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The world allergy organization guidelines for the assessment and management of anaphylaxis are being published concurrently in the journal of allergy and clinical immunology to facilitate retrieval by all health care professionals worldwide through pubmed and other search engines and in the world allergy organization journal to facilitate rapid access by all members of the wao. The recommendations for assessment and basic initial management of anaphylaxis, as summarized in fig 1, fig 2, fig 3, fig 4, fig 5 and in table 1, table 2, table 3, table 4, table 5, table 6, table 7, table 8, table 9 in the guidelines, are also being disseminated through posters, pocket cards, and applications (apps) for mobile devices.the main barriers to implementation of the recommendations in the guidelines include the erroneous perception that anaphylaxis is a rare disease and the lack of universal availability of essential medications, supplies, and equipment for its assessment and management worldwide. Additional barriers include lack of awareness that hypotension and shock are often absent in patients with anaphylaxis, that serum tryptase or plasma histamine levels are not necessarily increased, that death can occur within a few minutes, and that prompt basic initial treatment can be life-saving.the wao member societies were extensively involved in the development of these unique anaphylaxis guidelines, and will be involved with their dissemination and implementation. Their continued anaphylaxis education efforts will help to surmount the above-listed barriers.in the online full-length version of the world allergy organization guidelines for the assessment and management of anaphylaxis, available at www.jacionline.org, a complete list of references is provided to support the recommendations that are made.

Background Cross-linking of mast cell–bound IgE releases proinflammatory mediators, cytokines, and proteolytic enzymes and is a key event in allergic inflammation. Objective We sought to study the effect of proteases released on effector cell activation on receptor-bound IgE and their possible role in the regulation of allergic inflammation. Methods Using molar ratios of purified recombinant tryptase and human IgE, we studied whether tryptase can cleave IgE. Similar experiments were performed with mast cell lysates in the presence or absence of protease inhibitors. IgE cleavage products were detected in supernatants of allergen cross-linked, cultivated mast cells and in tissue fluids collected from patients' skin after IgE-mediated degranulation. The effects of protamine, an inhibitor of heparin-dependent proteases on IgE-mediated allergic in vivo skin inflammation in human subjects were studied. Results We show that β-tryptase, a major protease released during mast cell activation, cleaves IgE. IgE degradation products were detected in tryptase-containing tissue fluids collected from sites of allergic inflammation. The biologic significance of this mechanism is demonstrated by in vivo experiments showing that protease inhibition enhances allergic skin inflammation. Conclusion We suggest that IgE cleavage by effector cell proteases is a natural mechanism for controlling allergic inflammation.

Background With an impressive series of replication studies, filaggrin (FLG) has become the gene with the most widely replicated association to atopic eczema (AE). However, studies published to date demonstrate differences concerning study design and strength of associations. Objectives We sought to provide a general and overall estimate of FLG effect sizes and to estimate allele and carrier frequencies. Methods We searched Medline and Institute for Scientific Information Web of Knowledge databases for relevant studies and abstracts from professional societies that were published through June 30, 2007. Initially, we accounted for different study types and evaluated an overall estimate for case-control and family studies. In a second step, we combined those 2 study types and used a random-effects analysis approach to calculate overall odds ratios (ORs). Tests of asymmetry were applied to detect potential publication bias. Results Nine studies that met the inclusion criteria were included in the meta-analysis. For the combined genotype (R501X or 2282del4), we found an overall OR of 4.09 (95% CI, 2.64-6.33) from the case-control studies and a summary OR of 2.06 (95% CI, 1.76-2.42) from the family studies. Conclusion The powerful effect of FLG variation on AE risk exceeds that of any other investigated candidate gene for AE thus far and makes FLG one of the strongest genes known to date for complex diseases. Clinical implications These results underline the importance of a genetically determined epidermal barrier disruption in AE.

Background Patients with atopic diseases are characterized by high levels of specific IgE production. However, little is known about the composition of their B-cell repertoires. Objectives We sought to analyze the complete PBMC-derived IgE repertoire and to compare clonal expansions between different patients. Methods We have analyzed the IgE-bearing B-cell receptor repertoire in highly atopic patients (>1000 IU/mL) using quantitative RT-PCR, complementarity determining region 3 spectratyping, and sequence analysis. Three representative patients were additionally followed during anti-IgE therapy. Results Atopic patients exhibited 100 to 1000 times more IgE-specific transcripts than control individuals. These patients used a variable region of the heavy immunoglobulin chain (VH) e repertoire highly similar to their IgM and IgG repertoires, with preference of VH3b, VH4, VH3a, and VH1 segments. Each patient harbored individual clonal expansions, most probably as correlation of allergen-specific IgE production. Common expansions within the complementary determining region 3 shared by several individuals with similar sensitization patterns were found in spectratyping analysis. However, these antigen-driven expansions showed differences on the sequence level. In omalizumab-treated patients the clinical improvement was paralleled by a clear increase in the ratio of IgG/IgE transcripts. Conclusion The IgE repertoire in atopic patients follows the VH use patterns seen for other immunoglobulins and seems to preferentially recruit individual rearrangements rather than public expansions. Clinical implications The detailed analysis of the IgE B-cell repertoire is highly suitable to follow changes in IgE uses during different therapy modalities.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. OBJECTIVES: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. METHODS: We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. RESULTS: Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSION: Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. CLINICAL IMPLICATIONS: These findings underline the crucial role of the skin barrier in preventing allergic sensitization. &nbsp

