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BACKGROUND Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4+ T cells and low TCR-Vα7.2+ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Cough from an allergological as well as from the ENT aspect Abstract. Cough is a common problem in the allergological, but less so in the rhinological consultation. The differential diagnostic spectrum for cough is extensive and may range from rhinitis and asthma to eosinophilic esophagitis and rarer diseases. In the case of chronic cough (> 2 months), the four most frequent causes must be sought, or be excluded (upper airway cough syndrome, asthma [cough-variant-asthma], non-asthmatic eosinophilic bronchitis, gastroesophageal reflux disease). Aeroallergens such as pollen, house-dust mites or occupational substances play a major role in allergies. Nevertheless, it is not uncommon for cough to be a main symptom of an antibody deficiency or a Sicca symptom complex. The more chronic the cough, the more thoroughly an investigation is indicated - often interdisciplinary. Therapy depends on the cause of the cough. In allergic respiratory diseases, allergy-specific immunotherapy may be indicated.

Background Anaphylaxis is a medical emergency and requires prompt treatment to prevent life threatening conditions. Epinephrine considered as the first-line drug is often not administered. We aimed first to analyze the use of epinephrine in patients with anaphylaxis in the emergency department of a University Hospital and secondly to identify factors that influence the use of epinephrine. Methods We performed a retrospective analysis of all patients who were admitted with moderate or severe anaphylaxis to the emergency department between 1 January 2013 to 31 December 2018. Patient characteristics and treatment information were extracted from the electronic medical database or manually of the full emergency department discharge report. Results A total of 531 (0.2%) patients with moderate or severe anaphylaxis out of 260'485 patients admitted to the emergency department were included. Epinephrine was administered in 252 patients (47.3%). In a multivariate logistic regression cardiovascular (ORCARD = 2.94, CI 1.96–4.46, p RESP=3.14, CI 1.95–5.14, p INTEGU = 0.98, CI 0.54–1.81, p = 0.961) and gastrointestinal symptoms (ORGAST=0.62, CI 0.39–1.00, p = 0.053). Conclusions Less than half of the patients with moderate and severe anaphylaxis received epinephrine according to guidelines. In particular, gastrointestinal symptoms seem to be misrecognized as serious symptoms of anaphylaxis. Training of the rescue service and emergency department medical staff and further awareness are crucial to increase the administration rate of epinephrine in anaphylaxis.

Background Clinical management of allergic diseases has been hampered by the lack of safe and convenient tests to reliably identify culprit allergens and to closely follow changes in disease activity over time. Because allergy diagnosis is a complex and laborious multistep procedure, there is an urgent need for simpler but still functionally accurate ex vivo assays allowing objective diagnosis, substantiating treatment choices, and quantifying therapeutic responses. Objective In this study, we sought to develop a novel functional cell-based assay that relies on passive sensitization of allergic effector cells with patient serum, circumventing current limitations in allergy diagnosis. Methods We genetically engineered a conditional homeobox B8 (Hoxb8)-immortalized progenitor line from the bone marrow of mice that are transgenic for the human high-affinity IgE receptor (FceRIα). These cells can be reproducibly differentiated into mature Hoxb8 mast cells within 5 days of culture in virtually unlimited numbers. Results We demonstrate that the established Hoxb8 mast cell assay can be used to accurately measure total IgE levels, identify culprit allergens, longitudinally monitor allergen-specific immunotherapy, and potentially determine the time point of tolerance induction upon allergen-specific immunotherapy in patients with allergy. To facilitate the analysis of large testing volumes, we demonstrate a proof-of-concept for a high-throughput screening application based on fluorescent cell barcoding using the engineered Hoxb8 mast cells. Conclusions Our results indicate that this novel mast cell assay could represent a valuable tool to support clinicians in the identification of IgE-mediated allergies and in the quantification of treatment efficacy as well as duration of therapeutic response.

Purpose Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe delayed drug hypersensitivity reaction with exanthema, eosinophilia, and organ manifestations. After culprit drug withdrawal, systemic corticosteroids (CS) are the most widely used treatment, often requiring high doses for months. Blocking the IL-5/IL‑5 receptor axis with mepolizumab, reslizumab, and benralizumab is a promising targeted treatment with a good safety profile and no immunosuppressive effect. The aim of this study is to summarize current experience with the anti-IL5/IL-5-receptor therapy in DRESS. Methods A retrospective analysis of all patients diagnosed with DRESS and treated with mepolizumab, reslizumab, or benralizumab in DRESS was performed. In addition, a PubMed–Medline search for publications on DRESS with anti-IL-5/IL‑5 receptor treatment was performed. Results Of the 14 cases identified, 6 patients were treated with mepolizumab, 6 with benralizumab, 1 patient with reslizumab, and 1 patient was switched from benralizumab to mepolizumab. The main indication for an IL‑5 blockade was a therapy-refractory course (7/14 [50.0%]), recurrent relapses (3/14 [21.4%]), and severe organ dysfunction (2/14 [14.3%]). In 13/14 (93%) cases, a rapid clinical improvement with suppression of eosinophilia and reduction of CS could be achieved. In all but two cases under mepolizumab (dose 100–600 mg) or reslizumab (dose according to body weight), two or more doses were necessary until resolution of DRESS. In 4/7 cases under benralizumab, a single 30 mg dose was sufficient. Conclusion Blockade of the IL-5/IL‑5 receptor axis appears to be a promising treatment in DRESS with fast clinical improvement, which may allow more rapid reduction of CS, and a good safety profile. In addition, a summary of recommendations on when to use blockade of the IL-5/IL‑5 receptor axis in DRESS treatment is provided.

