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Background: Prodromes are signs and symptoms preceding attacks. Many Hereditary Angioedema patients are able to foretell the onset of attacks by having a prodrome. However, the clinical significance and practical value of prodromes as predictors of attacks needs to be assessed by objective measures. Objective: To prospectively evaluate associations between prodromes and attacks. Methods: 48 patients reported four occasions of prodromes, attacks or both. Pre-defined domains and scalable dimensions were assessed in each episode by a disease-specific instrument. Results: Participants reported 192 different events. Significant differences were found across all dimensions, indicating that prodromes are distinct from attacks. Positive correlations were found between the same attributes of prodromes and attacks. Specifically, pain was correlated in the extremities (r = .291, p < .05) and oropharyngeal clusters (r = .936, p < .01). Impairment was correlated across all clusters, most notably in the abdomen (r = .288, p < .05) and face (r = .588, p < .05) clusters. Dysfunction correlated for the abdomen (r = .366, p < .01), facial (r = .882, p < .01), extremities (r = .381, p < .05) and oropharyngeal (r = .790, p < .05) clusters. Experiencing a prodrome is associated with higher risk of attack in the abdomen (RR=2.30), urogenital (RR=16.39), facial (RR=2.94), extremities (RR=5.55) and oropharyngeal (RR=33.31) locations. Conclusions: Prodromes can be distinguished from attacks. Most patients with prodrome had subsequent attack, and their clinical features correlated in certain body locations. Experiencing prodromal signs and symptoms increase likelihood of having an attack.

Hereditary angioedema (HAE) is rare disease characterized by recurrent, unpredictable, and debilitating attacks of subcutaneous/submucosal tissue swelling.1,2 The reported median age of onset of HAE due to C1 inhibitor deficiency/dysfunction (type 1/2; C1-INH-HAE) is 11-12 years.1,3 Treatment options for pediatric patients are limited, owing to low childhood diagnosis rates and low representation in investigative clinical trials.4 We present a multicenter, open-label, single-arm, phase 3 study (NCT01386658) investigating the use of icatibant, a bradykinin B2 receptor antagonist, to treat HAE attacks in pediatric patients with a confirmed diagnosis of C1-INH-HAE.5 In Part 1, patients (aged 2 to

A disease-specific, patient-reported outcome instrument suitable for evaluation of prodromes and attacks of hereditary angioedema (HAE) is a clinical unmet need. We constructed such instrument and examined its validity, acceptability, and discriminative ability. Sixty-six patients participated in a survey addressing their demographics, social, and medical status. Discriminant content validity involved: (1) construct definition by in-depth cognitive debriefing interviews, (2) item selection identifying relevant categories, and (3) judgment of the format whereby questionnaires were tested on experienced patients and its content/reliability was validated. Prodromes and attacks affecting certain body systems (domains) were organized in “clusters”. Internal consistency, content, and convergent validities were analyzed. Analyses of variance and regression models were used to evaluate the discriminative ability of the instrument to differentiate between attacks and prodromes. The study demonstrates very high internal consistency (Cronbach’s α: attacks 0.88–0.98, prodromes 0.78–0.98). Analysis of variance confirmed significant differences between all dimensions and in pre-defined clusters (F (4, 61) = 45.74, p

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin and mucosal edema. The main treatment goal is to enable a "normal life" for all patients. However, due to high costs, there are limited options for the management of HAE in most developing and low-income countries. As a result, most of the recommended first-line treatments are not available. In this review, we attempt to highlight the disparities in health-care resources for the management of patients with HAE amongst different countries. Data was collected from HAE experts in countries who provide tabulated information regarding management and availability of HAE treatments in their countries. We reviewed the two most recent international HAE guidelines. Using India, the world's second most populous country, as a paradigm for HAE management in lower-income countries, we reviewed the evidence for second-line and non-recommended practices reported by HAE experts. Results suggest significant inequities in provision of HAE services and treatments. HAE patients in low-income countries do not have access to life-saving acute drugs or recently developed highly effective prophylactic medications. Most low-income countries do not have specialized HAE services or diagnostic facilities, resulting in consequent long delays in diagnosis. Suggestions for optimizing the use of limited resources as a basis for future discussion and reaching a global consensus are provided. There is an urgent need to improve HAE services, diagnostics and treatments currently available to lower-income countries. We recommend that all HAE stakeholders support the need for global equity and access to these essential measures.

