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Over one third of the human population is currently infected by one or more species of parasitic helminth, but the immune responses elicited by these infections remain poorly defined. Studies in helminth-exposed human populations and laboratory models suggest that helminth infection elicits a range of different effector cell types and that protective immunity and resistance to immune-mediated pathology depends on the balance between these responses. The aim of this thesis was to investigate how cytokines, the molecular mediators of the immune system, can be used to characterise human immune phenotype during natural and experimental helminth infection. Cytokines associated with innate inflammatory (TNFα, IL-6 and IL-9), Thl (IFNγ, IL-2 and IL-12p70), Th2 (IL-4, IL-5 and IL-13), Th17 (IL-17A, IL-21 and IL-23) and regulatory (IL-10 and TGFβ)immune phenotypes were analysed to provide the most comprehensive analysis of cytokine responses in human helminth infection conducted to-date. Using a multivariate statistical approach cytokines were analysed as combined immune profiles to reflect their complex interactions in vivo. In the first part of the study venous blood samples collected from a cross-sectional cohort of 284 Zimbabweans (age range: 3 -86 years) endemically-exposed to Schistosoma haematobium were cultured with antigens from different stages of the parasite's life-cycle(cercariae, adult worms and eggs) and the anti-schistosome vaccine candidate antigen glutathionine-S-transferase (GST). Cytokines responses were quantified in culture supernatants via enzyme-linked immunosorbent assay (ELISA). These assays were repeated 6 weeks after clearance of infection by anti-helminthic treatment. Parasitological and demographic characterisation of the cohort before, 6 weeks, 6 and 18 months after treatment allowed cytokine responses to be related to epidemiological patterns of infection before treatment and the risk of re-infection after treatment. The main findings of this study were:Cytokine responses to the antigens of S. haematobium cercariae are more proinflammatory than those elicited by adult worms and eggs prior to treatment, reflecting the distinct proteomes and exposure patterns of the 3 life-cycle stages Young children (5-10 years old) have a more regulatory and Th17-polarised cytokine response to S. haematobium antigens than older children and adults. These responses are significantly associated with schistosome infection intensity and may contribute to the development of resistance to schistosomiasis with age and exposure to infection Anti-helminthic treatment leads to a shift in S. haematobium cercariae, egg and GST specific cytokine responses towards a more pro-inflammatory phenotype The magnitude of change in S. haematobium-specific cytokine profiles after treatment is dependent on schistosome infection intensity at the time of treatment Individuals who remain un-infected up to 18 months after treatment to clear schistosome infection have a more pro-inflammatory and IL-21-polarised response to S. haematobium antigens 6 weeks after treatment than those who become re-infected, suggesting that post-treatment cytokine profiles promote resistance to re-infection. The second part of the study assayed systemic, parasite and allergen-specific cytokine responses in 45 adults with seasonally exacerbated allergy to grass pollen who were experimentally exposed to Trichuris suis. Cytokine responses in infected individuals were compared to those of 44 un-infected controls. This aspect of the study showed that: Exposure to T. suis promotes systemic and parasite-specific Th2 and regulatory cytokine responses, but does not alter cytokine responses to environmental allergens.

Allergic rhinitis is a condition which affects over 15% of the population in the United Kingdom. The pathological process involves two stages—nasal inflammation, and the development of a nasal hyperresponsiveness to allergen and a range of other nonspecific stimuli. There is currently little information on the pathological process underlying hyperresponsiveness. This thesis presents an investigation into the potential role of kinins and nitric oxide in causing nasal hyperresponsiveness in man. In the non-allergic subject, platelet activating factor (PAF) can be used to induce a nasal hyperresponsiveness which is similar to that observed in allergic rhinitis. The data obtained suggests that PAF-induced nasal hyperresponsiveness is mediated by an action of kinins at the bradykinin B2 receptor. Experiments in subjects with seasonal allergic rhinitis also imply a similar role for kinins in allergen-induced hyperresponsiveness. Furthermore, the kinins may be involved in the recruitment of inflammatory cells which is seen in the hyperresponsive state. Data is presented which indicates that kinin generation can potentiate inflammatory cell recruitment, both in vitro and in vivo in the human nasal airway. However, application of exogenous bradykinin alone does not cause a nasal hyperresponsiveness, nor an influx of inflammatory cells. While suggestions are made as to the precise role of kinins, the mechanism does not appear to be dependent on subsequent neuropeptide release. Interestingly, modulating the degree of nitric oxide in the human nasal airway can also induce a hyperresponsiveness. The data therefore imply that activation of the bradykinin B2 receptor is necessary in both PAF- and allergen-induced nasal hyperresponsiveness in man. In addition, the generation of kinins may be important in the recruitment of inflammatory cells in allergic rhinitis.