Background The diagnostic approach for beta-lactam (BL) drug hypersensitivity reactions (DHR) is based on the history, clinical signs, skin tests (ST), in vitro tests, and drug provocation tests (DPT). The aim of this study was to assess the performance of an allergy workup with ST in a real-world use. Methods In this cross-sectional study the rate of positive ST in subjects with suspected DHR to penicillins and cephalosporins was investigated. Of special interest were correlations of ST positivity: 1) to the time intervals between index reaction and the allergic work-up, 2) time interval from drug exposure to the onset of signs, 3) pattern of manifestation in delayed DHR and involvement of test area in the index reaction, and 4) potential advantage of patch testing in delayed DHR. Results 175 patients were included between January 2018 and April 2019 (63.4% female), 45 (25.7%) with immediate DHR manifestation and 130 with delayed DHR manifestation (74.3%). A total of 44 patients (25.1%) had a positive ST (immediate DHR 37.8% versus 20.0% in delayed DHR). ST positivity decreased in both groups after 3 years from 47.8% [95%CI 29.2–67] to 23.5% [95%CI 9.6–47.3] in immediate DHR and 23.0% [95%CI 15-4-32.9] to 12.9% [95%CI 5.1–28.9] in delayed DHR. The proportion of positive ST was higher in patients with more severe forms of delayed DHR, and in subjects with a shorter latency period of onset of symptoms after drug exposure: 0-3d: 29.5% [95%CI 19.6–41.9] vs. >3d: 11.6% [95%CI 6.0–21.2]). No sensitization was shown in delayed urticaria or angioedema. ST done outside the skin area involved during the index reaction were negative in all cases (0/38 vs. 26/84 in cases with involved area). The combination of patch test and intradermal test (IDT) revealed an additional positive result in 2/77 cases. Additional in vitro testing reduced the proportion of negative test results to 72%. Conclusion In most patients with negative test results, we could not clarify the cause of the BL-associated adverse events even with further investigations (including DPT). How to prevent new drug-induced adverse events in such patients has hardly been investigated yet. Corresponding cohort studies could improve the data situation.

Allergies to gadolinium-based contrast agents (GBCAs) are rare and manifest usually as an immediate drug hypersensitivity reaction (DHR), compatible with an immunoglobulin E (IgE)-mediated mechanism. Although the molecular structures of GBCA show some similarities and are either linear or macrocyclic, the frequency and pattern of cross-reactivity remain unclear. However, cross-reactivity has been described. The aim of this investigation was to assess cross-reactivity in patients with GBCA allergy based on skin tests and exposure. We retrospectively evaluated a total of 28 cases with a proven allergy to a GBCA, including 11 from the database of the allergy division of the Inselspital, Bern and 17 published cases from the literature, retrieved with a PubMed-MEDLINE search. The majority of cases were immediate DHR, with 8/11 cases from the database (72.7%) and 16/17 published cases (94.1%). In both groups macrocyclic GBCA were most often identified as causative drugs. A cross-reactivity based on skin test results was found in 2 out of 11 database cases (18.2%) and in 6 out of 17 literature cases (35.3%). Cross-reactivity occurred within macrocyclic GBCA in 1/11 database cases and 3/17 literature cases, and included both macrocyclic and linear GBCA in 1/11 and 4/17 subjects. There was no cross sensitization among linear GBCA. Skin test-negative GBCA were well tolerated, even in cases with sensitization to linear and macrocyclic GBCA. Overall, cross-reactivity in GBCA allergy is rare (approximately 29%), and may occur among macrocyclic GBCA or in between macrocyclic and linear GBCA. IgE to linear GBCA seems to be rarely cross-reactive. Skin test is helpful in identifying safe alternatives, as no reaction to skin test-negative GBCA was observed.

Zusammenfassung. Betalactamantibiotikaallergien sind die am häufigsten erwähnten Medikamentenallergien. In der Hausarztpraxis oder im Falle einer Hospitalisation äussern Patienten oft, an einer Penicillinallergie zu leiden, weswegen in diesen Fällen meist keine Betalactamantibiotika verwendet werden. Häufig handelt es sich bei einer vermeintlichen Allergie jedoch um Nebenwirkungen wie Diarrhoe, Nausea oder Bauchschmerzen. Der grösste Teil dieser Patienten verträgt Betalactamantibiotika ohne Probleme, weswegen eine allergologische Abklärung wichtig ist. Hierfür ist eine gute Anamnese und Dokumentation zentral, da Hautteste und in vitro Verfahren eine eingeschränkte Sensitivität haben. Ergänzend kann mittels Provokationstest eine fragliche Allergie oder alternative, potentiell kreuzreaktive Betalactamantibiotika in Hinblick auf ihre Verträglichkeit geprüft werden. Die Kreuzreaktivität mit Cephalosporinen, insbesondere der 3. Generation und höher, wird meist überschätzt. Kreuzreaktionen zu Carbapenemen sind selten.

