Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNOKC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Allergy and Environmental Medicine (GPA), German Respiratory Society (DGP), and the Austrian Society for Allergy and Immunology (ÖGAI).

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of ß-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.

Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for Pediatric Allergology (GPA), the German Contact Dermatitis Research Group (DKG), the German Society for Pneumology (DGP), the German Society of Otorhinolaryngology, Head and Neck Surgery, the Austrian Society of Allergology and Immunology (ÖGAI), the Austrian Society of Dermatology and Venereology (ÖGDV), the German Academy of Allergology and Environmental Medicine (DAAU), and the German Documentation Center for Severe Skin Reactions (dZh).

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The role of IgG1 and IgG4 as dominant IgE-blocking antibodies shifts during allergen immunotherapy.

BACKGROUND: The induction of allergen-specific IgE-blocking antibodies is a hallmark of allergen immunotherapy (AIT). The inhibitory bioactivity has largely been attributed to IgG4; however, our recent studies indicated the dominance of IgG1 early in AIT. OBJECTIVES: Here, the IgE-blocking activity and avidity of allergen-specific IgG1 and IgG4 antibodies were monitored throughout 3 years of treatment. METHODS: Serum samples from 24 patients were collected before and regularly during AIT with birch pollen. Bet v 1-specific IgG1 and IgG4 levels were determined by ELISA and ImmunoCAP, respectively. Unmodified and IgG1- or IgG4-depleted samples were compared for their inhibition of Bet v 1-induced basophil activation. The stability of Bet v 1-antibody complexes was compared by ELISA and by surface plasmon resonance. RESULTS: Bet v 1-specific IgG1 and IgG4 levels peaked at 12 and 24 months of AIT, respectively. Serological IgE-blocking peaked at 6 months and remained high thereafter. In the first year of therapy, depletion of IgG1 clearly diminished the inhibition of basophil activation while the absence of IgG4 hardly reduced IgE-blocking. Then, IgG4 became the main inhibitory isotype in most individuals. Both isotypes displayed high avidity to Bet v 1 ab initio of AIT, which did not increase during treatment. Bet v 1-IgG1 complexes were enduringly more stable than Bet v 1-IgG4 complexes were. CONCLUSIONS: In spite of the constant avidity of AIT-induced allergen-specific IgG1 and IgG4 antibodies, their dominance in IgE-blocking shifted in the course of treatment. The blocking activity of allergen-specific IgG1 should not be underestimated, particularly early in AIT.

Guideline on allergen immunotherapy in IgE-mediated allergic diseases: S2K Guideline of the German Society of Allergology and Clinical Immunology (DGAKI), Society of Pediatric Allergology and Environmental Medicine (GPA), Medical Association of German Allergologists (AeDA), Austrian Society of Allergology and Immunology (ÖGAI), Swiss Society for Allergology and Immunology (SSAI), German Dermatological Society (DDG), German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), German Society of Pediatrics and Adolescent Medicine (DGKJ), Society of Pediatric Pulmonology (GPP), German Respiratory Society (DGP), German Professional Association of Otolaryngologists (BVHNO), German Association of Paediatric and Adolescent Care Specialists (BVKJ), Federal Association of Pneumologists, Sleep and Respiratory Physicians (BdP), Professional Association of German Dermatologists (BVDD).

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Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Society of Allergology (AeDA), German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Austrian Society for Allergology and Immunology (ÖGAI), and the Paul-Ehrlich Society for Chemotherapy (PEG).

This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach - even in cases where the need to administer a BLA is acute - is guided by patient history and risk - benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole.

A novel role for neutrophils in IgE-mediated allergy: Evidence for antigen presentation in late-phase reactions.

