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1.  Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001611.
In a systematic review and meta-analysis, Bahi Takkouche and colleagues examine the associations between exposure to tobacco smoke and allergic disorders in children and adults.
Please see later in the article for the Editors' Summary
Background
Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.
Methods and Findings
We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.
We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92–1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06–1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14–1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03–1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24–1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04–1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17–1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01–1.11]). Food allergy was associated with SHS (1.43 [1.12–1.83]) when cohort studies only were examined, but not when all studies were combined.
The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.
Conclusions
We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The immune system protects the human body from viruses, bacteria, and other pathogens. Whenever a pathogen enters the body, immune system cells called T lymphocytes recognize specific molecules on its surface and release chemical messengers that recruit and activate other types of immune cells, which then attack the pathogen. Sometimes, however, the immune system responds to harmless materials (for example, pollen; scientists call these materials allergens) and triggers an allergic disease such as allergic rhinitis (inflammation of the inside of the nose; hay fever is a type of allergic rhinitis), allergic dermatitis (also known as eczema, a disease characterized by dry, itchy patches on the skin), and food allergy. Recent studies suggest that all these allergic (atopic) diseases are part of a continuous state called the “atopic march” in which individuals develop allergic diseases in a specific sequence that starts with allergic dermatitis during infancy, and progresses to food allergy, allergic rhinitis, and finally asthma (inflammation of the airways).
Why Was This Study Done?
Allergic diseases are extremely common, particularly in children. Allergic rhinitis alone affects 10%–30% of the world's population and up to 40% of children in some countries. Moreover, allergic diseases are becoming increasingly common. Allergic diseases affect the quality of life of patients and are financially costly to both patients and health systems. It is important, therefore, to identify the factors that cause or potentiate their development. One potential risk factor for allergic diseases is active or passive exposure to tobacco smoke. In some countries up to 80% of children are exposed to second-hand smoke so, from a public health point of view, it would be useful to know whether exposure to tobacco smoke is associated with the development of allergic diseases. Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical approach for combining the results of several studies) to investigate this issue.
What Did the Researchers Do and Find?
The researchers identified 196 observational studies (investigations that observe outcomes in populations without trying to affect these outcomes in any way) that examined the association between smoke exposure and allergic rhinitis, allergic dermatitis, or food allergy. When all studies were analyzed together, allergic rhinitis was not associated with active smoking but was slightly associated with exposure to second-hand smoke. Specifically, compared to people not exposed to second-hand smoke, the pooled relative risk (RR) of allergic rhinitis among people exposed to second-hand smoke was 1.10 (an RR of greater than 1 indicates an increased risk of disease development in an exposed population compared to an unexposed population). Allergic dermatitis was associated with both active smoking (RR = 1.21) and exposure to second-hand smoke (RR = 1.07). In the populations of children and adolescents included in the studies, allergic rhinitis was associated with both active smoking and exposure to second-hand smoke (RRs of 1.40 and 1.09, respectively), as was allergic dermatitis (RRs of 1.36 and 1.06, respectively). Finally food allergy was associated with exposure to second-hand smoke (RR = 1.43) when cohort studies (a specific type of observational study) only were examined but not when all the studies were combined.
What Do These Findings Mean?
These findings provide limited evidence for a weak association between smoke exposure and allergic disease in adults but suggest that both active and passive smoking are associated with a modestly increased risk of allergic diseases in children and adolescents. The accuracy of these findings may be affected by the use of questionnaires to assess smoke exposure and allergic disease development in most of the studies in the meta-analysis and by the possibility that individuals exposed to smoke may have shared other characteristics that were actually responsible for their increased risk of allergic diseases. To shed more light on the role of smoking in allergic diseases, additional studies are needed that accurately measure exposure and outcomes. However, the present findings suggest that, in countries where many people smoke, 14% and 13% of allergic rhinitis and allergic dermatitis, respectively, among children may be attributable to active smoking. Thus, the elimination of active smoking among children and adolescents could prevent one in seven cases of allergic rhinitis and one in eight cases of allergic dermatitis in such countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001611.
The UK National Health Service Choices website provides information about allergic rhinitis, hay fever (including personal stories), allergic dermatitis (including personal stories), and food allergy (including personal stories)
The US National Institute of Allergy and Infectious Disease provides information about allergic diseases
The UK not-for-profit organization Allergy UK provides information about all aspects of allergic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on allergic rhinitis and allergic dermatitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and food allergy (in English and Spanish)
doi:10.1371/journal.pmed.1001611
PMCID: PMC3949681  PMID: 24618794
2.  Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases 
Allergo Journal International  2014;23(8):282-319.
Summary
The present guideline (S2k) on allergen-specific immunotherapy (AIT) was established by the German, Austrian and Swiss professional associations for allergy in consensus with the scientific specialist societies and professional associations in the fields of otolaryngology, dermatology and venereology, pediatric and adolescent medicine, pneumology as well as a German patient organization (German Allergy and Asthma Association; Deutscher Allergie- und Asthmabund, DAAB) according to the criteria of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).
AIT is a therapy with disease-modifying effects. By administering allergen extracts, specific blocking antibodies, toler-ance-inducing cells and mediators are activated. These prevent further exacerbation of the allergen-triggered immune response, block the specific immune response and attenuate the inflammatory response in tissue.
Products for SCIT or SLIT cannot be compared at present due to their heterogeneous composition, nor can allergen concentrations given by different manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients. Non-modified allergens are used for SCIT in the form of aqueous or physically adsorbed (depot) extracts, as well as chemically modified allergens (allergoids) as depot extracts. Allergen extracts for SLIT are used in the form of aqueous solutions or tablets.
The clinical efficacy of AIT is measured using various scores as primary and secondary study endpoints. The EMA stipulates combined symptom and medication scores as primary endpoint. A harmonization of clinical endpoints, e. g., by using the combined symptom and medication scores (CSMS) recommended by the EAACI, is desirable in the future in order to permit the comparison of results from different studies. The current CONSORT recommendations from the ARIA/GA2LEN group specify standards for the evaluation, presentation and publication of study results.
According to the Therapy allergen ordinance (TAV), preparations containing common allergen sources (pollen from grasses, birch, alder, hazel, house dust mites, as well as bee and wasp venom) need a marketing authorization in Germany. During the marketing authorization process, these preparations are examined regarding quality, safety and efficacy. In the opinion of the authors, authorized allergen preparations with documented efficacy and safety, or preparations tradeable under the TAV for which efficacy and safety have already been documented in clinical trials meeting WAO or EMA standards, should be preferentially used. Individual formulations (NPP) enable the prescription of rare allergen sources (e.g., pollen from ash, mugwort or ambrosia, mold Alternaria, animal allergens) for specific immunotherapy. Mixing these allergens with TAV allergens is not permitted.
Allergic rhinitis and its associated co-morbidities (e. g., bronchial asthma) generate substantial direct and indirect costs. Treatment options, in particular AIT, are therefore evaluated using cost-benefit and cost-effectiveness analyses. From a long-term perspective, AIT is considered to be significantly more cost effective in allergic rhinitis and allergic asthma than pharmacotherapy, but is heavily dependent on patient compliance.
