Natural course of pollen-induced allergic rhinitis from childhood to adulthood: A 20-year follow up.

BACKGROUND: Allergic rhinitis (AR) is one of the most common chronic diseases worldwide. There are limited prospective long-term data regarding persistency and remission of AR. The objective of this study was to investigate the natural course of pollen-induced AR (pollen-AR) over 20 years, from childhood into early adulthood. METHODS: Data from 1137 subjects in the Barn/Children Allergi/Allergy Milieu Stockholm Epidemiologic birth cohort (BAMSE) with a completed questionnaire regarding symptoms, asthma, treatment with allergen immunotherapy (AIT) and results of allergen-specific IgE for inhalant allergens at 4, 8, 16 and 24 years were analyzed. Pollen-AR was defined as sneezing, runny, itchy or blocked nose; and itchy or watery eyes when exposed to birch and/or grass pollen in combination with allergen-specific IgE ≥0.35kUA/L to birch and/or grass. RESULTS: Approximately 75% of children with pollen-AR at 4 or 8 years had persistent disease up to 24 years, and 30% developed asthma. The probability of persistency was high already at low levels of pollen-specific IgE. The highest rate of remission from pollen-AR was seen between 16 and 24 years (21.5%); however, the majority remained sensitized. This period was also when pollen-specific IgE-levels stopped increasing and the average estimated annual incidence of pollen-AR decreased from 1.5% to 0.8% per year. CONCLUSION: Children with pollen-AR are at high risk of persistent disease for at least 20 years. Childhood up to adolescence seems to be the most dynamic period of AR progression. Our findings underline the close cross-sectional and longitudinal relationship between sensitization, AR and asthma.

[Allergic rhinitis in children and adults - international recommendations adapted to the clinical situation in Sweden]. / Allergisk rinit hos barn och vuxna.

Allergic rhinitis is the most common chronic disease in Sweden, with impact on quality of life and with a heavy economic burden for the society. More than 20 years have passed since national recommendations were launched, and meanwhile both ARIA (Allergic rhinitis and its impact of asthma) and EUFOREA (The European Forum for Research and Education in Allergy and Airway Diseases) have presented international guidelines which in this article have been adapted to the clinical situation in Sweden. Visual analogue scale (VAS) is recommended for symptom evaluation, and the importance of correct allergen analysis and examination for coexisting asthma is emphasized. Treatment is recommended according to EUFOREA. Follow-up is important, and if VAS is ≥5 the disease is regarded as uncontrolled and must lead to a change of treatment. Since self-treatment is common in allergic rhinitis the importance of patient cooperation and information is underlined.

Development of sensitization to peanut and storage proteins and relation to markers of airway and systemic inflammation: A 24-year follow-up.

BACKGROUND: Long-time data of peanut allergy over time is sparse. We aimed to study the longitudinal development of sensitization to peanut extract and storage protein allergen molecules and associations with asthma status, airway and systemic inflammation markers. METHODS: The Swedish birth cohort BAMSE followed 4089 participants with questionnaires, clinical investigations and blood sampling between 0 and 24 years. Information on (i) background factors at 2 months, (ii) peanut allergy symptoms and IgE data (ImmunoCAP) at 4, 8, 16, and 24 years, and (iii) IgE to storage proteins, lung function data including exhaled nitric oxide (FENO) as well as systemic inflammatory markers at 24 years of age were collected. RESULTS: The prevalence of peanut extract sensitization, defined as IgE ≥ 0.35 kUA /L, was 5.4%, 8.0%, 7.5%, and 6.2% at 4, 8, 16, and 24 years of age, respectively. Between 8 and 24 years of age, (33/1565) participants developed IgE-ab to peanut extract (median 1,4, range 0.7-2.6 kUA /L), and among those 85% were also sensitized to birch. Only six individuals developed sensitization to Ara h 2 (≥0.1 kUA /L) between 8 and 24 years of age, of whom three had an IgE-ab level between 0.1-0.12 kUA /L. Storage protein sensitization was associated with elevated FENO, blood eosinophils and type 2 inflammation-related systemic proteins. CONCLUSION: Sensitization to peanut extract after 4 years of age is mainly induced by birch cross-sensitization and IgE to Ara h 2 rarely emerges after eight years of age. Storage protein sensitization is associated with respiratory and systemic inflammation.

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.