Background: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects ≤17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Methods: Eligible subjects (age ≥6 years, with ≥4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (≤17 vs. >17 years) were performed for key efficacy endpoints. Results: Ten subjects were ≤17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects

Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin and mucosal edema. The main treatment goal is to enable a “normal life” for all patients. However, due to high costs, there are limited options for the management of HAE in most developing and low-income countries. As a result, most of the recommended first-line treatments are not available. In this review, we attempt to highlight the disparities in health-care resources for the management of patients with HAE amongst different countries. Data was collected from HAE experts in countries who provide tabulated information regarding management and availability of HAE treatments in their countries. We reviewed the two most recent international HAE guidelines. Using India, the world’s second most populous country, as a paradigm for HAE management in lower-income countries, we reviewed the evidence for second-line and non-recommended practices reported by HAE experts. Results suggest significant inequities in provision of HAE services and treatments. HAE patients in low-income countries do not have access to life-saving acute drugs or recently developed highly effective prophylactic medications. Most low-income countries do not have specialized HAE services or diagnostic facilities, resulting in consequent long delays in diagnosis. Suggestions for optimizing the use of limited resources as a basis for future discussion and reaching a global consensus are provided. There is an urgent need to improve HAE services, diagnostics and treatments currently available to lower-income countries. We recommend that all HAE stakeholders support the need for global equity and access to these essential measures. Supplementary Information The online version contains supplementary material available at 10.1007/s12016-021-08854-5.

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. Methods: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. Conclusions: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. Trial registration: The study is registered with ClinicalTrials.gov (NCT03472040).

Background Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1‐INH‐HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1‐INH (rhC1‐INH) for HAE attacks in children. Methods This open‐label, phase 2 study included children aged 2‐13 years with C1‐INH‐HAE. Eligible HAE attacks were treated intravenously with rhC1‐INH 50 IU/kg body weight (maximum, 4200 IU). The primary end‐point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end‐point was time to minimal symptoms (TTMS

A prodrome is a premonitory set of signs and symptoms indicating the onset of a disease. Prodromes are frequently reported by hereditary angioedema (HAE) patients, antedating attacks by a few hours or even longer. In some studies, high incidence of prodromes was reported by patients, with considerable number being able to predict oncoming attacks. Regrettably, prodromes have never received a consensual definition and have not been properly investigated in a systematic fashion. Therefore, their nature remains elusive and their contribution to the diagnosis and treatment of disorders is uncertain. The term "prodrome," as used in various pathologies, denotes different meanings, timing, and duration, so it may not be equally suitable for all clinical situations. Perception of a prodrome is unique for each individual patient depending on self-experience. As modern drugs delegate the administration decision to the patients, early detection of a developing attack may help mitigate its severity and allow deployment of appropriate therapy. New diagnostic instruments were recently developed that can assist in defining the attributes of prodromes and their association with attacks. We will review the prodrome phenomenon as exhibited in certain clinical situations, with an emphasis on prodromes of HAE.

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

Background Icatibant is a bradykinin B2-receptor antagonist used for the treatment of hereditary angioedema attacks resulting from C1-inhibitor deficiency. Treatment is not adjusted by body weight however the impact of body mass index (BMI) on the effectiveness of icatibant is not documented in the literature. We examined disease characteristics and icatibant treatment effectiveness in patients stratified by BMI in the Icatibant Outcome Survey, an ongoing, international, observational study monitoring the real-world safety and effectiveness of icatibant. Methods Attack and treatment characteristics as well as outcomes following treatment with icatibant were compared among patients with underweight, normal, overweight, and obese BMI. Results Data from 2697 icatibant-treated attacks in 342 patients (3.5, 44.7, 34.8, and 17.0% patients of underweight, normal, overweight, and obese BMI, respectively) were analyzed. There was no significant difference in the frequency and severity of attacks across BMI groups, although obese patients tended to have more attacks of high severity. There was no impact of BMI on the frequency of laryngeal attacks, but patients with normal BMI had fewer cutaneous attacks and more abdominal attacks. Most attacks (71.9–83.8%) were treated with a single icatibant injection without the need for rescue with plasma-derived C1-inhibitor (pdC1-INH), regardless of BMI. Patients with obese BMI used pdC1-INH as rescue treatment more often (P

Summary Background Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. Methods We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Findings Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p Interpretation Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. Funding Pharming Technologies.

