitized to peanuts and (b) undergoing anaphylaxis. This analysis discovered a profound impact on metabolites involved with purine metabolism, resulting in an elevation of uric acid levels. This discovery led to further investigations which confirmed that uric acid is essential for peanut sensitization in mice. This discovery was only possible due to the use of a comprehensive metabolomics approach.</p> <p>The analytical methodology was then applied to the study of metabolomic changes in sensitized mice as they experienced peanut-induced anaphylaxis. A number of metabolomic changes including taurine level elevation were correlated with peanut-induced anaphylaxis. Finally, a serendipitous opportunity arose to analyze blood serum samples from peanut allergic children that had undergone an oral peanut challenge. The comprehensive metabolomic study of these samples revealed massive changes in their serum metabolomes as a result of peanut exposure. A number of lipids and lysophospho-lipids were shown to have increased dramatically and may represent novel biomarker candidates for peanut-induced anaphylaxis in humans.</p> <p>In summary, this thesis had demonstrated that comprehensive metabolomic analyses can be successfully applied to complex syndromes such as peanut allergy and yield useful mechanistic and clinical insights to this disorder.</p> / Doctor of Philosophy (PhD)

Background: Despite the clinical severity and rising prevalence of peanut allergy, there is a marked absence of widespread, practical treatments available for peanut-allergic patients. Peptide immunotherapy, a disease-modifying treatment that uses short peptides recognized by T cells, has been shown to reduce allergic symptoms of allergic rhinoconjunctivitis. This project investigated the ability of peptides from the major peanut allergen Ara h 1 to protect against peanut-induced anaphylaxis and induce immunomodulatory changes in a mouse model. Methods: Mice transgenic for the human leukocyte antigen DRB1*0401 were sensitized to peanut epicutaneously and treated with two intraperitoneal injections of peptides from Ara h 1. Mice were then challenged with intraperitoneal whole peanut and observed for signs of anaphylaxis. Flow cytometry was used to isolate peanut-specific CD4+ T cells labelled with Ara h 1 peptide-loaded tetramers and additional Th1, Th2, and regulatory markers. Results: Peptide-treated mice were protected from severe peanut-induced anaphylaxis. Control mice treated with a sham peptide experienced a mean maximum temperature drop of 3.2°C, while mice treated with Ara h 1 peptides experienced a drop of 1.6°C (p=0.067 vs control). Maximum clinical score was 2.5 in control mice, and 1.4 in treated mice (p=0.0097). Mean hematocrit for control mice was 52.5%, and 47% for treated mice (p=0.013). PD-1+CD4+ T cells were significantly increased in the mesenteric lymph nodes (p = 2.28e-0.05) and spleens (p = 0.014) of peptide-treated mice. MIP1-a+CD4+ T cells were significantly decreased in the peritoneal lavage (p = 0.008). Conclusion: Ara h 1 peptide immunotherapy protected against severe peanut-induced anaphylaxis in a mouse model. Peptide-treated mice experienced significantly reduced drops in core body temperature, clinical signs of allergic reaction, and hemoconcentration. Clinical protection was associated with decreased expression of the pro-inflammatory chemokine macrophage 1-a and increased expression of the surface marker programmed cell death protein 1. / Thesis / Doctor of Philosophy (PhD) / Peanut allergy is a growing public health concern. Its prevalence has doubled in the past 10 years and currently stands at 2%. Reactions to peanut account for the majority of food-induced fatal allergic reactions, termed anaphylaxis. Currently, there are no treatments available for patients with peanut allergy. Healthcare workers can only offer peanut-allergic patients advice on peanut avoidance and rescue medications in case of accidental ingestion. This research project investigated the ability of a new treatment called peptide immunotherapy to prevent severe allergic reactions to peanut in a mouse model of peanut allergy. Peptide treatment uses small portions of the peanut allergen to shift the immune response from pro-inflammatory to anti-inflammatory. After peptide treatment, peanut-allergic mice were protected from severe allergic reactions in response to peanut and their immune cells produced lower levels of pro- inflammatory molecules.

