Susan Waserman

The September epidemic of asthma exacerbations in children: A search for etiology

Background Predictable peaks of asthma exacerbation requiring hospital treatment, of greatest magnitude in children and of uncertain etiology, occur globally after school returns. Objective We wished to determine whether asthmatic children requiring emergency department treatment for exacerbations after school return in September were more likely to have respiratory viruses present and less likely to have prescriptions for control medications than children with equally severe asthma not requiring emergent treatment. Methods Rates of viral detection and characteristics of asthma management in 57 (of 60) children age 5 to 15 years presenting to emergency departments with asthma in 2 communities in Canada between September 10 and 30, 2001, (cases) were compared with those in 157 age-matched volunteer children with asthma of comparable severity studied simultaneously (controls). Results Human picornaviruses were detected in 52% of cases and 29% of controls (P =.002) and viruses of any type in 62% of cases and 41% of controls (P =.011). Cases were less likely to have been prescribed controller medication (inhaled corticosteroid, 49% vs 85%; P < .0001; leukotriene receptor antagonist, 9% vs 21%; P =.04). Conclusion Respiratory viruses were detected in the majority of children presenting to emergency departments with asthma during the September epidemic of the disease and in a significant minority of children with asthma in the community. The latter were more likely to have anti-inflammatory medication prescriptions than children requiring emergent treatment. Such medication may reduce the risk of emergency department treatment for asthma during the September epidemic.

IL-33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization

BACKGROUND Allergen exposure at lung and gut mucosae can lead to aberrant T(H)2 immunity and allergic disease. The epithelium-associated cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are suggested to be important for the initiation of these responses. OBJECTIVE We sought to investigate the contributions of TSLP, IL-25, and IL-33 in the development of allergic disease to the common allergens house dust mite (HDM) or peanut. METHODS Neutralizing antibodies or mice deficient in TSLP, IL-25, or IL-33 signaling were exposed to HDM intranasally or peanut intragastrically, and immune inflammatory and physiologic responses were evaluated. In vitro assays were performed to examine specific dendritic cell (DC) functions. RESULTS We showed that experimental HDM-induced allergic asthma and food allergy and anaphylaxis to peanut were associated with TSLP production but developed independently of TSLP, likely because these allergens functionally mimicked TSLP inhibition of IL-12 production and induction of OX40 ligand (OX40L) on DCs. Blockade of OX40L significantly lessened allergic responses to HDM or peanut. Although IL-25 and IL-33 induced OX40L on DCs in vitro, only IL-33 signaling was necessary for intact allergic immunity, likely because of its superior ability to induce DC OX40L and expand innate lymphoid cells in vivo. CONCLUSION These data identify a nonredundant, IL-33-driven mechanism initiating T(H)2 responses to the clinically relevant allergens HDM and peanut. Our findings, along with those in infectious and transgenic/surrogate allergen systems, favor a paradigm whereby multiple molecular pathways can initiate T(H)2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease.

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics

BackgroundPrevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.ObjectiveThe World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.MethodsWe identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.ResultsCurrently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.ConclusionsWAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.

Impact of CD40 Ligand, B Cells, and Mast Cells in Peanut-Induced Anaphylactic Responses

The effector immune mechanisms underlying peanut-induced anaphylaxis remain to be fully elucidated. We investigated the relative contribution of Igs, mast cells (MCs), and FcεRI in the elicitation of anaphylaxis in a murine model. Assessment of peanut hypersensitivity reactions was performed clinically and biologically. Our data show that wild-type (WT; C57BL/6 strain) mice consistently developed severe anaphylaxis (median clinical score: 3.5/5), an ∼8°C drop in core body temperature, and significantly increased plasma levels of histamine and leukotrienes. CD40 ligand- and B cell-deficient mice presented evidence of allergic sensitization as demonstrated by production of Th2-associated cytokines by splenocytes and a late-phase inflammatory response that were both indistinguishable to those detected in WT mice. However, CD40 ligand- and B cell-deficient mice did not exhibit any evidence of anaphylaxis. Our data also show that MC-deficient (KitW/KitW-v) mice did not suffer, unlike their littermate controls, anaphylactic reactions despite the fact that serum levels of peanut-specific Igs were similarly elevated. Finally, FcεRI-deficient mice experienced anaphylactic responses although to a significantly lesser degree than those observed in WT mice. Thus, these data demonstrate that the presence of peanut-specific Abs along with functional MCs comprise a necessary and sufficient condition for the elicitation of peanut-induced anaphylaxis. That the absence of FcεRI prevented the development of anaphylaxis only partially insinuates the contribution of an IgE-independent pathway, and suggests that strategies to impair MC degranulation may be necessary to improve the efficacy of anti-IgE therapy.

Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions

BACKGROUND Food anaphylaxis is an acute and life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal and near-fatal reactions in North America. Because prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies. OBJECTIVE To investigate the impact of blocking mast cell mediators in a mouse model of peanut-induced anaphylaxis. METHODS Mice were sensitized with peanut protein and cholera toxin via oral gavage weekly for 4 weeks. One week after the last sensitization, separate groups of mice were treated with either a (1) 5-lypoxygenase inhibitor, (2) a platelet-activating factor (PAF) receptor antagonist, (3) histamine receptor antagonists, or (4) a PAF receptor antagonist along with histamine receptor antagonists before peanut challenge. RESULTS Treatment targeting either leukotrienes or histamine alone had no beneficial effects. In contrast, PAF antagonism significantly attenuated the magnitude and duration of the anaphylactic reactions. Particularly, it prevented severe reactions. Moreover, 83% of PAF-treated versus 43% of untreated mice reached recovery within 120 minutes after peanut challenge. Notably, combined blockade of PAF and histamine had a clearly greater beneficial effect. In fact, all but 1 mouse developed mild, if any, anaphylactic reactions. In addition, combination therapy was associated with a significant decrease in vascular leakage and release of vasoactive mediators after peanut challenge. CONCLUSION Combination therapy blocking both PAF and histamine markedly reduces the severity of peanut-induced anaphylaxis, and thus it may be a potential life-saving therapeutic approach in peanut and, likely, other food-induced anaphylaxis.

Gaps in anaphylaxis management at the level of physicians, patients, and the community: a systematic review of the literature.

To cite this article: Kastner M, Harada L, Waserman S. Gaps in anaphylaxis management at the level of physicians, patients, and the community: a systematic review of the literature. Allergy 2010; 65: 435–444.

Role of food labels in accidental exposures in food-allergic individuals in Canada

BACKGROUND Little is known about the impact of food labeling on the allergic consumer. OBJECTIVE To determine the proportion of food-allergic individuals attributing an accidental exposure to inappropriate labeling, failure to read a food label, or ignoring a precautionary statement and to identify factors associated with accidental exposures. METHODS Food-allergic individuals or their caregivers were recruited from a Canadian registry of individuals with a physician-confirmed diagnosis of peanut allergy and from allergy awareness organizations. Participants completed questionnaires regarding accidental exposures due to specific food labeling issues. The association between accidental exposures and characteristics of food-allergic individuals or their caregivers was estimated using multivariate logistic regression models. RESULTS Of 1,862 potential participants, 1,454 (78.1%) responded. Of the 47.8% (95% confidence interval [CI], 45.1%-50.5%) of respondents who experienced an accidental exposure, 47.0% (95% CI, 43.1%-50.9%) attributed the event to inappropriate labeling, 28.6% (95% CI, 25.1%-32.2%) to failure to read a food label, and 8.3% (95% CI, 6.3%-10.7%) to ignoring a precautionary statement. Food-allergic individuals who were allergic to peanut, tree nut, fish, or shellfish were less likely to experience an accidental exposure due to the allergen not being identified in plain language. CONCLUSIONS A considerable proportion of accidental exposures are attributed to inappropriate labeling, failure to read labels, and ignoring precautionary statements. Clear and consistent labeling of food allergens combined with increased consumer education is necessary to improve consumer confidence and compliance and to reduce accidental exposures.

Role for IL-4 in macromolecular transport across human intestinal epithelium

Increased epithelial permeability is associated with intestinal inflammation, but there is little information on factors that regulate barrier function in the absence of or before inflammation. We examined if interleukin (IL)-4, or serum from atopic individuals, could alter the barrier function of human colonic epithelial (T84) monolayers to antigenic-sized macromolecules. IL-4 and atopic serum significantly decreased T84 monolayer resistance and increased transepithelial horseradish peroxidase (HRP) transport. Bidirectional transport studies demonstrated that IL-4 selectively enhanced apical-to-basal movement of HRP. HRP transport induced by IL-4 was inhibited by cold (4 degrees C) and the tyrosine kinase inhibitor genistein, but not the protein kinase C inhibitor staurosporine. Electron microscopic analysis demonstrated that both transcellular and paracellular pathways were affected. Anti-IL-4 antibodies abolished the increase in HRP transport in response to both IL-4 and serum. We speculate that enhanced production of IL-4 in allergic conditions may be a predisposing factor to inflammation by allowing uptake of luminal antigens that gain access to the mucosal immune system.

Distinct immune effector pathways contribute to the full expression of peanut-induced anaphylactic reactions in mice

BACKGROUND Food-induced anaphylaxis is often a severe allergic reaction characterized by multiorgan dysfunction and a potentially fatal outcome. OBJECTIVES We sought to investigate the relative contribution of immunoglobulin-dependent effector pathways to anaphylactic responses to food (ie, peanut). METHODS Wild-type and various mutant mice were sensitized with peanut protein and cholera toxin by means of oral gavage weekly for 4 weeks. Mice were subjected to different cellular depletion and Fc receptor blocking strategies before challenge with peanut 1 week after the last sensitization. RESULTS Our data indicate that pathways other than the classical mast cell (MC)-IgE pathway contribute to the full spectrum of anaphylactic reactions to peanut. We show that the single deletion of MCs, basophils, or phagocytes (ie, macrophages) prevents the most significant clinical outcome: death. Remarkably, the combined deficiency of MCs and phagocytes, but not MCs and basophils, averted nearly all clinical and physiological signs of anaphylaxis. Furthermore, blockade of both IgE and IgG1 signaling was necessary to abolish anaphylactic responses to peanut. Although MC responses occurred through IgE and IgG1, phagocyte responses were fully mediated through IgG1. CONCLUSIONS Peanut-induced anaphylaxis is a process that involves the concerted action of multiple immune effector pathways, and thus interventions targeting a single pathway (eg, MC-IgE) might not be sufficient to fully prevent anaphylactic responses.

Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo

Eosinophil degranulation of peroxidase promotes DC activation and mobilization from the intestine to LNs to induce Th2 immunity and food allergy.