General Stress Among Young Adults with Asthma During the COVID-19 Pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected the lives of the global population. OBJECTIVE: To explore anxiety and stress in relation to COVID-19 among young adults, and the potential influence of asthma and allergic rhinitis. METHODS: This cross-sectional study included 1644 participants from the population-based birth cohort BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology), participating in a follow-up at age 24 years and a COVID-19 follow-up conducted in August-November 2020 (mean age, 25.3 years). Anxiety and concern related to COVID-19 were analyzed as general anxiety, concern of own health and health of family members, and contact with online health care providers due to concern about COVID-19. Stress was measured with the perceived stress scale. RESULTS: Around half the participants reported increased anxiety due to COVID-19, and this was more common among females (57.0%, compared with 42.6% in males; P < .001). Young adults with asthma reported more concern about their own health (adjusted odds ratio, 1.50; 95% CI, 1.12-2.02) and perceived stress (adjusted regression coefficient [adjusted ß], 1.49; 95% CI, 0.52-2.45) compared with peers without asthma, and this was more pronounced among females and those with uncontrolled asthma. Symptoms of allergic rhinitis were not associated with increased concern or anxiety in relation to COVID-19. CONCLUSIONS: Young adults with asthma experience more COVID-19-related health concerns, compared with those without asthma, especially females and participants with uncontrolled asthma This needs to be considered in the care of young people with asthma.

Food allergy and hypersensitivity reactions in children and adults-A review.

Adverse reactions after food intake are commonly reported and a cause of concern and anxiety that can lead to a very strict diet. The severity of the reaction can vary depending on the type of food and mechanism, and it is not always easy to disentangle different hypersensitivity diagnoses, which sometimes can exist simultaneously. After a carefully taken medical history, hypersensitivity to food can often be ruled out or suspected. The most common type of allergic reaction is immunoglobulin E (IgE)-mediated food allergy (prevalence 5-10%). Symptoms vary from mild itching, stomach pain, and rash to severe anaphylaxis. The definition of IgE-mediated food allergy is allergic symptoms combined with specific IgE-antibodies, and therefore only IgE-antibodies to suspected allergens should be analyzed. Nowadays, methods of molecular allergology can help with the diagnostic process. The most common allergens are milk and egg in infants, peanut and tree nuts in children, and fish and shellfish in adults. In young children, milk/egg allergy has a good chance to remit, making it important to follow up and reintroduce the food when possible. Other diseases triggered by food are non-IgE-mediated food allergy, for example, eosinophilic esophagitis, celiac disease, food protein-induced enterocolitis syndrome, and hypersensitivity to milk and biogenic amines. Some of the food hypersensitivities dominate in childhood, others are more common in adults. Interesting studies are ongoing regarding the possibilities of treating food hypersensitivity, such as through oral immunotherapy. The purpose of this review was to provide an overview of the most common types of food hypersensitivity reactions.

Prevalence and early-life risk factors for tree nut sensitization and allergy in young adults.

BACKGROUND: Tree nut allergy may cause anaphylaxis. There are limited population-based studies on prevalence and early-life risk factors. METHODS: We evaluated the prevalence of reported symptoms and allergic sensitization to tree nuts at age 24 years in the BAMSE population-based cohort study and assessed early-life factors associated with the development of tree nut allergy. We estimated tree nut allergy prevalence, by analysing questionnaire data on tree nut ingestion and symptoms at age 12, 16 and 24 years, and IgE sensitization at age 24 years to hazelnut, walnut, pecan, cashew, pistachio, Brazil nut, almond extracts and allergen molecules Cor a 1, 9, 14 (hazelnut), Jug r 1 (walnut) and Ana o 3 (cashew). We evaluated eczema, asthma, food allergies, inherited risk of allergy and gender as potential early-life risk factors. RESULTS: Data were available for 2215/4089 (54%) BAMSE study participants, for estimation of the prevalence of tree nut sensitization (21.2%), tree nut allergy symptoms (9.8%) and combined sensitization and symptoms (7.9%, 2.1% for storage protein sensitization and symptoms, 4.3% for any sensitization and non-mild symptoms). Sixty-three per cent of sensitized individuals (295/470) were asymptomatic, but only 76/470 (16%) storage protein sensitized individuals. Egg allergy (ORadj 8.50 95% CI 2.15-33.6), eczema (ORadj 2.53 95% CI 1.21-5.32) and asthma (ORadj 5.59 95% CI 2.35-13.3)) at pre-school age were associated with future development of tree nut symptoms and storage protein sensitization. At age 24 years, tree nut allergy was associated with current eczema and with markers of current asthma severity. Sensitization to storage proteins was more strongly associated with symptoms than sensitization to whole extract for all tree nuts evaluated. CONCLUSIONS: In this Swedish cohort, we found tree nut whole extract sensitization is common but usually asymptomatic. Storage protein sensitization is a more reliable indicator of tree nut symptoms. Tree nut allergy is associated with early onset, persistent and severe atopic disease.

Male sex is strongly associated with IgE-sensitization to airborne but not food allergens: results up to age 24 years from the BAMSE birth cohort.

