Long-term Prophylaxis Research Articles

Management of Hereditary Angioedema in Pediatric, Pregnant, and Breast-Feeding Patients: An Expert Opinion – A Secondary Publication

Hereditary angioedema (HAE) is a rare inherited condition marked by recurrent skin and submucosal edema. HAE is caused by a C1 inhibitor deficiency or decreased C1 inhibitor function. The initial attack may occur during childhood or pregnancy, with symptoms ranging from classic angioedema to nonspecific stomach cramps. In this review, we discuss strategies for children and pregnant women to manage HAE attacks effectively and safely in light of the recent increase in HAE diagnosis. To begin, an aggressive work-up is necessary to confirm HAE-1/2 and to determine the most effective countermeasures. Secondly, in the event of an acute attack, plasma-derived C1-inhibitor is the first line of defense for children and pregnant women. Icatibant is also appropriate for use, except in pregnant women. Fresh frozen plasma (FFP) may be suggested as an alternative. Thirdly, proactive measures to prevent HAE attacks should be considered whenever a procedure is performed that may result in an exacerbation. Finally, FFP, attenuated androgen, and antifibrinolytic agents are recommended for long-term prophylaxis in South Korea where the C1 inhibitor is scarce. However, when making a decision, it is necessary to consider both the efficacy and the risk of adverse effects. For proper management, written action plans and first-aid kits are required. The action plans should be customized to the patient’s unique circumstances.

Clinical Characteristics and Quality of Life in a Cohort of Polish Pediatric Patients with Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare genetic disease. It is characterized by recurrent attacks of angioedema. Evidence to what extent it affects patient functioning is limited in the pediatric population. We aimed to determine the clinical characteristics and management of Polish children with HAE and to measure the health-related quality of life (HRQoL) of these patients. This cross-sectional study was conducted among 21 pediatric patients and their caregivers, as well as 21 respective controls randomly selected from the general population. During routine follow-up visits, standardized pediatric quality of life questionnaires (PedsQLTM 4.0) were administered to all caregivers and adolescents (≥13 years). Caregivers also completed a structured medical interview regarding the clinical characteristics and treatment of children with HAE during the previous six months. During this period, 57% of patients had low (group I), 24% moderate (group II), and 19% high (group III) HAE activity, corresponding to ≥10 attacks per 6 months. None of the patients received long-term prophylaxis. The children in group III had a lower HRQoL than other groups and controls on all dimensions of the PedsQLTM 4.0. The lowest scores in all groups were observed in the emotional functioning domain. Our data demonstrate that the burden of HAE on the quality of life of pediatric patients and their families encompasses a wide range of daily functioning.

De novo hepatitis B infection following liver transplantation with core antibody positive grafts: The role of surface antibody status in guiding long-term prophylaxis.

Liver transplantation (LT) with hepatitis B core antibody (anti-HBc) positive grafts to hepatitis B surface-antigen (HBsAg) negative recipients is safe and has likely contributed to improvements in organ access over the years. The incidence of de novo hepatitis B infection (HBV) in these instances is low with appropriate prophylaxis and is affected by recipient immunologic status. There is debate as to whether hepatitis B surface antibody (anti-HBs) positivity may safely inform prophylaxis discontinuation post-LT. In this retrospective study of all hepatitis B surface antigen (HBsAg) negative recipients of anti-HBc positive organs at three large academic centers between January 2014 and December 2019, nine LT recipients discontinued prophylaxis after developing anti-HBs antibodies 1 year or later post-LT. Three of the nine patients (33%) developed de novo HBV, defined by positive HBsAg or hepatitis B virus (HBV) DNA, during the study period. The remaining six patients had no evidence of HBV infection after a mean follow-up of 37 months. The patients without de novo HBV had higher anti-HBs titers at the time of prophylaxis discontinuation and were less likely to have negative anti-HBs at the time of transplant or negative anti-HBc at any time point. These results suggest that quantitative anti-HBs titer thresholds rather than qualitative anti-HBs positivity at 1 year or later after LT should be used to identify patients at decreased risk of de novo infection and help guide prophylaxis duration.

Effect of lanadelumab on attack frequency and QoL in Japanese patients with hereditary angioedema: Report of five cases.

