Despite the efficacy of allergen-specific immunotherapy (AIT), the role of trained immunity and tolerance in this process has not been elucidated.
Here, we have performed a comprehensive longitudinal ...analysis of the systemic innate immune cell repertoire during the course of AIT.
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.
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.
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.
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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 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.
Although mRNA-based vaccines against SARS-CoV-2 induce a robust immune response and prevent infections and hospitalizations, there are limited data on the antibody response in individuals with ...humoral immunodeficiency. The aim of this study was to evaluate the humoral immune response after two vaccine doses with BNT162b2 or mRNA-1273 in patients with humoral immunodeficiency disease.
This cross-sectional study assessed 39 individuals with hypogammaglobulinemia under immunoglobulin replacement therapy. IgG anti-SARS-CoV-2 spike protein antibodies (anti-S) were measured 4 weeks to 4 months after two doses of an mRNA vaccine against SARS-CoV-2. The proportion of patients, who developed a humoral immune response to the spike protein were evaluated and compared to 19 healthy controls.
After vaccination with two vaccine doses, 26/39 patients (66.7%) with humoral immunodeficiency disease and all healthy controls developed anti-S. In subjects with baseline IgG <3 g/l, only 1/5 (20%) showed a humoral immune response. 10 out of 26 with CVID (38.5%) and 7/9 under immunosuppressive drugs (77.8%) developed no immune response (13 subjects with no response) compared to 0/19 in healthy controls. Subgroup analysis in patients without immunosuppressive drugs revealed lower anti-S in patients with moderate to severe humoral immunodeficiency disease: baseline IgG <3 g/l: 12.0 AU/ml (95%CI 12.0-125.0), baseline IgG 3-5 g/l: 99.9 AU/ml (95%CI 14.4-400.0), baseline IgG >5 g/l: 151.5 AU/ml (95%CI 109.0-400.0), healthy controls 250.0 AU/ml (95%CI 209.0-358.0), p = 0.007.
In most patients with mild to moderate humoral immunodeficiency we found only slightly lower anti-S antibodies compared with healthy controls after two vaccine doses with BNT162b2 and mRNA-1273. However, in patients with a decreased baseline IgG below 3 g/l and/or under immunosuppressive drugs, we found severely impaired humoral immune responses.
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 testnegative 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.
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 ...analyse 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.
We performed a retrospective analysis of all patients admitted with moderate or severe anaphylaxis to the emergency department between 1 January 2013 and 31 December 2018. Patient characteristics and treatment information were extracted from the electronic medical database of the emergency department.
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 (Odds Ratio OR = 2.94, CI 1.96-4.46, p <0.001) and respiratory symptoms (OR = 3.14, CI 1.95-5.14, p<0.001) were associated with increased likelihood of epinephrine administration, in contrast to integumentary symptoms (OR = 0.98, CI 0.54-1.81, p = 0.961) and gastrointestinal symptoms (OR = 0.62, CI 0.39-1.00, p = 0.053).
Less than half of the patients with moderate and severe anaphylaxis received epinephrine according to guidelines. In particular, gastrointestinal symptoms seem to be misrecognised as serious symptoms of anaphylaxis. Training of the emergency medical services and emergency department medical staff and further awareness are crucial to increase the administration rate of epinephrine in anaphylaxis.
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.
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.
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.
Anaphylaxis is the most severe form of acute systemic and potentially life-threatening reactions triggered by mast and basophilic cells. Recent studies show a worldwide incidence between 50 and 112 ...occurrences per 100,000 person-years. The most identified triggers are food, medications, and insect venoms. We aimed to analyze triggers and clinical symptoms of patients presenting to a Swiss university emergency department for adults.
Six-year retrospective analysis (01/2013 to 12/2018) of all patients (> 16 years of age) admitted with moderate or severe anaphylaxis (classification of Ring and Messmer ≥ 2) to the emergency department. Patient and clinical data were extracted from the electronic medical database of the emergency department.
Of the 531 includes patients, 53.3% were female, the median age was 38 IQR 26-51 years. The most common suspected triggers were medications (31.8%), food (25.6%), and insect stings (17.1%). Organ manifestations varied among the different suspected triggers: for medications, 90.5% of the patients had skin symptoms, followed by respiratory (62.7%), cardiovascular (44.4%) and gastrointestinal symptoms (33.7%); for food, gastrointestinal symptoms (39.7%) were more frequent than cardiovascular symptoms (36.8%) and for insect stings cardiovascular symptoms were apparent in 63.8% of the cases.
Average annual incidence of moderate to severe anaphylaxis during the 6-year period in subjects > 16 years of age was 10.67 per 100,000 inhabitants. Medications (antibiotics, NSAID and radiocontrast agents) were the most frequently suspected triggers. Anaphylaxis due to insect stings was more frequently than in other studies. Regarding clinical symptoms, gastrointestinal symptoms need to be better considered, especially that initial treatment with epinephrine is not delayed.
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.
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.
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.
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.
Background H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects. Objective We sought to analyze the influence ...of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT). Method In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures. Results Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A2 -stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-γ and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC. Conclusions LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells.
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