Meta-analyses provide unequivocal evidence of the efficacy of SCIT and SLIT for certain allergen sources and age groups. Data from controlled studies differ in terms of scope, quality and dosing regimens and require product-specific evaluation. Therefore, evaluating individual preparations according to clearly defined criteria is recommended. A broad transfer of the efficacy of certain preparations to all preparations administered in the same way is not endorsed. The website of the German Society for Allergology and Clinical Immunology (www.dgaki.de/leitlinien/s2k-leitlinie-sit; DGAKI: Deutsche Gesellschaft für Allergologie und klinische Immunologie) provides tables with specific information on available products for AIT in Germany, Switzerland and Austria. The tables contain the number of clinical studies per product in adults and children, the year of market authorization, underlying scoring systems, number of randomized and analyzed subjects and the method of evaluation (ITT, FAS, PP), separately given for grass pollen, birch pollen and house dust mite allergens, and the status of approval for the conduct of clinical studies with these products.
Strong evidence of the efficacy of SCIT in pollen allergy-induced allergic rhinoconjunctivitis in adulthood is well-documented in numerous trials and, in childhood and adolescence, in a few trials. Efficacy in house dust mite allergy is documented by a number of controlled trials in adults and few controlled trials in children. Only a few controlled trials, independent of age, are available for mold allergy (in particular Alternaria). With regard to animal dander allergies (primarily to cat allergens), only small studies, some with methodological deficiencies are available. Only a moderate and inconsistent therapeutic effect in atopic dermatitis has been observed in the quite heterogeneous studies conducted to date. SCIT has been well investigated for individual preparations in controlled bronchial asthma as defined by the Global Initiative for Asthma (GINA) 2007 and intermittent and mild persistent asthma (GINA 2005) and it is recommended as a treatment option, in addition to allergen avoidance and pharmacotherapy, provided there is a clear causal link between respiratory symptoms and the relevant allergen.
The efficacy of SLIT in grass pollen-induced allergic rhinoconjunctivitis is extensively documented in adults and children, whilst its efficacy in tree pollen allergy has only been shown in adults. New controlled trials (some with high patient numbers) on house dust mite allergy provide evidence of efficacy of SLIT in adults.
Compared with allergic rhinoconjunctivitis, there are only few studies on the efficacy of SLIT in allergic asthma. In this context, newer studies show an efficacy for SLIT on asthma symptoms in the subgroup of grass pollen allergic children, adolescents and adults with asthma and efficacy in primary house dust mite allergy-induced asthma in adolescents aged from 14 years and in adults.
Aspects of secondary prevention, in particular the reduction of new sensitizations and reduced asthma risk, are important rationales for choosing to initiate treatment early in childhood and adolescence. In this context, those products for which the appropriate effects have been demonstrated should be considered.
SCIT or SLIT with pollen or mite allergens can be performed in patients with allergic rhinoconjunctivitis using allergen extracts that have been proven to be effective in at least one double-blind placebo-controlled (DBPC) study. At present, clinical trials are underway for the indication in asthma due to house dust mite allergy, some of the results of which have already been published, whilst others are still awaited (see the DGAKI table “Approved/potentially completed studies” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit (according to www.clinicaltrialsregister.eu)). When establishing the indication for AIT, factors that favour clinical efficacy should be taken into consideration. Differences between SCIT and SLIT are to be considered primarily in terms of contraindications. In individual cases, AIT may be justifiably indicated despite the presence of contraindications.
SCIT injections and the initiation of SLIT are performed by a physician experienced in this type of treatment and who is able to administer emergency treatment in the case of an allergic reaction. Patients must be fully informed about the procedure and risks of possible adverse events, and the details of this process must be documented (see “Treatment information sheet”; available as a handout via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). Treatment should be performed according to the manufacturer‘s product information leaflet. In cases where AIT is to be performed or continued by a different physician to the one who established the indication, close cooperation is required in order to ensure that treatment is implemented consistently and at low risk. In general, it is recommended that SCIT and SLIT should only be performed using preparations for which adequate proof of efficacy is available from clinical trials.
Treatment adherence among AIT patients is lower than assumed by physicians, irrespective of the form of administration. Clearly, adherence is of vital importance for treatment success. Improving AIT adherence is one of the most important future goals, in order to ensure efficacy of the therapy.
Severe, potentially life-threatening systemic reactions during SCIT are possible, but – providing all safety measures are adhered to – these events are very rare. Most adverse events are mild to moderate and can be treated well.
Dose-dependent adverse local reactions occur frequently in the mouth and throat in SLIT. Systemic reactions have been described in SLIT, but are seen far less often than with SCIT. In terms of anaphylaxis and other severe systemic reactions, SLIT has a better safety profile than SCIT.
The risk and effects of adverse systemic reactions in the setting of AIT can be effectively reduced by training of personnel, adhering to safety standards and prompt use of emergency measures, including early administration of i. m. epinephrine. Details on the acute management of anaphylactic reactions can be found in the current S2 guideline on anaphylaxis issued by the AWMF (S2-AWMF-LL Registry Number 061-025).
AIT is undergoing some innovative developments in many areas (e. g., allergen characterization, new administration routes, adjuvants, faster and safer dose escalation protocols), some of which are already being investigated in clinical trials.
Cite this as Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, Friedrichs F, Fuchs T, Hamelmann E, Hartwig-Bade D, Hering T, Huttegger I, Jung K, Klimek L, Kopp MV, Merk H, Rabe U, Saloga J, Schmid-Grendelmeier P, Schuster A, Schwerk N, Sitter H, Umpfenbach U, Wedi B, Wöhrl S, Worm M, Kleine-Tebbe J. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases – S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int 2014;23:282–319
doi:10.1007/s40629-014-0032-2
PMCID: PMC4479478  PMID: 26120539
allergen-specific immunotherapy; AIT; Hyposensitization; guideline; allergen; allergen extract; allergic disease; allergic rhinitis; allergic asthma
3.  Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children 
Background
Maternal diet during pregnancy may influence childhood allergy and asthma.
Objective
To examine the associations between maternal intake of common childhood food allergens during early pregnancy and childhood allergy and asthma.
Methods
We studied 1277 mother-child pairs from a United States pre-birth cohort unselected for any disease. Using food frequency questionnaires administered during the first and second trimesters, we assessed maternal intake of common childhood food allergens during pregnancy. In mid-childhood (mean age 7.9 years), we assessed food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum specific IgE levels. We examined the associations between maternal diet during pregnancy and childhood allergy and asthma. We also examined the cross-sectional associations between specific food allergies, asthma, and atopic conditions in mid-childhood.
Results
Food allergy was common (5.6%) in mid-childhood, as was sensitization to at least one food allergen (28.0%). Higher maternal peanut intake (each additional z-score) during the first trimester was associated with 47% reduced odds of peanut allergic reaction (OR 0.53, 95%CI 0.30–0.94). Higher milk intake during the first trimester was associated with reduced asthma (OR 0.83, 95%CI 0.69–0.99) and allergic rhinitis (OR 0.85, 95%CI 0.74–0.97). Higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis (OR 0.64, 95%CI 0.46–0.90). Peanut, wheat, and soy allergy were each cross-sectionally associated with increased childhood asthma, atopic dermatitis, and allergic rhinitis (ORs 3.6 to 8.1).
Conclusion
Higher maternal intake of peanut, milk, and wheat during early pregnancy was associated with reduced odds of mid-childhood allergy and asthma.
doi:10.1016/j.jaci.2013.11.040
PMCID: PMC4004710  PMID: 24522094
maternal diet; pregnancy; food allergy; sensitization; asthma; allergic rhinitis; peanut; milk; wheat; childhood
4.  Characteristics and severity of asthma in children with and without atopic conditions: a cross-sectional study 
BMC Pediatrics  2015;15:172.
