"Hay fever" in children : the real story

Rhinitis, allergic (AR) and non-allergic (NAR), and chronic rhinosinusitis (CRS) are different expressions of upper airway inflammation. Chronic upper airway symptoms are common in childhood and adolescence. There is a need for more epidemiologic data of these different entities of upper airway symptoms in the aspects of prevalence, natural course, co-morbidity and risk factors. The aim of this thesis was to provide epidemiologic data from a pediatric general population for a better understanding of the different phenotypes of upper airway inflammation from childhood to adolescence. To do this, we used the BAMSE birth cohort with 4089 children followed from birth up to 16 years of age with repeated questionnaires and clinical follow-ups. We found that AR was already common at 4 years (5.4%) and that the prevalence increased to 14% at 8 years. 87% of the 4-year-olds with AR had persistent disease up to 8 years. In contrast, among the 8.1% with NAR at 4 years, 74% had no rhinitis symptoms at 8 years. We also found that co-morbidity with asthma and eczema was common, not only for AR, but also for NAR. Oral allergy syndrome (OAS) was found among 31% of 8-year-olds and 63% of the 16-year-olds with allergic rhinitis to birch pollen. Parental allergic disease increased the risk of the child of developing AR as well as NAR at 8 years of age. There was an increased risk of AR in particular if the parents had hay fever or if both parents were allergic. An increased risk of NAR was seen if one parent had two or more allergy-related diseases. We found no difference in risk between maternal and paternal heredity. The prevalence of reported symptoms of allergic rhinitis to birch pollen (ARbp) increased from 2.5% at 4 years to 10.6% at 8 years and 17.8% at 16 years. Bet v 1-specifi IgE was the most prevalent specific IgE against PR-10 allergen molecules and had the highest median levels. We found an increased probability for the onset of ARbp at 16 years with increasing levels of Bet v 1-specifi IgE or increasing number of other IgE-reactive PR-10 proteins at 4 years. In addition we found that the levels of Bet v 1 at 4 years were associated with severity of ARbp at 16 years. The prevalence of CRS at 16 years of age was estimated to be between 0.3% and 1.5%. Adolescents with CRS more often reported symptoms of allergic rhinitis and asthma and had a lower health-related quality of life than those without CRS. In conclusion, the results from this thesis show that both AR and NAR in children are common, are associated with asthma and eczema and affected by parental allergy- related diseases. There are differences between AR and NAR regarding the prognosis and the pattern of heredity for allergic diseases. AR may possibly be predicted by the levels of Bet v 1-specifi IgE or number of IgE-reactive PR-10 proteins in early childhood and by parental hay fever. The prevalence of OAS among individuals with birch pollen allergy seems to increase during childhood. The prevalence of CRS in adolescence seems to be low but for those affected, the symptoms may be bothersome

Associations between the 17q21 region and allergic rhinitis in 5 birth cohorts

Non peer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

The complex pathophysiology of allergic rhinitis : Scientific rationale for the development of an alternative treatment option

Allergic rhinitis (AR) poses a global health problem and can be challenging to treat. Many of the current symptomatic treatments for AR have been available for decades, yet there has been little improvement in patient quality of life or symptom burden over the years. In this review, we ask why this might be and explore the pathophysiological gaps that exist within the various AR treatment classes. We focus on the benefits and drawbacks of different treatment options and delivery routes for AR treatments and consider how, given what is known about AR pathophysiology and symptomatology, patients may be offered more effective treatment options for rapid, effective, and sustained AR control. In particular, we consider how a new AR preparation, MP-AzeFlu (Dymista ® , Meda, Sweden), comprising a formulation of an intranasal antihistamine (azelastine hydrochloride), an intranasal corticosteroid (fluticasone propionate), and excipients delivered in a single spray, may offer benefits over and above single and multiple AR therapy options. We review the evidence in support of this treatment across the spectrum of AR disease. The concept of AR control is also reviewed within the context of new European Union and Contre les Maladies Chroniques pour un VIeillissement Actif-Allergic Rhinitis and its Impact on Asthma initiatives

Dietary fibre in relation to asthma, allergic rhinitis and sensitization from childhood up to adulthood

Background: Dietary fibre may reduce the risk of allergy. Our aim was to investigate the association between fibre intake in childhood, asthma, allergic rhinitis and IgE sensitization up to adulthood. Methods: The individual fibre intake of 2285 participants from the Swedish population-based birth cohort BAMSE was estimated between 98- and 107-item food frequency questionnaires at ages 8 and 16 years, respectively. At 8, 16 and 24 years, asthma and allergic rhinitis symptoms were assessed by questionnaires, and sensitization to common allergens by serum IgE. Longitudinal associations were analysed by generalized estimating equations, adjusting for potential confounders. Results: An inverse overall association was indicated between fibre intake at 8 years and allergic rhinitis symptoms up to 24 years (OR per 5 g/d 0.86; 95% CI 0.77-0.96), particularly in combination with airborne (0.74; 0.62-0.89) and food (0.69; 0.54-0.88) allergen sensitization. Higher fibre intake was also associated with specific allergen sensitization, for example, birch (0.77; 0.67-0.88) and soy (0.68; 0.53-0.87). No association was observed with asthma. Regarding sources, fruit (0.79; 0.67-0.94) and other (potatoes, chips/popcorn, legumes, and nuts, 0.71; 0.50-0.99), but not cereal or vegetable fibre were associated with allergic rhinitis. In additional analyses, including long-term fibre intake at 8 and 16 years, excluding participants with food-related allergic symptoms to examine reverse causation, as well as adjusting for antioxidant intake, associations were attenuated and became non-significant. Conclusion: Higher fibre intake in mid-childhood may be inversely associated with allergic rhinitis and sensitization to specific allergens up to adulthood. However, avoidance of food triggers of allergic symptoms in allergic rhinitis patients may contribute to the protective associations

High dose pollen intralymphatic immunotherapy : Two RDBPC trials question the benefit of dose increase

Background: The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Methods: Two randomized double-blind placebo-controlled trials of ILIT for grass pollen-induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000–3000–10,000 (5000 + 5000 with 30 minutes apart) SQ-U with 1 month in between was evaluated. Results: Doses up to 10,000 SQ-U were safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass-specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000–3000–3000 SQ-U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph node-derived dendritic but not T cells. Quality of life and nasal provocation response did not improve in any study. Conclusion: Intralymphatic immunotherapy in high doses after SCIT appears to further reduce grass pollen-induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3000 SQ-U should be avoided