Lanadelumab, a recombinant human anti-kallikrein monoclonal antibody, is recommended as the first-line option for long-term prophylaxis (LTP) in hereditary angioedema (HAE). However, the efficacy of lanadelumab and its effects on the quality of life (QoL) in Japanese HAE patients using real-world data have not been reported. Herein, we report the outcomes of five HAE patients who were treated with lanadelumab at two Japanese institutions. We retrospectively collected data on attack frequency and on-demand treatment frequency using an angioedema quality of life (AE-QoL) questionnaire. Our data corresponded to five Japanese HAE patients who started lanadelumab treatment: four with HAE due to C1-inhibitor deficiency (HAE-1) and one with HAE with a normal C1-inhibitor (HAE-nC1-INH). Two HAE-1 patients showed a reduction in both attacks and number of on-demand treatments. The other HAE-1 patients had an increase in the number of on-demand treatments, although there was no apparent reduction in attacks. The HAE-nC1-INH patient showed a slight increase in both attacks and number of on-demand treatments. Only one HAE-1 patient discontinued treatment after 1 month owing to side effects, including dizziness and headache. All four who continued treatment showed improved AE-QoL total and domain scores. Therefore, in this study, using real-world data, we demonstrated that lanadelumab reduced attack frequency and improved QoL in Japanese HAE patients.

Berotralstat in hereditary angioedema due to C1 inhibitor deficiency: first real-world evidence from a Canadian center.

Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022. We conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy. From June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3. Berotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.

Antimicrobial prophylaxis for vesicoureteral reflux: which subgroups of children benefit the most?

While the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that long-term antimicrobial prophylaxis reduced the risk of urinary tract infection (UTI) recurrences by 50%, 10 children had to be treated for one to benefit (i.e., observed number needed to treat (NNT) of 10). Accordingly, we re-analyzed RIVUR data to systematically identify subgroups of children with vesicoureteral reflux (VUR) with a smaller NNT. Using patient-level data from the RIVUR trial, we applied penalized regression methods including the baseline age, VUR grade, type of index UTI, and bowel-bladder dysfunction (BBD) as covariates to identify subgroups. We identified four relevant subgroups of children that appear to benefit from long-term antimicrobial prophylaxis, all with observed NNTs smaller than or equal to 5: children with grade IV VUR, BBD, and febrile index UTI (1% of the sample), children with BBD and febrile index UTI (7% of the sample), children with BBD (12% of the sample), and children with grade IV VUR (8% of the sample). Use of long-term antimicrobial prophylaxis appears to be particularly relevant for children with BBD (and any grade of VUR) and those with grade IV VUR (regardless of BBD status). However, because details regarding the treatment of BBD are not available, further studies are needed to fully determine the role of prophylactic antimicrobials in the management of children with VUR who have BBD.

Von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease

AbstractLong-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

The current situation of hereditary angioedema patients in Germany: results of an online survey.

Hereditary angioedema (HAE) is a rare hereditary disease with an estimated prevalence of approximately 1 in 50,000. An online survey was performed between January and June 2021 on a total of 99 HAE patients (with 92 of them aged 15 years and older and 7 of them being parents of patients under the age of 15 years). They were asked about their current situation, with a focus on the disease. The survey results show that HAE has a strong influence on the patients' quality of life. In particular, the anxiety and uncertainty of not knowing when a swelling attack will occur is considered burdensome by the patients. In addition, there can be physical problems during an attack (depending on its severity) that severely burden and limit patients in their everyday lives. Only one-third of the patients surveyed stated that no or only very minor physical limitations occurred during their most recent swelling attack. Almost three-quarters of all patients receive regular treatment at an HAE center. The patients are mostly satisfied with the therapy and particularly with long-term prophylactics (LTPs). When an LTP was used, the frequency and severity of the swelling attacks, and their duration, were significantly lower and/or shorter than when no LTP was used. Despite the high level of satisfaction with their current medication, 62% of patients expressed a strong/very strong interest in an oral LTP. In the group of patients already using an LTP, 74% reported a strong/very strong interest in an oral medication for long-term prophylaxis. The simplicity and minimal time involved in LTP use are considered beneficial to patients' quality of life.

