The importance and evolution of bleeding disorder registries.

Registries are excellent sources of data to address questions that are typically not evaluated in randomized clinical trials, including natural history, disease prevalence, treatment approaches and adverse events, and models of care. Global and regional registries can provide data to identify differences in outcomes and in haemophilia care between countries, economic settings, and regions, while facilitating research and data sharing. In this manuscript, we highlight five bleeding disorder registries: Country registries from Australia and China, Paediatric Network on Haemophilia Management (PedNet) data on children who have received emicizumab, data from the European Haemophilia Safety Surveillance (EUHASS) system, and data on women and girls with haemophilia from the World Federation of Haemophilia (WFH) registries. Data from these and other bleeding disorder registries have been and will continue to be used to advance patient care, understand treatment patterns and adverse reactions, and identify areas of increased need and focus.

Nimesulide-Induced Fixed Drug Eruption Followed by Etoricoxib-Induced Fixed Drug Eruption: An Unusual Case Report and Review of the Literature.

Fixed drug eruption (FDE) is a well-recognized, non-immediate, drug hypersensitivity reaction, often attributed to the use of various medications, most commonly non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Cross-reactivity between related NSAIDs in FDE has been reported, but among chemically unrelated NSAIDs, is rare. Herein, we present a rare well-documented case where a patient initially displayed tolerance to etoricoxib after experiencing a nimesulide-induced FDE. Subsequently, the patient developed an etoricoxib-induced FDE, accompanied by the development of bullous lesions. This case report and the literature review on comparable FDE occurrences shed light on the intricate nature of FDEs, suggesting the possibility of cross-reactivity between chemically related and unrelated NSAIDs or the emergence of new drug-specific T cells without cross-reactivity after multiple exposures to a drug in a susceptible patient. Our case underscores the importance of increased awareness and vigilance among both physicians and patients in the realm of personalized medicine. Further research is needed to unravel the intricate mechanisms behind these drug eruptions, improve diagnostic approaches, and enhance patient care.

Challenges in ageing persons with haemophilia.

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.

Five-Membered Nitrogen Heterocycles Angiotensin-Converting Enzyme (ACE) Inhibitors Induced Angioedema: An Underdiagnosed Condition.

Angiotensin-converting enzyme (ACE) inhibitors are used primarily in the treatment of hypertension, heart failure, and in the acute phase of myocardial infarction. Lisinopril [N2-[(1S)-1-car-boxy-3-phenylpropyl]-L-lysyl-L-proline], enalapril [(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline] and ramipril [2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid] are all five-membered heterocycles and three of the most prevalent ACE inhibitors in clinical use worldwide. ACE inhibitor-induced angioedema (AE) is clinically characterized by self-limited edema of the dermis and subcutaneous lipid tissue, localized on face skin, oral mucosa and tongue in most cases. However, severe episodes of intestinal AE misdiagnosed as acute appendicitis and laryngeal AE requiring incubation have been reported. The pathophysiology of ACE inhibitor-induced angioedema is attributed to the accumulation of bradykinin, which is a potent vasodilator with proinflammatory activity that is normally degraded by angiotensin-converting enzyme (ACE) and aminopeptidase P; however, a small proportion of treated patients is affected. Given that patients do not respond to anti-H1 antihistamines and steroids, early clinical recognition and discontinuation of the ACE inhibitors are the treatments of choice for the long-term management of ACE inhibitor- induced angioedema. The search period of the present review was set up until November 2023, and its aim is to shed light on the broader context of ACE inhibitor-induced angioedema, exploring aspects such as clinical presentation, pathophysiology, and therapeutic considerations in this potentially life-threatening condition. The exploration of alternative drug options such as angiotensin II receptor blockers, the potential association of coadministration of DPP-4 inhibitors with ACE inhibitors, the presentation of angioedema and the significant clinical importance of this condition are also discussed. By focusing on the chemical structure of ACE inhibitors, specifically their nitrogen-based heterocycles-an attribute shared by over 880 drugs approved by the FDA within the pharmaceutical industry-this review emphasizes the pivotal role of nitrogen scaffolds in drug design and underscores their relevance in ACE inhibitor pharmacology.

