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 .).

Digital technology for anaphylaxis management impact on patient behaviour: A randomized clinical trial.

BACKGROUND: Epinephrine is the first-line treatment for anaphylaxis. Patients at risk should always carry an epinephrine autoinjector (EAI). Several EAI gaps have been identified. We sought to evaluate satisfaction using a medical device (digital technology comprising an EAI smart case connected to a mobile APP) with functions that overcome most of the EAI limitations and to determine whether patient behaviour and anaphylaxis management improve with its use. METHODS: This was a randomized, open-label, crossover clinical trial in a tertiary hospital involving patients with history of anaphylaxis carrying an EAI. The study was conducted in two three-month periods, one with and one without the medical device. The primary endpoint was satisfaction with the medical device. Usability, adherence, anxiety and anaphylaxis episodes were evaluated as secondary endpoints. RESULTS: A total of 100 patients were included (mean age 38.1 years, 74% female), and 95 completed the trial. The satisfaction visual analogue scale (VAS) after using the medical device was higher than before its use (89.1 [95% CI, 60.2-99.1] vs 56.3 [95% CI, 48.1-81.4]; P < .0001). The adherence VAS improved from 59.7 (95% CI, 54.0-65.3) to 88.6 (95% CI, 84.2-92.9) (P < .0001). Overall, 90% patients found the medical device easy to use. Patients' anxiety decreased from 52.2% to 29.3% (P < .001). Seven episodes of anaphylaxis occurred during the study, all in patients without the medical device (P = .025). Eighty-eight per cent of patients felt more involved in the management of anaphylaxis when using the medical device. CONCLUSION: This is the first clinical trial evaluating digital technology for EAIs, showing a change of behaviour in patients at risk of anaphylaxis, increasing satisfaction, improving adherence, and reducing anxiety, with good usability.

Food-dependent NSAID-induced hypersensitivity (FDNIH) reactions: Unraveling the clinical features and risk factors.

BACKGROUND: In up to 70%-80% of patients with a suspected non-steroidal anti-inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food-dependent NSAID-induced hypersensitivity (FDNIH). METHODS: We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID. RESULTS: 199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%. CONCLUSION: Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

Peripheral Corticotropin-Releasing Factor Triggers Jejunal Mast Cell Activation and Abdominal Pain in Patients With Diarrhea-Predominant Irritable Bowel Syndrome.

INTRODUCTION: To determine the effect of peripheral CRF on intestinal barrier function in diarrhea-predominant IBS (IBS-D). Irritable bowel syndrome (IBS) pathophysiology has been linked to life stress, epithelial barrier dysfunction, and mast cell activation. Corticotropin-releasing factor (CRF) is a major mediator of stress responses in the gastrointestinal tract, yet its role on IBS mucosal function remains largely unknown. METHODS: Intestinal response to sequential i.v. 5-mL saline solution (placebo) and CRF (100 µg) was evaluated in 21 IBS-D and 17 healthy subjects (HSs). A 20-cm jejunal segment was perfused with an isosmotic solution and effluents collected at baseline, 30 minutes after placebo, and 60 minutes after CRF. We measured water flux, albumin output, tryptase release, stress hormones, cardiovascular and psychological responses, and abdominal pain. A jejunal biopsy was obtained for CRF receptor expression assessment. RESULTS: Water flux did not change after placebo in IBS-D and HS but significantly increased after CRF in IBS-D (P = 0.007). Basal luminal output of albumin was higher in IBS-D and increased further after CRF in IBS-D (P = 0.042). Basal jejunal tryptase release was higher in IBS-D, and CRF significantly increased it in both groups (P = 0.004), the response being higher in IBS-D than in HS (P = 0.0023). Abdominal pain worsened only in IBS-D after CRF and correlated with jejunal tryptase release, water flux, and albumin output. IBS-D displayed jejunal up-regulation of CRF2 and down-regulation of CRF1 compared with HS. DISCUSSION: Stress via CRF-driven mast cell activation seems to be relevant in the pathophysiology of IBS-D.

Safety of Adrenaline Use in Anaphylaxis: A Multicentre Register.

