An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.

Cross-protection of AIT-induced antibodies to related allergens requires a high degree of structural identity.

BACKGROUND: In contrast to sublingual immunotherapy (SLIT) with recombinant Mal d 1 (rMal d 1-SLIT), SLIT with rBet v 1 (rBet v 1-SLIT) induced Mal d 1-cross-reactive antibodies without IgE-blocking activity. To elucidate whether the development of cross-protective IgG responses depends on the degree of molecular identity of allergens we compared the cross-reactivity, cross-blocking activity, and affinity of SLIT-induced antibodies with allergens of varying amino acid sequence identities to Bet v 1 and Mal d 1, namely Cor a 1.04 (hazelnut), Pru av 1 (cherry), and Dau c 1 (carrot). METHODS: Allergen-specific antibodies were quantified by ELISA. IgE blocking was analyzed by inhibition of allergen-induced basophil activation and IgE-facilitated allergen-presentation to T cells. The affinity of SLIT-induced antibodies was studied by acidic dissociation ELISA and competition ELISA. Identical surface areas on allergens were predicted using an in-house designed script based on structural alignments. RESULTS: rBet v 1-SLIT-induced IgG antibodies cross-reacted with all allergens except Dau c 1. rMal d 1-SLIT-induced antibodies predominantly cross-reacted with Pru av 1 and displayed significantly higher IgE blocking to Pru av 1 than rBet v 1-SLIT-induced antibodies. rMal d 1-SLIT-induced IgG1 showed higher affinity to Mal d 1 and Pru av 1. Surface analysis revealed 84% identical area on Mal d 1 and Pru av 1. Furthermore, we identified two surface areas potentially containing epitopes present on these allergens and absent on Bet v 1. CONCLUSION: In summary, our findings suggest that a relatively high threshold of similarity is required to establish effective cross-blocking antibodies to related allergens. Apparently, the structural identity between Bet v 1 and Mal d 1 is below this threshold. Therefore, this study may explain why immunotherapy with birch pollen allergen often fails to reduce birch pollen-related apple allergy.

Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis.

BACKGROUND: Chronic nodular prurigo (CNPG) is an inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuroimmunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type 2 cytokines such as IL-4, IL-13, and IL-31. OBJECTIVES: This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD). METHODS: We profiled skin lesions from patients with CNPG in comparison with AD and healthy control individuals using single-cell RNA sequencing combined with T-cell receptor sequencing. RESULTS: We found type 2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14-IL24+ secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin B in fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings. CONCLUSIONS: These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD but is rather characterized by upregulated stromal remodeling mechanisms that might have a direct impact on itch fibers.

Diagnostic difficulties in pediatric annular dermatoses.

The polymorphic presentation of annular dermatoses in the pediatric population renders them a diagnostic challenge to the clinician. They include various distinct disease entities that can be vaguely categorized according to the age of onset. Herein, we report on a young girl with clinical characteristics of Wells' syndrome, while histological findings favored the diagnosis of annular erythema of infancy (AEI). Although morphological and histological similarities do exist, AEI and eosinophilic annular erythema (EAE) of childhood are considered as distinct entities in the literature. Wells' syndrome (WS) is an eosinophilic dermatosis and histologically characterized by eosinophilic dermal infiltration with the hallmark feature of "flame figures." Based on this case, we discuss and review the differential diagnoses of annular dermatoses in children.

Anaphylactic reaction to carboplatin diagnosed by skin testing-a reliable tool in platinum-based immediate-type hypersensitivity reactions.

Immediate-type hypersensitivity reactions (IHRs) to carboplatin (CA) are most commonly reported in ovarian cancer patients. A 54-year-old woman with stage IV melanoma suffering from metastasis in the entire right lower extremity was presented to our allergy outpatient clinic for diagnostic work-up due to an anaphylactic reaction with palmoplantar erythema, conjunctivitis along with facial erythema, and an incipient decrease in blood pressure during a chemotherapy regimen with dacarbazine and carboplatin upon re-administration. A subsequently carried out allergological work-up with skin testing (ST) revealed CA to be the culprit drug, whereas cisplatin (CI) was confirmed to be a safe alternative for the patient for following treatments. Here, we report a case of an IHR to carboplatin in a melanoma patient, with CI serving as a safe alternative diagnosed by skin testing.

