Since barrier protection measures to avoid contact with allergens are being increasingly developed, we assessed the clinical efficacy and tolerability of a topical nasal microemulsion made of glycerol esters in patients with allergic rhinitis.
Randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial in which adult patients with allergic rhinitis or rhinoconjunctivitis due to sensitization to birch, grass or olive tree pollens received treatment with topical microemulsion or placebo during the pollen seasons. Efficacy variables included scores in the mini-RQLQ questionnaire, number and severity of nasal, ocular and lung signs and symptoms, need for symptomatic medications and patients’ satisfaction with treatment. Adverse events were also recorded.
Demographic characteristics were homogeneous between groups and mini-RQLQ scores did not differ significantly at baseline (visit 1). From symptoms recorded in the diary cards, the ME group showed statistically significant better scores for nasal congestion (0.72 vs. 1.01; p = 0.017) and mean total nasal symptoms (0.7 vs. 0.9; p = 0.045). At visit 2 (pollen season), lower values were observed in the mini-RQLQ in the ME group, although there were no statistically significant differences between groups in both full analysis set (FAS) and patients completing treatment (PPS) populations. The results obtained in the nasal symptoms domain of the mini-RQLQ at visit 2 showed the highest difference (−0.43; 95% CI: -0.88 to 0.02) for the ME group in the FAS population. The topical microemulsion was safe and well tolerated and no major discomforts were observed. Satisfaction rating with the treatment was similar between the groups.
The topical application of the microemulsion is a feasible and safe therapy in the prevention of allergic symptoms, particularly nasal congestion.
ClinicalTrials.gov Identifier: NCT01478425
Allergic rhinitis; Rhinoconjunctivitis; Allergen avoidance; Barrier measures; Corticosteroids use; Nasal symptoms; Natural pollen exposure; Quality of life; Efficacy; Safety
Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation.
The Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Patient ages at first symptoms and at diagnosis were recorded at enrolment, and the delay between first symptoms and diagnosis was calculated.
The median [range] diagnostic delay in HAE type I and II patients across eight countries was 8.5 years [0–62.0]. The median delay in diagnosis was longer for HAE type II versus type I (21 versus 8 years, respectively), although this did not quite reach statistical significance.
Although it can be difficult to differentiate HAE symptoms from those of more common angioedema sub-types (e.g. idiopathic or acquired angioedema), our results show that HAE type I and II patients have an unacceptable delay in diagnosis, even those with a family history of the disease. Raising physician awareness of this disabling and potentially fatal disease may lead to a more accurate diagnosis and timely treatment.
Bradykinin; C1-inhibitor; Diagnosis; Hereditary angioedema; Icatibant
A T helper cell (TH) 17-biased response has been observed in patients with allergic asthma, particularly in those with neutrophil accumulation in the lung. Therefore, we sought to test the hypothesis that neutrophils might be an important source of interleukin (IL)-17 in allergic asthma.
Whole peripheral blood cells from non-asthmatic control subjects (n = 17) and patients with mild asthma (n = 7), moderate but persistent asthma (n = 4), or acute asthma (n = 6) were analyzed for IL-17A expression in CD177+ neutrophils. IL-17A expression was also analyzed in CD3+CD4+ and CD3+CD8+ lymphocyte populations. Asthmatic patients were classified as allergic to fungi, indoor allergens, or other allergens (e.g., pollen) based on a positive intradermal allergy test reaction.
The percentage of CD177+ neutrophils in whole blood of asthmatic patients was higher than in healthy controls and highest in the moderate asthma group. Furthermore, the percentage of CD177+IL-17+ neutrophils was elevated in patients with mild asthma, whereas the CD4+ IL-17+ lymphocyte population was higher in asthmatic patients and highest in those with moderate but persistent asthma. We also found that the four patients that were allergic to fungi had the highest percentage of CD177+IL17+ neutrophils and CD8+IL17+ lymphocytes.
IL17+CD177+ Neutrophils increase in allergic asthma patients especially when allergic to fungi. This cell population, through release of IL-17, might be contributing during the initial phase asthmatic disease and/or during disease progression but its role has not yet been established.
Neutrophils; IL-17; Allergic asthma; Blood
Allergen-specific immunotherapy has been demonstrated to have potential for the treatment of allergic diseases. Transgenic animals are currently the best available bioreactors to produce recombinant proteins, which can be secreted in milk. It has not been clearly demonstrated whether milk from transgenic animals expressing recombinant allergens has immunomodulatory effects on allergic asthma.