Background For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). Objective To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Methods Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). Results A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. Conclusions In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures.OBJECTIVE: To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS).METHODS: The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE.RESULTS: In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 [41.7%] vs 38 of 58 [65.5%], respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001).CONCLUSION: From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment.TRIAL REGISTRATION: ClinicalTrials.gov: NCT01034969.

The term "swelling" has been used in the old scriptures to illustrate a change of normal figure and, as such, an expression of illness. It should be noted that in ancient times, human diseases were very often regarded a punishment from God. Hence, it is not surprising that one of the oldest tests for infidelity involved swelling as an inflicted punishment. The great Greek physician Hippocrates (377-460 BC), considered one of the most outstanding figures in the history of medicine and "Father of the Western Medicine," already used the term oídēma to describe swelling of organs. It took many centuries later until the first description of angioedema as a distinct medical entity was minted by Quinke in 1882. The historical progression in angioedema research has been characterized by intermittent "leaps" in interest and scientific achievements. As an example, it took 75 years from the accurate description of hereditary angioedema (HAE) by Osler (1888), until a group of researchers headed by Donaldson (1963) disclosed the central role of C1 inhibitor in angioedema pathophysiology. What followed was a result of a collective effort by many researchers and scientific groups who were able to elucidate the intricate connections between the implicated biochemical pathways. Still, scientific progress was hardly translated into effective therapy, and another 45 years had to elapse until the renewed interest in HAE was boosted by studies on the efficacy and safety of novel therapies about 10 years ago. In the twenty-first century, HAE ceased to be an "orphan disease" and its future is far more optimistic. It is better managed now by specialized angioedema centers, harmonized clinical guidelines, educational programs, laboratory services, and continued basic and clinical research. Patient associations worldwide are offering support and guidance, and governments and healthcare systems are gradually addressing patient and family needs.

To evaluate the efficacy and safety of a structured gradual exposure protocol (SGEP) with extensively heated and baked milk in promoting allergy resolution in children with cow milk allergy (CMA).In a case control study, children with CMA aged 1-4 years who were treated with SGEP including extensively heated and baked milk, were compared with children treated with strict avoidance. Data were collected from medical records and from validated telephone questionnaires. Data analysis was performed using a nonparametric Kaplan-Meier and proportional hazard Cox regression model, after evaluation of the adequacy of the case control matching.There were 43 children with milk allergy-26 (62%) males with a mean age at intervention of 21 months (range, 12-47 months)-who were treated with SGEP and followed to a mean age of 40 months (range, 20-82 months). The median age at resolution of CMA was compared with a matched group of 67 children treated with strict avoidance at least until 4 years of age or followed until earlier resolution, with a mean age at follow-up of 71 months (range, 11-176 months). The median estimated age at CMA resolution in the SGEP group was 36 months (95% CI, 34.5-49.7) compared with 98 months (95% CI, 82.4-114.1) in controls (P .001). At last follow-up, 86% of treated children were tolerant to unheated milk proteins vs 52% of controls (P = .003).A structured protocol with extensively heated and baked milk seems to promote faster resolution of CMA.

Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

BACKGROUND Severe attacks of hereditary angioedema (HAE) are debilitating and potentially life threatening, and can increase anxiety and the use of medical resources. OBJECTIVE This post hoc assessment evaluated recombinant human C1 esterase inhibitor (rhC1-INH) used to treat acute severe HAE attacks. METHODS In a double-blind, randomized-controlled trial (RCT), patients with an HAE attack (baseline visual analog scale score of ≥50 mm, with severe attacks defined as ≥75 mm) were randomly assigned to receive rhC1-INH (50 IU/kg for patients who weighed

Background: Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self-administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self-administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self-administration. Methods: In this phase IIIb, open-label, multicenter study, adult patients were trained to self-administer a single 30-mg icatibant subcutaneous injection to treat their next attack. Icatibant-naïve patients were treated by an HCP prior to self-administration. Evaluations included adverse event (AE) reporting, a validated questionnaire for convenience, and visual analog scale for efficacy. Results: A total of 151 patients were enrolled; 104 had an attack requiring treatment during the study, and 97 patients (19 naïve) were included in the self-administration cohort. Recurrence or worsening of HAE symptoms (22 of 97) was the most commonly reported AE; rescue medications including icatibant (N = 3) and C1-inhibitor concentrate (N = 6) were used in 13 cases. Overall, 89 of 97 patients used a single injection of icatibant. No serious AEs or hospitalizations were reported. Most patients (91.7%) found self-administration preferable to administration in the clinic. The median time to symptom relief (3.8 h) was comparable with results from controlled trials of icatibant. Conclusions: With appropriate training, patients were successfully able to recognize HAE attacks and decide when to self-administer icatibant. This, coupled with the patient-reported high degree of satisfaction, convenience and ease of use supports the adoption of icatibant self-administration in clinical practice. Fil: Aberer, W.. Medical University Graz; Austria Fil: Maurer, M.. Charite – Universitatsmedizin; Alemania Fil: Reshef, A.. The Sheba Medical Center; Israel Fil: Longhurst, H.. Bart’s and The London Hospital; Reino Unido Fil: Kivity, S.. The Tel Aviv Medical Center; Israel Fil: Bygum, A.. Odense University Hospital; Dinamarca Fil: Caballero, T.. Biomedical Research Network on Rare Diseases; España Fil: Bloom, B.. Global Clinical Research; Estados Unidos Fil: Nair, N.. Global Clinical Research; Estados Unidos Fil: Malbrán, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Británico de Buenos Aires; Argentina

Introduction Replacement therapy with subcutaneous C1-esterase inhibitor (C1-INH[SC]) 60 IU/kg twice weekly is approved for routine prophylaxis to prevent hereditary angioedema (HAE) attacks. Coagulation and fibrinolytic parameters levels tend to be elevated in HAE patients. We evaluated the effects of C1-INH(SC) on these parameters. Methods In the COMPACT study, subjects received 40 IU/kg or 60 IU/kg of plasma-derived C1-INH(SC) and a corresponding placebo, as prophylaxis over 16 weeks each. In the open-label extension (OLE), subjects received 40 IU/kg or 60 IU/kg of C1-INH(SC) for up to 140 weeks. Exploratory analyses included the assessment of coagulation and fibrinolytic parameters (D-dimer, Prothrombin Fragments [PF] 1+2, activated Partial Thromboplastin Time [aPTT], Fibrinogen, and Prothrombin International Normalized Ratio [PT-INR]) at prescheduled visits. Results Coagulation and fibrinolytic parameters were reported above the normal range at baseline. Treatment with C1-INH(SC) 60 IU/kg resulted in median decrease from baseline for D-dimer (COMPACT [baseline to Week 14]: 605.0 to 330.0 ng/mL; OLE [baseline to Week 140]: 510.0 to 330.0 ng/mL) and PF 1+2 (COMPACT [baseline to Week 14]: 264.0 to 185.0 pmol/L; OLE [baseline to Week 140]: 218.5 to 159.0 pmol/L). The aPTT, Fibrinogen, and PT-INR levels were stable relative to baseline over the treatment period. Results refer only to the Food and Drug Administration (FDA) approved 60 IU/kg dose. Conclusions A reduction or stabilization in coagulation and fibrinolytic parameters was observed in HAE patients treated prophylactically with C1-INH(SC). No related thromboembolic events were reported during treatment with C1-INH (SC).