BACKGROUND Despite the efficacy of allergen-specific immunotherapy (AIT), the role of trained immunity and tolerance in this process has not been elucidated. OBJECTIVE Here, we have performed a comprehensive longitudinal analysis of the systemic innate immune cell repertoire during the course of AIT. METHODS Patients with allergy received standard preseasonal subcutaneous AIT with allergoids to birch and/or grass. Healthy controls were monitored without any intervention. Flow cytometry of innate lymphoid cell (ILC), natural killer cell, monocyte cell, and dendritic cell (DC) subsets was performed at baseline, 3 months (birch season), 6 months (grass seasons), and 12 months after the therapy in patients or at similar seasonal time points in controls. Additional analyses were performed in the third-year birch and grass season. RESULTS We observed a durable decrease in group 2 ILCs and an increase of group 1 ILCs after AIT, with dynamic changes in their composition. We found that an expansion of CD127+CD25++ clusters caused observed shifts in the heterogeneity of group 1 ILCs. In addition, we observed development of CD127+CD25++c-Kit+ group 3 ILC clusters. Moreover, we found an increase in the number of intermediate monocytes in parallel with a reduction in nonclassical monocytes during the first year after AIT. Classical and intermediate monocytes presented significant heterogeneity in patients with allergy, but AIT reduced the HLA-DR++ clusters. Finally, an increase in plasmacytoid DCs and CD141+ myeloid DCs was observed in individuals with allergy, whereas the number of CD1c+ myeloid DCs was reduced during the first year of AIT. CONCLUSION AIT induces changes in the composition and heterogeneity of circulating innate immune cells and brings them to the level observed in healthy individuals. Monitoring of ILCs, monocytes, and DCs during AIT might serve as a novel biomarker strategy.

Cough from an allergological as well as from the ENT aspect

Les allergies alimentaires (AA) sont relativement frequentes dans la pratique quotidienne. Il convient de faire la distinction entre AA primaire et secondaire.

Background Eosinophilic esophagitis (EoE) is a chronic inflammatory disease that has been known since the early 1990s. Swallowed topical corticosteroids (STC) belong to the therapeutic cornerstones. We describe a delayed hypersensitivity reaction to Jorveza®, a newly developed orodispersible budesonide tablet licensed for the treatment of eosinophilic esophagitis. Case presentation A 32-year-old Caucasian woman with EoE was newly treated with Jorveza®. Hours after the first intake, she felt a “strange pruritus” in the throat. This sensation worsened with each subsequent intake. On day 4 she developed oral mucosal symptoms (paresthesia of the tongue, sore and an itchy throat). Intraoral, throat and facial swellings, but no systemic reaction were observed. Patch testing using two commercial test series as well as the orodispersible budesonide tablet revealed a strong sensitization, proving a T cell mediated allergy to budesonide. Conclusions Orodispersible budesonide is increasingly prescribed for the treatment of eosinophilic esophagitis. The development of oropharyngeal symptoms after initiating should alert the treating physician to the possibility of a hypersensitivity reaction.

Background A drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T cell mediated hypersensitivity reaction. Relapses of symptoms in the recovery phase are frequent and linked to the reduction of the corticosteroid treatment, to viral reactivations or to the exposure to new drugs. Here, we analyzed, how often the exposure to new drugs leads to new sensitization or drug-related relapses without detectable sensitization. Methods 46 patients with DRESS treated in the allergy division of the Inselspital, Bern University Hospital, were retrospectively assessed. Drug-related relapses were analyzed in terms of frequency and whether a possible sensitization evaluated by skin tests and/or lymphocyte transformation tests (LTT) to the new drugs was detectable. Furthermore, drug tolerance was evaluated in a subset of patients. Results 56 relapses were observed in 27 of 46 patients with DRESS (58.7%). 33 (58.9%) of these relapses were associated with the use of new drugs, 30 drug-related relapses were evaluated by patch test and/or lymphocyte transformation test. In 8/30 (26.7%) drug-related relapses, a sensitization to the new drug was demonstrated, suggesting the emergence of a multiple drug hypersensitivity syndrome (MDH). 14 patients experienced 22 drug-related relapses without any detectable sensitization and only 1/6 patients developed new symptoms upon reexposure. Conclusion Patients with DRESS frequently suffered from drug related relapses. Half of the patients with drug-related relapses developed a MDH with proven sensitizations not only to the DRESS inducing drugs, but also to newly applied drugs. When not sensitized, drugs involved in drug related relapses could be reintroduced, if needed. Here, we propose a procedure for drug testing and future management of drug-related relapses in DRESS.