We aimed to determine whether the oral administration of milk containing a mite allergen can down-regulate allergen-specific airway inflammation. Transgenic CD-1 mice that express a recombinant group 2 allergen from Dermatophagoides pteronyssinus (Dp2) in their milk were generated using an embryonic gene-microinjection technique. Mouse pups were fed transgenic Dp2-containing milk or wild-type milk. Subsequently, these mice were sensitized and challenged with Dp2 to induce allergic airway inflammation.
Upon sensitization and challenge, mice fed transgenic Dp2 milk had decreased T-helper 2 (Th2) and increased T-helper 1 (Th1) responses in the airway compared with mice fed wild-type milk. Moreover, pre-treatment with transgenic Dp2 milk attenuated airway inflammation and decreased airway hyper-responsiveness.
This study provides new evidence that oral administration of transgenic milk containing the Dp2 allergen down-regulated and moderately protected against allergic airway inflammation. Milk from transgenic animals expressing allergens may have potential use in the prevention of allergic asthma.
Transgenic mice; Allergen; Asthma; Immunotherapy; Group 2 allergen of Dermatophagoides pteronyssinus; Tolerance
Studies on time trends of allergic sensitization among adults are rare. The aim of the study was to compare the prevalence of allergic sensitization to common airborne allergens among adults 15 years apart and to identify risk factors for allergic sensitization.
Clinical examinations including skin prick test (SPT) and structured interviews were performed in two random population samples in 1994 and 2009. Furthermore, specific IgE was analyzed in 2009. SPT data were available for 483 subjects in 1994 and for 463 subjects in 2009 in ages 20–60 years. Specific IgE was analyzed in 692 subjects in ages 20–79 years.
Sensitization to cat (16% to 26%, p < 0.001), dog (13% to 25%, p < 0.001), birch (13% to 18%, p = 0.031) and timothy (12% to 21%, p < 0.001), based on SPT, increased significantly from 1994 to 2009. Sensitization to any positive SPT increased from 35% to 39%, p = 0.13.The proportion of having ≥3 positive SPT reactions increased from 40% to 56%, p = 0.002. The sensitization pattern yielded similar results based on specific IgE. Risk factors for allergic sensitization were having a family history of allergy (OR 3.1, 95% CI 2.0-4.8 for any positive SPT; OR 2.7, 95% CI 1.8-4.0 for any elevated IgE) and urban living (OR 1.7, 95% CI 1.0-2.7; OR 1.5, 95% CI 1.0-2.4).
The prevalence of allergic sensitization to major airborne allergens as well as multi-sensitization increased significantly between the study years. Young age, a family history of allergy and urban living were significant risk factors for allergic sensitization.
Allergic sensitization; Epidemiology; IgE; Population study; Prevalence; Skin prick test
Atmospheric contamination caused by Asian sand-dust (ASD) storms aggravates asthma in both human adults and children. This study aims to investigate a series of manifestations in allergic airway disease caused by co-exposure to allergens and ASD for 6 weeks and 14 weeks.
CD-1 Mice were instilled intratracheally with 0.1 mg of ASD/mouse four times (6 weeks) or eight times (14 weeks) at 2-week intervals (total dose of 0.4 mg or 0.8 mg/mouse) with or without ovalbumin (OVA). The pathologic changes in the airway, cytological alteration in bronchoalveolar lavage fluid (BALF), and levels of inflammatory cytokines/chemokines in BALF, and OVA-specific IgE and IgG1 antibodies in serum were measured in the treated CD-1 mice.
Four-time co-exposure to OVA and ASD aggravates allergic airway inflammation along with Th2-cytokine IL-13 and eosinophil-relevant cytokine/chemokines IL-5, Eotaxin and MCP-3 in BALF, and fibrous thickening of the subepithelial layer in the airway. On the other hand, eight-time co-exposure attenuates these changes along with a significant increase of TGF-β1 in BALF. Adjuvant effects of ASD toward IgG1 and IgE production in sera were, however, still seen in the eight-time co-exposure.
These results indicate that the immune responses in airways are exacerbated by four-time co-exposure to ASD with OVA, but that there is a shift to suppressive responses in eight-time co-exposure, suggesting that the responses are caused by TGF-β1-related immune tolerance.
Insufficient knowledge of food allergy and anaphylaxis has been identified by caregivers as an important barrier to coping, and a potential cause of fear and anxiety, particularly for those with children newly diagnosed with food allergy.