Background
Childhood allergic diseases have a major impact on a child’s quality of life, as well as that of their parents. We studied the coexistence of reported allergies in children who use asthma medication. Additionally, we tested the hypothesis that asthma severity is greater among children with certain combinations of co-morbid allergic conditions.
Methods
For this cross-sectional study, 703 children (ages 4 to 12 years) from the PACMAN cohort study were selected. All of the children were regular users of asthma medication. The study population was divided into nine subgroups according to parental-reported allergies of the child (hay fever, eczema, food allergy or combinations of these). In order to assess whether these subgroups differed clinically, the groups were compared for child characteristics (age, gender, family history of asthma), asthma exacerbations in the past year (oral corticosteroids (OCS) use; asthma-related emergency department (ED) visits), asthma control, fractional exhaled nitric oxide level (FeNO), and antihistaminic usage.
Results
In our study, 79.0 % of the parents reported that their child suffered from at least one atopic condition (hay fever, food allergy and eczema), and one quarter of the parents (25.6 %) reported that their child suffered from all three atopic conditions. Having more than one atopic condition was associated with an increased risk of OCS use (OR = 3.3, 95 % CI = 1.6 – 6.6), ED visits (OR = 2.3, 95 % CI = 1.2 – 4.6) in the past year and inadequate short term asthma control (OR = 1.9, 95 % CI = 1.3 – 2.8).
Conclusions
Children who use asthma medication often also have other allergic conditions. Parental reported allergies were associated with a higher risk of more severe asthma (more asthma complaints and more asthma exacerbations).
doi:10.1186/s12887-015-0481-x
PMCID: PMC4636786  PMID: 26545978
Allergy; Asthma; Atopic condition; Eczema; Exacerbation; FeNO; Food allergy; Hay fever
5.  TREATMENT OF ASTHMA AND FOOD ALLERGY WITH HERBAL INTERVENTIONS FROM TRADITIONAL CHINESE MEDICINE 
Prevalence of asthma and allergy has increased over the past 2–3 decades in Westernized countries. Despite increased understanding of the pathogenesis of asthma and allergic diseases, control of severe asthma is still difficult. Asthma is also associated with high prevalence of anxiety in particular adolescents. There is no effective treatment for food allergy. Food allergy is often associated with severe and recalcitrant eczema. Novel approaches for treatment of asthma and food allergy and comorbid conditions are urgently needed. Traditional Chinese medicine (TCM), used in Asia for centuries, is beginning to play a role in Western health care. There is increasing scientific evidence supporting the use of TCM for asthma treatment.
This review article discusses promising TCM interventions for asthma, food allergy and comorbid conditions and explores their possible mechanisms of action. Since 2005, several controlled clinical studies of “anti-asthma” herbal remedies have been published. Among the herbal medicines, anti-asthma herbal medicine intervention (ASHMI) is the only anti-asthma TCM product that is a US FDA investigational new drug (IND) that has entered clinical trials. Research into ASHMI’s effects and mechanisms of actions in animal models is actively being pursued. Research on TCM herbal medicines for treating food allergy is rare. The herbal intervention, Food Allergy Herbal Formula-2 (FAHF-2) is the only US FDA botanical IND under investigation as a multiple food allergy therapy. Published articles and abstracts, as well as new data generated in preclinical and clinical studies of ASHMI and FAHF-2 are the bases for this review. The effect of TCM therapy on food allergy associated recalcitrant eczema, based on case review, is also included.
Laboratory and clinical studies demonstrate a beneficial effect of ASHMI treatment on asthma. The possible mechanisms underlying the efficacy are multiple. Preclinical studies demonstrated the efficacy and safety of FAHF-2 for treating food allergy in a murine model. A clinical study demonstrated that FAHF-2 is safe, well tolerated, and exhibited beneficial immunomodulatory effects. A clinical report showed that TCM treatment reduced eczema scores and improved quality of life. Herbal interventions, ASHMI and FAHF-2 may be further developed as botanical drugs for treating asthma and food allergy. TCM may also be of benefit for comorbid conditions such as anxiety and recalcitrant eczema. More controlled studies are warranted.
In conclusion, novel approaches for treatment of asthma and food allergy and comorbid conditions such as anxiety and eczema are urgently needed. This article discusses promising interventions for such conditions from traditional Chinese medicine (TCM) and explores their possible mechanisms of action.
doi:10.1002/msj.20294
PMCID: PMC4118473  PMID: 21913200
Herbal interventions; traditional Chinese medicine; ASHMI; FAHF-2; asthma; food allergy
6.  IgE mediated food allergy in Korean children: focused on plant food allergy 
Asia Pacific Allergy  2013;3(1):15-22.
Food allergy (FA) is a worldwide problem, with increasing prevalence in many countries, and it poses a clearly increasing health problem in Korea. In Korea, as a part of International Study of Asthma and Allergy in Childhood (ISAAC), a series of nation-wide population studies for prevalence of allergic disease in children were carried out, with the Korean version of ISAAC in 1995, 2000, and 2010. From the survey, the twelve-month prevalence of FA showed no significant differences from 1995 to 2000 in both age groups (6-12 years-old, 6.5% in 1995 and 5.7% in 2000; 12-15 year-olds, 7.4% in 1995 and 8.6% in 2000). The mean lifetime prevalence of FA which had ever been diagnosed by medical doctor was 4.7% in 6-12 year-olds and 5.1% in 12-15 year-olds respectively in 2000. In Korean children, the major causes of FA are almost same as in other countries, although the order prevalence may vary, a prime example of which being that peanut and tree nut allergies are not prevalent, as in western countries. Both pediatric emergency department (ED) visits and deaths relating to food induced anaphylaxis have also increased in western countries. From a study which based on data from the Korean Health Insurance Review and Assessment Service (KHIRA) from 2001 to 2007, the incidence of anaphylaxis under the age of 19 was 0.7-1 per 100,000 person-year, and foods (24.9%) were the most commonly identified cause of childhood anaphylaxis. In another epidemiologic study, involving 78889 patients aged 0-18 years who visited the EDs of 9 hospitals during June 2008 to Mar 2009, the incidence of food related anaphylaxis was 4.56 per 10,000 pediatric ED visits. From these studies, common causes of food related anaphylaxis were seafood, buckwheat, cow's milk, fruits, peanut and tree nuts. Although systematic epidemiologic studies have not reported on the matter, recently, plant foods related allergy has increased in Korean children. Among 804 children with moderate to severe atopic dermatitis, we reveals that the peanut sensitization rate in Korea reaches 18%, and that, when sensitized to peanut, patients showed a significant tendency to have co-sensitization with house dust mites, egg white, wheat, and soybean. The higher specific IgE to peanut was related to the likelihood of the patient developing severe systemic reactions. In another study, based on the data analysis of 69 patients under 4 years of age who had suspected peanut and tree nut allergy, 22 (31.9%) were sensitized to walnut (>0.35 kU/L, 0.45-27.4 kU/L) and 6 (8.7%) experienced anaphylaxis due to a small amount of walnut exposure. Furthermore, in this review, clinical and immunological studies on plant food allergies, such as buckwheat allergy, rice allergy, barley allergy, and kiwi fruit allergy, in Korean children are discussed.
doi:10.5415/apallergy.2013.3.1.15
PMCID: PMC3563016  PMID: 23403730
Food allergy; Korean children; Anaphylaxis; Plant food allergy
7.  Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies 
PLoS Medicine  2014;11(10):e1001748.