Comparison of Permethrin-Based Treatment Strategies against Scabies in Infants and Young Children.

OBJECTIVE: To optimize the permethrin-based therapies for scabies infestations in infants and young children, the efficacies of 3 different regimens were evaluated. STUDY DESIGN: The retrospective analysis encompassed 85 infants and children aged <4 years with scabies. The children had received either topical permethrin 5% on the entire body on days 1/8, on days 1/8/15, on days 1/8/15 plus interim applications restricted to hands and feet on days 2/3/4//9/10/11, or alternative treatments. RESULTS: The intensified regimen, consisting of full-body permethrin applied on days 1/8/15 and hands/feet on days 2/3/4//9/10/11, resulted in cure of scabies in 73.5% of the cases. The cure rates were significantly greater compared with full-body permethrin given on days 1/8, which led to eradication in 44%, and were greater compared with the clearance in children who had received full-body permethrin on days 1/8/15 (53.8%) or alternative treatments (60%). For patients in whom permethrin had previously been applied, the intensified regimen resulted in eradication of scabies in 71.4% of the cases, compared with 30% and 55.6% after full-body permethrin on days 1/8 and 1/8/15, respectively. CONCLUSIONS: The intensified regimen of full-body permethrin plus interim applications on hands/feet, which aims at reducing the number of mites present on the frequently heavily infested palmoplantar sites in addition to the standard entire body application, appears efficacious in curing scabies in young children.

Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA²LEN position paper.

BACKGROUND: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. METHODS: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. RESULTS: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. CONCLUSION: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.

Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

IgE-cross-blocking antibodies to Fagales following sublingual immunotherapy with recombinant Bet v 1.

BACKGROUND: Evidence has accumulated that birch pollen immunotherapy reduces rhinoconjunctivitis to pollen of birch homologous trees. Therapeutic efficacy has been associated with IgE-blocking IgG antibodies. We have recently shown that sera collected after 16 weeks of sublingual immunotherapy with recombinant Bet v 1 (rBet v 1-SLIT) display strong IgE-blocking bioactivity for Bet v 1. Here, we assessed whether rBet v 1-SLIT-induced IgG antibodies display cross-blocking activity to related allergens in Fagales pollen. METHODS: IgE, IgG1 and IgG4 reactivity to recombinant Bet v 1, Aln g 1, Car b 1, Ost c 1, Cor a 1, Fag s 1, Cas s 1 and Que a 1 were assessed in pre- and post-SLIT samples of 17 individuals by ELISA. A basophil inhibition assay using stripped basophils re-sensitized with a serum pool containing high Bet v 1-specific IgE levels was established and used to assess CD63 expression in response to allergens after incubation with pre-SLIT or post-SLIT samples. IgG1 and IgG4 were depleted from post-SLIT samples to assess its contribution to IgE-cross-blocking. RESULTS: Sublingual immunotherapy with recombinant Bet v 1 boosted cross-reactive IgE antibodies and induced IgG1 and IgG4 antibodies with inter- and intra-individually differing reactivity to the homologs. Highly variable cross-blocking activities of post-SLIT samples to the different allergens were found. IgG1 and IgG4 antibodies displayed cross-blocking activity with individual variance. CONCLUSIONS: Our mechanistic approach suggested that immunotherapy with the reference allergen Bet v 1 induces individual repertoires of cross-reactive IgG1 and IgG4 antibodies. The cross-blocking bioactivity of these antibodies was also highly variable and neither predictable from protein homology nor IgE-cross-reactivity.

IgE-blocking antibodies following SLIT with recombinant Mal d 1 accord with improved apple allergy.