Background: Chlorhexidine (CHX) is a widely utilized disinfectant that can cause IgE-mediated urticaria/anaphylaxis. The cross-reactivity of patients with IgE-mediated CHX allergy with other disinfectants, which share structural similarities with CHX like polyhexanide (polyhexamethylene biguanide; PHMB), alexidine (ALX), or octenidine (OCT), is unknown. Methods: Forty-four patients with anaphylaxis or urticaria upon CHX exposure and positive skin prick test (SPT) and/or positive CHX ImmunoCAP test (Phadia TFS, Uppsala, Sweden) were recruited. IgE to the biguanide and/or hexamethylene structure was investigated with PHMB ImmunoCAP (n = 32) and by basophil activation tests (BAT) with CHX and ALX (n = 37). Inhibition tests of CHX and PHMB ImmunoCAPs by CHX, ALX, PHMB, and OCT were performed. Results: IgE reactivity to PHMB as surrogate marker for biguanide/hexamethylene reactivity was detected in 5/32 sera. Seven of 37 patients showed a positive BAT with ALX, but only under optimized conditions. Binding to CHX ImmunoCAP was inhibited by ALX in 1/32 sera, and binding to PHMB was blocked by ALX (1/5) and by OCT in another (1/5). In SPT, 9/10 patients were positive for CHX and 3 of them with ALX (only at highest concentration at 5 mg/mL). A further patient reacted primarily with OCT and showed IgE cross-reactivity with CHX, ALX, and PHMB. Conclusion: The IgE response to CHX seems polyclonal. The chloroguanide ending of CHX is the main epitope for the IgE and is suitable as screening assay to detect CHX reactivity. IgE-reactivities with the biguanide or hexamethylene components of other disinfectants (ALX, PHMB) can be detected by SPT, PHMB ImmunoCAP, and ALX-BAT in 15%-33% of CHX-allergic patients.

Allergische Erkrankungen und deren Behandlung spielen in der Grundversorgung eine wichtige Rolle. Insbesondere bei Beschwerden wahrend der Schwangerschaft stellt sich die Frage nach einer vertraglichen Therapie.

Background Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare inherited disease. In most HAE-affected subjects, defined trigger factors precede angioedema attacks. Mechanisms of how trigger factors stimulate the contact activation pathway with bradykinin generation are not well elucidated. In recent studies, hypersensitivity reactions and food were stated as relevant triggers. We investigated HAE affected people for possible hypersensitivity reactions or intolerances and their relation in triggering angioedema attacks. Methods A questionnaire was filled in, recording date of birth, gender, and self-reported angioedema attacks associated with the ingestion of foodstuffs, administration of drugs, hymenoptera stings and hypersensitivity reactions against inhalation allergens. All participants performed a skin prick test against inhalation allergens and food. In patients who stated an association of possible hypersensitivity with angioedema, a serological ImmunoCAP test was also performed. Results From the 27 women and 15 men analyzed, 79% stated trigger factors. From those food was mentioned in 36%. The suspected food included tomato, green salad, fish, citrus fruits, apple, onion, garlic, cheese, chili, kiwi, milk, tree nuts, strawberry, pineapple, shrimps, bread, banana, leek, chicken and alcohol, and were associated with abdominal angioedema. Neither the skin prick test nor the ImmunoCAP-test turned out positive for the tested food allergens. Conclusion Food seems to be a relevant trigger factor, causing angioedema in HAE affected patients. The reason, however, is not IgE-mediated hypersensitivity, but most probably an intolerance reaction to food products.

Eine Hypersensitivitat auf endogenes Progesteron kann zu vielfaltigen, zyklisch rezidivierenden Hautveranderungen fuhren. Die klinischen Manifestationen konnen von Urtikaria, Angioodemen, Erythema multiforme und Ekzemen bis hin zur Anaphylaxie reichen. Am haufigsten manifestieren sich Ekzeme und Hautschwellungen (Urtikaria, Angioodeme), die auch kombiniert auftreten konnen. Bei einer zyklischen Hautsymptomatik ist an eine autoimmune Progesterondermatitis zu denken. Mittels einer Hauttestung mit Progesteron kann die Verdachtsdiagnose bekraftigt werden. Je nach Leidensdruck und Symptomatik stehen mehrere Therapieoptionen zur Wahl.