Hereditary Angioedema: Novel Molecules for Treatment of Acute Attacks and Long-Term Prophylaxis

Hereditary angioedema (HAE) is a rare disease caused by a genetic alteration of the SERPING1 gene and characterized by recurrent attacks of angioedema that involve the skin, and the mucosae of the gastrointestinal tract and upper airways, which significantly affect the quality of life of patients. Nowadays there are effective drugs for both 1. treating acute attacks and 2. preventing attacks with a long-term prophylaxis. However, there are some unmet needs for HAE treatment, and therefore several novel molecules are under active testing for this clinical condition. Novel drugs will simplify the mode of administration (oral versus parenteral for both on demand treatment or long-term prophylaxis), prolong the interval between administrations (up to 3–6 months of efficacy with a single administration), target more specifically the central enzymes involved in the generation of bradykinin, the ultimate mediator of angioedema (prekallikrein, activated plasma kallikrein or activated factor XII), and potentially determine a definitive cure for the disease by genetic manipulation of the altered gene (SERPING1) or other downstream genes (KLKB1). In this review we provide a panoramic view of all new medications that are under active experimentation and will probably transform and enrich all of the therapeutic armamentarium for treating this disease.

A Cross-Sectional Study of Quality of Life in Patients Enrolled in the Romanian Hereditary Angioedema Registry.

Hereditary angioedema (HAE) is a rare potentially life-threatening genetic disorder characterized by recurrent episodes of angioedema without wheals that can affect any part of the body. The unpredictability of the attacks and the risk of passing the disease to the offspring result in significant physical and emotional burdens for patients, with a negative impact on quality of life. Data about the health-related quality of life in HAE patients from Romania are scarce. This study aimed to evaluate the disease-specific quality of life in patients with HAE from Romania and to determine associated factors. The study included adult patients with HAE enrolled in the Romanian HAE Registry. Disease-specific quality of life was measured using the Hereditary Angioedema Quality of Life questionnaire, a cross-culturally adapted, internationally validated structured survey. The survey was completed by 94 patients (64.9% females; 35.1% males). The mean age of the participants was 44.9 years (SD 14.1). Most patients (88.3%) had type I HAE and were from urban areas (63.8%). The mean ages at symptom onset and diagnosis were 15.1 (SD 11.1) and 36.1 (SD 14.1) years, respectively. The mean diagnosis delay was 20.5 years (SD 14.2). In the evaluated period, all patients had at least one vial of on-demand treatment at home, and 10 were on long-term prophylaxis treatment. The general and dimensional quality of life scores were slightly above the median values of the reference scales. While the general score was not associated with sex or residence, a statistically significant, negative, weak correlation was detected with diagnostic delay. The results suggest that despite the availability of on-demand treatment for all patients, there is a need for other diagnostic and therapeutic interventions to improve the management of the disease and the quality of life for HAE patients from Romania.

Comorbidities in Angioedema Due to C1-Inhibitor Deficiency: An Italian Survey

BackgroundHereditary angioedema due to C1-inhibitor deficiency (HAE) is characterized by unpredictable recurrent episodes of swelling affecting the skin and the mucosa tissues, including gastrointestinal tract and/or oro-pharyngeal-laryngeal mucosae. Long-term prophylaxis (LTP) are used to prevent attacks. ObjectiveSince C1-inhibitor (C1-INH) plays a pivotal role in several biological pathways, we investigated the possible association of comorbidities with C1-INH deficiency and the use of LTP with androgens (AA) or tranexamic acid (TXA). MethodsThis retrospective cohort study involved adult patients with HAE referring to Milan and Padua angioedema centers in the period 1979-2021. A qualitative comparison was performed to analyze comorbidities vs. general population. The incidence of comorbidities was evaluated during LTP with AA or TXA vs. patients without LTP. ResultsA total of 446 patients were studied. A greater prevalence among patients was found for: heart diseases (9.6% vs. 4.8%), acute myocardial infarction (5.6% vs. 1.4%), HCV infection (10.5% vs. 2.5%), and appendectomy (15.9% vs. 4.3%). In patients taking AA a greater incidence was found for: hypertension (22.8% vs. 10.8%; OR 2.02), hypercholesterolemia (19.5% vs. 5.3%; OR 3.97), diabetes mellitus (5% vs. 1.4%; OR 3.21), hepatic angioma (4.4% vs. 0.7%; OR 8.35), and focal nodular hyperplasia (2.5% vs. 0.4%; OR 6.9). No association with TXA and comorbidities was found. ConclusionIn this large patient population with a rare disease followed for up to a 43-year period, we found a greater prevalence of comorbidities hitherto unreported in the literature and an association between comorbidities and LTP with AA.