Allergic Rhinitis (AR) is a chronic inflammatory disease of sino-nasal mucosa, is IgE-mediated, and affects 10-40% of the global population. This study aimed to compare the efficacy of nasal administration of Beclomethasone Dipropionate (BDP) delivered via Spray-sol with nasal spray in patients suffering from AR. We included 28 AR patients assigned to one of the two following treatments: the Spray-sol group (BDP via Spray-sol) (n = 13) and the spray group (BDP using a common nasal spray) (n = 15). Both treatments were administered twice daily for 4 weeks. A nasal endoscopy evaluation and Total Nasal Symptom Score were performed at baseline and after treatment. The Spray-sol group showed better results than the spray group regarding nasal endoscopy (edema, p < 0.01; irritation, p < 0.01; secretion, p < 0.01) and nasal symptoms (nasal congestion, p < 0.05; rhinorrhea, p < 0.05; sneezing, p < 0.05; and total score, p < 0.05). No side effects were recorded. These data supported the fact that the use of BDP delivered with Spray-sol is more effective than BDP nasal spray in AR patients. Further studies are needed to confirm these encouraging results.

Allergic rhinitis (AR) is a common chronic upper respiratory disease where exposure to allergens causes an IgE mediated inflammatory response. AR is estimated to affect between 10-40% of the population worldwide and is responsible for significant economic and medical burden. The primary symptoms of AR include rhinorrhoea, nasal congestion, itchy nose and eyes and sneezing. There is currently no cure for AR and the current treatment options are typically focused on achieving symptom relief. Whilst the symptoms of AR manifest predominately in the upper respiratory tract, the pathophysiology of the disease is complex, and involves interactions between the mucosal and systemic immune systems. As such, there is an increasing need to better understand the complex immunological mechanisms which underpin the disease. Doing so may lay the foundation for strategies to reduce AR symptoms through modifying the disease process itself or via the development of novel therapies. In a series of six studies, this thesis investigated the pathophysiology and treatment of AR via immune and molecular phenotyping of the gut microbiome, peripheral blood, and nasal mucosa.

Rhinitis is a disorder of the nasal mucosa commonly attributed to specific immunoglobulin E (spIgE) mediated inflammation towards allergens. Allergic rhinitis (AR) is diagnosed when serum spIgE or skin prick test (SPT) is positive and non-allergic rhinitis (NAR) defined when these tests are negative. However, these systemic tests determine spIgE at distant sites instead of the nose itself. Evidence has shown that spIgE may be locally synthesized by the nasal mucosa and escape systemic detection, a condition termed local allergic rhinitis or entopy. This can be diagnosed by the nasal allergen provocation test (NAPT) which is unpopular due to its lengthy procedure. There is a need for simple local nasal assessments to determine nasal allergy. This thesis assessed alternative local diagnostic methods in the nose. The pitfall of systemic testing to identify nasal allergy was assessed in two systematic reviews which identified IgE mediated nasal allergy confirmed by positive NAPT or presence of nasal spIgE among those diagnosed with NAR. Other diagnostic markers for allergy were also studied through nasal endoscopy and radiological assessment. Middle turbinate oedema (seen on nasal endoscopy) and central mucosal thickening with or without sinus involvement (seen on radiology) were highly specific features of AR but were poorly sensitive. Local nasal sampling was then assessed as an alternative diagnostic tool. Inferior turbinate biopsy, nasal brushing and serum samples were collected and SPT performed among 166 consecutive patients who underwent inferior turbinate surgery. In the first phase of the study, three minimally invasive nasal sampling methods were compared (cytology brush, dental brush and nasal curette). The cytology brush was found to be optimal for protein harvest and further studied. Turbinate tissue spIgE was found to be a highly sensitive local test to diagnose AR. Nasal brushing spIgE was found to be comparably sensitive to tissue spIgE. Finally, the clinical characteristics of those with NAR based on absent tissue spIgE were assessed. Determining AR among rhinitics requires complete assessment which does not end at conventional systemic tests. Additional local tests are needed in order to truly rule out spIgE mediated disease.