Background: Patients with mastocytosis often suffer from a variety of symptoms caused by mast cell mediators where treatments remain difficult, showing various success rates. Omalizumab, a monoclonal anti-IgE antibody, has been postulated to have a positive impact on mastocytosis-associated symptoms such as flush, vertigo, gastrointestinal problems, or anaphylaxis. Objective: To investigate the efficacy and safety of omalizumab in systemic mastocytosis. Methods: Patients with histologically proven mastocytosis were investigated in a multicenter prospective double-blind placebo-controlled trial to receive either omalizumab or placebo, dosed according to IgE and body weight. The primary endpoint was change in the AFIRMM activity score after 6 months of treatment. Different laboratory parameters were analyzed. Results: Sixteen patients were analyzed: 7 to omalizumab and 9 to placebo (mean age 47.7 ± 13.8 vs. 45.4 ± 8.8 years; 66.6 vs. 85.7% were female; mean disease duration 10.0 ± 5.1 vs. 4.5 ± 2.9 years, respectively). After 6 months the median AFIRMM score decreased 50% from 52.0 to 26.0 in the omalizumab group versus 104.0–102.0 in the placebo group (p = 0.286); however, the difference was not significant (p = 0.941). Secondary endpoints, including the number of allergic reactions, changes in major complaints, wheal-and-flare reaction due to mechanical irritation (Darier’s sign), and frequency of the use of mastocytosis-specific drugs improved in the omalizumab group, but not significantly. Adverse events like urticaria, bronchospasm, and anaphylactic shock showed no significant difference between the groups. No severe adverse events occurred. FcεRI (Fc-epsilon receptor) expression on basophils decreased after receiving omalizumab versus placebo. Conclusion: Omalizumab was safe and showed a tendency to improve mastocytosis-related symptoms, in particular diarrhea, dizziness, flush, and anaphylactic reactions, including the AFIRMM score and secondary endpoints; however, the difference was not significant. Due to the small study size and difference at baseline between the study groups, further studies are required to confirm our findings.

Sensitization to Hymenoptera venom in patients without a history of systemic allergic reactions to Hymenoptera stings is frequently found and can be due to the presence of specific IgE to cross-reactive carbohydrate determinants (CCD). This study investigates 105 pollen allergic subjects for the presence of specific IgE to honeybee or wasp venom, pollen, the MUXF3 carbohydrate epitope from bromelain and recombinant Hymenoptera venom components. In addition, in a subgroup of patients (n = 10) a basophil activation test (BAT) using bee and wasp venom was performed. Specific IgE to Hymenoptera venom was detected in 45.7% of the pollen allergic subjects and in 26.7% of the non-atopic controls, both without a history of systemic allergic reactions to Hymenoptera stings. The high sensitization rate in atopic patients could partially be explained by cross-sensitization between pollen and Hymenoptera venom due to specific IgE to CCDs. In our study population, only 20% showed a sensitization to CCDs. Primary sensitization due to sting exposure, high total IgE values or unspecific binding and detection of low affinity antibodies in the test procedure could be reasons. Thus, determination of specific IgE to Hymenoptera venom in patients without a history of systemic allergic reactions as screening test is not recommended.

Background Multiple drug hypersensitivity syndrome (MDH) is used to describe persons with a drug hypersensitivity reaction (DHR) to at least two chemically unrelated drugs, confirmed by skin test or in vitro assay. Methods Medical records of 25 patients with MDH, tested and confirmed at our allergy division, were retrospectively evaluated in terms of clinical course, involved drugs, daily drug dose, latency periods, test results of skin test and cellular assays, and tolerated drugs in subsequent pharmacological treatments. Results Multiple drug hypersensitivity syndrome almost exclusively appeared as a delayed, often severe DHR and started in 14/25 with a drug reaction with eosinophilia and systemic symptoms (DRESS). Penicillins (13/25, 52.0%) and cephalosporins (6/25, 24.0%), typical high-dose drugs, were most often identified as elicitors of MDH, especially at the first DHR, followed by aromatic antiepileptics (7/25, 28.0%), vancomycin (4/25, 16.0%), and antibiotic sulfonamides (4/25, 16.0%). Cephalosporins, clindamycin, and radio contrast media (RCM) were mainly involved in subsequent DHR. The median daily drug dose of all drug trigger was 1875.0 mg (662.5; 2100.0) at the first DHR and 600.0 mg (300.0; 1300.0) at subsequent DHR, P = .0420. Conclusion High-dose drugs, especially beta-lactam antibiotics, RCM and clindamycin, are common elicitors of subsequent DHR in patients with MDH. Macrolides, quinolones, doxycycline, nonaromatic antiepileptics, and paracetamol were often tolerated. As the same drugs elicited both flare-up reactions and real DHR, drug-induced flare-up reactions may be precursors of a possible second DHR and MDH. The administration of highly dosed drugs should be avoided in patients at risk for MDH.

Sensitization to Hymenoptera venom in patients without a history of systemic allergic reactions to Hymenoptera stings is frequently found and can be due to the presence of specific IgE to cross-reactive carbohydrate determinants (CCD). This study investigates 105 pollen allergic subjects for the presence of specific IgE to honeybee or wasp venom, pollen, the MUXF3 carbohydrate epitope from bromelain and recombinant Hymenoptera venom components. In addition, in a subgroup of patients (n = 10) a basophil activation test (BAT) using bee and wasp venom was performed. Specific IgE to Hymenoptera venom was detected in 45.7% of the pollen allergic subjects and in 26.7% of the non-atopic controls, both without a history of systemic allergic reactions to Hymenoptera stings. The high sensitization rate in atopic patients could partially be explained by cross-sensitization between pollen and Hymenoptera venom due to specific IgE to CCDs. In our study population, only 20% showed a sensitization to CCDs. Primary sensitization due to sting exposure, high total IgE values or unspecific binding and detection of low affinity antibodies in the test procedure could be reasons. Thus, determination of specific IgE to Hymenoptera venom in patients without a history of systemic allergic reactions as screening test is not recommended.