Tele-Monitoring Applications in Respiratory Allergy.

Respiratory allergic diseases affect over 500 million people globally and pose a substantial burden in terms of morbidity, mortality, and healthcare costs. Restrictive factors such as geographical disparities, infectious pandemics, limitations in resources, and shortages of allergy specialists in underserved areas impede effective management. Telemedicine encompasses real-time visits, store-and-forward option triage, and computer-based technologies for establishing efficient doctor-patient communication. Recent advances in digital technology, including designated applications, informative materials, digital examination devices, wearables, digital inhalers, and integrated platforms, facilitate personalized and evidence-based care delivery. The integration of telemonitoring in respiratory allergy care has shown beneficial effects on disease control, adherence, and quality of life. While the COVID-19 pandemic accelerated the adoption of telemedicine, certain concerns regarding technical requirements, platform quality, safety, reimbursement, and regulatory considerations remain unresolved. The integration of artificial intelligence (AI) in telemonitoring applications holds promise for data analysis, pattern recognition, and personalized treatment plans. Striking the balance between AI-enabled insights and human expertise is crucial for optimizing the benefits of telemonitoring. While telemonitoring exhibits potential for enhancing patient care and healthcare delivery, critical considerations have to be addressed in order to ensure the successful integration of telemonitoring into the healthcare landscape.

Recent Advancements in the Atopic Dermatitis Mechanism.

Atopic dermatitis (AD) is a recurrent, chronic, inflammatory, itchy skin disorder that affects up to 20% of the pediatric population and 10% of the adult population worldwide. Onset typically occurs early in life, and although cardinal disease features are similar across all ages, different age groups and ethnicities present distinct clinical characteristics. The disease imposes a significant burden in all health-related quality of life domains, both in children and adults, and a substantial economic cost both at individual and national levels. The pathophysiology of AD includes a complex and multifaceted interplay between the impaired dysfunctional epidermal barrier, genetic predisposition, and environmental contributors, such as chemical and/or biological pollutants and allergens, in the context of dysregulated TH2 and TH17 skewed immune response. Regarding the genetic component, the loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD. More recently, epigenetic factors have facilitated AD development, including the dysbiotic skin microbiome and the effect of the external exposome, combined with dietary disorders. Notably, the interleukin (IL)-31 network, comprising several cell types, including macrophages, basophils, and the generated cytokines involved in the pathogenesis of itch in AD, has recently been explored. Unraveling the specific AD endotypes, highlighting the implicated molecular pathogenetic mechanisms of clinically relevant AD phenotypes, has emerged as a crucial step toward targeted therapies for personalized treatment in AD patients. This review aims to present state-of-the-art knowledge regarding the multifactorial and interactive pathophysiological mechanisms in AD.

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

Recommendations for a minimum data set for monitoring gene therapy in hemophilia: communication from the ISTH SSC Working Group on Gene Therapy.

Independent data collection is crucial in addressing the challenges associated with gene therapy for hemophilia, which is a promising treatment option but requires careful monitoring and management of short-term and potential long-term safety concerns. The International Society on Thrombosis and Haemostasis has identified a minimum efficacy and safety data set included in the World Federation of Hemophilia Gene Therapy Registry that should be collected on a national basis at specific time points for each patient who has been treated with the gene therapy products. This Gene Therapy Minimum Data Set (GT-MDS) was developed to facilitate data collection and to ensure capturing the most relevant data and most known and unknown safety and efficacy parameters recently cited by the European Medicine Agencies. The concept of assembling a minimum data set is not about creating a new data set but rather about identifying a subset of critical and essential topics that should always be included. The GT-MDS is structured into 3 sections and comprises an abridged list of 6 topics during routine gene therapy follow-up, keeping the number of data points low but allowing for rapid and independent data evaluation. The World Federation of Hemophilia Gene Therapy Registry data set, developed by the World Federation of Hemophilia, the International Society on Thrombosis and Haemostasis, and other organizations, including industry partners in 2020, is comprehensive. The GT-MDS reports the minimum relevant information that should not be lost and is mandatory to be collected for all patients who undergo gene therapy. Therefore, the implementation of the gene therapy registry and the minimum data set empowers and enhances data collection at a global level.