Using data from two population-based birth cohorts, Danielle Belgrave and colleagues examine the evidence for atopic march in developmental profiles for allergic disorders.
Please see later in the article for the Editors' Summary
Background
The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.
Methods and Findings
Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time.
Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.
Conclusions
The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼7% of those with symptoms) follow trajectory profiles resembling the atopic march.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Our immune system protects us from viruses, bacteria, and other pathogens by recognizing specific molecules on the invader's surface and initiating a sequence of events that culminates in the death of the pathogen. Sometimes, however, our immune system responds to harmless materials (allergens such as pollen) and triggers allergic, or atopic, symptoms. Common atopic symptoms include eczema (transient dry itchy patches on the skin), wheeze (high pitched whistling in the chest, a symptom of asthma), and rhinitis (sneezing or a runny nose in the absence of a cold or influenza). All these symptoms are very common during childhood, but recent epidemiological studies (examinations of the patterns and causes of diseases in a population) have revealed age-related changes in the proportions of children affected by each symptom. So, for example, eczema is more common in infants than in school-age children. These findings have led to the idea of “atopic march,” a natural progression of symptoms within individual children that starts with eczema, then progresses to wheeze and finally rhinitis.
Why Was This Study Done?
The concept of atopic march has led to the initiation of studies that aim to prevent the development of asthma in children who are thought to be at risk of asthma because they have eczema. Moreover, some guidelines recommend that clinicians tell parents that children with eczema may later develop asthma or rhinitis. However, because of the design of the epidemiological studies that support the concept of atopic march, children with eczema who later develop wheeze and rhinitis may actually belong to a distinct subgroup of children, rather than representing the typical progression of atopic diseases. It is important to know whether atopic march adequately describes the natural history of atopic diseases during childhood to avoid the imposition of unnecessary strategies on children with eczema to prevent asthma. Here, the researchers use machine learning techniques to model the developmental profiles of eczema, wheeze, and rhinitis during childhood in two large population-based birth cohorts by taking into account time-related (longitudinal) changes in symptoms within individuals. Machine learning is a data-driven approach that identifies structure within the data (for example, a typical progression of symptoms) using unsupervised learning of latent variables (variables that are not directly measured but are inferred from other observable characteristics).
What Did the Researchers Do and Find?
The researchers used data from two UK birth cohorts—the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Manchester Asthma and Allergy Study (MAAS)—for their study (9,801 children in total). Both studies enrolled children at birth and monitored their subsequent health at regular review clinics. At each review clinic, information about eczema, wheeze, and rhinitis was collected from the parents using validated questionnaires. The researchers then used these data and machine learning methods to identify groups of children with similar patterns of onset of eczema, wheeze, and rhinitis over the first 11 years of life. Using a type of statistical model called a latent disease profile model, the researchers found that the data were best described by eight latent classes—no disease (51.3% of the children), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%).
What Do These Findings Mean?
These findings show that, in two large UK birth cohorts, the developmental profiles of eczema, wheeze, and rhinitis were heterogeneous. Most notably, the progression of symptoms fitted the profile of atopic march in fewer than 7% of children with symptoms. The researchers acknowledge that their study has some limitations. For example, small differences in the wording of the questions used to gather information from parents about their children's symptoms in the two cohorts may have slightly affected the findings. However, based on their findings, the researchers propose that, because eczema, wheeze, and rhinitis are common, these symptoms often coexist in individuals, but as independent entities rather than as a linked progression of symptoms. Thus, using eczema as an indicator of subsequent asthma risk and assigning “preventative” measures to children with eczema is flawed. Importantly, clinicians need to understand the heterogeneity of patterns of atopic diseases in children and to communicate this variability to parents when advising them about the development and resolution of atopic symptoms in their children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001748.
The UK National Health Service Choices website provides information about eczema (including personal stories), asthma (including personal stories), and rhinitis
The US National Institute of Allergy and Infectious Diseases provides information about atopic diseases
The UK not-for-profit organization Allergy UK provides information about atopic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on eczema, wheezing, and rhinitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and asthma (in English and Spanish)
Information about ALSPAC and MAAS is available
Wikipedia has pages on machine learning and latent disease profile models (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001748
PMCID: PMC4204810  PMID: 25335105
8.  Impact of primary food allergies on the introduction of other foods amongst Canadian children and their siblings 
Background
Food-allergic children frequently avoid other highly allergenic foods. The NIAID 2010 guidelines state that individuals with an IgE-mediated food allergy should avoid their specific allergens and physicians should help patients to decide whether certain cross-reactive foods also should be avoided. Patients at risk for developing food allergy do not need to limit exposure to foods that may be cross-reactive with the major food allergens. The purpose of this study was to determine if parents of food-allergic children are given advice regarding introduction of allergenic foods; if these foods are avoided or delayed; if there is anxiety when introducing new foods; and if introducing other allergenic foods leads to any allergic reaction. The study also determined if there was a similar pattern seen amongst younger siblings.
Methods
An online survey was administered between December 2011 and March 2012 via Anaphylaxis Canada’s website, available to Canadian parents and caregivers who are registered members of the organization and who have a child with a food allergy.
Results
644 parents completed the online survey. 51% of families were given advice regarding the introduction of other allergenic foods. 72% were told to avoid certain foods, and 41% to delay certain foods. 58% of parents did avoid or delay other highly allergenic foods, mainly due to a fear of allergic reaction. 69% of children did not have an allergic reaction when these foods were subsequently introduced. 68% of parents felt moderate or high levels of anxiety when introducing other foods. A similar pattern was seen amongst the younger siblings.
Conclusions
Canadian parents and caregivers of children with food allergies receive varied advice from health care professionals regarding the introduction of new allergenic foods, and feel moderate to high levels of anxiety. A similar pattern may be seen amongst younger siblings. While the majority of children in our study did not have an allergic reaction to a new food, a significant proportion of children did react. A more consistent approach to the advice given by health care professionals may decrease parental anxiety. Further research to support the 2010 NIAID guidelines may be necessary to clarify recommendations.
doi:10.1186/1710-1492-10-26
PMCID: PMC4063690  PMID: 24949023
Food allergy; Siblings; Food introduction; Anxiety
9.  Food Allergy and Increased Asthma Morbidity in a School-Based Inner-City Asthma Study 
Background
Children with asthma have increased prevalence of food allergies. The relationship between food allergy and asthma morbidity is unclear.
Objective
We aimed to investigate the presence of food allergy as an independent risk factor for increased asthma morbidity using the School Inner-City Asthma (SICAS), a prospective study evaluating risk factors and asthma morbidity among urban children.
Methods
We prospectively surveyed 300 children from inner-city schools with physician-diagnosed asthma, followed by clinical evaluation. Food allergies were reported including symptoms experienced within one hour of food ingestion. Asthma morbidity, pulmonary function, and resource utilization were compared between children with food allergies and without.
Results
Seventy-three (24%) of 300 asthmatic children surveyed had physician- diagnosed food allergy, and 36 (12%) had multiple food allergies. Those with any food allergy independently had increased risk of hospitalization (OR: 2.35, 95% CI: 1.30–4.24, p=0.005), and use of controller medication (OR: 1.99, 95% CI: 1.06–3.74, p=0.03). Those with multiple food allergies also had an independently higher risk of hospitalization in the past year (OR: 4.10 95% CI: 1.47–11.45, p=0.007), asthma-related hospitalization (OR: 3.52, 95% CI: 1.12–11.03, p=0.03), controller medication use (OR: 2.38 95% CI: 1.00–5.66, p=0.05), and more provider visits (median 4.5 versus 3.0, p=0.008). Furthermore, lung function was significantly lower (% predicted FEV1 and FEV1/FVC ratios) in both food allergy category groups.