Kainate receptor knockout mice have unique differences within their immune system. They exhibit an attenuated TH2 branch, while maintaining a robust TH1 response. Specifically, blocking the formation of functional kainate receptors affects mast cells and their related pathologies. While they seem to develop and activate normally in vivo and in vitro, KAR KO mast cells release more inflammatory mediators upon degranulation. These mice experience severe anaphylactic shock due to two compounding abnormalities. First, KAR KO mast cells release significantly more histamine in vivo upon IgE-mediated activation. Second, the animals over-respond to exogenous histamine with drastic temperature drops compared to WT. This report shows that the kainate receptor plays an important role in mast cell-mediated immune responses.

Background: Food allergy, an abnormal immunologic response to food protein, has an estimated prevalence of 6% in young children and 3.7% in adults in the U.S. The only proven therapy for food allergy is strict elimination of the offending allergens. As a result, caregivers and patients could experience constant anxiety and stress that affects their quality of life. Additionally, food allergy can lead to significant economic impact on the health care system, since severe reactions often lead to ED visits and hospitalizations. Objectives: The first major objective was to determine the economic burden of Food Allergy and Anaphylaxis (FAA) patients in the U.S. by estimating the direct medical and indirect costs. The second principal objective involved assessing the Health Related Quality of Life (HRQL) of food allergic patients by measuring their health utilities and disease specific quality of life. Methods: Economic burden was estimated by measuring certain direct medical and indirect costs from a societal perspective. Costs were estimated using a bottom-up approach -- calculating the average cost of illness per patient and multiplying it by reported prevalence estimates. FAA patients with an emergency department (ED) visit, office based physician visit, outpatient department visit, and hospital admission were identified from a list of federally administered databases using ICD-9 codes. Sensitivity analyses were conducted to measure the robustness of the estimates. The cross-sectional HRQL study measured health utilities in food allergic adults and children, and quality of life in allergic adults using EQ-5D and FAQL-AF questionnaires respectively. These questionnaires were administered in an online survey format. Regression models were specified to explore the deviations in HRQL scores between patients with different disease related characteristics. Results: The findings reveal that for a given year (2007), direct medical costs worth $225 million and indirect costs worth $115 million were incurred. Owing to the irregularities in the reporting and diagnosis of food allergy, these values might be an underestimation. Simulations from probabilistic sensitivity analysis generated mean direct medical costs of $307 million and indirect costs of $203 million. Survey responses were collected online for eight months, during which 45 adults and 94 parents (acting as proxy for their food allergic child) responded. Adults reported a mean utility of 0.874 compared to 0.918 for children. Gender, number of food allergies and frequency of carrying epinephrine device had significant impacts on HRQL scores. An effect size of 0.003 was estimated comparing health utilities of food allergic adults with the general U.S. population. Conclusions: This was the first research to examine economic burden of FAA, and elucidate health utilities for food allergic patients. A large proportion of costs were incurred due to ambulatory visits. Effect size calculation revealed that health utilities of food allergic patients were very similar to the general U.S. population.