Real-world outcomes in patients with hereditary angioedema prescribed lanadelumab versus other prophylaxis.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by painful, debilitating, and potentiallyfatal swelling attacks. Lanadelumab is approved as long-term prophylaxis (LTP) in patients with HAE. However, realworld data on LTP use in patients with HAE are limited. To describe clinical characteristics, attack history, and quality of life (QoL) of patients with HAE type I/II whowere receiving lanadelumab or other LTPs. Data were drawn from the Adelphi HAE Disease Specific Program, a cross-sectional survey of HAE physicians conducted in the United States from July to November 2021. Physician-reported disease characteristics, HAE attack frequency, and QoL were compared among patients receiving lanadelumab or other LTPs for at least 12 months. Physicians reported data for 144 patients, of whom 29 had received lanadelumab and 115 had received another prophylaxis for at least 12 months. The mean +/- standard deviation number of attacks in the previous 12 months was loweramong patients receiving lanadelumab than other LTPs (2.3 +/- 3.1 versus 3.4 +/- 2.8, respectively; p = 0.075). Although bothgroups had similar current disease activity and severity, more patients receiving lanadelumab versus other LTPs had high disease activity (51.7% versus 12.5%, respectively; p < 0.0001) and disease severity rated as severe (51.7% versus 16.1%, respectively; p = 0.0001) at diagnosis. Physicians reported that more patients who received lanadelumab had good or very good QoL(72.4%) than those receiving other LTPs (36.5%) (p = 0.003). Analysis of these findings suggests lower attack frequency, lower symptomatic impact, and better QoL inpatients treated with lanadelumab than another prophylaxis in a real-world setting.

An expert panel's review on patients with hereditary angioedema switching from attenuated androgens to oral prophylactic therapy.

Background: Hereditary angioedema (HAE) is a rare condition marked by swelling episodes in various body parts, including the extremities, upper airway, face, intestinal tract, and genitals. Long-term prophylaxis (LTP), prescribed to control recurring HAE attacks, is integral to its management. Previously, attenuated androgens (AAs) were the only oral LTP options. However, in 2020, berotralstat, an oral plasma kallikrein inhibitor, was approved in the United States. A 2018 survey of adults with HAE type I or type II showed that almost all the patients who used prophylactic HAE medication preferred oral treatment (98%) and felt that it fit their lifestyle better than injectable treatment (96%). Still, guidelines lack consensus on transitioning patients from AAs to alternative oral prophylactic therapy. Objective: This paper aims to share expert insights and patient feedback on transitioning from AAs to berotralstat, an alternative oral prophylactic therapy, from the perspective of clinicians with extensive experience in treating patients with HAE. Methods: A panel of five HAE specialists convened for a virtual half-day roundtable discussion in April 2023. Results: Discussions about transitioning from AAs to berotralstat were prompted by routine consultations, patient inquiries based on independent research, ineffective current treatment, or worsening AA-related adverse effects. For patients who switched from AAs, the physicians reported that the decision was influenced by the alternative therapy's ability to prevent HAE attacks, its safety, and the once-daily administration schedule. All expert panel members identified fewer AA-related adverse effects; better quality of life; and less severe, shorter, and less frequent HAE attacks as clinical or patient goals they hoped to achieve through the treatment switch. Conclusion: The emergence of new, highly specific LTP drugs for HAE calls for the development of comprehensive recommendations and guidelines for transitioning from AAs to alternative oral prophylactic therapy. The expert panel highlighted key factors to consider during the development of such guidelines.

Long-term efmoroctocog alfa prophylaxis improves perceived pain, mental, and physical health in patients with hemophilia A: post hoc analysis of phase III trials using patient-reported outcomes.