Allergic patients display abnormal immune responses to harmless antigens, including abnormal Th2 polarization and induction of allergen-specific T and B cells, resulting in development of allergy instead of tolerance. Allergen-specific immunotherapy (AIT) is currently the only causative treatment of allergic disorders. Yet, understanding of the underlying differences in allergen-specific responses between allergy and tolerance is lacking. We investigated whole-genome transcriptomics of circulating birch and grass specific CD4+ T cells in patients before and during AIT, as well in non-allergic healthy controls. Detailed immunophenotyping with flow cytometry and CD4+ MHC class II tetramer staining with low RNA/single cell next generation sequencing were performed. At baseline, out of the season, there were more allergen-specific CD4+ T cells in allergic patients than in controls. At this time, over 1500 genes were differently expressed in allergen-specific CD4+T cells in patients, but they were less upregulated in signal transduction, inflammatory response and coagulation categories as compared to controls. During AIT we noted further increase of allergen-specific CD4+ cells with subsequent gene expression change. Finally, we found increase in allergen-specific Treg cells in patients upon AIT, but not in tolerant controls. Yet, at early AIT time points, allergen-specific Treg cells displayed gene profiles suggesting their insufficient functions. In summary, in vivo allergen exposure causes profound changes in the transcriptomic profiles of allergen-specific T cells. These gene profiles seem to be deficient at baseline in allergic patients, but AIT is skewing them into the tolerant controls levels.

Background Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease for which there are no available laboratory parameters to clearly define the disorder. Therapy is often difficult and various treatment options have been proposed. In this paper, we have evaluated the most effective therapies for InH-AAE on the basis of current literature and report the therapeutic effect of omalizumab in three patients with InH-AAE. Methods Literature was searched with a combination of MeSH/EMTREE terms and freetext search for angioedema and therapy/omalizumab in the databases Medline (Ovid), PubMed/Premedline, Embase, Cochrane library and Scopus with no time or language restrictions. In three patients affected by InH-AAE the therapeutic effect of omalizumab was demonstrated by clinical outcome. In one patient the FcεRI receptor density on basophils was monitored under therapy with omalizumab. Results From the review of the current literature, 25 out of 286 publications dealing with relevant therapeutic recommendations for InH-AAE were analyzed. Six publications with 98 patients referred to tranexamic acid, of which 27 had a complete, 70 a partial and 1 no response. In three case reports ecallantide showed 2 patients with a complete and 1 a partial response. In four case reports for Icatibant 2 had a complete and 3 a partial response. When evaluated in three reports, C1-INH found complete and partial responses in 2 patients each. One patient had a complete response to progestin. Omalizumab was described in 6 reports with 20 patients, all of whom showed a complete response. All three patients described in our study responded to omalizumab with a complete remission. Density of FcεRI receptors on basophils, monitored in patient 1 on a long-term course of 31 months, decreased from 74,051.61 to a minimal level of 1907 receptors per cell. Conclusions Omalizumab seems to be the most effective therapy in InH-AAE. The continuous decrease of FcεRI-receptor density on basophils under therapy with omalizumab along with clinical improvement observed in one patient, could serve as a new approach for further studies to evaluate FcεRI-receptor density as a surrogate marker for therapeutic efficacy and for dosing and determining injection intervals of omalizumab. Trial registration BASEC-Nr. Req-2016-00692. Retrospectively registered 24.11.2016. Electronic supplementary material The online version of this article (doi:10.1186/s13601-017-0164-9) contains supplementary material, which is available to authorized users.

En Suisse, ce sont chaque annee trois a quatre personnes qui decedent en raison d’une reaction allergique severe suite a une piqure d’insecte. Cet article de revue detaille les principaux insectes, facteurs de risque et manifestations cliniques des reactions allergiques consecutives aux piqures d’insectes, ainsi que leur traitement aigu. Les derniers procedes diagnostiques ainsi que les traitements – et en particulier l’immunotherapie specifique au venin d’insectes – y sont egalement presentes.

Die Hymenopterengiftallergie ist weltweit eine der wichtigsten Ursachen fur allergische und anaphylaktische Reaktionen, die bis zum Tod fuhren kann. Auch wenn sich durch Globalisierung und Klimawandel andere Hymenopterenarten verbreiten konnen, sind in Mitteleuropa Honigbienen- und Wespenstiche die haufigsten Ausloser der Allergie. Der Nachweis eines erhohten basalen Tryptasewerts hat sich als Risikofaktor fur schwere allergische Reaktionen nach Insektenstichen mehrfach bestatigt, sodass dessen Bestimmung heutzutage in der Diagnostik unerlasslich ist. Bis heute sind 12 Bienen- und 6 Wespengiftallergene identifiziert. Therapeutisch ist die spezifische Immuntherapie (SIT) mit Insektengiften immer noch die einzige kausale und auch effektive Behandlung. Wahrend fast alle Patienten mit Wespengiftallergie durch die Immuntherapie mit Wespengift geschutzt sind, entwickeln etwa 20 % der Bienengiftallergiker trotz Bienengiftimmuntherapie bei Reexposition noch – meist leichtere – Allgemeinreaktionen. Aufgrund der aktuellen Forschungsrichtung mit Identifizierung IgE-induzierender Allergene rucken andere Therapieansatze in den Hintergrund.