Allergic rhinitis is a common disease in Australia, with an estimated 3.17 million Australians affected. Allergic rhinitis represents a significant burden to the community in quality of life and wellbeing, impaired performance, loss of productivity and health care costs. A review was undertaken firstly of the research literature on the efficacy and effectiveness of acupuncture for allergic rhinitis, then secondly of the research into the mechanisms of acupuncture in allergic rhinitis. A total of 4 systematic reviews, 15 randomised controlled trials (RCTs) and other non- randomised studies on acupuncture treatment for allergic rhinitis were reviewed. Acupuncture was reported to significantly reduce signs and symptoms of allergic rhinitis in both children and adults. Evidence of acupuncture efficacy for persistent (perennial) allergic rhinitis was reported to be stronger than for intermittent (seasonal) allergic rhinitis. Multiple physiological pathways appear to mediate the anti-inflammatory effects of acupuncture including the hypothalamic-pituitary-arenal (HPA) axis, sympathetic pathways, descending inhibitory pathways and possibly parasympathetic cholinergic pathways. Studies have also suggested that acupuncture may down-regulate pro- inflammatory neuropeptides and neurotrophins and may shift the Th1/Th2 balance in T helper cells and hence alter allergic status, however the evidence for these actions is inconclusive.

Background: The association between allergic disease and behavioral symptoms in childhood is not well established. Objective: To longitudinally examine the relationship of allergic diseases and atopy at age four with validated measures of internalizing, anxiety, and depressive symptoms at age 7 years.Methods: Children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), a birth cohort study, completed skin prick testing (SPT) and clinical examinations at 1, 2, 3, 4, and 7 years of age. At age seven, parents completed the Behavior Assessment System for Children, Second Edition (BASC-2), a validated psychological assessment of internalizing disorders composite scale including subscales anxiety and depression. The associations between rhinitis, persistent wheezing, eczema, and allergic sensitization at age four and internalizing disorders at age seven are examined by logistic and linear regression adjusting for maternal education, gender, parental asthma, BMI, and sleep disturbance. Results: In a cohort of 546 children with complete information on allergic disease and behavioral symptoms, the prevalence of internalizing disorders was 13.4%, anxiety disorders 15.2%, and depression was 10.8%. Allergic rhinitis at age 4 years was significantly associated with having elevated BASC-2 scores in the clinically `at risk’ range for internalizing disorders, (aOR=3.2 [1.8-5.8]), anxiety disorders (aOR=2.0 [1.2-3.6]), and depressive disorders (aOR=3.2 [1.7-6.5]). Atopic persistent wheeze at age 4 years was significantly associated with BASC-2 `at risk’ score for internalizing disorders (aOR=2.7 [1.2-6.3]). Aeroallergen sensitization and food sensitization alone were not associated with BASC-2 `at risk’ score for internalizing, anxiety, or depressive disorders. Presence of more than one allergic disease (rhinitis, persistent wheeze, or eczema) was significantly associated with BASC-2 `at risk’ score for internalizing disorders (aOR=4.0 [2.0-8.0]), anxiety disorders (aOR=2.5 [1.2-5.0]), and depressive disorders (aOR=3.5 [1.6-7.7]). Presence of rhinitis plus another allergic disease had an even stronger association than rhinitis alone with internalizing disorders (aOR=5.2 [2.6-10.8]), anxiety disorders (aOR=2.5 [1.2-5.4]), and depressive disorders (aOR=4.4 [1.9-10.0]). Multivariate linear regression showed same associations between allergic diseases and BASC-2 continuous outcome.Conclusions: Children with allergic diseases at age 4, in particular rhinitis, persistent wheeze, are more likely to be at-risk for internalizing disorders including anxiety and depression at 7 years. Furthermore, there was an additive risk of having more than one allergic disease on the subsequent development of an internalization disorder.