Hemophilia-associated bleeding and resultant joint pain and mobility restrictions can predispose patients to poor health-related quality of life (HRQoL). Therefore, efficacy of a treatment needs to address more than just annualized bleed rates. Describe the evolution of HRQoL, pain, and activity in patients with hemophilia A, treated with efmoroctocog alfa prophylaxis. A post hoc analysis from Kids A-LONG (NCT01458106), A-LONG (NCT01181128), and long-term extension study ASPIRE (NCT01454739) assessed change in pain and activity-related patient-reported outcomes (PROs). Physical health, pain, and HRQoL were assessed by PROs for a cumulative treatment duration of up to ~6 years. The primary endpoint was change from baseline in EuroQoL (EQ)-5D and Haemophilia Quality of Life Questionnaire (Haem-A-QoL). 118 adult/adolescents and 71 pediatric patients were included. The proportion of adults and adolescents reporting no problem in the EQ-5D analysis of 'pain/discomfort' significantly increased from A-LONG baseline (35.04%; 41/117) to ASPIRE month 30 (44.68%; 21/47; p = 0.024). Mean (standard deviation) Haem-A-QoL subdomain scores for 'feeling' and 'physical health' at A-LONG baseline improved by -3.24 (15.13; p = 0.018) and -3.85 (23.07; p = 0.047), respectively, at study end. Proportion of pediatric patients reporting no problem on the EQ-5D analysis of 'pain/discomfort', significantly increased from A-LONG baseline (75.0%; 42/56) to ASPIRE baseline (95.56%; 43/45; p = 0.046). Satisfaction levels for pediatric patients were high at A-LONG baseline and maintained until study end. Long-term efmoroctocog alfa prophylaxis reduces pain and improves HRQoL in adult and adolescent patients with hemophilia A. In pediatric patients, it reduces perceived pain and maintains satisfaction levels. NCT01458106, NCT01181128, NCT01454739.

Impact of long-term vs. short-term and single day vs. single dose of antibiotic prophylaxis in reducing infection rates after orthognathic surgery: a systematic review and meta-analysis.

This review was designed to examine the effect of long-term (≥2 days) vs. short-term (1 day) and single-day vs. single preoperative doses of antibiotic prophylaxis on surgical site infection (SSI) rates after orthognathic surgery. PubMed, Web of Science, Embase, and Scopus were searched for randomized controlled trials (RCTs) without any date or language restriction till 1st September 2023. SSI rates were pooled to generate risk ratio (RR). Eight RCTs comparing long-term vs. short-term and three RCTs comparing single day vs. single preoperative dose of antibiotic prophylaxis were included. Meta-analysis showed that the use of long-term antibiotic prophylaxis significantly reduced the risk of SSI after orthognathic surgery as compared to short-term antibiotics [RR:0.42 (95% CI: 0.23, 0.76) I2=0%]. Meta-analysis also noted that patients receiving a single day of antibiotic prophylaxis had significantly reduced risk of SSI as compared to those receiving only a preoperative single dose of antibiotics [RR:0.28 (95%: 0.09, 0.82) I2=0%]. Evidence from a limited number of RCTs with moderate to high risk of bias shows that two to seven days of long-term antibiotic prophylaxis reduces the risk of SSI as compared to single-day antibiotic therapy. Also, a single day of antibiotics may be more beneficial than a single pre-operative dose of antibiotic.

Simoctocog alfa (Nuwiq®) in children: early steps in life's journey for people with severe hemophilia A.

People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq®) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.

COVID-19 infection and vaccination in patients with hereditary angioedema: a multicentric study.

Background. Due to similarities between the pathophysiological mechanisms of hereditary angioedema (HAE) and COVID-19, it has been hypothesized that SARS-CoV-2 infection may trigger HAE attacks or, alternatively, that HAE patients may experience different of COVID-19 disease severity. Furthermore, the potential for COVID-19 vaccination to trigger angioedema attacks in patients with HAE is still not completely defined. The objective is to characterize the exacerbations and clinical manifestations associated with COVID-19 infection and describe the adverse effects of COVID-19 vaccination in patients with HAE.Methods. Retrospective observational, descriptive, non-interventional, multicenter study conducted in four Allergy Units and Departments in Central Portugal between March 2020 and July 2022. HAE patient data were obtained from electronic medical records. Results. The study included 34 patients (67.6% female): 26 with HAE type 1, 5 with HAE type 2, and 3 with HAE with normal C1 inhibitor. Most patients with HAE type 1 and 2 were receiving long-term prophylaxis. Among the 32 patients who received COVID-19 vaccination, 86 doses, were administered with one angioedema attack (1.2%) associated with vaccination. A small increase in the average number of attacks was observed in the year following COVID vaccination (7.1 versus 6.2 in the previous year, p = 0.029), however, this difference is unlikely to be clinically significant, as the context of the COVID-19 pandemic likely introduced numerous confounders. During the study period, 16 HAE patients had COVID-19, all presenting with mild disease. Four out of 16 patients (25%) reported angioedema attacks during COVID-19, and 43.8% during the convalescence period (3 months after infection). Conclusions. Patients with HAE can safely receive COVID-19 vaccination. The severity of COVID-19 infection does not appear to be increased in HAE patients.