The purpose of the study was to better understand the experiences of caregivers of children with a first allergic reaction to food, and to identify any deficiencies in the information received at diagnosis.
A mixed-methods study consisting of an online survey administered to the Anaphylaxis Canada online registry (a patient support group database of approximately 10,000 members), and a follow-up qualitative interview with a subset of survey participants. Analysis consisted of frequency analysis (quantitative and qualitative data) and descriptive statistics to calculate proportions and means with standard deviations. Qualitative analyses were guided by the constant comparative method of grounded theory methodology.
Of 293 survey respondents, 208 were eligible to complete the survey (first allergic reaction to food within 12 months of the study), and 184 respondents consented. Identified gaps included education about food allergy, anaphylaxis management, for example, how to use epinephrine auto- injectors, and coping strategies for fear and anxiety. The qualitative follow-up study supported these findings, yielding 3 major themes: 1) lack of provision of information following the episode on the recognition and management of food allergy related allergic reactions, 2) prolonged wait times for an allergist, and 3) significant family anxiety.
The online survey highlighted multiple deficiencies at diagnosis, findings which were supported by the follow up qualitative study. Results will inform the development of educational strategies for patients newly diagnosed with food allergy.
Anaphylaxis; Food allergy; Qualitative methods
Debate is intensifying about how to assess the full range of impacts from medical research. Complexity increases when assessing the diverse funding streams of funders such as Asthma UK, a charitable patient organisation supporting medical research to benefit people with asthma. This paper aims to describe the various impacts identified from a range of Asthma UK research, and explore how Asthma UK utilised the characteristics of successful funding approaches to inform future research strategies.
We adapted the Payback Framework, using it both in a survey and to help structure interviews, documentary analysis, and case studies. We sent surveys to 153 lead researchers of projects, plus 10 past research fellows, and also conducted 14 detailed case studies. These covered nine projects and two fellowships, in addition to the innovative case studies on the professorial chairs (funded since 1988) and the MRC-Asthma UK Centre in Allergic Mechanisms of Asthma (the ‘Centre’) which together facilitated a comprehensive analysis of the whole funding portfolio. We organised each case study to capture whatever academic and wider societal impacts (or payback) might have arisen given the diverse timescales, size of funding involved, and extent to which Asthma UK funding contributed to the impacts.
Projects recorded an average of four peer-reviewed journal articles. Together the chairs reported over 500 papers. All streams of funding attracted follow-on funding. Each of the various categories of societal impacts arose from only a minority of individual projects and fellowships. Some of the research portfolio is influencing asthma-related clinical guidelines, and some contributing to product development. The latter includes potentially major breakthroughs in asthma therapies (in immunotherapy, and new inhaled drugs) trialled by university spin-out companies. Such research-informed guidelines and medicines can, in turn, contribute to health improvements. The role of the chairs and the pioneering collaborative Centre is shown as being particularly important.
We systematically demonstrate that all types of Asthma UK’s research funding assessed are making impacts at different levels, but the main societal impacts from projects and fellowships come from a minority of those funded. Asthma UK used the study’s findings, especially in relation to the Centre, to inform research funding strategies to promote the achievement of impact.
Asthma; Asthma UK; Research impacts; Societal impacts; Clinical guidelines; University spin-out companies; Product development; Immunotherapy; Payback Framework; Research funding strategy
Azelastine has been shown to be effective against seasonal allergic rhinitis (SAR). The Environmental Exposure Unit (EEU) is a validated model of experimental SAR. The objective of this double-blind, four-way crossover study was to evaluate the onset of action of azelastine nasal spray, versus the oral antihistamines loratadine 10 mg and cetirizine 10 mg in the relief of the symptoms of SAR.
70 participants, aged 18-65, were randomized to receive azelastine nasal spray, cetirizine, loratadine, or placebo after controlled ragweed pollen exposure in the EEU. Symptoms were evaluated using the total nasal symptom score (TNSS). The primary efficacy parameter was the onset of action as measured by the change from baseline in TNSS.
Azelastine displayed a statistically significant improvement in TNSS compared with placebo at all time points from 15 minutes through 6 hours post dose. Azelastine, cetirizine, and loratadine reduced TNSS compared to placebo with an onset of action of 15 (p < 0.001), 60 (p = 0.015), and 75 (p = 0.034) minutes, respectively. The overall assessment of efficacy was rated as good or very good by 46% of the participants for azelastine, 51% of the participants for cetirizine, and 30% of the participants for loratadine compared to 18% of the participants for placebo.