Background Clinical manifestations of hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) usually begin in childhood, often intensifying during puberty. Currently there are insufficient efficacy/safety data for HAE therapies in children and adolescents due to the small number of pediatric patients enrolled in studies. Objective The objective of this phase 3 study was to evaluate the efficacy/safety of a single subcutaneous dose of icatibant (0.4 mg/kg; maximum 30 mg) in pediatric patients with C1-INH-HAE. Methods Patients aged 2 years to younger than 18 years were categorized as prepubertal (children) and pubertal/postpubertal (adolescents). The primary end point was time to onset of symptom relief—earliest time posttreatment to 20% or more improvement in composite symptom score. Results Thirty-two patients received icatibant (safety population: 11 children with attack, 10 adolescents without attack, and 11 adolescents with attack). The efficacy population consisted of 11 children and 11 adolescents with edematous attacks. Most attacks in the efficacy population (16 [72.7%]) were cutaneous, 5 (22.7%) were abdominal, and 1 (4.5%) was both cutaneous and abdominal; none was laryngeal. Overall, the median time to onset of symptom relief was 1.0 hour, the same for children and adolescents. Thirty-two treatment-emergent adverse events (all mild or moderate) occurred in 9 (28.1%) patients. Gastrointestinal symptoms were most common (9 events in 3 [9.4%] patients). Injection-site reactions affected most (90.6%) patients (particularly erythema and swelling), but almost all resolved by 6 hours postdose. Icatibant demonstrated a monophasic plasma concentration-time profile. Time to peak concentration was approximately 0.5 hours postdose. Conclusions Symptom relief was rapid, and a single icatibant injection in pediatric patients with C1-INH-HAE was well tolerated (ClinicalTrials.gov identifier, NCT01386658).

Recombinant human C1-esterase inhibitor (rhC1-INH) is efficacious and well tolerated for managing hereditary angioedema (HAE) attacks in adults. However, there are insufficient data on its efficacy and safety in adolescents.To evaluate the efficacy and safety profiles of rhC1-INH for acute HAE attacks in adolescents.Adolescents (aged 12-18 y) with HAE enrolled in 2 randomized controlled trials and 2 open-label extension trials were included and received intravenous rhC1-INH for acute attacks. Times to the beginning of sustained symptom relief (visual analog scale change from baseline ≥20 mm) and minimal symptoms (visual analog scale score of20 mm across locations) were assessed. Safety parameters included hypersensitivity reactions, anti-rhC1-INH antibodies, and host-related impurities.Sixteen adolescents (50 attacks, aged 14-18 y) received rhC1-INH. Attacks were managed with single-dose rhC1-INH 50 U/kg (46.0%) and single-dose rhC1-INH 2100 U (16%), and 32.0% were treated with additional doses after receiving an initial rhC1-INH 2100 U dose (total dose, 4200-6300 U). Most attacks (88.0%) occurred at a single location; 59.1% (26 of 44) were abdominal. Across the first 5 attacks, median times to the beginning of symptom relief ranged from 19.0 to 78.5 minutes; median times to minimal symptoms ranged from 120 to 190 minutes. Pharmacokinetics showed that rhC1-INH restored functional plasma C1-esterase inhibitor levels to the normal (70%) range for almost all evaluable patients. No severe or drug-related adverse events or hypersensitivity reactions occurred. No treatment-emergent antibodies to rhC1-INH or host-related impurities were observed.rhC1-INH is efficacious and well tolerated among adolescents with HAE.