BACKGROUND: The use of intramuscular adrenaline to treat anaphylaxis is suboptimal, despite being the first-line treatment recommended by national and international anaphylaxis guidelines. Fear of potentially severe side effects may be one of the underlying factors. The aim of this study was to assess the incidence and severity of adverse side effects after the use of adrenaline in anaphylaxis, as well as potential risk factors. METHODS: Observational study based on a multicenter online registry of cases of adrenaline administration for suspected anaphylaxis. RESULTS: 277 registered valid cases were included: 138 (51.49%) female, median age 29 years (12-47), and 6 children under 2 years with a median age of 9 months (1-21). Side effects occurred in 58 cases (21.64%), with tremors, palpitations, and anxiety being the most frequent. There was a significant association of developing side effects with older age, higher dose of adrenaline, or use of the intravenous route. Potentially severe adverse effects (high blood pressure, chest discomfort, or ECG alterations) occurred only in 8 cases (2.99%); in these cases, no differences were found according to age or adrenaline dose, but again, intravenous administration was associated with more severe adverse events. CONCLUSION: This study shows that side effects affect less than 1 in 5 patients who receive adrenaline for an anaphylactic reaction, and are usually mild and transient. Therefore, in an emergency situation such as anaphylaxis, restricting adrenaline administration due to potential adverse effects would, in general, not be justified.

Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions.

BACKGROUND: Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-derived mediators into the circulation. OBJECTIVES AND METHODS: We report here that a plasma protease cascade, the factor XII-driven contact system, critically contributes to the pathogenesis of anaphylaxis in both murine models and human subjects. RESULTS: Deficiency in or pharmacologic inhibition of factor XII, plasma kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human factor XII restored susceptibility for allergen/IgE-mediated hypotension. Activated mast cells systemically released heparin, which provided a negatively charged surface for factor XII autoactivation. Activated factor XII generates plasma kallikrein, which proteolyzes kininogen, leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of factor XII, plasma kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal conditions or in healthy control subjects. The severity of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the intensity of contact system activation, and bradykinin formation. CONCLUSIONS: In summary, the data collectively show a role of the contact system in patients with anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.

Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations.

BACKGROUND AND AIMS: Altered intestinal barrier is associated with immune activation and clinical symptoms in diarrhoea-predominant IBS (IBS-D). Increased mucosal antigen load may induce specific responses; however, local antibody production and its contribution to IBS aetiopathogenesis remain undefined. This study evaluated the role of humoral activity in IBS-D. METHODS: A single mucosal jejunal biopsy, luminal content and blood were obtained from healthy volunteers (H; n=30) and IBS-D (n=49; Rome III criteria) participants. Intraepithelial lymphocytes, mast cells, B lymphocytes and plasma cells were studied by imaging techniques. Differential gene expression and pathway analysis were assessed by microarray and PCR techniques. Blood and luminal immunoglobulins (Igs) were quantified. Gastrointestinal symptoms, respiratory atopy and stress and depression were also recorded. RESULTS: Patients with IBS-D showed a higher number and activation of mucosal B lymphocytes and plasma cells (p<0.05). Mast cell density was increased in patients with IBS-D (non-atopic) and in close proximity to plasma cells (p<0.05). Microarray profiling identified differential humoral activity in IBS-D, involving proliferation and activation of B lymphocytes and Igs production (p<0.001). Mucosal humoral activity was higher in IBS-D, with upregulation of germline transcripts and Ig genes (1.3-fold-1.7-fold increase; p<0.05), and increased IgG(+) cells and luminal IgG compared with H (p<0.05), with no differences in blood. Biological markers of humoral activity correlated positively with bowel movements, stool form and depression. CONCLUSIONS: Enhanced small bowel humoral immunity is a distinctive feature of IBS-D. Mucosal Ig production contributes to local inflammation and clinical manifestations in IBS-D.

Identification and characterization of a novel splice site mutation in the SERPING1 gene in a family with hereditary angioedema.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal-dominant disease caused by mutations in SERPING1 gene. The main clinical feature of C1INH deficiency is the spontaneous edema of the subcutaneous and submucosal layers. More than 280 different mutations scattering the entire SERPING1 gene have been reported. We identified and characterized a new mutation in SERPING1 gene in a Spanish family with hereditary angioedema. The mutation (c.685 + 2 T > A) disrupts the donor splice site of intron 4 leading to the loss of exon 4 in mutant mRNA. We demonstrated that mutant mRNA is mostly degraded, probably by the surveillance pathway no-go mRNA decay. Bioinformatic analysis showed that the mutant protein, if produced, would be non-functional since the protein lacks a stretch of 45 amino acids affecting the functional RCL loop. Finally, we found a reduction of the wild-type mRNA expression in c.685 + 2 T > A carriers.