Association of patient, treatment and disease characteristics with patient-reported outcomes: Results of the ECHO Registry.

INTRODUCTION: Patient-reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under-reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen. AIM: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA. METHODS: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses. RESULTS: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended-half-life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health-related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores. CONCLUSION: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real-world practice with ≤1 year's follow-up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well-being.

Icatibant averting mechanical ventilation in acute ischemic stroke patient with alteplase-induced orolingual angioedema.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline. METHODS: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant. RESULTS: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration. CONCLUSIONS: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke.

Patient Adherence to Written Instructions following Complete Allergological Evaluation for Suspected Beta-Lactam Allergy: A Tertiary Hospital Study in Greece.

BACKGROUND: Beta-lactam (BL) antibiotics are among the most prescribed groups of drugs worldwide and have been implicated in a variety of allergic reactions. There is a paucity of literature regarding patient adherence to prescribed instructions following comprehensive allergy assessments. OBJECTIVE: The objective was to follow up the clinical course of BL allergy in patients who underwent thorough allergological investigation for suspected BL allergy at a tertiary hospital and ascertain patients' compliance with the provided written instructions. MATERIALS: An observational study in patients referred for suspected BL allergy who underwent a comprehensive allergy workup (in vivo ± in vitro tests, DPT in culprit and/or alternative BL) and who subsequently received written instructions was conducted. Data on the nature of the reported drug hypersensitivity reaction, the culprit BL drug, the allergological workup, and the detailed instructions provided in a written drug allergy report were collected retrospectively. Patients' compliance with the instructions was recorded by a telephone survey using a pre-defined questionnaire. RESULTS: Among the 212 patients meeting the inclusion criteria, 87 patients (72.4% women; mean age 50.1 years; age range 6-84 years) responded to the telephone survey and were included in this study. Surprisingly, 45 out of 87 (51.7%) patients did not adhere to the written instructions. The primary factor contributing to non-compliance was the fear of re-occurrence of a drug-induced allergic reaction (personal and/or triggered by their treating physician reluctance), accounting for 77.7% of cases. The analysis demonstrated that the initial reaction's severity and type, as well as the outcomes of skin testing, did not correlate with compliance to instructions (p > 0.05). Surprisingly enough, a drug provocation test (DPT), irrespectively of the result, emerged as a negative predictor for adherence, with only 40.6% of DPT patients complying compared to 77.8% of those who did not undergo DPT (p = 0.005; odds ratio = 0.195; 95% confidence interval: 0.058-0.655). Variables such as performing DPT with alternative or incriminated drugs or the result of the DPT (positive-negative) were not associated with patient compliance. Conversely, the type of instructions provided exhibited a noteworthy correlation with compliance. Patients who were explicitly instructed to entirely avoid all BL antibiotics demonstrated markedly higher adherence rates (83.3%) compared to those who were advised to have a partial or complete release of BLs (31.8% and 58.1%, respectively; p < 0.05). Notably, among compliant patients who received either the original culprit drug or the alternative (32 out of 87, 36.7%), no allergic reactions were reported. In contrast, among the 12 patients with written avoidance of all BLs, subsequent BL intake led to immediate reactions (Grade I and IV) in 2 patients (16.6%). CONCLUSIONS: A notable disparity in patient adherence to written instructions prohibiting or releasing beta-lactams was demonstrated. Less than half of the patients ultimately complied with the provided instructions, underscoring the need for tailored patients' education and strategies to improve adherence in the management of suspected BL allergy.

Case of Polyethylene Glycol Allergy Confirmed with Basophil Activation Test and Oral Challenge Successfully Immunized with SARS-CoV-2 Vaccine.