Azelastine’s onset of action for symptom relief was faster than that of cetirizine and loratadine. The overall participant satisfaction in treatment with azelastine is comparable to cetirizine and statistically superior to loratadine. These results suggest that azelastine may be preferential to oral antihistamines for the rapid relief of SAR symptoms.
Allergic rhinitis; Azelastine; Environmental exposure unit; Onset of action; Cetirizine; Loratadine
Multiple studies have demonstrated that early-life exposure to pets or siblings affords protection against allergic disease; these associations are commonly attributed to the “hygiene hypothesis”. Recently, low diversity of the infant gut microbiota has also been linked to allergic disease. In this study, we characterize the infant gut microbiota in relation to pets and siblings.
The study population comprised a small sub-sample of 24 healthy, full term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mothers reported on household pets and siblings. Fecal samples were collected at 4 months of age, and microbiota composition was characterized by high-throughput signature gene sequencing.
Microbiota richness and diversity tended to be increased in infants living with pets, whereas these measures were decreased in infants with older siblings. Infants living with pets exhibited under-representation of Bifidobacteriaceae and over-representation of Peptostreptococcaceae; infants with older siblings exhibited under-representation of Peptostreptococcaceae.
This study provides new evidence that exposure to pets and siblings may influence the early development of the gut microbiota, with potential implications for allergic disease. These two traditionally protective “hygiene hypothesis” factors appear to differentially impact gut microbiota composition and diversity, calling into question the clinical significance of these measures. Further research is required to confirm and expand these findings.
Infants; Gut microbiota; Gut microbiome; Hygiene hypothesis; Microflora hypothesis; Pets; Siblings; Atopy; Allergic disease; Environmental exposures
Helminth infections and allergies are associated with TH2 responses. Whereas the development of TH2 responses and allergic disorders in pediatric populations has been examined in affluent countries, no or little data exist from low income regions of the world.
The aim of this study is to examine factors influencing the development of TH2 responses of children born in areas endemic for helminth infections and to relate these factors to atopic sensitization at 4 years of age.
Data were collected from pregnant mothers on helminth infections, education and socioeconomic status (SES). Total IgE, IL-5 in response to mitogen, and helminth antigens were measured in children at 2, 5, 12, 24 and 48 months of age. Skin prick testing (SPT) and allergen-specific IgE were determined at 4 years of age.
Strong TH2 responses were seen at 5 months of age and increased with time. Although maternal filarial infection was associated with helminth-antigen specific TH2 responses, it was low maternal education or SES but not helminth infection, which was associated with the development of high total IgE and PHA-induced IL-5. At 4 years of age when allergen reactivity was assessed by SPT, the high general TH2 responses did not translate into higher prevalence of SPT. The risk factor for SPT reactivity was low maternal education which decreased the risk of SPT positivity to allergens (adjusted OR, 0.32; 95% CI, 0.12 – 0.87) independently of maternal filarial infection which tended to reduce the child’s risk for being SPT positive (adjusted OR, 0.35; 95% CI, 0.07 – 1.70).
In areas endemic for helminths, potent TH2 responses were seen early in life, but did not translate into a higher SPT reactivity to allergens. Therefore, in many parts of the world TH2 responses in general and IgE in particular cannot be used for diagnosis of allergic diseases.
TH2; IgE; IL-5; Helminth; Atopy; Skin prick test; Children
The editors of Allergy, Asthma & Clinical Immunology would like to thank all of our reviewers who have contributed to the journal in Volume 8 (2012).
Uncontrolled asthma remains a frequent cause of emergency department (ED) visits and hospital admissions. Improper asthma inhaler device use is most likely one of the major causes associated with uncontrolled asthma and frequent ED visits.
To evaluate the inhaler technique among asthmatic patients seen in ED, and to investigate the characteristics of these patients and factors associated with improper use of inhaler devices and its relationship with asthma control and ED visits.
A cross-sectional study of all the patients who visited the ED with bronchial asthma attacks over a 9-month period was undertaken at two major academic hospitals in Saudi Arabia. Information was collected about demographic data and asthma management and we assessed the inhaler techniques for each patient using an inhaler technique checklist.