A novel splice site mutation in the SERPING1 gene leads to haploinsufficiency by complete degradation of the mutant allele mRNA in a case of familial hereditary angioedema.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal-dominant and life-threatening disorder caused by mutations in SERPING1 gene. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. Here we report the case of a patient with HAE-C1INH without family history of angioedema. By sequencing the SERPING1 gene we detected a novel mutation (c.1249 + 5G > A) affecting the 5' donor splice site in intron 7. We analyzed the SERPING1 cDNA expecting a defect in splicing process but only the wild type allele was detected. SNP analysis of the cDNA sequence demonstrated that only one of the two alleles was present, indicating that the mRNA from the mutated allele was completely degraded. This study reinforces the concept of incomplete penetrance of this disorder since the patients' mother never presented any sign of angioedema despite carrying the same mutation.

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier.

OBJECTIVE: Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. DESIGN: A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117(+) cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. RESULTS: Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. CONCLUSION: The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.

Systemic inflammation biomarkers during angioedema attacks in hereditary angioedema.

Background: Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks. Methods: Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients F12 gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured. Results: Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6-88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 vs. baseline) and D-dimer in 71% (p=0.001 vs. baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema. Conclusion: The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.

Serum Amyloid A as a Potential Biomarker for Disease Activity in Chronic Spontaneous Urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is an inflammatory skin disease with a complex physiopathology. Serum amyloid A (SAA), an acute-phase reactant, has been proposed as a potential biomarker in urticaria but has yet to be studied in a population with CSU or correlated with disease activity as indicated by the Urticaria Activity Score summed over 7 days (UAS7). OBJECTIVE: We sought to determine SAA-1 levels in patients with CSU and correlate them with its activity and control, as well as with clinical features of CSU and other potential blood biomarkers. METHODS: We conducted a retrospective multicenter study of 67 patients with CSU, from whom we obtained demographic and clinical data, UAS7 as an indicator of CSU activity, and blood and serum markers. RESULTS: SAA-1 levels positively correlated with UAS7 (rs = 0.47, P < .001). SAA-1 levels were higher in patients with noncontrolled (UAS7 > 6) CSU than in those with controlled (UAS ≤ 6) CSU (P < .001) and were also higher in patients with concomitant angioedema (P = .003) or delayed pressure urticaria (P = .003). CONCLUSION: We propose SAA-1 as a potential biomarker for activity in CSU. Further studies are required to evaluate its potential role as a biomarker for other CSU outcomes, such as response to treatment.

Challenging dogmas: Intravenous versus oral beta-lactam antibiotic provocation tests.

Background: Drug provocation tests (DPT) are considered the gold standard procedure to ascertain the diagnosis of beta-lactam (BL) allergy. Regarding route of administration, current recommendations prioritize oral challenges, considering them safer, and reserving the intravenous route for drugs for which this is the only formulation. Objective: To compare in terms of tolerance and safety two protocols of BL DPT, using an oral protocol (OR-DPT) and an intravenous protocol (IV-DPT). Methods: A descriptive, retrospective study was performed, including adult patients who underwent IV-DPT or OR-DPT for suspected immediate or delayed hypersensitivity to BL antibiotics, over a period of 4 years (between January 2018 and December 2021). Demographical data, index hypersensivity reactions' characteristics and tolerance to DPT were reviewed. Results: A total of 1036 patients underwent DPT, mean age of 56.8 (standard deviation, SD, 17.8) years, 655 were women (63.2%). Immediate drug hypersensitivity reactions (DHR) had occurred in 564 of patients (54.4%). OR-DPT were performed in 439 (42.4%) and IV-DPT in 597 (57.6%). The frequency of reactions during DPT, regardless of the route used, was low (3.6%): only 16 (3.6%) in OR-DPT and 21 (3.5%) in IV-DPT. From IV-DPT, 16 out 21 DHR during DPT were immediate compared with 4 out of 16 in OR-DPT. Adjusted relative risk of developing a hypersensitivity reaction during IV-DPT versus OR-DPT was 1.13 (95% confidence interval (CI)0.57-2.22). Conclusion: The results suggest that OR-DPT and IV-DPT are both safe procedures when adequately performed. However, IV-DPT protocols showed a higher rate of immediate DHR during DPT probably due to the selection of basal high-risk patients to undergo IV-DPT. In conclusion, IV-DPT may be considered as an option for challenges in drug-allergy studies, entailing a precise administration.