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) may affect health-related quality of life (HRQoL). A specific HRQoL questionnaire for adult patients with C1-INH-HAE, the HAE-QoL, has recently been developed in Spain. Objective: The objective of this study was to perform a cross-cultural validation and psychometric study of the HAE-QoL in an international setting. Methods: Cross-cultural adaptation of the Spanish HAE-QoL draft version and an international rating phase with experts were performed. The resultant version of the HAE-QoL, a clinical questionnaire, and Short Form 36-item Health Survey Version 2.0 (SF-36v2) were pilot tested internationally. Item reduction was based on both descriptive and exploratory factor analysis. Psychometric properties were assessed. Results: Cross-cultural adaptation of the HAE-QoL was performed in 18 countries. The draft version of the HAE-QoL was pilot tested in 332 patients, and accurate data were obtained from 290 patients from 11 countries. The reduction process resulted in a new version with 25 items and 7 dimensions (treatment difficulties, physical functioning and health, disease-related stigma, emotional role and social functioning, concern about offspring, perceived control over illness, and mental health). Strong psychometric properties were observed (Cronbach´s α 0.92; test-retest reliability 0.87). Convergent validity showed mild to moderate correlations with SF-36v2 physical and mental component summaries (0.45 and 0.64, respectively) and with SF-36v2 dimensions (P < .004). HAE-QoL scores discriminated significantly among severity groups (median: asymptomatic 133.5 vs severe 84.0; P < .001); between patients with and without long-term prophylaxis (median: 101 vs 90; P = .001); and between patients with and without psychiatric and/or psychological care (median: 74 vs 103; P ≤ .001). Conclusions: The HAE-QoL, currently available in 18 languages, showed good reliability and validity evidence. Fil: Prior, Nieves. Hospital Universitario Severo Ochoa; España Fil: Remor, Eduardo. Universidad Autónoma de Madrid; España Fil: Pérez Fernández, Elia. Fundacion Hospital Alcorcon; España Fil: Caminoa, Magdalena. Instituto de Investigacion Hospital Universitario la Paz ; España Fil: Gómez-Traseira, Carmen. Instituto de Investigacion Hospital Universitario la Paz ; España Fil: Gayá, Francisco. Instituto de Investigacion Hospital Universitario la Paz ; España Fil: Aabom, Anne. Odense University Hospital; Dinamarca Fil: Aberer, Werner. Medical University; Austria Fil: Betschel, Stephen. Saint Michael's Hospital; Canadá Fil: Boccon Gibod, Isabelle. Joseph Fourier University; Francia. Grenoble University Hospital; Francia Fil: Bouillet, Laurence. Joseph Fourier University; Francia. Grenoble University Hospital; Francia Fil: Bygum, Anette. Odense University Hospital; Dinamarca Fil: Csuka, Dorottya. Semmelweis University; Hungría Fil: Farkas, Henriette. Semmelweis University; Hungría Fil: Gomide, Maria. Universidade de Sao Paulo; Brasil Fil: Grumach, Anete. Universidade de Sao Paulo; Brasil Fil: Leibovich, Iris. Chaim Sheba Medical Center; Israel Fil: Malbrán, Alejandro. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Moldovan, Dumitru. Mures County Hospital; Rumania Fil: Mihaly, Eniko. Mures County Hospital; Rumania Fil: Obtulowicz, Krystyna. Jagiellonian University; Polonia Fil: Perpén, Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina Fil: Peveling Oberhag, Adriane. University Medical Center Mainz; Alemania Fil: Porebski, Grzegorz. Jagiellonian University; Polonia Fil: Chavannes, Celine Rayonne. Saint Michael's Hospital; Canadá Fil: Reshef, Avner. Chaim Sheba Medical Center; Israel Fil: Staubach, Petra. University Medical Center Mainz; Alemania Fil: Wiednig, Michaela. Medizinische University; Austria Fil: Caballero, Teresa. Instituto de Investigacion Hospital Universitario la Paz ; España

Background We analyzed the clinical response of pediatric and adolescent hereditary angioedema (HAE) patients to pdC1-INH in the International Multicenter Prospective Angioedema C1-INH Trials (I.M.P.A.C.T.) 1 and 2. Methods Patients included in this post hoc analysis of prospectively collected data were between 10 and 18 yr old with type I or II HAE and a documented history of abdominal or facial attacks. Patients received a single injection of pdC1-INH concentrate (Berinert®, CSL Behring, Marburg, Germany) 20 U/kg. Efficacy end-points were time from the administration of study drug to onset of symptom relief and time to complete relief of all symptoms. Results Seven pediatric patients were included in I.M.P.A.C.T.1 with only 1 attack analyzed per patient. Median time to onset of relief was 0.42 h and to complete resolution was 8.08 h. No patient experienced a worsening of symptoms during the 0–4-h assessment period. Nine patients who experienced a total of 115 attacks were included in the analysis of I.M.P.A.C.T.2. Abdominal attacks were rated as ‘severe’ more frequently than were other types of attacks. The number of attacks per patient ranged from 2 to 42, and study participation ranged from 1 to 38 months. Median times to onset of symptom relief and to complete symptom resolution were 0.49 h and 14.1 h, respectively. Of 4 treatment-emergent adverse events in both studies, only 2 were considered related to treatment. Conclusions Study results showed that outcomes with pdC1-INH treatment of HAE in pediatric patients are comparable with outcomes in adults.