Conclusions
Food allergy is highly prevalent in inner-city school-aged children with asthma. Children with food allergies have increased asthma morbidity and health resource utilization with decreased lung function, and this association is stronger in those with multiple food allergies.
doi:10.1016/j.jaip.2013.06.007
PMCID: PMC3777668  PMID: 24058900
asthma; food allergy; hospitalization; morbidity; prevalence; resource utilization; risk
10.  Variably severe systemic allergic reactions after consuming foods with unlabelled lupin flour: a case series 
Introduction
Lupin allergy remains a significant cause of food-induced allergic reactivity and anaphylaxis. Previous work suggests a strong association with legume allergy and peanut allergy in particular. Both doctors and the public have little awareness of lupin as an allergen.
Case presentation
Case 1 was a 41-year-old Caucasian woman without previous atopy who developed facial swelling, widespread urticaria with asthma and hypotension within minutes of eating a quiche. Her lupin allergy was confirmed by both blood and skin tests. Her lupin sensitivity was so severe that even the miniscule amount of lupin allergen in the skin testing reagent produced a mild reaction.
Case 2 was a 42-year-old mildly atopic Caucasian woman with three episodes of worsening urticaria and asthma symptoms over 6 years occurring after the consumption of foods containing lupin flour. Blood and skin tests were positive for lupin allergy.
Case 3 was a 38-year-old Caucasian woman with known oral allergy syndrome who had two reactions associated with urticaria and vomiting after consuming foods containing lupin flour. Skin testing confirmed significant responses to a lupin flour extract and to one of the foods inducing her reaction.
Case 4 was a 54-year-old mildly atopic Caucasian woman with a 7 year history of three to four episodes each year of unpredictable oral tingling followed by urticaria after consuming a variety of foods. The most recent episode had been associated with vomiting. She had developed oral tingling with lentil and chickpeas over the previous year. Skin and blood tests confirmed lupin allergy with associated sensitivity to several legumes.
Conclusions
Lupin allergy can occur for the first time in adults without previous atopy or legume sensitivity. Although asymptomatic sensitisation is frequent, clinical reactivity can vary in severity from severe anaphylaxis to urticaria and vomiting. Lupin allergy may be confirmed by skin and specific immunoglobulin E estimation. Even skin testing can cause symptoms in some highly sensitive individuals. The diagnosis of lupin allergy in adults may be difficult because it is frequently included as an undeclared ingredient. Better food labelling and medical awareness of lupin as a cause of serious allergic reactions is suggested.
doi:10.1186/1752-1947-8-55
PMCID: PMC3943371  PMID: 24529316
Anaphylaxis; Food labelling; Gluten-free spaghetti; Lupin allergy; Oral allergy
11.  214 Cross Reactivity Between Cypress Pollen and Plant Food in Queretaro, Mexico 
The World Allergy Organization Journal  2012;5(Suppl 2):S87-S88.
Background
Food allergy prevalence is growing continuously. Reasons are unknown. It is suggested that environmental factors have a greater impact than genetic. The hay may be responsible for developing food allergy to plants. The geographical and climatological condition of Querétaro city, and having a large industrial corridor are risk factors for development allergic problems. In Mexico there are no prevalence studies on food allergy and therefore the most common food allergens. The objectives of the study are to identify common allergen sensitization and to determine if there is cross-reactivity between cypress pollen and plants most commonly consumed in Queretaro.
Methods
We performed a correlation study in patients allergic to cypress pollen to determine if there is cross reactivity between it and plant food by spick prick test and specific IgE titers by inmunocap technique.
Results
Studied 45 patients, 23 (51,1%) males and 22 (48,8%) women, 43 patients had allergic rhinitis (95,5%), 23 had asthma (51,1) and 12 had atopic dermatitis (26,6%). As background, 16 patients (35,5%) had no first-degree relatives with atopy, in 17 (37,7%), the father had a history of allergy, the mother was allergic in 31,1%, and 24,4% (11) had at least one sibling with allergy. 51,1% (23) were born by eutosia, and 22 (48,8%) via cesarean section. 24 (53,3%) received mixed feeding, 17 (37,7%) were breastfeed and only 4 (8,8%) received only formula. The average time of breastfeeding was 5,3 months. Person correlation coefficients were found in descending order relationship with oregano (0.69), corn (0.65), wheat (0.63), oats (0.63), bean (0.597), melon (0.569), tomatoe (0.538), lentil (0.537), peanut (0.515), chickpea (0.480), soybean (0.479), carrot (0.474), avocado (0.457), apple (0.438), pepper (0.418), celery (0.187).
Conclusions
Although the literature reported association between cypress with tomato only, we found relationship with apple, wheat, celery, peanuts, melon, lentil, tomatoes, beans, avocados, soybeans, chickpeas, corn and pepper.
doi:10.1097/01.WOX.0000411971.25029.9d
PMCID: PMC3512868
12.  Season of Birth is Associated with Food Allergy in Children 
Background
The prevalence of food allergy is rising and etiologic factors remain uncertain. Evidence implicates a role of vitamin D in the development of atopic diseases. Based on seasonal patterns of UVB exposure (and consequent vitamin D status), we hypothesized that food allergy patients are more often born in fall or winter.
Objective
Investigate whether season of birth is associated with food allergy.
Methods
We performed a multicenter chart review of all patients presenting to three Boston emergency departments (EDs) for food-related acute allergic reactions between 1/1/01 and 12/31/06. Months of birth among food allergy patients were compared to those of patients visiting the ED for reasons other than food allergy.
Results
We studied 1,002 food allergy patients. Among younger children with food allergy (age <5 years) – but not among older children or adults – 41% were born in spring/summer compared to 59% in fall/winter (P=0.002). This approximately 40/60 ratio differed from birth season of children treated in the ED for non-food allergy reasons (P=0.002). Children <5 years old born in fall/winter had a 53% higher odds of food allergy compared to controls. This finding was independent of the suspected triggering food and allergic comorbidities.
Conclusions
Food allergy is more common in Boston children who were born in the fall and winter seasons. We propose that these findings are mediated by seasonal differences in UVB exposure. These results add support to the hypothesis that seasonal fluctuations in sunlight and perhaps vitamin D may be involved in the pathogenesis of food allergy.
doi:10.1016/j.anai.2010.01.019
PMCID: PMC2941399  PMID: 20408340
Food allergy; season of birth; epidemiology; UVB; vitamin D
13.  292 The Relationship Between Maternal Atopy and Childhood Asthma 
Background
The diagnostic difficulty of childhood asthma leads to widespread under-diagnosis, which negatively affects the quality of life of asthmatic children. The presence of atopy in children is often used as a clinical tool to assist in making the diagnosis. However, local studies have demonstrated that atopy occurs in fewer asthmatic children than previously thought. This brings into question the association between allergy and asthma. The purpose of this study was to determine if a family history of allergy is predictive of atopic asthma in children, by comparing allergy, history of asthma and allergic symptoms, in mothers of atopic versus non-atopic asthmatic children.