A real-world study of hereditary angioedema patients due to C1 inhibitor deficiency treated with danazol in the Brazilian Public Health System.

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is an ultra-rare autosomal dominant inherited disease that affects 1 in 67,000 people in the world. The attacks are based on subcutaneous and submucosal edema that can lead to death if not properly managed. Considering the lack of information on the clinical management of Brazilian patients with HAE, this study aimed to identify and characterize patients with HAE-C1-INH that used danazol prophylactic treatment in the Brazilian Public Health System (SUS) and the healthcare resource utilization (HCRU). This was an observational retrospective database study with patients treated with danazol from January 2011 until December 2021 within the SUS. The HAE cohort included patients with 12 years or older with at least one record for ICD-10 D84.1, one claim for danazol record, and at least 6 months of available history in the database. Our study included 799 patients treated in the SUS, with a mean (SD) age at danazol initiation of 40 years (16). The number of patients with HAE showed a similar distribution over this 10-year period analyzed with the highest number of patients in 2015 (n = 509) and 2016 (n = 480). A total of 253 (32%) patients had a record of at least one attack. Of those, 45 (17.8%) had at least one procedure HAE-related hospital admission, and 128 (50.6%) had at least one HAE-related hospital admission. The mean (SD) hospitalization length of stay was 5 (8) days. Over 14% (n = 36) of HAE patients with attack (n = 253) had at least one HAE-related ICU admission. This database study is the strategy used to allow us to find and describe the characteristics of patients with HAE who use danazol for long-term prophylaxis in the SUS and identify HCRU outcomes of interest such as hospitalizations, inpatient, and outpatient settings. The high rate of attacks, hospitalizations, and general resource uses highlights the necessity to increase awareness of new strategies and accurate approaches to treat HAE patients. Therefore, our findings are important indicators that our health system and guidelines need to be revised and improved to properly diagnose, treat, and assist patients with HAE.

Real-World Efficacy and Safety of Plasma-Derived Von Willebrand Factor-Containing Factor VIII Concentrates in Patients With Von Willebrand Disease in Italy.

Plasma-derived von Willebrand factor-containing factor VIII concentrates (pd-VWF/FVIII-C) are the mainstay of treatment in von Willebrand disease (VWD). Real-world data on efficacy and safety of these pd-VWF/FVIII-C are required. To retrospectively evaluate the efficacy and safety of pd-VWF/FVIII-C (Fanhdi® and Alphanate®, Grifols) in clinical practice in Italy. A multicentric, observational, retrospective study at 10 Italian centers was conducted. Eligible patients diagnosed with inherited VWD (ISTH criteria) were treated with either Fanhdi® or Alphanate® for bleeding episodes, prevention of surgical bleeding and secondary long-term prophylaxis (SLTP) according to clinical practice with medical records collected from January 2007 to December 2019. Efficacy/safety of pd-VWF/FVIII-C was assessed according to FDA-agreed objective criteria following regulatory procedures. Fifty-seven patients (M/F: 21/36) were enrolled in the study with the following VWD types: VWD1 (n = 29, 52%), VWD2A (n = 10, 18%), VWD2B (n = 7, 12%), VWD2M (n = 2, 4%), VWD2N (n = 1, 2%), VWD2 unclassified (n = 1, 2%), and VWD3 (n = 7, 12%). These pd-VWF/FVIII-C were used to manage 58 bleeding episodes (n = 24 patients), 100 surgeries (n = 47 patients), and 7 SLTP (n = 6 patients). Global clinical efficacy with these pd-VWF/FVIII-C was reported to be excellent/good in 85% of bleeding episodes, 98% of surgeries, and 100% of SLTP. As far as safety, no adverse-drug-related episodes, immunogenic or thrombotic events were reported. This study confirmed that Fanhdi® and Alphanate® were effective and safe in the management of bleeding episodes, the prevention of bleeding during surgeries and for SLTP in Italian patients with inherited VWD.

Real-life Experience of Subcutaneous Plasma Derived C1-Inhibitor as Long-term Prophylaxis in HAE-C1INH.

Real-life Experience of Subcutaneous Plasma Derived C1-Inhibitor as Long-term Prophylaxis in HAE-C1INH.