ABSTRACT This qualitative study utilized a systems theory approach and followed the premise that families are systems that seek a balanced state, interact with their environment, and are goal directed to explore the impact of anaphylaxis on families from a parental perspective. The purpose of this study was to explore the role of family leisure in families while living with a child diagnosed with anaphylaxis. This was done by exploring parental meanings and experiences of living with anaphylaxis and how this impacted their family leisure. Five research questions guided the inquiry relating to experiences and meanings of anaphylaxis, experiences and participation in family leisure, valuations and meanings of family leisure, caregiving as a constraint to family leisure, and gender considerations. A local support group for families and individuals living with anaphylaxis (WRASE) was contacted and aided in identifying parents who would be interested in participating in this study. Specific attention was given to obtaining a sample that included different allergies, ages of children, and number of children in the household. Four families were selected and both parents were interviewed separately in all but one case. Four core themes emerged from the in-depth interviews and included An Emotional Journey, Seeking Community Support and Dealing with Negative Feedback, Impact on Family Leisure, and The Increased Domestic Workload and Changing Role of Mother. In essence, parents experienced intense feelings of fear, paranoia, and stress as they sought to manage their child’s allergy and these feelings were just as intense during their family leisure time. Role changes and strain were particularly severe for the mothers in this study. The parents of children with anaphylaxis have received little attention in social science research to date. This research adds to the literature on chronic illness and also offers new insight into how anaphylaxis affects family leisure. Key findings in this area were the lack of opportunities for travel and social isolation. Furthermore, it was found that leisure, although often thought to be beneficial in managing stress and improving family functioning, may not be available to those living with anaphylaxis.

ABSTRACT This qualitative study utilized a systems theory approach and followed the premise that families are systems that seek a balanced state, interact with their environment, and are goal directed to explore the impact of anaphylaxis on families from a parental perspective. The purpose of this study was to explore the role of family leisure in families while living with a child diagnosed with anaphylaxis. This was done by exploring parental meanings and experiences of living with anaphylaxis and how this impacted their family leisure. Five research questions guided the inquiry relating to experiences and meanings of anaphylaxis, experiences and participation in family leisure, valuations and meanings of family leisure, caregiving as a constraint to family leisure, and gender considerations. A local support group for families and individuals living with anaphylaxis (WRASE) was contacted and aided in identifying parents who would be interested in participating in this study. Specific attention was given to obtaining a sample that included different allergies, ages of children, and number of children in the household. Four families were selected and both parents were interviewed separately in all but one case. Four core themes emerged from the in-depth interviews and included An Emotional Journey, Seeking Community Support and Dealing with Negative Feedback, Impact on Family Leisure, and The Increased Domestic Workload and Changing Role of Mother. In essence, parents experienced intense feelings of fear, paranoia, and stress as they sought to manage their child’s allergy and these feelings were just as intense during their family leisure time. Role changes and strain were particularly severe for the mothers in this study. The parents of children with anaphylaxis have received little attention in social science research to date. This research adds to the literature on chronic illness and also offers new insight into how anaphylaxis affects family leisure. Key findings in this area were the lack of opportunities for travel and social isolation. Furthermore, it was found that leisure, although often thought to be beneficial in managing stress and improving family functioning, may not be available to those living with anaphylaxis.

Background: The qHPV vaccine has the potential to significantly reduce the burden of HPV-related diseases, including cervical cancer. However, a recent systematic review of clinical trials has suggested that the risk of bronchospasm may be increased by this vaccine, and a large observational study has reported an increased risk of anaphylaxis. Objectives: To determine whether qHPV vaccination increases the risk of incident asthma, asthma exacerbation, and anaphylaxis. Methods: A population-based retrospective cohort of grade 8 girls eligible for Ontario’s HPV immunization program between 2007 and 2011 was identified using the province’s administrative health and immunization databases. Cohort members were followed from September 1st of their grade 8 year until their date of death or end of study (March 31st, 2012). The self-controlled case series method, a self-matched, case-based analysis was used to assess the effect of qHPV vaccination on the risk of SRREs, and rate ratios (RRs) and 95% confidence intervals for each outcome was estimated using conditional Poisson regression. Results: The cohort consisted of 125,575 girls with a mean age of 13.2 years, 57.7% of whom received at least one dose of the qHPV vaccine. During an average of 2.5 years of follow-up, 1473 cases of incident asthma, 901 of asthma exacerbation and 38 of anaphylaxis were identified. HPV vaccination was not associated with an increased risk of incident asthma or asthma exacerbation (RRadj 0.76, 95% CI 0.37-1.54 and RRadj 0.74, 95% CI 0.27-2.00, respectively), and these associations were unchanged by the presence of risk factors and time since vaccination. There was also no evidence of an increased risk of anaphylaxis following qHPV vaccination as demonstrated by an absence of cases of anaphylaxis occurring on the day of vaccination. Conclusions: This large, population-based study provides strong evidence that the qHPV vaccine does not increase the risk of developing or exacerbating asthma, and additional evidence for the lack of an increased risk of anaphylaxis in the younger populations targeted by HPV immunization programs. These findings add to the growing body of evidence on the safety of the qHPV vaccine. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2014-04-16 19:20:41.019

