Hereditary angioedema due to C1 inhibitor deficiency: real-world experience from the Icatibant Outcome Survey in Spain

Bradykinin; Hereditary angioedema; IcatibantBradicinina; Angioedema hereditario; IcatibantBradicinina; Angioedema hereditari; IcatibantBackground The Icatibant Outcome Survey (IOS) is an international registry monitoring the use of icatibant, a bradykinin B2 receptor antagonist indicated for the acute treatment of hereditary angioedema (HAE) attacks. Our goal was to assess disease characteristics and icatibant treatment outcomes in patients with HAE due to C1 inhibitor deficiency (HAE type 1 or 2 (HAE-1/2)) from Spain relative to other countries participating in IOS. Methods Descriptive retrospective analyses of data are reported from 10 centers in Spain vs 51 centers in 12 other participating countries (July 2009 to January 2019). Results No meaningful differences were identified between patients in Spain (n = 119) and patients across other countries (n = 907) regarding median age at symptom onset (15.0 vs 12.0 years) or diagnosis (22.3 vs 20.5 years). Overall HAE attack rates (total attacks/total years of follow-up) were 2.66 in Spain and 1.46 across other countries. Patients in Spain reported fewer severe/very severe HAE attacks before treatment (41.0% vs 45.9%; P < 0.0001) and, for icatibant-treated attacks, longer median time to treatment (2.9 vs 1.0 h), time to attack resolution (18.0 vs 5.5 h), and total attack duration (24.6 vs 8.0 h). Use of androgens for long-term prophylaxis was higher in Spain (51.2% vs 26.7%). Conclusion Patients with HAE-1/2 in Spain reported fewer severe/very severe attacks, administered icatibant later, and had longer-lasting attacks than did patients across other countries in IOS. These differences may indicate varying disease management practices (e.g., delayed icatibant treatment) and reporting. Efforts to raise awareness on the benefits of early on-demand treatment may be warranted.The Icatibant Outcome Survey is funded and supported by Shire International GmbH, a Takeda company, Zurich, Switzerland. Under direction of the authors, Alpa Parmar, PhD, CMPP, Latoya M. Mitchell, PhD, CMPP, and Sophia Shumyatsky, PharmD, CMPP, employees of Excel Medical Affairs, provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, and copyediting also was provided by Excel Medical Affairs. Takeda Development Center Americas, Inc. provided funding to Excel Medical Affairs, provided funding to Excel Medical Affairs for support in editing this manuscript. The interpretation of the data was made by the authors independently

Real-World Safety and Effectiveness Evidence of a Microcrystalline Tyrosine-Associated Mite Allergoid in Children and Adolescents with Allergic Rhinitis

Rinitis al·lèrgica; Infants i adolescents; Tirosina microcristal·linaRinitis alérgica; Niños y adolescentes; Tirosina microcristalinaAllerghic rhinitis; Children and adolescents; Microcrystalline tyrosineEvidence regarding allergen immunotherapy (AIT) in pediatric population is scarce. We have assessed safety and effectiveness of subcutaneous AIT with a microcrystalline tyrosine (MCT)-associated mite allergoid, Acarovac Plus®, in children and adolescents with allergic rhinitis (AR), with and without asthma, in the real-world setting. This was a retrospective, multicenter study including children and adolescents aged 5 years to 17 years with AR, with and without asthma, and sensitized to mites, receiving AIT with Acarovac Plus® during ≥6 months. Primary and secondary objectives were safety and effectiveness, respectively. Effectiveness variables were assessed during 12 months before and after AIT and included unscheduled visits to the healthcare center and emergency room admissions, rhinitis and asthma symptoms according to ARIA and GEMA classifications, respectively, medication use, and patients’ and physicians’ disease perception graded on a visual analog scale (VAS). All 79 patients included had a mean (SD) age of 12.7 (3.3) years. Two patients experienced systemic adverse reactions (none severe). Unscheduled visits to the healthcare center and emergency room admissions decreased (mean (SD) 3.02 [2.48] and 0.63 [1.35] vs. 1.08 [1.38] and 0.09 [0.38], before and after treatment, p < 0.001 and p = 0.001, respectively). After AIT, rhinitis and asthma classification changed (p < 0.0001 for all classifications), showing improvements in symptoms and a significant decrease in rhinitis and use of medication for asthma and VAS scores grading patients’ and physicians’ disease perception (p < 0.001). In conclusion, these results show that AIT with an MCT-associated mite allergoid appears safe and effective in children and adolescents with AR treated in the real-world setting.This study was supported by Allergy Therapeutics Ibérica