The 4th Georg Rajka International Symposium on Atopic Dermatitis presented a comprehensive view of our current understanding and management of atopic dermatitis (AD). These proceedings highlight contributions related to the history of AD doctrines; genetic and epigenetic background; epidemiology; maturation of the immune system; infection and innate-adaptive immunity; epidermal inflammation, including neurogenic inflammation and pruritus; animal models; skin barrier; evidence-based therapy and education programs; prognostic and severity markers; and allergy testing. Several studies in animal models and human subjects point to impaired skin barrier function as a primary defect that facilitates the effect of environmental factors and immune dysregulation found in AD. The new frontier in AD therapy should, in the near future, reflect our better understanding of the skin barrier. The influence of environmental factors on the skin and other epithelial barriers in the perinatal period needs to be better understood to implement appropriate prevention programs.

Long before the discovery of IgE it was reported that human dander extract can elicit immediate-type skin reactions in patients with severe atopy and that this skin sensitivity can be passively transferred with serum. Several recent findings have rekindled the interest in this phenomenon and led to the concept that IgE autoreactivity may play a pathogenetic role in severe and chronic forms of atopy. The elucidation of the nature of several environmental allergens has revealed striking structural and immunologic similarities with human proteins. It was also reported that patients predominantly with severe and chronic manifestations of atopy (eg, atopic dermatitis) contain IgE autoantibodies against a wide variety of proteins expressed in histogenetically unrelated human cell types and tissue specimens. Last, complementary DNAs coding for autoallergens were isolated from human expression complementary DNA libraries and recombinant autoallergens were produced. The autoallergens characterized to date represent mainly intracellular proteins, but some of them could be detected as IgE immune complexes in sera of sensitized patients. We suggest that at least two pathomechanisms could play a role in autoallergy. First, autoallergens may cross-link effector cell-bound IgE autoantibodies and, by release of inflammatory mediators, lead to immediate-type symptoms. Second, IgE-mediated presentation of autoallergens may activate autoreactive T cells to release proinflammatory cytokines, contributing to the magnitude of the allergic tissue reaction.

Background Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA -negative, corticosteroid-responsive subjects with HESs. Objective We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES. Methods MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored. Results Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ≥12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons. Conclusion Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA -negative HES.

Background Patients with atopic eczema (AE) regularly experience colonization with Staphylococcus aureus that is directly correlated with the severity of eczema. Recent studies show that an impaired IL-17 immune response results in diseases associated with chronic skin infections. Objective We sought to elucidate the effect of IL-17 on antimicrobial immune responses in AE skin. Methods T cells infiltrating atopy patch test (APT) reactions were characterized for IL-17 secretion to varying stimuli. IL-17–dependent induction of the antimicrobial peptide human β-defensin 2 (HBD-2) in keratinocytes was investigated. Results Approximately 10% of APT-infiltrating T cells secreted IL-17 after phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Among these, 33% belonged to the newly characterized subtype T H 2/IL-17. Despite the capacity to secrete IL-17, specific T-cell clones released only low amounts of IL-17 on cognate allergen stimulation, whereas IL-4, IFN-γ, or both were efficiently induced. IL-17 secretion was not enhanced by IL-23, IL-1β, or IL-6 but was enhanced by the S aureus –derived superantigen staphylococcal enterotoxin B. Both healthy and AE keratinocytes upregulated HBD-2 in response to IL-17, but coexpressed IL-4/IL-13 partially inhibited this effect. In vivo , additional application of staphylococcal enterotoxin B induced IL-17 in APT reactions, whereas IL-4, IFN-γ, and IL-10 were marginally regulated. Induced IL-17 upregulated HBD-2 in human keratinocytes in vivo . Conclusion IL-17–capable T cells, in particular T H 2/IL-17 cells, infiltrate acute AE reactions. Although IL-17 secretion by specific T cells is tightly regulated, it can be triggered by bacteria-derived superantigens. The ineffective IL-17–dependent upregulation of HBD-2 in patients with AE is due to a partial inhibition by the type 2 microenvironment, which could partially explain why patients with AE do not clear S aureus .