Background: About 1 in every 6 Americans suffer from seasonal allergies, aka allergic rhinitis (AR), every year. Typical symptoms of AR include sneezing, stuffy nose and watery eyes. Currently, two types of medications, anti-histamines and corticosteroids, are widely used for relieving AR symptoms; however, in addition to the concern about drug resistance after their long-term use, they also cause side effects such as dry mouth and dizziness. Introduction: AR results from an abnormally heightened immune response triggered by unharmful substances in the environment. Therefore, a therapy capable of regulating the overall immune function of the body should alleviate the discomfort caused by AR. The intestine is the largest immune organ of the body. And consumption of probiotics can induce positive changes in the composition of the microbiota that reside in the intestine within a short period of time. As a result, several trials have been conducted to investigate the therapeutic effects of probiotics on AR. However, because of the generally small sample size of these studies, it is difficult to reach a definite conclusion. Therefore, we performed a meta-analysis to assess if probiotics consumption leads to improvement of AR symptoms. Method: Key words of “probiotics” and “seasonal allergy” were used to search PubMed, Cochrane and CINAHL to identify randomized controlled trials for the meta-analysis. Out of the 69 initially identified papers, 9 were eventually included in the analysis. Studies excluded were either duplicates, reported un-relevant outcomes, or provided insufficient data for further analysis. The meta-analysis was conducted through CMA 2.0, commercial comprehensive meta-analysis software. Standardized mean difference was calculated for subjective symptoms scores and serum biomarker levels for each study as the effect size, and the random effects model was applied to calculate the overall effect. Results: In the Forest plot, the Hedges’ g value for overall symptom score was 0.451 with a p value of 0.02, indicating that probiotics consumption induced a moderate improvement in symptoms, and the improvement is statistically significant. On the other hand, the Hedges’ g value for blood biomarkers level was -0.15 with a p value of 0.127, meaning probiotics performed worse than placebo at decreasing the inflammation at cellular or molecular level, as measured by serum biomarkers, but this inferior effect was not statistically significant. Conclusion: The use of probiotics is beneficial at relieving allergic symptoms for AR patients, but contradictory findings were discovered when it comes to the measurement of serum biomarkers levels. Future studies are needed to identify reliable biomarkers for AR, and studies with similar design but larger sample size would be helpful to further investigate the effectiveness of probiotics in the management of AR.

Allergic rhinitis (AR) is an IgE-mediated disease of the upper respiratory tract characterized by symptoms of rhinorrhea, nasal obstruction, itching, and sneezing in response to allergen exposure. Allergic rhinitis is common in childhood, affecting 42% of six year old children, and is associated with an increased risk of asthma. Thus, determining early childhood risk factors may be important for not only AR, but also asthma. The study hypothesis is that size of the specific aeroallergen wheal area in ages one through three is significantly associated with AR at age four.Two specific aims were completed to test this hypothesis. The first specific aim of this study was to determine the size of the skin prick test (SPT) wheal area from 15 individual aeroallergens during early childhood (age one through three) and its association with AR at age four. The second aim was to determine if any individual age-specific aeroallergen wheal area association persisted in a multivariate logistic regression model after controlling for covariates and multiple testing. The analysis was extended further to address a more specific phenotype, allergic eosinophilic rhinitis (AER), defined as AR with nasal eosinophilia. We examined if the individual aeroallergen wheal areas were associated with AER in univariate and multivariate analysis.This study was part of the Cincinnati Childhood Asthma and Air Pollution Study where allergen skin prick tests (SPT) were performed at ages one through four at annual clinical visits. SPT wheal circumferences were traced, recorded on transpore tape, and digitized which allowed accurate estimates of wheal areas by planimetry. Timothy and Alternaria wheal areas at age two were significantly associated to AR at age four (aOR 1.06; 95% CI, 1.02 - 1.11; p = 0.01) and (aOR 1.07; 95% CI 1.0-1.15; p = 0.04), respectively. Fescue, dog, and Penicillium wheal areas at age three were significantly associated with AR at age four (aOR 1.08; 95% CI, 1.02 - 1.15; p = 0.02), (aOR 1.06; 95% CI, 1.01 - 1.12; p = 0.03) and (aOR 1.14; 95% CI, 1.06 - 1.23; p = 0.001), respectively. At age three, maple and Penicillium wheal areas were significantly associated with AER at age four, (aOR 1.07; 95% CI, 1.01 - 1.13; p = 0.02) and (aOR 1.18; 95% CI, 1.06 - 1.32; p = 0.002), respectively. The conclusion of this study is that the size of aeroallergen wheal area during the first three years of life predicts AR phenotypes at age four. The significance of this finding is that the risk of AR at age four can be attributed to the wheal area of a few aeroallergens. This finding can be used to refine high-risk populations in AR intervention trials. Future studies should investigate if this AR finding extend to earlier into preschool years, to school age children, why these allergens are immunogenic and if wheal area predicts lower respiratory (ex. asthma) phenotypes.