BACKGROUND: We recently reported that 16 weeks of sublingual immunotherapy (SLIT) with recombinant (r) Mal d 1, but not rBet v 1, significantly improved birch pollen-related apple allergy. Allergen-specific IgE-blocking IgG antibodies have been associated with clinical efficacy. OBJECTIVE: We compared the quantity, quality, and IgE-blocking bioactivity of SLIT-induced Mal d 1-specific IgG antibodies in both treatment groups. METHODS: Pre- and post-SLIT sera were assessed for rMal d 1-specific IgG antibodies in ELISA and for their ability to inhibit apple allergen-induced upregulation of CD63 on basophils from nontreated individuals with birch pollen-related apple allergy. Post-SLIT sera depleted of IgG1 or IgG4 were compared for their IgE-blocking activity. IgG1 binding to rMal d 1 was competed with rMal d 1 and rBet v 1 in ELISA. RESULTS: SLIT with rMal d 1 and rBet v 1 induced comparable levels of rMal d 1-specific IgG1, IgG2, IgG3, and IgG4 antibodies. Only post-rMal d 1 SLIT sera displayed IgE-blocking activity, which was significantly reduced by depletion of IgG1 and less so by IgG4 depletion. In competition ELISA, IgG1 binding to Mal d 1 in post-rMal d 1 SLIT sera was fully inhibited with rMal d 1 but not with rBet v 1. Correspondingly, Bet v 1 was the more potent competitor for IgG1 binding to Mal d 1 in post-rBet v 1 SLIT sera. CONCLUSION: rMal d 1 SLIT for 16 weeks induced functional, primarily Mal d 1-specific IgE-blocking antibodies, whereas rBet v 1 SLIT induced Bet v 1-specific, Mal d 1-cross-reactive IgG antibodies with limited cross-blocking activity. These results provide a possible explanation for the limited effectiveness of birch pollen immunotherapy in birch pollen-related food allergy and indicate a dominant protective role of functional IgE-blocking IgG1 antibodies in the early phase of allergy treatment.

Hypopyon sign as an unusual complication of varicella infection in a girl with atopic dermatitis.

Varicella-zoster virus (VZV) infection, also known as chickenpox, is a common childhood affliction. Generalized small itchy single-standing vesicles on erythematous skin are typical. Both cutaneous and systemic complications of the VZV infection may commonly occur. A three-year-old girl with a previous history of mild atopic dermatitis presented in our Pediatric Dermatology Clinic in poor general condition, with a skin rash predominantly consisting of generalized large blisters with hypopyon sign and erosions. On a closer look, scattered erythematous papules and vesicles were also visible. A positive Tzanck smear from an intact pinhead-sized vesicle and VZV PCR confirmed the clinical diagnosis of chickenpox. Cultures from hypopyon material revealed Staphylococcus aureus superinfection. We report an exceptional, not-yet described complication of chickenpox with hypopyon-forming superinfection in an atopic child. In addition, our case nicely underscores the necessity of early VZV vaccination, which has been available and recommended now for more than 10 years in pediatric vaccination programs to avoid severe complications.

Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: Results of the PURIST Study.

BACKGROUND: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. METHODS: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). RESULTS: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively. CONCLUSIONS: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.

Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy.