BACKGROUND: Up to half of the population in high-income countries has allergen-specific IgE antibodies. However, data regarding sex differences of IgE-sensitization from childhood to adulthood is limited. OBJECTIVE: To explore IgE-sensitization to common foods and airborne allergens in relation to sex over time in a population-based cohort followed up to young adulthood. METHODS: The Swedish population-based birth cohort BAMSE includes 4089 subjects who have been followed regularly with questionnaires and clinical investigations. A recent 24-year follow-up included 3069 participants (75%). Sera collected at 4, 8, 16 and 24 years were analyzed for IgE-antibodies to 14 common foods and airborne allergens. RESULTS: At 24 years sensitization to foods had decreased compared to previous follow-ups affecting 8.4%, while sensitization to airborne allergens was more common, affecting 42.2%. Male sex was associated with IgE-sensitization to airborne allergens at all ages (overall OR: 1.68, 95% CI 1.46-1.94) while there was no statistically significant association between sex and sensitization to food allergens (overall OR: 1.10, 95% CI 0.93-1.32). Levels of allergen-specific IgE did not differ significantly between males and females for any of the tested foods or airborne allergens at any age, following adjustment for multiple comparisons. CONCLUSION: IgE-sensitization to airborne allergens increases with age up to young adulthood, whereas sensitization to food allergens seems to level off. Male sex is strongly associated with IgE-sensitization to airborne allergens from early childhood up to young adulthood. In contrast, there is little evidence for associations between sex and IgE-sensitization to foods.

Sensitization to grass pollen allergen molecules in a birth cohort-natural Phl p 4 as an early indicator of grass pollen allergy.

BACKGROUND: Grass pollen allergy is one of the most common allergies worldwide. OBJECTIVE: The aim of this study was to evaluate the usefulness of grass pollen allergen molecules for prediction of grass pollen allergy during childhood and up to adolescence. METHOD: Questionnaire data and sera obtained from the study subjects at the ages of 4, 8, and 16 years from the population-based Barn/Children Allergy Milieu Stockholm Epidemiology birth cohort were used. Sera from 763 representative subjects with serum samples available at all 3 ages were analyzed for IgE reactivity to 8 Phleum pratense (Phl p) allergens (MeDALL [Mechanisms for the Development of Allergies] chip) and to timothy grass extract (ImmunoCAP). Allergic rhinitis to grass pollen (ARg) was defined as upper airway symptoms during grass pollen exposure. RESULTS: The prevalence of sensitization to any Phl p molecule was higher compared with that to timothy extract at all 3 ages: at the age of 4 years, 9.7% versus 6.8%; at the age of 8 years, 28.4% versus 15.3%; and at the age of 16 years, 37.1% versus 27.1%. General estimating equations analyses revealed that among children sensitized at the age of 4 years, the overall odds ratio (OR) of later ARg (up to 16 years) was increased only for IgE reactivity to Phl p 1 (OR = 4.9) and natural Phl p 4 (OR = 6.9). The likelihood of later symptoms increased with the number of allergen molecules; at the age of 4 years, 2 or more molecules predicted ARg to 78% and 3 or more molecules predicted ARg to 95%. A positive test result for timothy extract predicted ARg to 70%. CONCLUSIONS: Natural Phl p 4 is a hitherto unrecognized early indicator of grass pollen allergy, in addition to Phl p 1. To identify grass pollen sensitization and predict later ARg, allergen molecules are of added value to timothy extract alone and may help clinicians improve prediction of grass pollen allergy.

Human papillomavirus and infiltration of CD8- and Foxp3-positive immune cells in sinonasal inverted papillomas.

Background: Sinonasal inverted papilloma (IP) is a benign tumor with a high risk of local recurrence and a potential to malignify and Human papillomavirus (HPV) has been suggested an etiological factor. p16INK4a (p16) overexpression is considered a surrogate marker for HPV, but whether p16 and HPV correlate to IP is uncertain. Besides, a prognostic role of tumor infiltrating lymphocytes (TILs) are observed in many tumors, however their role in IP is sparsely studied. Aims/objectives: We hence analyzed IPs for the presence and the prognostic role of HPV and p16 overexpression together with CD8+ and FoxP3+ TILs in a population-based study. Material and methods: 98 IP patients diagnosed 2001-2010 were identified from the Swedish Cancer Registry and analyzed for HPV by PCR and p16, CD8 and FoxP3 was by immunohistochemistry. Results: In total, 12.2% of the IPs were HPV-positive (nine HPV-11, two HPV-6 and one HPV-45). Patients with HPV-positive lesions were younger (p = .003) and tended to present with more dysplasia. No correlation was observed between TILs and prognosis. Conclusions and significance: Our data suggests that patients with HPV-positive IPs present with different clinical characteristics, suggesting possibly different disease entities. Moreover, recurrences may occur >5 years, which should be considered in the follow-up.