A total of 450 asthma patients were included in the study. Of these, 176(39.1%) were males with a mean age of 42.3 ±16.7 years and the mean duration of asthma was 155.9 ± 127.1 weeks. The improper use of asthma inhaler devices was observed in 203(45%) of the patients and was associated with irregular clinic follow-ups (p = 0.0001), lack of asthma education (p = 0.0009), uncontrolled asthma ACT (score ≤ 15) (p = 0.001), three or more ED visits (p = 0.0497), and duration of asthma of less than 52 weeks (p = 0.005). Multiple logistic regression analysis revealed that a lack of education about asthma disease (OR =1.65; 95% CI: 1.07, 2.54) or a lack of regular follow-up (OR =1.73; 95% CI: 1.08, 2.76) was more likely to lead to the improper use of an asthma inhaler device.
Improper asthma inhaler device use is associated with poor asthma control and more frequent ED visits. We also identified many avoidable risk factors leading to the improper use of inhaler devices among asthma patients visiting the ED.
Asthma control; Inhaled corticosteroid; Emergency department; Inhaler devices; Asthma education
A diagnosis of peanut allergy has a major impact on an individual’s quality of life. Exposure to even small amounts of peanut can trigger serious reactions. Common cleaning agents can easily remove peanut allergen from surfaces such as table tops. Parents of children with peanut allergy frequently ask if peanut allergen can persist on surfaces if they have not been cleaned.
The purpose of this study was to determine the persistence of peanut allergen on a typical table surface over time.
Five mL of peanut butter was evenly smeared on a 12 inch by 12 inch (30.5 by 30.5 cm) square on a nonporous (laminated plastic) table surface. Five squares were prepared in the same manner. The table was kept in a regular hospital office at room temperature and ambient lighting. No cleaning occurred for 110 days. Samples were taken at regular intervals from different areas each time. A monoclonal-based ELISA for arachis hypogaea allergen 1 (Ara h 1), range of detection 1.95-2000 ng/mL, was used to assess peanut allergen on the table surface.
At baseline, there was no detectable Ara h 1 allergen. Immediately post application and for 110 days of collecting, detectable Ara h 1 was found each time a sample was taken. There was no obvious allergen degradation over time. Active cleaning of the contaminated surface with a commercial cleaning wipe resulted in no detectable Ara h 1 allergen.
Peanut allergen is very robust. Detectable Ara h 1 was present on the table surface for 110 days. Active cleaning of peanut contaminated surfaces easily removed peanut residue and allergen. Regular cleaning of surfaces before and after eating should be reinforced as a safety measure for all individuals with peanut allergy.
Food allergy; Peanut allergen; Contamination; Ara h 1
The gene ORMDL3 was shown to be associated with early-onset asthma susceptibility in multiple independent genome-wide and candidate-gene association studies. Asthmatic patients have elevated expression levels of this gene. ORMDL3 encodes a transmembrane protein localized in the endoplasmic reticulum (ER) that may be involved in ER stress and inflammation. It is essential to validate the genetic associations linking ORMDL3 with asthma through functional studies that confirm the biological relevance of this gene in disease. We investigated the effects of manipulating ORMDL3 expression levels in vitro in airway cells on innate immune inflammatory responses, ER stress and activation of the unfolded protein response (UPR).
ORMDL3 expression levels were manipulated in airway cells using an overexpression plasmid and siRNA technologies. Successful modulation of ORMDL3 was confirmed at both the gene and protein level. The functional impact of modulation of ORMDL3 expression levels on inflammatory responses and activation of the UPR were quantified using complementary cellular and molecular immunology techniques.
Cells with altered ORMDL3 levels responded equally well to innate immune stimuli and produced similar levels of pro-inflammatory cytokines compared to wild-type cells. Treatment with ER stress inducers, thapsigargin and tunicamycin, resulted in activation of the unfolded protein response (UPR). However, we observed no difference in UPR activation in cells with ORMDL3 knockdown compared to cells with normal ORMDL3 levels.
Our results suggest that ORMDL3 variation in the airway epithelium is unlikely to play a significant role in modulating innate immune responses and the UPR in the lung.
Immune response; Epithelium; Cytokines; Chemokines; Host defense
Immunostimulatory therapy is now being recognized as an alternative to conventional chemotherapy for a variety of disease conditions, involving the impaired immune response of the host. In the present study, the immunostimulatory effect of the butanolic extract obtained from S. mialhesi aerial parts, was evaluated in vivo.
The immunostimulant potential of the plant extract on the phagocytic activity was measured by the carbon clearance rate test.