BACKGROUND: Neutrophils and allergen-specific T cells accumulate in patients with allergic late-phase reactions (LPRs). Their presence is associated with severe inflammation. Cytokines, such as GM-CSF, IFN-γ, and IL-3, which are typically found in patients with allergic LPRs, have been proposed to convert neutrophils into antigen-presenting cells (APCs). OBJECTIVE: We sought to assess the antigen-processing and antigen-presenting capacities of neutrophils from allergic patients. METHODS: Neutrophils were isolated from peripheral blood of donors with birch pollen allergy and stimulated with GM-CSF, IFN-γ, and IL-3. The viability and expression of HLA-DR, CD80, and CD86 were assessed by using flow cytometry. HLA-DM expression was analyzed by means of immunoblotting. Allergen uptake was studied after fluorescence labeling of the major birch pollen allergen Bet v 1. Bet v 1 was digested with neutrophilic endolysosomal extracts, and the resulting fragments were sequenced by using mass spectrometry. Neutrophils were used as APCs in coculture experiments with autologous HLA-DR-restricted and Bet v 1-specific T-cell clones reactive with epitopes in different regions of the allergen. In all experiments monocytes were used for comparison. Fluids from suction blisters formed on top of LPRs induced by using intradermal allergen injection were assessed for HLA-DR+ neutrophils by using flow cytometry. RESULTS: The cytokines significantly enhanced the survival, allergen uptake, and expression of HLA-DM and HLA-DR on neutrophils. Neutrophils rapidly degraded Bet v 1 into fragments containing all relevant T-cell epitopes. Cytokine-activated, allergen-pulsed neutrophils induced proliferative and cytokine responses of Bet v 1-specific T cells irrespective of epitope specificity, confirming that they fully processed and presented the allergen. HLA-DR+ neutrophils were detected in patients with cutaneous allergic LPRs. CONCLUSION: Neutrophils can serve as APCs for local allergen-specific effector T cells in patients with allergic LPRs.

Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32.

BACKGROUND: BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein. OBJECTIVE: We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen-induced rhinitis and controlled asthma. METHODS: A double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 µg, n = 60) or high dose (160 µg, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC. RESULTS: Although statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year. CONCLUSIONS: Injections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

Predominant Api m 10 sensitization as risk factor for treatment failure in honey bee venom immunotherapy.

BACKGROUND: Component resolution recently identified distinct sensitization profiles in honey bee venom (HBV) allergy, some of which were dominated by specific IgE to Api m 3 and/or Api m 10, which have been reported to be underrepresented in therapeutic HBV preparations. OBJECTIVE: We performed a retrospective analysis of component-resolved sensitization profiles in HBV-allergic patients and association with treatment outcome. METHODS: HBV-allergic patients who had undergone controlled honey bee sting challenge after at least 6 months of HBV immunotherapy (n = 115) were included and classified as responder (n = 79) or treatment failure (n = 36) on the basis of absence or presence of systemic allergic reactions upon sting challenge. IgE reactivity to a panel of HBV allergens was analyzed in sera obtained before immunotherapy and before sting challenge. RESULTS: No differences were observed between responders and nonresponders regarding levels of IgE sensitization to Api m 1, Api m 2, Api m 3, and Api m 5. In contrast, Api m 10 specific IgE was moderately but significantly increased in nonresponders. Predominant Api m 10 sensitization (>50% of specific IgE to HBV) was the best discriminator (specificity, 95%; sensitivity, 25%) with an odds ratio of 8.444 (2.127-33.53; P = .0013) for treatment failure. Some but not all therapeutic HBV preparations displayed a lack of Api m 10, whereas Api m 1 and Api m 3 immunoreactivity was comparable to that of crude HBV. In line with this, significant Api m 10 sIgG4 induction was observed only in those patients who were treated with HBV in which Api m 10 was detectable. CONCLUSIONS: Component-resolved sensitization profiles in HBV allergy suggest predominant IgE sensitization to Api m 10 as a risk factor for treatment failure in HBV immunotherapy.

Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (ÖGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM).

Drug hypersensitivity reactions are unpredictable adverse drug reactions. They manifest either within 1-6 h following drug intake (immediate reactions) with mild to life-threatening symptoms of anaphylaxis, or several hours to days later (delayed reactions), primarily as exanthematous eruptions. It is not always possible to detect involvement of the immune system (allergy). Waiving diagnostic tests can result in severe reactions on renewed exposure on the one hand, and to unjustified treatment restrictions on the other. With this guideline, experts from various specialist societies and institutions have formulated recommendations and an algorithm for the diagnosis of allergies. The key principles of diagnosing allergic/hypersensitivity drug reactions are presented. Where possible, the objective is to perform allergy diagnostics within 4 weeks-6 months following the reaction. A clinical classification of symptoms based on the morphology and time course of the reaction is required in order to plan a diagnostic work-up. In the case of typical symptoms of a drug hypersensitivity reaction and unequivocal findings from validated skin and/or laboratory tests, a reaction can be attributed to a trigger with sufficient confidence. However, skin and laboratory tests are often negative or insufficiently reliable. In such cases, controlled provocation testing is required to clarify drug reactions. This method is reliable and safe when attention is paid to indications and contraindications and performed under appropriate medical supervision. The results of the overall assessment are discussed with the patient and documented in an "allergy passport" in order to ensure targeted avoidance in the future and allow the use of alternative drugs where possible.

Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies.

BACKGROUND: Early events of specific immunotherapy (SIT) are induction of allergen-specific IL-10-producing T(R)1 cells and production of IgG antibodies, but there is little knowledge about the long-term immune mechanisms responsible for sustained allergen tolerance. OBJECTIVE: Bet v 1-specific immune responses of 16 patients with birch pollen allergy were characterized up to 54 months at defined time points before, during, and after a 3-year period of SIT. METHODS: We sought to analyze allergen-specific T- and B-cell responses. Bet v 1-specific IL-5-, IFN-γ-, and IL-10-secreting T cells were quantified in peripheral blood, and birch pollen-specific IgE and IgG antibody levels were determined in serum. Furthermore, the inhibitory capacity of SIT-induced IgG was evaluated by blocking allergen binding to IgE and inhibition of facilitated allergen presentation. RESULTS: Seasonal increases in Bet v 1-specific T(H)2 cell numbers ceased to appear after the first year of SIT without deviation to a T(H)1-dominated immune response. Furthermore, the frequency of IL-10-producing T(R)1 cells, which had increased during the first year of SIT, returned to pretreatment levels in the second year. In contrast, allergen-specific IgG antibody concentrations continuously increased during SIT but started to decrease after cessation of treatment. Functional analysis confirmed the ability of the IgG antibodies to inhibit IgE-allergen interactions, which peaked at the end of SIT but then slowly started to decrease. CONCLUSION: Long-term allergen tolerance achieved by SIT is associated with the development of peripheral T-cell tolerance characterized by decreased reactivity of Bet v 1-specific T(H)2 cells and enriched allergen-specific IgG competing with IgE antibodies for allergen binding.

Birch pollen immunotherapy leads to differential induction of regulatory T cells and delayed helper T cell immune deviation.

Correction of an imbalance between allergen-specific T cell subsets is considered a critical event in establishing allergen tolerance by specific immunotherapy (SIT). In a comprehensive, longitudinal study, distinct T cell populations and Ig subtypes were analyzed in subjects allergic to birch pollen during decisive time points of SIT (i.e., induction and maintenance phase), as well as in and out of birch pollen season. An increase in Bet v 1-specific, IL-10-secreting T cells, fulfilling the criteria of inducible type 1 regulatory T (Tr1) cells, was observed by the end of the induction phase; this resulted in a decreased ratio of allergen-specific IL-5(+) Th2/Tr1 cells. In contrast, CD4(+)CD25(+)CD127(low) regulatory T cell numbers did not change. Furthermore, enhanced concentrations of allergen-specific IgG Abs were observed, whereas allergen-specific IgE and IgA levels remained unchanged. After 1 y of SIT, a reduced ratio of allergen-specific Th2/IFN-gamma(+) Th1 cells was apparent. Although untreated and SIT-treated allergic subjects developed enhanced Th2 cell responses during birch pollen season, only SIT-treated patients experienced elevated numbers of allergen-specific Tr1 cells, which were associated with reduced skin prick test reactivity and diminished clinical symptoms. In coculture assays, allergen-specific Tr1 cells showed an IL-10- and dose-dependent inhibition of CD4(+)CD25(-) T effector cells. Thus, SIT has differential effects on regulatory T cell subsets, resulting in an early induction of allergen-specific Tr1 cells associated with an increase in allergen-specific IgG, and it leads to a delayed shift from an allergen-specific Th2- to a Th1-dominated immune response.

[Systemic contact eczema against Balsam of Peru]. / Hämatogen-allergisches Kontaktekzem auf Perubalsam.

Balsam of Peru (PB; Myroxylon pereirae) is a natural product derived from resin of a tropical tree (MyroxyIon balsamum (L.) Harms var. pereirae (Royle) Baillon). Because of its antiseptic and aromatic properties PB or PB-components can be found worldwide not only in many health care and cosmetic products, but also in food items and semiluxury food. PB contains a wide variety of potent contact allergens leading to hypersensitivity reactions not only after topical application but also oral uptake. We report a 51-year-old brewer with chronic eczema of the hands who showed delayed-type patch test reactions against PB and fragrance-mix. Oral PB-challenge led to exacerbation of the eczema 5 and in a repeated test 2 days later. We here review this probably quite often overlooked disease and the therapeutic consequences which require profound knowledge about the wide distribution of PB when advising the patient about a PB-restricted diet. In addition, this unusual case report demonstrates that one has to consider marked delayed hypersensitivity reaction when investigating a systemic contact allergy.