Systemic inflammation biomarkers during angioedema attacks in hereditary angioedema

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

Personalized Surgery Service in a Tertiary Hospital: A Method to Increase Effectiveness, Precision, Safety and Quality in Maxillofacial Surgery Using Custom-Made 3D Prostheses and Implants

Personalized surgery; Tertiary hospital; Virtual planningCirugía personalizada; Hospital terciario; Planificación virtualCirurgia personalitzada; Hospital terciari; Planificació virtualPersonalized surgery (PS) involves virtual planning (VP) and the use of 3D printing technology to design and manufacture custom-made elements to be used during surgery. The widespread use of PS has fostered a paradigm shift in the surgical process. A recent analysis performed in our hospital—along with several studies published in the literature—showed that the extensive use of PS does not preclude the lack of standardization in the process. This means that despite the widely accepted use of this technology, standard individual roles and responsibilities have not been properly defined, and this could hinder the logistics and cost savings in the PS process. The aim of our study was to describe the method followed and the outcomes obtained for the creation of a PS service for the Oral and Maxillofacial Surgery Unit that resolves the current absence of internal structure, allows for the integration of all professionals involved and improves the efficiency and quality of the PS process. We performed a literature search on the implementation of PS techniques in tertiary hospitals and observed a lack of studies on the creation of PS units or services in such hospitals. Therefore, we believe that our work is innovative and has the potential to contribute to the implementation of PS units in other hospitals

Angioedema severity and impact on quality of life: Chronic histaminergic angioedema versus chronic spontaneous urticaria

Histamine-mediated angioedema is the most frequent form of angioedema. It is classified as idiopathic histaminergic acquired angioedema (IH-AAE)1 when allergies and other causes have been excluded and a positive treatment response to antihistamines, corticosteroids, or omalizumab has been reported. Idiopathic histaminergic acquired angioedema may occur in isolation, when it is termed chronic histaminergic angioedema (CHA), or it may be associated with wheals in chronic spontaneous urticaria angioedema (CSU-AE). The term CHA is equivalent to IH-AAE and mast cell-mediated angioedema. However, this term reflects the chronic and recurrent course of the disease. Therefore, we propose that the term CHA be internationally discussed in the following guidelines. Chronic spontaneous urticaria is classically characterized by the presence of recurrent episodes of wheals (hives) with or without angioedema for at least 6 weeks.2 Chronic histaminergic angioedema is typically considered a subtype of CSU without wheals. However, a recent study3 found several features that differentiate CHA from CSU, which suggests that CHA is a separate entity. Quality of life (QoL) studies specifically for CHA patients have not been performed, and their QoL has been assessed only in the context of CSU-AE

Активность микрофлоры как показатель токсичности морских донных отложений шельфовой зоны Черного моря и Керченского пролива

Изучена потенциальная активность донной микрофлоры в местах утечки остатков химических токсикантов, затопленных в период Второй Мировой войны ХХ в. Отмечены особенности восстановления жизнедеятельности микрофлоры при различных уровнях загрязнения донных отложений мышьяком и хлорированными органическими сульфидами. Полученные результаты перспективно использовать при оценке экологического состояния донных отложений в загрязненных прибрежных акваториях

Angioedema Due to Acquired Deficiency of C1-Inhibitor: A Cohort Study in Spain and a Comparison With Other Series