Our research revealed that at different doses (50, 100 and 500 mg/kg), S. mialhesi extract increased the phagocytic activity in a dose dependant manner when compared with the control and thus the clearance rate of carbon was faster after the administration of the plant extract.
S. mialhesi extract exhibited a dose-dependent immunostimulant effect on the reticuloendothelial system, which could be attributed to the presence of active principles in this butanolic extract.
Immunostimulatory activity; Phagocytic activity; Carbon clearance rate; Reticuloendothelial system; Stachys mialhesi de Noé
A seasonal effect of month of birth and risk of allergic disease has been suggested by numerous studies. Few studies have directly measured pollen exposures at different points during pregnancy and in early life, and assessed their effects on risk of respiratory disease outcomes.
Pollen exposure was calculated for the first and last 12 weeks of pregnancy and the first 12 weeks of infancy for all children conceived by women residing in Stockholm, Sweden, between 1988 and 1995. Hospital admission data for respiratory conditions in the first year of life was also collected.
Out of 110,381 children, 940 had been hospitalised for asthma by 12-months of age. Pollen levels showed both marked seasonal variations and between year differences. Exposure to high levels of pollen in the last 12 weeks of pregnancy was associated with an increased risk of asthma hospitalisation (aOR = 1.35, 95% CI = 1.07-1.71 for highest quartile versus remaining infants). Exposure to high levels of pollen in the first three months of life was associated with a reduced risk (aOR = 0.76, 95% CI = 0.59-0.98) but only in children of heavy smoking mothers.
High levels of pollen exposure during late pregnancy were somewhat unexpectedly associated with an elevated risk of hospitalisation for asthma within the first year of life.
Pollen; Early life exposure; Asthma; Hospitalisation
The immunological and clinical parameters that are associated with asthma remission are poorly understood. The cytokine and local mediator changes associated with the resolution of asthma symptoms were examined in three groups of subjects 12–18 years of age (n = 15 in each group): (a) continuing asthma group (CA) who had persistent symptoms since early childhood, (b) an age, sex and atopic status-matched group who had persistent symptoms in early childhood but in whom these had resolved (RA), and (c) a non-atopic, non-asthmatic control group. Clinical parameters, sputum cell counts, peripheral blood mononuclear cell (PBMC) cytokine production and activation marker expression were determined. All of the CA had methacholine airway hyperresponsiveness compared with only half of the RA subjects. The CA showed elevated numbers of eosinophils and increased ECP and IL-5 in sputum, which were not observed in the RA. PBMC cytokine studies revealed increased production of the type 1 cytokines IL-12, IFN-γ and TNF-α in the CA group compared with the RA group, under a range of activation conditions, however, the production of IL-4 and IL-5 were unchanged. These findings suggest that decreased type 1 cytokine expression as well as decreased eosinophilic inflammation is associated with the resolution of asthma symptoms.
Asthma in children; Eosinophils; IL-5; TNF-α; IL-12
Allergy to peanuts results in severe anaphylactic responses in affected individuals, and has dramatic effects on society and public policy. Despite the health impacts of peanut-induced anaphylaxis (PIA), relatively little is known about immune mechanisms underlying the disease. Using a mouse model of PIA, we evaluated mice with deletions in four distinct immune molecules (IL7Rα, L-selectin, CD34, CD103), for perturbed responses.
PIA was induced by intragastric sensitization with peanut antigen and cholera toxin adjuvant, followed by intraperitoneal challenge with crude peanut extract (CPE). Disease outcome was assessed by monitoring body temperature, clinical symptoms, and serum histamine levels. Resistant mice were evaluated for total and antigen specific serum IgE, as well as susceptibility to passive systemic anaphylaxis.
PIA responses were dramatically reduced in IL7Rα−/− and L-selectin−/− mice, despite normal peanut-specific IgE production and susceptibility to passive systemic anaphylaxis. In contrast, CD34−/− and CD103−/− mice exhibited robust PIA responses, indistinguishable from wild type controls.
Loss of L-selectin or IL7Rα function is sufficient to impair PIA, while CD34 or CD103 ablation has no effect on disease severity. More broadly, our findings suggest that future food allergy interventions should focus on disrupting sensitization to food allergens and limiting antigen-specific late-phase responses. Conversely, therapies targeting immune cell migration following antigen challenge are unlikely to have significant benefits, particularly considering the rapid kinetics of PIA.