Methods
A random sample of children and their mothers attending the Children's Chest and Allergy Clinic at Steve Biko Academic Hospital were enrolled. Skin-prick testing or radioallergosorbent test results, of the children were obtained from the child's hospital records. Mothers completed a detailed questionnaire which included demographic details, a history of symptoms suggestive of ‘atopy’ and allergic diseases and a history of asthma. Skin prick testing was performed on the mothers.
Results
100 children and their parents were enrolled. 64 mothers to atopic children were used as the study group and 36 mothers to non-atopic children were used as the control group. Of the 48 mothers with a positive skin prick test, 30 (64%) had atopic children (P = 0.836). Of the 16 mothers with asthma, 14 (88%) had atopic children (P = 0.045). Of the 70 mothers with a history of symptoms suggestive of an allergic disease, 45 (64%) had children with atopic asthma (P = 1.0). Of the 77 mothers who were considered to be allergic, 50 (65%) had children with atopic asthma (P = 0.806).
Conclusions
Both maternal skin prick positivity and a history of symptoms suggestive of allergic disease, are poor predictors of atopic asthma in children. This is true even in the mothers were considered to be allergic. However maternal asthma is a specific predictor of childhood atopic asthma with a good positive predictive and a high odds ratio. Further studies need to be conducted to compare the epidemiology of allergic asthma in different population groups.
doi:10.1097/01.WOX.0000412049.82446.27
PMCID: PMC3513181
14.  Prevalence and Clinical Impact of IgE-Mediated Food Allergy in School Children With Asthma: A Double-Blind Placebo-Controlled Food Challenge Study 
Purpose
Recent studies indirectly suggest a possible link between food allergy (FA) and asthma. Most of them have evaluated the occurrence of FA in asthmatic children, especially in the first year of life, using questionnaire-based studies or specific IgE (sIgE) assay. The aim of this study was to evaluate the prevalence and clinical impact of IgE-mediated FA in school children with asthma using a double-blind placebo-controlled food challenge (DBPCFC).
Methods
The study group consisted of school children with atopic asthma who were admitted to the Department of Pediatric Allergology, Gastroenterology and Nutrition, Medical University of Lodz, for the evaluation of food hypersensitivity. The diagnosis of FA was established using questionnaires, sIgE analysis, and the DBPCFC. Asthma severity and asthma control state were also assessed.
Results
A relationship between consumed food and complaints was reported in 180 children (49.7%). Seventy children (19.3%) were sensitized to food allergens. IgE-mediated FA was confirmed in 24 children (6.6%), while 11 children (3%) demonstrated respiratory symptoms. Food-induced asthma exacerbations were observed in 9 patients (2.5%). Statistically significant differences in the prevalence of atopic dermatitis (P<0.002), urticaria (P<0.03), digestive symptoms (P<0.03), rhinitis (P<0.02), sIgE level (P<0.001), positive family history of atopy (P<0.001) and FA in history (P<0.001) were found between asthmatic children with FA and those without. Children with food-induced asthma exacerbations demonstrated significantly greater severity, poorer controls, and worse morbidity compared to those without.
Conclusions
Although food-induced respiratory reactions in children with asthma were rare, they were classified as severe and associated with worse morbidity, greater severity, and poorer control. As the most commonly observed symptoms were coughing and rhinitis, which can be easily misdiagnosed, a proper diagnosis is essential for improving the management of both clinical conditions.
doi:10.4168/aair.2015.7.6.547
PMCID: PMC4605927  PMID: 26333701
Food allergy; asthma; children; double-blind placebo-controlled food challenge
15.  Analysis of Food Allergy in Atopic Dermatitis Patients – Association with Concomitant Allergic Diseases 
Indian Journal of Dermatology  2014;59(5):445-450.
Background:
A few reports demonstrate the comorbidity of food allergy and allergic march in adult patients.
Aims and Objectives:
To evaluate, if there is some relation in atopic dermatitis patients at the age 14 years and older who suffer from food allergy to common food allergens to other allergic diseases and parameters as bronchial asthma, allergic rhinitis, duration of atopic dermatitis, family history and onset of atopic dermatitis.
Materials and Methods:
Complete dermatological and allergological examination was performed; these parameters were examined: food allergy (to wheat flour, cow milk, egg, peanuts and soy), the occurrence of bronchial asthma, allergic rhinitis, duration of atopic dermatitis, family history and onset of atopic dermatitis. The statistical evaluation of the relations among individual parameters monitored was performed.
Results:
Food allergy was altogether confirmed in 65 patients (29%) and these patients suffer significantly more often from bronchial asthma and allergic rhinitis. Persistent atopic dermatitis lesions and positive data in family history about atopy are recorded significantly more often in patients with confirmed food allergy to examined foods as well. On the other hand, the onset of atopic dermatitis under 5 year of age is not recorded significantly more often in patients suffering from allergy to examined foods.
Conclusion:
Atopic dermatitis patients suffering from food allergy suffer significantly more often from allergic rhinitis, bronchial asthma, persistent eczematous lesions and have positive data about atopy in their family history.
doi:10.4103/0019-5154.139867
PMCID: PMC4171910  PMID: 25284847
Bronchial asthma; atopic dermatitis; family history; food allergy; onset of atopic dermatitis; persistent eczematous lesions; allergic rhinitis
16.  Health-related quality of life in food hypersensitive schoolchildren and their families: parents' perceptions 
Background
About 20% of schoolchildren and adolescents in Sweden suffer from perceived food hypersensitivity (e.g. allergy or intolerance). Our knowledge of how child food hypersensitivity affects parents HRQL and what aspects of the hypersensitivity condition relate to HRQL deterioration in the family is limited. Thus the aim of this study was to investigate the parent-reported HRQL in families with a schoolchild considered to be food hypersensitive. The allergy-associated parameters we operated with were number of offending food items, adverse food reactions, additional hypersensitivity, allergic diseases and additional family members with food hypersensitivity. These parameters, along with age and gender were assessed in relation to child, parent and family HRQL.
Methods
In May 2004, a postal questionnaire was distributed to parents of 220 schoolchildren with parent-reported food hypersensitivity (response rate 74%). Two questionnaires were used: CHQ-PF28 and a study-specific questionnaire including questions on allergy-associated parameters. In order to find factors that predict impact on HRQL, stepwise multiple linear regression analyses were carried out.
Results
An important predictor of low HRQL was allergic disease (i.e. asthma, eczema, rhino conjunctivitis) in addition to food hypersensitivity. The higher the number of allergic diseases, the lower the physical HRQL for the child, the lower the parental HRQL and the more disruption in family activities. Male gender predicted lower physical HRQL than female gender. If the child had sibling(s) with food hypersensitivity this predicted lower psychosocial HRQL for the child and lower parental HRQL. Food-induced gastro-intestinal symptoms predicted lower parental HRQL while food-induced breathing difficulties predicted higher psychosocial HRQL for the child and enhanced HRQL with regards to the family's ability to get along.
Conclusion
The variance in the child's physical HRQL was to a considerable extent explained by the presence of allergic disease. However, food hypersensitivity by itself was associated with deterioration of child's psychosocial HRQL, regardless of additional allergic disease. The results suggest that it is rather the risk of food reactions and measures to avoid them that are associated with lower HRQL than the clinical reactivity induced by food intake. Therefore, food hypersensitivity must be considered to have a strong psychosocial impact.
doi:10.1186/1477-7525-4-48
PMCID: PMC1564003  PMID: 16901348
17.  Referrals to a regional allergy clinic - an eleven year audit 
BMC Public Health  2010;10:790.