[Background] Data on acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) from 4 European countries (France, Italy, Germany, and Hungary) were recently published.[Objective] To report data from a group of 50 patients with acquired C1-INH deficiency from Spain, of whom 46 had angioedema, and compare them with other European series.[Methods] We performed a retrospective observational study of 46 patients with C1-INH-AAE and 4 asymptomatic patients. Clinical and biological characteristics and associated diseases were assessed and compared with other European series.[Results] Women accounted for 73.9% of cases. The prevalence of C1-INH-AAE related to hereditary forms was 1/10.1. Overall, 8.7% patients were aged <40 years. Diagnostic delay was 1.1 years. Angioedema mainly affected the face (91.3%), followed by the oropharynx (63%), extremities (50%), and abdomen (37%). Only 1 patient underwent orotracheal intubation. Erythema marginatum was present in 1 patient. A hematologic disorder was recorded in 50% of patients. Angioedema preceded all benign conditions, mostly monoclonal gammopathy of undetermined significance, but appeared very close to or after malignant hematologic diseases (median, 2.2 and 0.29 years). Autoimmune diseases were associated in 50% (autoimmune thyroiditis, 21.5%; systemic lupus erythematosus, 10.9%). Half of them coexisted with hematologic disorders. Anti-C1-INH antibodies were found in 67% of tested patients and were not related to the associated disease. Long-term prophylaxis was necessary in 52.2%, most of whom responded to tranexamic acid.[Conclusions] This study emphasizes the possibility of C1-INH-AAE in patients younger than 40 and in autoimmune diseases other than systemic lupus erythematosus such as autoimmune thyroiditis.Peer reviewe

Determinants and Differences in Satisfaction with the Inhaler Among Patients with Asthma or COPD

Satisfaction with the inhaler is an important determinant of treatment adherence in patients with asthma and chronic obstructive pulmonary disease (COPD). However, few studies have compared these 2 groups to identify the factors associated with satisfaction with the inhaler. To assess and compare satisfaction with the inhaler in patients with asthma or COPD and to determine the variables associated with high inhaler satisfaction. A multicenter, cross-sectional study of 816 patients (406 with asthma and 410 with COPD) was conducted. Satisfaction was assessed with the Feeling of Satisfaction with Inhaler (FSI-10) questionnaire. All participants completed the Test of Adherence to Inhalers and either the Asthma Control Test (ACT) or the COPD Assessment Test (CAT). Overall, the asthma group was significantly more satisfied with the inhaler (mean [standard deviation] FSI-10 scores: 44.1 [6.5] vs 42.0 [7.7]; P <.001) and more satisfied on most (7 of 10; 70%) items. Patients with asthma were significantly more satisfied with the inhaler regardless of the adherence level or the type of nonadherence pattern. Younger age, good disease control (ACT ≥20 or CAT ≤10), previous inhaler training, and absence of unwitting nonadherence were all independently and significantly associated with high inhaler satisfaction. Age, disease control, and training in inhalation technique all play a more significant role than the specific diagnosis in explaining satisfaction with the device in patients with asthma and COPD. These findings underscore the need to provide better training and more active monitoring of the inhalation technique to improve patient satisfaction, treatment adherence, and clinical outcomes

Mediadores mastocitarios durante la anafilaxia: Utilidad y limitaciones de la triptasa como marcador diagnóstico actual e implicación del sistema de contacto y de la coagulación en la anafilaxia