In 186 persons (68 patients suffering from different so-called autoimmune diseases, 30 kidney recipients, 38 control patients from a surgical ward, and 50 healthy volunteers) the immune response to horse IgG was examined. The lowest rate of sensitization was found in kidney transplant recipients (3%) and the highest in autoimmune patients (33%). After excluding 39 patient who had received horse serum treatment prior to the examination, it was found that without previous injection of horse serum, 27% of the patients with autoimmune disease were sensitized to horse IgG. Compared to the other groups (kidney transplant recipients, 4%: surgical controls, 0%; healthy volunteers, 3%), this difference was statistically significant (p is less than 0.01).

To further an understanding of the effects of radiographic contrast media (RCM) infusions, 43 patients underwent clinical evaluation, including allergy history and skin testing, at least 48 hr before receiving a bolus of Renografin-60 (meglumine diatrizoate [52] and sodium diatrizoate [8]) for intravenous pyelography. Venous plasma samples were obtained serially before and at 2, 4, 10, 30, and 60 min after the infusion. Each sample was assayed for histamine by isotopic enzyme assay, for complement by total hemolytic activity, and for fibrin split products by radioimmunoassay. Immediate generalized reactions occurred in 6 of the patients. Each of the 43 patients had a change in at least 1 of the mediators measured. Plasma histamine rose in 40% of the patients (mean, 3.1 ± 1.62 ng/ml). Plasma complement hemolytic activity decreased in 63% (mean, 29 ± 19%). Fibrin split products were detected in 41%. In comparing the 6 patients who experienced reactions to the 37 who did not, there were no statistically significant differences in rise in plasma histamine, decrease in complement activity, presence of fibrin split products, personal history of allergy, prior exposure or reaction to RCM, skin tests to RCM, and histamine or saline. Although histamine levels, complement activity, and fibrin split products changed in a substantial number of patients undergoing RCM infusions, these changes did not correlate with immediate generalized reactions or with the previously described clinical parameters. It is probable that other modulating factors play significant roles in determining whether or not a reaction occurs.

Ten healthy volunteers (five atopic, five nonatopic) and seven patients suffering from allergic bronchial asthma and rhinitis/conjunctivitis as well as showing dual reactions after intradermal or bronchial allergen challenge were investigated. Using the suction blister technique, we obtained skin-blister fluid (SBF) from dual skin reactions 30, 60, 180, and 300 min after allergen injection and from normal untested skin. The biologic activity of SBF was tested by intradermal reinjection of the fluid into the donor. SBF taken from dual skin reactions 30 or 60 min after allergen injection produced late cutaneous reactions (LCRs) quite similar to those induced by the allergen. SBF taken from LCR areas 180 or 300 min after antigen testing had much weaker effects, similar to SBF from untested skin. A possible content of allergen extract in SBF from allergen-tested skin areas was not responsible for the observed effects as demonstrated in passive cutaneous anaphylaxis experiments in monkeys. High doses of SBF from untested skin were able to induce LCRs similar to but weaker than LCRs produced by SBF taken at early phases from dual skin reactions. Similar volumes of autologous heparin-plasma or serum did not induce LCRs. It is concluded that during the initial phase of dual skin reactions, factors are formed that are able to induce LCRs. The generation of these mediators seems to be caused at least in part by the extravasation of plasma.

Thromboxanes may be involved in late cutaneous reactions (LCRs). A new selective inhibitor of thromboxane biosynthesis was studied for its effect on immediate skin test reactions (WFRs) and LCRs in nine adult nonatopic volunteers (open study) and eight adult atopic patients (double-blind study vs. placebo). WFRs and LCRs were elicited by intradermal injections of 25 micrograms of compound 48/80 and 200 IU of rabbit anti-human IgE antibodies, and the patients' receiving injections of 0.32, 1.6, 8, 40, and 200 IU of anti-IgE antibodies. Dazoxiben (100 mg orally three times once every 4 hr) increased the diameter of wheals (p less than 0.005 in volunteers; p less than 0.05 in six patients receiving no additional drug treatment), favored their dispersion (lymphangitis/pseudopodia), and caused systemic reactions (headache, chills) in at least two out of eight patients. Edema formation during LCRs was markedly depressed in 13 out of 16 persons. Flare diameter and erythemata during LCRs were not altered. These data suggest a role of thromboxanes and their natural antagonists (e.g., prostacyclin) in the regulation of allergic inflammatory processes.