Background
Allergy is a serious and apparently increasing public health problem yet relatively little is known about the types of allergy seen in routine tertiary practice, including their spatial distribution, co-occurrence or referral patterns. This study reviewed referrals over an eleven year period to a regional allergy clinic that had a well defined geographical boundary. For those patients confirmed as having an allergy we explored: (i) differences over time and by demographics, (ii) types of allergy, (iii) co-occurrence, and (iv) spatial distributions.
Methods
Data were extracted from consultant letters to GPs, from September 1998 to September 2009, for patients confirmed as having an allergy. Other data included referral statistics and population data by postcode. Simple descriptive analysis was used to describe types of allergy. We calculated 11 year standardised morbidity ratios for postcode districts and checked for spatial clustering. We present maps showing 11 year rates by postcode, and 'difference' maps which try to separate referral effect from possible environmental effect.
Results
Of 5778 referrals, 961 patients were diagnosed with an allergy. These were referred by a total of 672 different GPs. There were marked differences in referral patterns between GP practices and also individual GPs. The mean age of patients was 35 and there were considerably more females (65%) than males. Airborne allergies were the most frequent (623), and there were very high rates of co-occurrence of pollen, house dust mite, and animal hair allergies. Less than half (410) patients had a food allergy, with nuts, fruit, and seafood being the most common allergens. Fifteen percent (142) had both a food and a non-food allergy. Certain food allergies were more likely to co-occur, for example, patients allergic to dairy products were more likely to be allergic to egg.
There were age differences by types of allergy; people referred with food allergies were on average 5 years younger than those with other allergies, and those allergic to nuts were much younger (26 Vs 38) than those with other food allergies.
There was clear evidence for spatial clustering with marked clustering around the referral hospital. However, the geographical distribution varied between allergies; airborne (particularly pollen allergies) clustered in North Dartmoor and Exmoor, food allergies (particularly nut allergies) in the South Hams, and on small numbers, some indication of seafood allergy in the far south west of Cornwall and in the Padstow area.
Conclusions
This study shows marked geographical differences in allergy referrals which are likely to reflect a combination of environmental factors and GP referral patterns. The data suggest that GPs may benefit from education and ongoing decision support and be supported by public education on the nature of allergy. It suggests further research into what happens to patients with allergy where there has been low use of tertiary services and further research into cross-reactivity and co-occurrence, and spatial distribution of allergy.
doi:10.1186/1471-2458-10-790
PMCID: PMC3022859  PMID: 21190546
18.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
19.  Severe asthma and the omalizumab option 
Atopic diseases and asthma are increasing at a remarkable rate on a global scale. It is now well recognized that asthma is a chronic inflammatory disease of the airways. The inflammatory process in many patients is driven by an immunoglobulin E (IgE)-dependent process. Mast cell activation and release of mediators, in response to allergen and IgE, results in a cascade response, culminating in B lymphocyte, T lymphocyte, eosinophil, fibroblast, smooth muscle cell and endothelial activation. This complex cellular interaction, release of cytokines, chemokines and growth factors and inflammatory remodeling of the airways leads to chronic asthma. A subset of patients develops severe airway disease which can be extremely morbid and even fatal. While many treatments are available for asthma, it is still a chronic and incurable disease, characterized by exacerbation, hospitalizations and associated adverse effects of medications. Omalizumab is a new option for chronic asthma that acts by binding to and inhibiting the effects of IgE, thereby interfering with one aspect of the asthma cascade reviewed earlier. This is a humanized monoclonal antibody against IgE that has been shown to have many beneficial effects in asthma. Use of omalizumab may be influenced by the cost of the medication and some reported adverse effects including the rare possibility of anaphylaxis. When used in selected cases and carefully, omalizumab provides a very important tool in disease management. It has been shown to have additional effects in urticaria, angioedema, latex allergy and food allergy, but the data is limited and the indications far from clear. In addition to decreasing exacerbations, it has a steroid sparing role and hence may decrease adverse effects in some patients on high-dose glucocorticoids. Studies have shown improvement in quality of life measures in asthma following the administration of omalizumab, but the effects on pulmonary function are surprisingly small, suggesting a disconnect between pulmonary function, exacerbations and quality of life. Anaphylaxis may occur rarely with this agent and appropriate precautions have been recommended by the Food and Drug Administration (FDA). As currently practiced and as suggested by the new asthma guidelines, this biological agent is indicated in moderate or severe persistent allergic asthma (steps 5 and 6).
doi:10.1186/1476-7961-6-4
PMCID: PMC2478654  PMID: 18489791
20.  Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations. 
BMJ : British Medical Journal  1996;312(7038):1074-1078.
OBJECTIVE--To investigate clinical features of acute allergic reactions to peanuts and other nuts. DESIGN--Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre. SUBJECTS--62 patients aged 11 months to 53 years seen between October 1993 and September 1994. MAIN OUTCOME MEASURES--Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies. RESULTS--Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods. CONCLUSIONS--Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.
PMCID: PMC2350892  PMID: 8616415
21.  Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis 
Objective To investigate whether filaggrin gene defects, present in up to one in 10 western Europeans and North Americans, increase the risk of developing allergic sensitisation and allergic disorders.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, ISI Science Citation Index, BIOSIS, ISI Web of Knowledge, UK National Research Register, clinical trials.gov, the Index to Theses and Digital dissertations, and grey literature using OpenSIGLE.
Study selection Genetic epidemiological studies (family, case-control) of the association between filaggrin gene defects and allergic sensitisation or allergic disorders.
Data extraction Atopic eczema or dermatitis, food allergy, asthma, allergic rhinitis, and anaphylaxis, along with relevant immunological variables relating to the risk of allergic sensitisation as assessed by either positive skin prick testing or increased levels of allergen specific IgE.
Data synthesis 24 studies were included. The odds of developing allergic sensitisation was 1.91 (95% confidence interval 1.44 to 2.54) in the family studies and 1.57 (1.20 to 2.07) in the case-control studies. The odds of developing atopic eczema was 1.99 (1.72 to 2.31) in the family studies and 4.78 (3.31 to 6.92) in the case-control studies. Three studies investigated the association between filaggrin gene mutations and allergic rhinitis in people without atopic eczema: overall odds ratio 1.78 (1.16 to 2.73). The four studies that investigated the association between filaggrin gene mutations and allergic rhinitis in people with atopic eczema reported a significant association: pooled odds ratio from case-control studies 2.84 (2.08 to 3.88). An overall odds ratio for the association between filaggrin gene mutations and asthma in people with atopic eczema was 2.79 (1.77 to 4.41) in case-control studies and 2.30 (1.66 to 3.18) in family studies. None of the studies that investigated filaggrin gene mutations and asthma in people without atopic eczema reported a significant association; overall odds ratio was 1.30 (0.7 to 2.30) in the case-control studies. The funnel plots suggested that publication bias was unlikely to be an explanation for these findings. No studies investigated the association between filaggrin gene mutations and food allergy or anaphylaxis.