Introducción: La anafilaxia es una reacción de instauración rápida y potencialmente mortal, donde los mediadores mastocitarios tienen un papel clave en su fisiopatología. El diagnóstico de la anafilaxia es clínico, ya que actualmente no se dispone de marcadores biológicos que nos permitan confirmar el diagnóstico. Recientemente, en un modelo murino se ha descrito el posible papel de la heparina derivada de los mastocitos en la activación del sistema de contacto, una cascada de proteasas que termina escindiendo el cininógeno de alto peso molecular (HK) para liberar bradicinina (BK), proteína con múltiples efectos inflamatorios. Objetivo: Esta Tesis Doctoral la componen dos trabajos. El objetivo del primer trabajo fue determinar las concentraciones de triptasa sérica seriada durante la anafilaxia y evaluar su utilidad como marcador diagnóstico y de gravedad, así como también los factores de riesgo para presentar una anafilaxia grave. El objetivo del segundo trabajo fue investigar el papel del sistema de contacto, de la coagulación y la correlación con la triptasa durante la anafilaxia. Métodos: Se trata de dos estudios prospectivos con pacientes que acudieron al Servicio de Urgencias del Hospital Vall d´Hebron con un episodio de anafilaxia. Se recogieron las características demográficas, los factores de riesgo de los pacientes, la etiología, las características clínicas y el tratamiento de la anafilaxia. Se midió la triptasa sérica a las 1-2 horas (T1), a las 4-6 horas(T2), a las 12-24 horas (T3) después del inicio de la anafilaxia y en condiciones basales (TB). En el segundo estudio, dado que se trataba de un estudio exploratorio, se compararon 10 pacientes durante la anafilaxia y en condiciones basales y con controles sanos ajustados por sexo y edad. Se determinó mediante inmunodetección la proteólisis plasmática del HK, de la calicreína plasmática (PK) y del factor XII (FXII). La heparina liberada por los mastocitos se determinó mediante la actividad del anti-Xa y se analizó la vía intrínseca de la coagulación midiendo los niveles de TTpa. Resultados: En el primer trabajo se incluyeron un total de 102 pacientes, 63 mujeres, de edad media de 47,4±19,1 años. La concentración de la triptasa a T1 (19.3±15.4µg/L) fue significativamente más alta que en T2, T3, TB (todos <11,4µg/L; P<0,0001). No obstante, la triptasa no se elevó en el 36,3% de los casos. Además, en el 60,6% de estos pacientes no se observaron cambios en los niveles de triptasa comparando T1 y TB (ΔT1-TB=0). La concentración de triptasa fue más elevada en las anafilaxias más graves (P<0,0001) y se correlacionaba positivamente con la gravedad (P<0,001; r=0,49). La anafilaxia fue más grave y la concentración de triptasa más elevada cuando la etiología eran los fármacos comparado con los alimentos tanto en T1 (P=0,045) como en TB (P=0,019). La edad y los factores de riesgo cardiovascular se asociaron a una anafilaxia más grave (P=0,001). En el segundo trabajo se observó una extensa proteólisis del HK, de la PK y del FXII en el plasma de los pacientes durante la anafilaxia, no observándose en los mismos en condiciones basales ni en los controles. El grado de escisión del HK se correlacionó con la gravedad de la reacción y con los niveles de triptasa. El TTpa estaba alargado en 3 pacientes y los niveles de anti-Xa fueron más altos durante la anafilaxia que a nivel basal (4 kIE/L, IQR 2,5-5,5 versus 1 kIE/L IQR 0,25-1,75, p < 0,005). Conclusiones: La triptasa es un biomarcador relacionado con la gravedad de la anafilaxia. No obstante, no es un marcador óptimo para el diagnóstico de la anafilaxia, ya que en un número no despreciable de pacientes se mantiene inalterada. La edad avanzada y los factores de riesgo cardiovascular estaban asociados a una anafilaxia más grave. Además, se ha demostrado una activación del sistema de contacto y de la coagulación, así como un aumento de la actividad del anti-Xa en los pacientes durante la anafilaxia.Background: Anaphylaxis is a hypersensitivity reaction that is rapid in onset and potentially fatal, in which mast cell mediators play an important role in the physiopathology. The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis. Recently, the potential role of mast-cell-driven heparine activating the plasma contact system has been described in a murine model, a protease cascade which proteolyzes high molecular weight kininogen (HK) to liberate bradykinin (BK), a protein with inflamatory effects. Objective: This thesis comprises two studies. The aim of the first study was to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker and its relation to severity, as well as to evaluate risk factors for a severe anaphylaxis. The aim of the second study was to investigate the role of the plasma contact system, the coagulación system and the correlation with tryptase during anaphylaxis. Methods: Two prospective studies including patients with acute anaphylaxis (NDAID/FAAN criteria) attending the Emergency Department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1-2 hours (T1), 4-6 hours (T2) and 12-24 hours (T3) following onset of symptoms and in basal conditions (TB). In the second study, an exploratory research, plasma samples from ten patients with acute anaphylaxis were compared with baseline samples and with ten age- and sex- matched controls. The proteolysis of HK, plasma kalikrein (PK) and factor XII (FXII) were determined by immunoblotting. Mast cell activation and heparin release were determined by serum tryptase levels and anti-Xa activity and the intrisec pathway of the coagulation system with apTT. Results: A total of 102 patients were included in the first study, 63 females, mean age 47.4±19.1 years. Tryptase concentration at T1 (19.3±15.4µg/L) was significantly higher than at T2, T3 and TB (all<11.4µg/L; P<0.0001). Nevertheless, tryptase was not raised in 36.3% of cases. Furthermore, in 60.6% of these patients no changes were observed in tryptase levels comparing T1 and TB (ΔT1-TB =0). Tryptase was more frequently elevated in more severe anaphylaxis (P<0.0001) and positively correlated with the grades of severity (P<0.001, r=0.49). Anaphylaxis was more severe and tryptase concentration was higher when the causative agent was a drug compared to food both at T1 (P=0.045) and at TB (P=0.019). Age and coronary risk factors were associated with more severe anaphylaxis (P=0.001). In the second study, we noted extensive proteolysis of HK in the plasma of all anaphylactic patients at the onset of symptoms but not during remission and in none of 10 controls. Degree of HK breakdown correlated with the severity of anaphylactic reactions and with tryptase levels. All anaphylactic patients also showed activation of FXII and PK but not at baseline or in control patients. The apTT was prolonged in three patients and the levels of anti-Xa were higher during anaphylaxis compared with basal conditions or healthy controls (4 kIE/L, IQR 2.5-5.5 versus 1 kIE/L IQR 0.25-1.75, p < 0.005). Conclusion: Tryptase is a biomarker related to the severity of anaphylaxis. However, it is not an optimal marker, because its concentration remains unaltered in a considerable number of patients during acute anaphylaxis. Old age and coronary risk factors were associated with severe anaphylaxis. Furthermore, an activation of the contact and coagulation system, and an increase of activity of the anti-Xa was demonstrated in the patients