BACKGROUND: Birch pollen-related apple allergy is among the most prevalent food allergies in adolescent/adult subjects and mainly results from sensitization to the major birch pollen allergen Bet v 1 and subsequent cross-reaction with the apple protein Mal d 1. However, specific immunotherapy with birch pollen has inconsistent effects on apple allergy. OBJECTIVE: We sought to compare the safety and efficacy of sublingual immunotherapy (SLIT) with 2 formulations containing either rMal d 1 or rBet v 1 on birch pollen-related apple allergy. METHODS: Sixty participants with birch pollen-related apple allergy were randomized to daily sublingual application of placebo (n = 20) or 25 µg of rMal d 1 (n = 20) or rBet v 1 (n = 20) for 16 weeks. Adverse events were regularly recorded. Sublingual challenges with standardized doses of rMal d 1, skin prick tests with recombinant allergens, and measurements of allergen-specific IgE and IgG4 antibodies were performed before and after treatment. RESULTS: Both formulations caused comparable, mainly local adverse events. No systemic reactions occurred. Compared with the placebo and rBet v 1-treated groups, SLIT with rMal d 1 reduced rMal d 1-induced oral symptoms (P = .001 and P = .038) accompanied by longitudinally reduced rMal d 1-specific cutaneous reactions (P = .022) and enhanced IgG4/IgE ratios (P = .012). SLIT with rBet v 1 neither improved the clinical reactivity to rMal d 1 nor enhanced rMal d 1-specific IgG4/IgE ratios. Participants receiving placebo showed no allergen-specific changes. CONCLUSION: Sublingual treatment with a recombinant food allergen was safe and clinically effective, as determined by using standardized challenges. We present a promising approach for the effective treatment of birch pollen-related apple allergy.

Hereditary angioedema in Austria: prevalence and regional peculiarities.

BACKGROUND: Data on the prevalence and clinical features of Austrian patients with hereditary angioedema (HAE) with C1-inhibitor (C1-INH) deficiency (HAE-1) or dysfunction (HAE-2) are lacking. METHODS: Current baseline data were collected in a national survey. The records of HAE patients at the Medical University of Graz were analyzed with regard to clinical characteristics. RESULTS: A total of 137 patients were identified, yielding a prevalence of 1 : 64,396. The median age at the onset of symptoms was 6.5 years, and the median age at the time of correct diagnosis 21.0 years. The median delay in diagnosis was 15.0 years for newly diagnosed patients without a family history of HAE. Patients with a family history of HAE received an immediate diagnosis. HAE patients without a family history of HAE and born before 1960 had to wait a median of 16.0 years until they were diagnosed correctly. Patients born after 1980 still experienced a median diagnostic delay of 6.5 years. CONCLUSION: Patients with this condition still face an excessive diagnostic delay in some parts of Austria, or their disorder may even remain unrecognized by specialists. This underlines the need for better awareness of the disease.

Oral exposure to Mal d 1 affects the immune response in patients with birch pollen allergy.

BACKGROUND: Antibodies and T cells specific for the major birch pollen allergen Bet v 1 cross-react with structurally related food allergens, such as Mal d 1 in apple. OBJECTIVE: We sought to evaluate the effects of oral uptake of Mal d 1 on the allergen-specific immune response in patients with birch pollen allergy. METHODS: Patients received 50 µg of rBet v 1 sublingually on 2 consecutive days outside of the birch pollen season. One year later, equal amounts of rMal d 1 were administered. Blood samples were collected before and after oral exposure, as well as before and after the intermediate birch pollen season. Allergen-specific IgE levels were determined by using ImmunoCAP. Proliferation of allergen-stimulated PBMCs was assessed, as well as the expression of IL-5, IL-13, IL-10, IFN-γ, and forkhead box protein 3 (Foxp3) in isolated T cells (real-time PCR). Allergen-specific T-cell lines were analyzed for epitope recognition. RESULTS: Orally administered Bet v 1 transiently reduced Bet v 1-specific serum IgE levels, as well as Bet v 1- and Mal d 1-induced T-cell proliferation, and enhanced the expression of IL-5, IL-10, and Foxp3. Orally applied Mal d 1 significantly decreased Bet v 1- and Mal d 1-specific IgE levels and induced IL-5 and IL-10 but no Foxp3 expression. In contrast to Bet v 1, Mal d 1 triggered IFN-γ production and T cells with a different epitope repertoire. Inhalation of birch pollen significantly enhanced allergen-specific IgE levels, T-cell proliferation, and IL-5, IL-10, IL-13, and Foxp3 expression. CONCLUSION: Two sublingual administrations of 50 µg of Mal d 1 were well tolerated and induced transient immune responses seen during peripheral tolerance development. Thus recombinant Mal d 1 might be suitable and relevant for sublingual treatment of birch pollen-related apple allergy.