Conclusions Filaggrin gene defects increase the risk of developing allergic sensitisation, atopic eczema, and allergic rhinitis. Evidence of the relation between filaggrin gene mutations and atopic eczema was strong, with people manifesting increased severity and persistence of disease. Filaggrin gene mutations also increased the risk of asthma in people with atopic eczema. Restoring skin barrier function in filaggrin deficient people in early life may help prevent the development of sensitisation and halt the development and progression of allergic disease.
doi:10.1136/bmj.b2433
PMCID: PMC2714678  PMID: 19589816
22.  How dangerous is food allergy in childhood? The incidence of severe and fatal allergic reactions across the UK and Ireland 
Archives of Disease in Childhood  2002;86(4):236-239.
Aims: To discover the incidence of fatal and severe allergic reactions to food in a large population of children.
Methods: A retrospective search for fatalities in children 0–15 years from 1990 to February 1998, primarily of death certification at offices of national statistics. A prospective survey of fatal and severe reactions from March 1998 to February 2000, primarily through the British Paediatric Surveillance Unit. Main outcome measures were deaths and severe reactions. A case was deemed severe if one or more of the following criteria was met: cardiorespiratory arrest; need for inotropic support; fluid bolus >20 ml/kg; more than one dose of epinephrine; more than one dose of nebulised bronchodilator. A case was deemed near fatal if intubation was necessary.
Results: The UK under 16 population is 13 million. Over the past 10 years, eight children died (incidence of 0.006 deaths per 100 000 children 0–15 years per year). Milk caused four of the deaths. No child under 13 died from peanut allergy. Two children died despite receiving early epinephrine before admission to hospital; one child with a mild food allergic reaction died from epinephrine overdose. Over the past two years, there were six near fatal reactions (none caused by peanut) and 49 severe ones (10 caused by peanut), yielding incidences of 0.02 and 0.19 per 100 000 children 0–15 years per year respectively. Coexisting asthma is more strongly associated with a severe reaction than the severity of previous reactions.
Conclusions: If 5% of the child population have food allergy, the risk that a food allergic child will die from a food allergic reaction is about 1 in 800 000 per year. The food allergic child with asthma may be at higher risk. Prescribing an epinephrine autoinjector requires a careful balance of advantages and disadvantages.
doi:10.1136/adc.86.4.236
PMCID: PMC1719140  PMID: 11919093
23.  Health-related quality of life, assessed with a disease-specific questionnaire, in Swedish adults suffering from well-diagnosed food allergy to staple foods 
Background
Our aim was to investigate the factors that affect health related quality of life (HRQL) in adult Swedish food allergic patients objectively diagnosed with allergy to at least one of the staple foods cow’s milk, hen’s egg or wheat. The number of foods involved, the type and severity of symptoms, as well as concomitant allergic disorders were assessed.
Methods
The disease-specific food allergy quality of life questionnaire (FAQLQ-AF), developed within EuroPrevall, was utilized. The questionnaire had four domains: Allergen Avoidance and Dietary Restrictions (AADR), Emotional Impact (EI), Risk of Accidental Exposure (RAE) and Food Allergy related Health (FAH). Comparisons were made with the outcome of the generic questionnaire EuroQol Health Questionnaire, 5 Dimensions (EQ-5D). The patients were recruited at an outpatient allergy clinic, based on a convincing history of food allergy supplemented by analysis of specific IgE to the foods in question. Seventy-nine patients participated (28 males, 51 females, mean-age 41 years).
Results
The domain with the most negative impact on HRQL was AADR, assessing the patients’ experience of dietary restrictions. The domain with the least negative impact on HRQL was FAH, relating to health concerns due to the food allergy. One third of the patients had four concomitant allergic disorders, which had a negative impact on HRQL. Furthermore, asthma in combination with food allergy had a strong impact. Anaphylaxis, and particularly prescription of an epinephrine auto-injector, was associated with low HRQL. These effects were not seen using EQ-5D. Analyses of the symptoms revealed that oral allergy syndrome and cardiovascular symptoms had the greatest impact on HRQL. In contrast, no significant effect on HRQL was seen by the number of food allergies.
Conclusions
The FAQLQ-AF is a valid instrument, and more accurate among patients with allergy to staple foods in comparison to the commonly used generic EQ-5D. It adds important information on HRQL in food allergic adults. We found that the restrictions imposed on the patients due to the diet had the largest negative impact on HRQL. Both severity of the food allergy and the presence of concomitant allergic disorders had a profound impact on HRQL.
doi:10.1186/2045-7022-3-21
PMCID: PMC3702411  PMID: 23816063
Food allergy; Adults; Health-related quality of life; Instrument; Questionnaire
24.  Asthma and Food Allergy in Children: Is There a Connection or Interaction? 
This review explores the relationship between food allergy and asthma. They can share the same risk factors, such as parental allergy, atopic eczema, and allergen sensitization, and they often coincide in the same child. Coexistence may negatively influence the severity of both conditions. However, it remains to be determined whether food allergy may directly affect asthma control. An early food sensitization in the first year of life can predict the onset of asthma. Furthermore, asthmatic symptoms could rarely be caused by ingestion or inhalation of the offending food. Asthma caused by food allergy is severe and may be associated with anaphylactic symptoms. Therefore, an accurate identification of the offending foods is necessary in order to avoid exposure. Patients should be instructed to treat asthmatic symptoms quickly and to use self-injectable epinephrine.
doi:10.3389/fped.2016.00034
PMCID: PMC4821099  PMID: 27092299
anaphylaxis; asthma; children; food allergy; IgE; skin prick test; wheezing
25.  Quality of life in patients with food allergy 
Food allergy has increased in developed countries and can have a dramatic effect on quality of life, so as to provoke fatal reactions. We aimed to outline the socioeconomic impact that food allergy exerts in this kind of patients by performing a complete review of the literature and also describing the factors that may influence, to a greater extent, the quality of life of patients with food allergy and analyzing the different questionnaires available. Hitherto, strict avoidance of the culprit food(s) and use of emergency medications are the pillars to manage this condition. Promising approaches such as specific oral or epicutaneous immunotherapy and the use of monoclonal antibodies are progressively being investigated worldwide. However, even that an increasing number of centers fulfill those approaches, they are not fully implemented enough in clinical practice. The mean annual cost of health care has been estimated in international dollars (I$) 2016 for food-allergic adults and I$1089 for controls, a difference of I$927 (95 % confidence interval I$324–I$1530). A similar result was found for adults in each country, and for children, and interestingly, it was not sensitive to baseline demographic differences. Cost was significantly related to severity of illness in cases in nine countries. The constant threat of exposure, need for vigilance and expectation of outcome can have a tremendous impact on quality of life. Several studies have analyzed the impact of food allergy on health-related quality of life (HRQL) in adults and children in different countries. There have been described different factors that could modify HRQL in food allergic patients, the most important of them are perceived disease severity, age of the patient, peanut or soy allergy, country of origin and having allergy to two or more foods. Over the last few years, several different specific Quality of Life questionnaires for food allergic patients have been developed and translated to different languages and cultures. It is important to perform lingual and cultural translations of existent questionnaires in order to ensure its suitability in a specific region or country with its own socioeconomic reality and culture. Tools aimed at assessing the impact of food allergy on HRQL should be always part of the diagnostic work up, in order to provide a complete basal assessment, to highlight target of intervention as well as to evaluate the effectiveness of interventions designed to cure food allergy. HRQL may be the only meaningful outcome measure available for food allergy measuring this continuous burden.
doi:10.1186/s12948-016-0041-4
PMCID: PMC4757995  PMID: 26893591
Quality of life; Food allergy; Questionnaire; Specific questionnaire; Health-related quality of life (HRQL); Anaphylaxis

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