บทนำ: อาการของโรคเยื่อบุจมูกอักเสบเรื้อรัง มีความแตกต่างกันในแต่ละคน ตั้งแต่มีอาการเล็กน้อยจนถึงรุนแรงมาก และมีผลกระทบในการดำเนินชีวิตประจำวัน วัตถุประสงค์: เพื่อศึกษาความสัมพันธ์ระหว่างชนิดและขนาดของปฏิกิริยาผลบวกจากสารก่อภูมิแพ้ และปัจจัยที่มีผลกระทบต่อคุณภาพชีวิตของผู้ป่วยโรคเยื่อจมูกอักเสบเรื้อรัง วิธีการศึกษา: การศึกษาเชิงพรรณนา ณ จุดเวลาใดเวลาหนึ่งแบบตัดขวาง เก็บข้อมูลคุณภาพชีวิต คะแนนการประเมินอาการทางจมูก อาการอื่นๆ และผลทดสอบภูมิแพ้ทางผิวหนังของผู้ป่วยรายใหม่ที่ได้รับการวินิจฉัยว่าเป็นโรคเยื่อบุจมูกอักเสบเรื้อรัง ณ คลินิกโรคภูมิแพ้ โรงพยาบาลรามาธิบดี ตั้งแต่เดือนสิงหาคมถึงเดือนธันวาคม พ.ศ. 2560 ผลการศึกษา: ผู้ป่วย จำนวน 130 คน เป็นเพศหญิง จำนวน 85 คน คิดเป็นร้อยละ 65 พบว่า ชนิดและขนาดของปฏิกิริยาทดสอบภูมิแพ้ทางผิวหนังที่ให้ผลบวก มีความสัมพันธ์กับคุณภาพชีวิตแบบแปรผกผันเฉพาะไรฝุ่นชนิด Der f และแมลงสาบ (r = - 0.283 ถึง - 0.234, P < 0.05) อย่างไรก็ตาม คะแนนอาการทางจมูก (Total nasal symptom score, TNSS) และคะแนนอาการแสดงในระบบอื่นๆ (Total other symptom score, TOSS) มีความแตกต่าง ระหว่าง TNSS > 6 กับ TNSS ≤ 6 และ TOSS> 6 กับ TOSS ≤ 6 โดยพบว่า กลุ่มที่มีคะแนน มากกว่า 6 จะมีคุณภาพชีวิตต่ำกว่าทุกมิติอย่างมีนัยสำคัญทางสถิติ (P < 0.05) ยกเว้นคุณภาพชีวิตด้านการหยุดงาน(P = 0.16) สรุป: การศึกษานี้แสดงให้เห็นว่าชนิดและขนาดของปฏิกิริยาการทดสอบภูมิแพ้ทางผิวหนังที่ให้ผลบวกไม่มีความสัมพันธ์กับคุณภาพชีวิตของผู้ป่วย อย่างไรก็ตาม ความรุนแรงของอาการของโรคมีผลกระทบต่อระดับคุณภาพชีวิตอย่างมีนัยสำคัญ

บทนำ: โรคจมูกอักเสบเป็นโรคที่พบได้บ่อยและมีผลต่อคุณภาพชีวิต แต่สามารถรักษาควบคุมอาการได้ ปัจจุบัน ยังไม่มีข้อมูลความแตกต่างของระดับคุณภาพชีวิตและอาการแสดงหลังได้รับการรักษาหลัง 3 เดือน วัตถุประสงค์: เพื่อเปรียบเทียบคุณภาพชีวิตผู้ป่วยโรคจมูกอักเสบ ก่อนและหลัง การรักษาที่ระยะเวลา 3 เดือน วิธีการศึกษา: การศึกษาเชิงวิเคราะห์แบบไปข้างหน้า จากเหตุไปหาผลของผู้ป่วยรายใหม่ทุกราย ณ คลินิกโรคภูมิแพ้ โรงพยาบาลรามาธิบดี ตั้งแต่เดือนสิงหาคม พ.ศ. 2560 ถึงเดือนมีนาคม พ.ศ. 2561 ผลการศึกษา: ผู้ป่วย จำนวน 127 คน เป็นเพศหญิง คิดเป็นร้อยละ 65.4 โดยแบ่งเป็นกลุ่มโรคจมูกอักเสบจากภูมิแพ้ โรคจมูกอักเสบชนิดไม่แพ้ และโรคจมูกอักเสบไม่ทราบชนิด คิดเป็นร้อยละ 72.4 ร้อยละ 18.9 และร้อยละ 8.7 ตามลำดับ ซึ่งพบว่า ผู้ป่วยโรคจมูกอักเสบทุกชนิดมีคุณภาพชีวิตดีขึ้น ทั้งจากการประเมินด้วยแบบวัดคุณภาพชีวิตทั่วไปและแบบวัดคุณภาพชีวิตเฉพาะโรค รวมทั้งมีอาการทางจมูก และอาการระบบอื่นๆ ลดลงอย่างมีนัยสำคัญ (P < .05) สรุป: ผู้ป่วยโรคจมูกอักเสบเรื้อรังที่ได้รับการรักษามีคุณภาพชีวิตที่ดีขึ้น รวมทั้งมีอาการแสดงทางจมูกและระบบอื่นๆ ลดลงอย่างมีนัยสำคัญ ภายในระยะเวลา 3 เดือน