Anaphylaxis; Animal model; Food allergy; Immunity; Peanut allergy
Presenting processed antigens to CD4+ lymphocytes during the immune response involves major histocompatibility complex class II molecules. MHC class II genes transcription is regulated by four transcription factors: CIITA, RFXANK, RFX5 and RFXAP. Defects in these factors result in major histocompatibility complex class II expression deficiency, a primary combined immunodeficiency frequent in North Africa. Autosomal recessive mutations in the RFXANK gene have been reported as being the principal defect found in North African patients with this disorder. In this paper, we describe clinical, immunological and genetic features of 11 unrelated Algerian patients whose monocytes display a total absence of MHC class II molecules. They shared mainly the same clinical picture which included protracted diarrhoea and respiratory tract recurrent infections. Genetic analysis revealed that 9 of the 11 patients had the same RFXANK founder mutation, a 26 bp deletion (named I5E6-25_I5E6+1, also known as 752delG26). Immunological and genetic findings in our series may facilitate genetic counselling implementation for Algerian consanguineous families. Further studies need to be conducted to determine 752delG26 heterozygous mutation frequency in Algerian population.
Aerobic exercise appears to have clinical benefits for many asthmatics, yet a complete understanding of the mechanisms underlying these benefits has not been elucidated at this time.
The objective of this study was to determine feasibility for a larger, future study that will define the effect of aerobic exercise on cellular, molecular, and functional measures in adults with mild-moderate asthma.
Recruited subjects were randomized into usual care (sedentary) or usual care with moderate intensity aerobic exercise treatment groups.
Setting / Participants
Nineteen adults with mild-moderate asthma but without a recent history of exercise were recruited at the UAB Lung Health Center, Birmingham, AL.
The exercise group underwent a 12 week walking program exercising at 60 – 75% of maximum heart rate (HRmax). Subjects self-monitored HRmax levels using heart rate monitors; exercise diaries and recreation center sign-in logs were also used.
Main outcome measures
Functional measures, including lung function and asthma control scores, were evaluated for all subjects at pre- and post-study time-points; fitness measures were also assessed for subjects in the exercise group. Peripheral blood and nasal lavage fluid were collected from all subjects at pre- and post-study visits in order to evaluate cellular and molecular measures, including cell differentials and eosinophilic cationic protein (ECP).
Sixteen subjects completed the prescribed protocol. Results show that subjects randomized to the exercise group adhered well (80%) to the exercise prescription and exhibited a trend toward improved fitness levels upon study completion. Both groups exhibited improvements in ACQ scores. No changes were observed in lung function (FEV1, FEV1/FVC), cell differentials, or ECP between groups.
Results indicate that a moderate intensity aerobic exercise training program may improve asthma control and fitness levels without causing asthma deterioration in adult asthmatics. As such, these findings demonstrate the feasibility of the study protocol in preparation for a larger, clinical trial that will elucidate the functional consequences of aerobic exercise on asthmatic cellular and molecular responses.
The role of breast milk on the risk of childhood asthma is in dispute. The aim of this prospective study is to determine the relationship of immune markers in maternal serum during gestation and breast milk to asthma-like symptoms (AS) in infancy.
Pregnant women were recruited in Columbia and Charleston, South Carolina. Blood (median: three weeks before delivery) and breast milk (three weeks after delivery) samples were collected. Concentrations of interferon (IFN)-γ, IFN gamma-induced protein 10 (IP-10 or CXCL10), CCL11, interleukin (IL) 1β, IL-4, IL-5, IL-6, CXCL8, IL-10, IL-12(p70), IL-13, transforming growth factor (TGF)-β1, and immunoglobulin (Ig) A in both maternal serum and milk whey were determined via immunoassays. Asthma-like symptoms (AS) of the infant were ascertained at 6 and 12 months, respectively. Generalized estimating equations assessed relative risks (RRs) of immune markers for repeated measurements of AS, considering intra-individual correlations and adjusting for confounders. To provide comparable risk estimates, quartiles of the immune markers were used, except for IL-5 in whey and IgA in serum, which were dichotomized.
Of 178 women, 161 provided blood and 115 breast milk samples. IL-12(p70), IL-4, IL-10, IL-1β, and CCL11 in serum and in whey were not further considered for the statistical analyses since the proportion of non-detectable values was high. Most immune markers in serum and milk whey were moderately or highly correlated; however, IgA was negatively correlated. Infants in the highest quartile of IL-13 in both serum and whey were at a higher risk of AS (RR = 3.02 and 4.18; respectively) compared to infants in the first quartile. High levels of IL-5 in serum and whey was also identified as a risk. In addition, increased secretory IgA and TGF-β1 in breast milk reduced the risks of AS.