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P

Angiotensin-converting enzyme inhibitors (ACE-Is) are associated with angioedema, a potentially life-threatening adverse reaction. Although multiple studies have been conducted in tertiary care emergency departments (EDs), scarce data are available about the presentation and management of ACE-I-induced angioedema (AIIA) in the community hospital ED.To describe the frequency, presentation, and management of AIIA in patients seen in a community hospital ED.A 5-year medical record review of all patients seen with angioedema at a community hospital ED. Data abstraction focused on demographic factors, initial clinical characteristics, and ED management and disposition of patients with AIIA.We identified 166 ED visits for angioedema, including a subset of 50 visits for AIIA (30%; 95% confidence interval, 23%-38%). The AIIA was significantly more likely to be associated with an age of 65 years or older (P = .02), unilateral symptoms (P = .02), and absence of urticaria or itching (P.001). The ED treatment choices and admission rates were similar between patients with and without AIIA. Community hospital admission rates for AIIA (14%) were significantly lower than those from a comparable tertiary care study (41%) (P = .003); ambulance transport to the ED was nearly 3-fold higher in the tertiary care center study (P = .006). Admission was most strongly related to lack of improvement (P.001) and history of angioedema in AIIA (P = .009).Angioedema frequency, presentation, and management are similar in community and tertiary care EDs (30%). Urticaria or itching may help differentiate AIIA from allergic reactions, which are otherwise similar in community ED presentation and management.

Background Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. Objective To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. Methods This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. Results Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. Conclusion C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

Background Drug provocation tests (DPTs) are the gold standard in the diagnosis of β-lactam hypersensitivity. However, no consensus exists on the need for extended provocation tests, even though the effectiveness of the short DPT is relatively low and there has been an increase in the relative incidence of nonimmediate hypersensitivity reactions. Objective To evaluate the effectiveness of a 7-day (extended) DPT compared with a 1-day-only (short) DPT in the management of hypersensitivity reactions to β-lactam antibiotics. Methods Patients referred to the allergy clinic of the Sheba Medical Center for suspected β-lactam hypersensitivity from January 2008 to December 2012 underwent in vivo skin tests and an immediate short DPT with the culprit drug. Unless an immediate reaction was clearly documented, patients were offered a 7-day, extended DPT. Long-term effectiveness, calculated as the subsequent use of the tested antibiotic, and satisfaction levels were assessed with a telephone questionnaire. Results Of 49 negative DPT results, 26 (53%) were long and 23 (47%) were short. A total of 78% of the patients who underwent the long DPT reported that they used the drug compared with 61% of those who underwent only the short DPT ( P = .049). Most patients were very satisfied with the drug allergy evaluation process. Conclusions An extended DPT protocol increased the effectiveness of the allergy workup in our center without compromising patient satisfaction and safety, and it should be recommended to patients with a history of nonimmediate reaction to β-lactam.

Background Recommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE. Methods Monitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment. Results Plasma D-dimer levels were elevated in 80% of the patients (median [25th–75th percentiles]: 2149 [480–5105] μg/l; normal ≤250 μg/l) and were higher in patients with submucosal (abdominal, oropharyngeal–laryngeal) attacks (3095 [890–10000] μg/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450–4060] μg/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475–4568] μg/l rhC1INH; 2259 [586–7533] μg/l saline) and 2 h postinfusion (2389 [760–4974] μg/l rhC1INH; 2550 [310–8410] μg/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232–3240] μg/l rhC1INH; 418 [246–2318] μg/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls. Conclusion Elevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events.