Polyethylene glycols (PEG) or macrogols are polymers of ethylene oxide widely used in drugs either as active substances or, more commonly, as excipients. We report a Caucasian 32-year-old woman with referred anaphylaxis almost instantly after oral intake of a macrogol-containing laxative. Despite an anaphylactic reaction, the patient showed negative results for both the skin test and specific IgE to monomer, while the basophil activation test and oral challenge were positive. The patient was later successfully vaccinated with a polysorbate 80-containing SARS-CoV-2 vaccine following an additional work-up. As a result, the inactive form of PEG cannot be fully diagnosed, and it is considered a "hidden" allergen. Allergens like polysorbates need special consideration due to their possible cross-reactivity by their specific derivatives.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment-Results From CURE.

BACKGROUND: Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. OBJECTIVE: To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. METHODS: Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). RESULTS: Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). CONCLUSIONS: Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

Reported prevalence of von Willebrand disease worldwide in relation to income classification.

INTRODUCTION: The diagnosis of von Willebrand disease (VWD) is complex and challenging, especially when diagnostic resources are limited. This results in a lack of consistency in identifying and reporting the number of people with VWD and variations in the VWD prevalence worldwide. AIM: To analyze the reported prevalence of VWD worldwide in relation to income classification. METHODS: Data on the VWD prevalence from the World Federation of Hemophilia Annual Global Survey, national registries of Australia, Canada, and the United Kingdom, and the literature were analysed. The income level of each country was classified according to the World Bank. RESULTS: The mean VWD prevalence worldwide was 25.6 per million people. The VWD prevalence for high-income countries (HIC) of 60.3 per million people was significantly greater (p < .01) than upper middle (12.6), lower middle (2.5) and low (1.1) income countries. The type 3 VWD prevalence for HIC of 3.3 per million people was significantly greater (p < .01) than lower middle (1.3) and low income (0.7) countries. The reported VWD prevalence was greater among females than males. CONCLUSION: The reported VWD prevalence varied considerably across and within income classifications. The variability of type 3 VWD prevalence was less than the VWD prevalence (all types). The variability in detection and diagnosis of type 1 VWD presents a challenge in forming a consistent prevalence value across countries and income classifications.

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.

Adverse events in children and adolescents undergoing allergen immunotherapy for respiratory allergies-Report from the Allergen Immunotherapy Adverse Events Registry (ADER), a European Academy of Allergy and Clinical Immunology taskforce.

BACKGROUND: Although it has been shown that allergen immunotherapy (AIT) is well-tolerated in children, systematic and prospective surveillance of AIT safety in real life settings is needed. METHODS: The multinational Allergen Immunotherapy Adverse Events Registry (ADER) was designed to address AIT safety in real life clinical practice. Data on children ≤18 years old with respiratory allergies undergoing AIT were retrieved. Patient- and AIT-related features were collected and analyzed. The characteristics of adverse events (AE) and risk factors were evaluated. RESULTS: A total of 851 patients, 11.3 ± 3.4 years old, with rhinitis only (47.6%); asthma and rhinitis (44.5%); asthma (7.9%), receiving 998 AIT courses were analyzed. Sublingual immunotherapy (SLIT) accounted for 51% of the courses. In 84.5% of patients only one AIT treatment was prescribed. Pollen was the most frequent sensitizer (57.1%), followed by mites (53.4%), molds (18.2%) and epithelia (16.7%). Local and systemic AEs were reported in 85 patients (9.9%). Most AEs (83.1%) were mild and occurred in <30 min (87%). Respiratory and cutaneous symptoms were more frequent. Only 4 patients (0.47%) had severe AE (none after 6 weeks of maintenance). The risk of AE was higher in patients undergoing SCIT. CONCLUSIONS: AIT is safe and well tolerated in children and adolescents with respiratory allergies in real-life clinical practice. Though SCIT is more prone to AE compared to SLIT, overall severe reactions are rare and occur during build-up and early maintenance.