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.

Impact of IgE sensitization and rhinitis on inflammatory biomarkers and lung function in adolescents with and without asthma.

BACKGROUND: Both allergic and non-allergic rhinitis are associated with worse asthma control. However, it is unclear how IgE sensitization and/or rhinitis are associated with lung function. We therefore evaluated the effect of rhinitis and sensitization on lung function, including the periphery of the airway system, and inflammatory biomarkers in individuals with and without asthma. METHODS: Participants in the BAMSE longitudinal birth cohort study underwent measures of spirometry, impulse oscillometry, and FeNO at age 16 years. Questionnaires were used to obtain data on asthma and rhinitis. Blood samples were analyzed for eosinophils and allergen-specific IgE. RESULTS: Groups based on the combination of asthma, rhinitis, and sensitization were compared to a healthy reference group. Lower FEV1 /FVC levels were seen for groups with asthma only (adjusted mean difference -2.8% units (95% CI -4.7; -1.0), P < 0.01), asthma with sensitization (-2.0 (-3.9; -0.2), P < 0.05), and asthma with sensitization and rhinitis (-2.5 (-3.6; -1.4), P < 0.001). The index of peripheral airway resistance R5-20 was higher in groups with asthma and sensitization (adjusted median difference 94.9 Pa L-1  s-1 (95% CI 60.4; 129.3), P < 0.001), as well as asthma with sensitization and rhinitis (36.9(15.0; 58.8), P < 0.01). These groups also had increased FeNO and blood eosinophil levels. CONCLUSIONS: We found signs of peripheral airway obstruction and increased levels of inflammatory biomarkers in the presence of allergic asthma, irrespective of rhinitis status. Despite having a reduced FEV1 /FVC, peripheral airway engagement was not seen in non-sensitized adolescents with asthma. We suggest that small airway disease is a feature related to the eosinophilic inflammation in allergic asthma in adolescence.

Windows of opportunity for tolerance induction for allergy by studying the evolution of allergic sensitization in birth cohorts.

Allergic sensitization is a risk factor for developing IgE-mediated allergic diseases, which are a major cause of chronic illness world-wide. The introduction of allergen molecules to the field of allergy diagnostics has allowed dissecting the IgE response on a molecular level to pinpoint the specific disease-causing allergens. Studying birth cohorts is an essential tool for understanding the development and life course of allergy, enabling the possibility to design preventive strategies. Here we review the evolution of sensitization using data from some of the large European birth cohort studies. Differences and similarities between sensitization to food and various sources of inhalant allergens are discussed and allergen molecules of importance in early childhood predicting disease in adolescence are highlighted. Finally, we discuss windows of opportunity where intervention could be considered and address possible preventive strategies.

Mechanisms of the Development of Allergy (MeDALL): Introducing novel concepts in allergy phenotypes.

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases.

Fish and polyunsaturated fat intake and development of allergic and nonallergic rhinitis.

BACKGROUND: Rhinitis is one of the most common diseases in childhood. Fish, polyunsaturated fatty acid (PUFA), and vitamin D intakes have been hypothesized to affect the risk of allergic disease; however, it is unclear whether these are linked to the development of rhinitis. OBJECTIVE: We sought to assess potential associations between consumption of fish, dietary n-3 and n-6 PUFAs, and vitamin D at age 8 years and development of allergic rhinitis (AR) and nonallergic rhinitis (NAR) between the ages of 8 and 16 years. METHODS: We included 1970 participants from a birth cohort. Data on dietary intake was obtained from a food frequency questionnaire at age 8 years. The rhinitis definition was based on questionnaires and IgE measures. RESULTS: The prevalence of rhinitis symptoms at age 8 years was 19% (n = 380). Among the 1590 children without rhinitis symptoms at age 8 years, 21% (n = 337) had AR between ages 8 and 16 years, and 15% (n = 236) had NAR. Regular intake of oily fish and higher long-chain n-3 PUFA intake were associated with a reduced risk of cumulative incidence of NAR (adjusted odds ratio, 0.52 [95% CI, 0.32-0.87] for oily fish; odds ratio, 0.45 [95% CI, 0.30-0.67] for highest vs lowest tertile of long-chain n-3 PUFAs; P trend < .001). The results for rhinitis, irrespective of AR and NAR, were in line with the findings for NAR. CONCLUSION: Regular consumption of oily fish and dietary long-chain n-3 PUFAs in childhood might decrease the risk of rhinitis, especially NAR, between the ages of 8 and 16 years.