Objective Control of airway inflammation is the cornerstone of asthma management. The aim of the present pilot study was to assess the effects of a leukotriene receptor antagonist (LTRA) added to a basic treatment of inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA) on airway hyperresponsiveness, inflammation, and quality of life in well-controlled patients with asthma. Research design and methods Seventeen patients (age 18–65, 11 women) with well-controlled asthma presenting airway hyperresponsiveness to mannitol and methacholine challenge were given add-on montelukast on a stable ICS + LABA for 4 weeks. Quality of life and selected parameters of airway inflammation were measured at baseline and at study end. (ClinicalTrials.gov (NCT01725360)). Results Adding montelukast to ICS + LABA resulted in an increase in mean FEV1 (+4.5%, p = 0.057), cumulated higher dose of mannitol (+32.5%, p = 0.023) and methacholine (+17.2%, 0.237) in the provocation test, lower airway reactivity with mannitol and methacholine (response dose ratio (RDR) –50.0%, p = 0.024 and –44.3%, p = 0.006, respectively), and improved airway sensitivity to mannitol and methacholine (+12.1%, p = 0.590 and +48.0%, p = 0.129 for PD15 and PD20 FEV1, respectively). Changes in inflammation parameters (blood eosinophil count, serum eosinophil cationic protein, and exhaled nitric oxide) were consistent with these findings. Asthma-related quality of life improved significantly in all domains and overall (from 5.3 at baseline to 6.1 at the final visit, p

BACKGROUND Registration of trigger factors, prodromal symptoms, swelling localization, therapeutic behavior and gender-specific differences of the largest cohort of patients with hereditary angioedema due to C1-Inhibitor deficiency (C1-INH-HAE) in Switzerland. METHODS Questionnaire survey within a cohort study: Consenting eligible patients with diagnosed HAE according to clinical history, physical examination and laboratory results, including plasma values for C1-INH and C4 were selected. To each participant we sent a questionnaire assessing patients' birthday, sex, date of first symptoms and diagnosis, trigger factors, prodromal symptoms, frequency and localization of angioedema, medication use and co-morbidities. Clinical information was collected in each center and then transmitted to the cohort database. Frequencies and distributions were summarized. Associations between gender and trigger factors or prodromal symptoms or localization of angioedema were assessed in multivariate analyses correcting for patients' age. RESULTS Of 135 patients, data from 104 patients (77%) were available for analysis. Fifty- four percent were female, mean age at diagnosis was 19.5 years (SD 14.1), Mean age when completing the questionnaire was 44.0 (SD 19.8). More women than men were symptomatic (44/57 vs. 36/47; p = 0.005). This association remained when correcting for age at diagnosis (16.10. 95%CI (5.17 to 26.70); p = 0.004). Swelling episodes ranged between 1 and 136 episodes/year. Swelling was more common among female than among male (-13.15 (95% CI; -23.10 to -3.22), p = 0.010). Age at diagnosis was inversely associated with the total number of attacks 0.50 (-0.88 to -.011); p = 0.012). One third of patients were on danazol prophylaxis. CONCLUSION We found large differences of HAE in male and female both in terms of symptom number and swelling episodes. Women are more affected by intensity and frequency of angioedema episodes than men. Danazol treatment remains widely used as effective prophylaxis despite its side effects. New therapies which selectively influence the hormonal estrogen balance could open new therapeutic options mainly for women and maybe also for men.

Tierallergien sind nach der Hausstaubmilbenallergie der häufigste Grund allergischer Atemwegsbeschwerden in Innenräumen. Falls eine ständige Allergenexposition besteht werden die Symptome wie Rhinitis, Hautjuckreiz oder Asthma gewöhnlich nicht als heftig empfunden und können daher auch nicht einem Tier oder einer Tierquelle zugeordnet werden. In vielen Fällen basiert die Tierallergie auf einer perenniale Allergenexposition. Auch wenn wahrscheinlich alle Tiere Ursache einer Atemwegsallergie sein können, sind doch Katzen, Hunde und Pferde die häufigsten Auslöser. Die Diagnose einer Allergie auf ein Tier muss mit Sorgfalt gestellt werden, weil sie häufig emotionale Reaktionen, verschiedene Konflikte, aber auch Unverständnis auslöst. Seltener sind Pilzallergien, auch wenn sie als Allergiequellen seit Jahrzehnten zur Differentialdiagnose der Atemwegsallergie gehören, speziell beim Spätsommerasthma. Pilze sind ubiquitär und sind in Wohnräumen wie auch in der Natur stets präsent. Leider ist das Gebiet der Pilzallergie wenig erforscht und die diagnostischen Möglichkeiten sind begrenzt. Die erfolgversprechendste Therapie sowohl bei einer Tier- oder einer Pilzallergie wäre den Kontakt mit der jeweiligen Allergenquelle vollständig zu meiden. Zwar werden diverse präventive Empfehlungen abgegeben, aber oft gelingt die Umsetzung nicht zufriedenstellend. In ausgewählten Fällen kann die spezifische Immuntherapie sowohl bei der Tier- wie auch bei der Pilzallergie eine therapeutische Option sein.