The Mast Cell, Contact, and Coagulation System Connection in Anaphylaxis

Anaphylaxis is the most severe form of allergic reaction, resulting from the effect of mediators and chemotactic substances released by activated cells. Mast cells and basophils are considered key players in IgE-mediated human anaphylaxis. Beyond IgE-mediated activation of mast cells/basophils, further mechanisms are involved in the occurrence of anaphylaxis. New insights into the potential relevance of pathways other than mast cell and basophil degranulation have been unraveled, such as the activation of the contact and the coagulation systems. Mast cell heparin released upon activation provides negatively charged surfaces for factor XII (FXII) binding and auto-activation. Activated FXII, the initiating serine protease in both the contact and the intrinsic coagulation system, activates factor XI and prekallikrein, respectively. FXII-mediated bradykinin (BK) formation has been proven in the human plasma of anaphylactic patients as well as in experimental models of anaphylaxis. Moreover, the severity of anaphylaxis is correlated with the increase in plasma heparin, BK formation and the intensity of contact system activation. FXII also activates plasminogen in the fibrinolysis system. Mast cell tryptase has been shown to participate in fibrinolysis through plasmin activation and by facilitating the degradation of fibrinogen. Some usual clinical manifestations in anaphylaxis, such as angioedema or hypotension, or other less common, such as metrorrhagia, may be explained by the direct effect of the activation of the coagulation and contact system driven by mast cell mediators