Hereditary angioedema in Spain: medical care and patient journey.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a genetic rare disease characterized by recurrent, transient and unpredictable episodes of cold, non-pruriginous oedema without associated urticaria. The characteristics of the disease have a considerable impact on the quality of life of patients. The aim of this study was to increase understanding of the patient journey of HAE in Spain. METHODS: A multidisciplinary committee of 16 HAE experts (allergy, immunology, emergency department, hospital pharmacy and nursing) and 3 representatives of the Spanish Hereditary Angioedema Patient Association (AEDAF) who were patients or caregivers participated in the study. A review of the publications on HAE treatment was performed. Semi-structured interviews were performed to HAE experts, patients, or caregivers. Three meetings with the experts, patients and caregivers were held to share, discuss, and validate data obtained from literature and interviews and to build the model. RESULTS: Throughout the project, the patient journey has been drawn up, dividing it into the stages of pre-diagnosis, diagnosis and treatment/follow-up. Some areas for improvement have been identified. Firstly, there is a need to enhance awareness and training on HAE among healthcare professionals, with a particular emphasis on primary care and emergency department personnel. Secondly, efforts should be made to minimize patient referral times to allergy/immunology specialists, ensuring timely access to appropriate care. Thirdly, it is crucial to encourage the study of the relatives of diagnosed patients to early identify potential cases. Fourthly, equitable access to self-administered treatments should be ensured, facilitated by systems that enable medication delivery at home and proper education and training for patients. Equitable access to long-term prophylactic treatment should also be prioritized for all patients in need. To standardize HAE management, the development of consensus guidelines that reduce variability in clinical practice is essential. Lastly, promoting research studies to enhance knowledge of the disease and align its treatment with new developments in the healthcare field should be encouraged. CONCLUSIONS: The knowledge of the patient journey in HAE allowed us to identify improvement areas with the final aim to optimize the disease management.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients.

BACKGROUND: The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis. OBJECTIVE: It was the aim of this study to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker. METHODS: We performed a prospective study including patients with acute anaphylaxis (according to the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria) attending the emergency department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1-2 h (T1), 4-6 h (T2) and 12-24 h (T3) following onset of the episode and at basal conditions (TB). RESULTS: A total of 102 patients were included (63 females, mean age 47.4 ± 19.1 years). Tryptase concentration at T1 (19.3 ± 15.4 µg/l) was significantly higher than at T2, T3 and TB (all <11.4 µg/l; p < 0.0001). Importantly, tryptase was not raised in 36.3% of cases; furthermore, in 60.6% of these patients, no changes were observed in tryptase levels comparing T1 and TB (ΔT1-TB = 0). Tryptase was more frequently elevated in more severe anaphylaxis (p < 0.0001) and positively correlated with the grades of severity (p < 0.001, r = 0.49). Anaphylaxis was more severe and tryptase concentration higher when the causative agent was a drug compared to food, both at T1 (p = 0.045) and at TB (p = 0.019). Age and coronary risk factors were associated with more severe anaphylaxis (p = 0.001). CONCLUSION: Tryptase is a biomarker related to the severity of anaphylaxis. However, since its concentration remains unaltered in a considerable number of patients during acute anaphylaxis, there is a need for more reliable diagnostic biological tests.

Classification and Treatment of Angioedema without Wheals: A Spanish Delphi Consensus.

INTRODUCTION: Problems in the definition and classification of angioedema, leading to difficulties in its diagnosis and treatment, have been identified; therefore, an improvement in the current classification of angioedema is required. OBJECTIVE: The aim of this study was to propose a practical classification of angioedema without wheals that helps to establish a differential diagnosis and take appropriate therapeutic decisions. METHODS: An initial proposal of classification of angioedema without wheals was agreed by a scientific committee of experts and was subsequently validated by a panel of experts by means of consensus based on the Delphi methodology. Forty-five items on the classification, diagnosis, and treatment of angioedema without wheals were proposed for the survey. RESULTS: Most items (93.8%) were agreed after two rounds. All panelists agreed with the proposed classification, as well as with most of the clinical and treatment characteristics. The angioedema without wheals classification established three groups: histamine-mediated, bradykinin-mediated, and unknown mechanism angioedema. The clinical characteristics of the proposed types of angioedema were also agreed, except for the allergic histamine-mediated and unknown mechanism angioedema, which generated debate. Regarding treatments, although there was broad agreement with the proposed items, a lack of knowledge about some treatments in this pathology was observed. CONCLUSION: The proposed classification of angioedema without wheals was accepted with a high degree of agreement; however, knowledge of available treatments needs to be increased and the definition of angioedema of unknown mechanism needs to be improved.