Background: The aim of this study was to analyze the influence of total serum IgE and other potential risk factors on severity of systemic allergic Hymenoptera sting reactions. Methods: In a retrospective analysis of one thousand and two patients referred for insect allergy over 5 years, 865 reported systemic allergic sting reactions, most often by honey bees and wasps. In 758, total IgE, venom-specific IgE, and baseline tryptase levels were available and analyzed together with atopy state, age, and sex in relation to severity of sting reactions according to H. L. Mueller. Results: In a binary logistic regression model considering, besides IgE, also other risk factors for severity, an influence of total and specific IgE on severity of systemic allergic sting reactions could not be shown, while high severity of systemic allergic sting reactions was significantly more often reported in patients with a baseline tryptase of ≥11.4 μg/l (P Language: en

Background: Anaphylaxis is an acute generalized hypersensitivity reaction initiated by various triggers which involves the entire organism and which may be life threatening. Although international guidelines for the emergency treatment of anaphylaxis have been published, the therapeutic recommendations are implemented differently. In this study besides the etiology of anaphylaxis, we were interested in how and where the patients have been treated and whether or not this reaction did occur for the first time. Methods: From January 1 to December 31 of 2008 1,075 patients have been referred to the allergy unit of the communal hospital in Berne (Zieglerspital) for an allergological work-up. 54 (5.0%) of them had had an anaphylaxis defined as shock, drop of blood pressure or collapse. The examination consisted of a detailed history and a comprehensive allergological assessment. Results: The average age of the 54 patients ― 28 women (52%) - was 43 years. In 46 (85%) of them the cause for anaphylaxis was a Hymenoptera venom allergy. Other triggers were: drugs [3], exercise-induced [2], multi-factorial [2] and food [1]. 20/54 subjects (37%) had a recurrent systemic reaction; all of them were allergic to Hymenoptera venom. 6 of them (30%) possessed emergency medications (antihistamines/corticosteroids); none of them had an epinephrine-autoinjector. 48/54 patients (89%) have been treated in a hospital or by the emergency doctor; 2/6 were supported by family members, and 4 recovered spontaneously. For therapy most often corticosteroids (92%) and antihistamines (89%) were used; epinephrine, however, only in 9 cases (17%). Conclusion: This investigation shows that emergency treatment of anaphylaxis in the region of Bern does not concur with the advocated guidelines. Epinephrine as first-line therapy in anaphylaxis has been used rarely. More than one-third of the patients already had a previous allergic generalized reaction elicited by the same culprit (in our case hymenoptera stings). Only one-third of these carried emergency medications but none of them possessed an epinephrine-autoinjector.

Background: Approximately 20% of subjects with asthma experience an acute bronchoobstruction after ingestion of ASA/NSAID. In specialized clinics the inhalative broncho-provocation test (IPT) with L-ASA is a well-established method to confirm the diagnosis of aspirin-induced asthma (AIA). The objective of this investigation was to establish a new, short-during IPT with L-ASA as a diagnostic tool in an outpatient clinic. Method: In the years 2001 to 2005, 65 patients (35 F, 30 M, mean age 42 years (16 - 73 years), performed an IPT with L-ASS. Group 1 comprised 37 patients with asthma and nasal polyposis, Group 2 17 patients with asthma but without nasal polyposis, and Group 3 11 patients with only cutaneous symptoms after intake of aspirin/NSAID. The IPT was performed stepwise with 5, 15 and 40 mg L-ASA up to a cumulative dose of 60 mg. Patients with a negative IPT underwent an oral provocation test with aspirin. Results: In group 1 11/37 (30%), in group 2 6/17 (35%), and in group 3 none of 11 (0%) had a positive IPT. The threshold dose was in 13 out of 17 reactors (76%) ≤ 20 mg L-ASA. Except in 1 patient, the bronchial-obstructive reaction was well-reversible after the inhalation ofsalbutamol. 24 out of 48 patients with a negative IPT with L-ASA underwent consecutively an oral provocation test with aspirin. 4 of them reacted with mild clinical symptoms after a cumulative dose of> 500 mg ASA. Conclusion: Our modified schema of IPT with L-ASA up to a cumulative dose of 60 mg L-ASA is suitable for diagnosing an AIA in an ambulatory setting. The IPT with L-ASA is a sensitive and safe provocation test lasting about 3 h. A negative IPT at 60 mg L-ASA excludes a significant reaction following the intake of low-dose aspirin (100 - 300 mg), this information may be essential in the prophylaxis and treatment of cardiovascular diseases.