Maternal serum and whey levels of IL-5 and IL-13 are risk markers for AS; whey IgA and TGF-β1 seem to be protective. Only focusing on breast milk portend that milk cytokines IL-5 and IL-13 have adverse effects. However, similar immune exposures during late gestation and via milk suggest that both may enhance AS among infants.
Breast milk; Maternal serum; Immune markers; Cytokines; Chemokines; Asthma-like symptoms; Children; Longitudinal study
Cow’s milk and hen’s egg are the most frequently encountered food allergens in the pediatric population. Skin prick testing (SPT) with commercial extracts followed by an oral food challenge (OFC) are routinely performed in the diagnostic investigation of these children. Recent evidence suggests that milk-allergic and/or egg-allergic individuals can often tolerate extensively heated (EH) forms of these foods. This study evaluated the predictive value of a negative SPT with EH milk or egg in determining whether a child would tolerate an OFC to the EH food product.
Charts from a single allergy clinic were reviewed for any patient with a negative SPT to EH milk or egg, prepared in the form of a muffin. Data collected included age, sex, symptoms of food allergy, co-morbidities and the success of the OFC to the muffin.
Fifty-eight patients had negative SPTs to the EH milk or egg in a muffin and underwent OFC to the appropriate EH food in the outpatient clinic. Fifty-five of these patients tolerated the OFC. The negative predictive value for the SPT with the EH food product was 94.8%.
SPT with EH milk or egg products was predictive of a successful OFC to the same food. Larger prospective studies are required to substantiate these findings.
There has been no large study characterizing selection bias in allergy and evaluating school personnel’s ability to use an epinephrine auto-injector (EpiPen®). Our objective was to determine if the consent process introduces selection bias by comparing 2 methods of soliciting participation of school personnel in a study evaluating their ability to demonstrate the EpiPen®.
School personnel from randomly selected schools in Quebec were approached using a 1) partial or 2) full disclosure approach and were assessed on their ability to use the EpiPen® and identify anaphylaxis.
343 school personnel participated. In the full disclosure group, the participation rate was lower: 21.9% (95%CI, 19.0%-25.2%) versus 40.7% (95%CI, 36.1%-45.3%), but more participants achieved a perfect score: 26.3% (95%CI, 19.6%-33.9%) versus 15.8% (95%CI, 10.8%-21.8%), and identified 3 signs of anaphylaxis: 71.8% (95%CI, 64.0%-78.7%) versus 55.6% (95%CI, 48.2%-62.9%).
Selection bias is suspected as school personnel who were fully informed of the purpose of the assessment were less likely to participate; those who participated among the fully informed were more likely to earn perfect scores and identify anaphylaxis. As the process of consent can influence participation and bias outcomes, researchers and Ethics Boards need to consider conditions under which studies can proceed without full consent. Despite training, school personnel perform poorly when asked to demonstrate the EpiPen®.
Anaphylaxis; Epinephrine; Food allergy; School; Treatment; Selection bias; Consent bias; Volunteer bias
Goldenhar syndrome (GS) results from an aberrant development of the 1st and 2nd branchial arches. There is a wide range of clinical manifestations, the most common being microtia, hemifacial microsomia, epibulbar dermoids and vertebral malformations. We present two cases of GS and secondary immunodeficiency due to anatomical defects characteristic of this disorder. Case 1 (3-year-old female) averaged 6 episodes of sinusitis and otitis media per year. Case 2 (7-year-old female) also had recurrent otitis media, an episode of bacterial pneumonia, and 2 episodes of bacterial meningitis. Their immune evaluation included a complete blood count with differential, serum immunoglobulin levels and specific antibody concentrations, lymphocyte phenotyping, and mitogen and antigen responses, the results of which were all within normal ranges. Both children demonstrated major structural abnormalities of the inner and middle ear structures, retention of fluid in mastoid air cells, and chronic sinusitis by computed tomography. These two cases illustrate how a genetically-associated deviation of the middle ear cleft can cause recurrent infections and chronic inflammation of the middle ear and adjacent sinuses, even meninges, leading to a greatly reduced quality of life for the child and parents.
Goldenhar syndrome; Hemifacial microsomia; Oculo-auriculo-vertebral dysplasia; Recurrent infections; Sinusitis; Otitis; Meningitis; Immunodeficiency