Les neutrophiles contribuent à l'inflammation protectrice et pathologique. Ce projet de thèse consiste à déterminer le rôle des neutrophiles dans des modèles d'inflammation systémique graves et potentiellement mortelles, induite par le lipopolysaccharide (LPS, endotoxémie) ou par des complexes immuns antigène-anticorps (anaphylaxie). L'anaphylaxie est une réaction allergique qui peut être IgE- et/ou IgG-dépendante. L’endotoxémie est un modèle pertinent de l'inflammation au cours de maladies graves. Pour étudier les neutrophiles in vivo, nous avons utilisé un nouveau modèle murin de neutropénie inductible. Nous montrons que les neutrophiles et la Myélopéroxidase qu’ils produisent ont un rôle protecteur dans le choc endotoxique, indépendamment de l'environnement microbiologique. A l'inverse, les neutrophiles peuvent contribuer à l'anaphylaxie induite par les IgG chez la souris. Comme les récepteurs pour les IgG (FcγR) murins sont très différents des humains, nous avons développé un modèle de souris knock-in dans lequel les FcγR murins a été remplacé par les FcγR humains, activateurs et inhibiteur. Chez ces souris, nous montrons que des IgG humaines peuvent induire une anaphylaxie: le FcγRIIA a un rôle dominant, via l'activation des neutrophiles, et les médiateurs PAF et histamine. En parallèle, nous développons un modèle murin d’anaphylaxie à un curare, le Rocuronium, utilisé en clinique. Au même temps, dans une étude clinique, les résultats d’analyses des échantillons sanguins des patients suspectés d’avoir subi une anaphylaxie au curare soutien notre hypothèse de travail: que l’activation des neutrophiles par des IgG spécifiques est impliquée dans l'anaphylaxie humaine. / Neutrophils are agents of protective and pathological inflammation. This thesis work aimed to determine the role of neutrophils during severe, potentially fatal models of systemic inflammation induced by lipopolysaccharide (LPS, endotoxemia) or by IgG immune complexes (anaphylaxis). Anaphylaxis is a severe allergic reaction that may proceed via IgE- or IgG-dependant pathways. Endotoxemia is a model relevant to inflammation during critical illness. To study neutrophils in vivo, we employed a new mouse model of inducible neutropenia. We found, surprisingly, that neutrophils and neutrophil-derived MPO protect against the severity of endotoxic shock, independently of the microbiological environment, suggesting that neutrophils limit inflammation during endotoxemia. Conversely, neutrophils can contribute to IgG-induced anaphylaxis in mice. As mice and human IgG receptors (FcγR) are very different, we developed a novel mouse strain in which targeted insertion of human FcγR into the murine loci recapitulated hFcγR expression. Herein, using these mice, this work demonstrates that anaphylaxis induced by hIgG proceeds within a native context of activating and inhibitory hFcγRs, and that neutrophil activation via FcγRIIA is a dominant pathological pathway, involving the mediators PAF and histamine. Finally, we describe ongoing development of a mouse model of anaphylaxis in response to Rocuronium, a curare-based neuromuscular blocking agent (NMBA). In addition, as part of a collaborative clinical study we analysed blood samples from patients suspected of NMBA-induced anaphylaxis, finding evidence for the activation of a neutrophil- and IgG-dependent axis during human anaphylaxis.