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

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

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor

Prevenció; Atac d'angioedema; Inhibidor C1Prevención; Ataque de angioedema; Inhibidor C1Prevention; Angioedema attack; C1 inhibitorBACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456)

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

Genetic Variation of Kallikrein-Kinin System and Related Genes in Patients With Hereditary Angioedema

Kallikrein-Kinin System; Genetic variation; Hereditary angioedemaSistema calicreina-cinina; Variació genètica; Angioedema hereditariSistema calicreina-cinina; Variación genética; Angioedema hereditarioHereditary angioedema (HAE) is an autosomal dominant disease caused by C1-INH deficiency due to mutations in SERPING1 (C1-INH-HAE) in most of the cases, or by specific mutations in factor XII gene, F12 (F12-HAE). Identification of polymorphisms in the genes encoding proteins from key pathways driving HAE can help to understand how genetic diversity contributes to its phenotypic variability. Here, 15 genes related to the Kallikrein-Kinin System (KKS) were analyzed by next generation sequencing in 59 patients with C1-INH-HAE or F12-HAE from Brazil, Denmark and Spain, and 19 healthy relatives in a total of 31 families. We identified 211 variants, from which 23 occurred only in Danish subjects and 79 were found only in Brazilian individuals, resulting in 109/211 variations in common between European and Brazilian population in the HAE families analyzed. BDKRB2 and CPM presented a large number of variants in untranslated regions, 46/49 and 19/24, respectively; whereas ACE (n = 26), SERPING1 (n = 26), CPM (n = 24), and NOS3 (n = 16) genes presented the higher number of variants directly affecting amino acid sequence. Despite the large amount of variants identified, the lack of association between genotype and phenotype indicates that the modulation of HAE symptom requires a more complex regulation, probably involving pathways beyond the KKS, epigenetics and environmental factors. Considering the new HAE types recently described, molecules involved in the regulation of vasculature and in plasminogen activation become promising targets for future genetic studies

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

Chronic histaminergic angioedema; Urticaria; Quality of lifeAngioedema histaminérgico crónico; Urticaria; Calidad de vidaAngioedema histaminèrgic crònic; Urticària; Qualitat de vidaThis work was supported by Grants PI16/01304 and #PI20/01536 from the Instituto de Salud Carlos III and the Thematic Networks for Co-operative Research Centers: Reacciones Adversas y Alérgicas network (RD16/0006/0031) from Instituto de Salud Carlos III, cofounded by Fondo Europeo de Desarrollo Regional. The manuscript was edited for English language by American Journal Experts

El mastocito: célula clave en la microinflamación intestinal y en la regulación de la función barrera mediada por el estrés en el síndrome del intestino irritable con predominio de diarrea

El Síndrome del Intestino Irritable (SII), clásicamente considerada una enfermedad del colon, es un trastorno altamente prevalente, con gran impacto en la calidad de vida y pocas opciones terapéuticas eficaces. Se desconoce cuál es su etiología, pero el estrés se ha asociado al desarrollo y mantenimiento del SII, en base a que los pacientes afectos padecen más estrés crónico que la población sana. Los mecanismos fisiopatológicos subyacentes no se conocen con exactitud, pero destaca, como hallazgo común relacionado con la sintomatología, la alteración de la función barrera intestinal, junto con la presencia de microinflamación de la mucosa intestinal más pronunciada en los pacientes con el subtipo SII con predominio de diarrea (SII-D). Su diagnóstico se basa en criterios clínicos y en la exclusión de otras patologías gastrointestinales que cursan con síntomas similares, debido a la carencia de biomarcadores diagnósticos útiles. El mastocito a nivel intestinal interviene en la regulación de la motilidad, sensibilidad visceral y la función epitelial intestinal, por lo que cumple los requisitos para ser la célula candidata en modular la fisiopatología del SII. Este trabajo analiza la función del mastocito como regulador de la disfunción intestinal producida por el estrés. Para ello se han desarrollado tres trabajos, dos realizados con pacientes afectos de SII-D y un modelo experimental en ratas Wistar-Kyoto. En el primer trabajo, se realizó una biopsia de yeyuno a 20 pacientes con SII-D y a 14 voluntarios sanos, y se objetivó que en el yeyuno de pacientes con SII-D existe un incremento de linfocitos intraepiteliales, junto con una marcada hiperplasia y activación mastocitaria. Un hallazgo común fue que los pacientes presentaban más estrés basal que los voluntarios, y dado que el estrés se ha asociado al desarrollo y mantenimiento de los síntomas del SII, realizamos un modelo experimental de estrés crónico por aglomeración en ratas para comprobar si este era responsable de los cambios intestinales observados en nuestros pacientes y por ende, en el intestino del SII. Observamos que el estrés crónico psicosocial produce una inflamación intestinal, una hiperplasia y activación de mastocitos, que se acompaña de un aumento de la permeabilidad intestinal. Este último es dependiente del mastocito, ya que se revierte tras el tratamiento con ketotifeno, un estabilizador de la membrana del mastocito. Por lo tanto este modelo de estrés experimental, reproduce características fisiopatológicas del SII y representa un nuevo modelo experimental para el estudio de su fisiopatología. Por último, en el tercer trabajo, para estudiar el papel regulador del mastocito en la alteración de la barrera intestinal en el yeyuno de pacientes con SII-D en respuesta al estrés agudo, realizamos una perfusión yeyunal segmentaria a 21 pacientes y a 11 voluntarios sanos y recogimos los efluentes intestinales de forma basal, tras la administración de placebo y tras la administración periférica de CRF (factor liberador de corticotropina), principal neuromediador del estrés. Observamos que el estrés agudo producía un aumento de la liberación luminal de triptasa, de forma paralela a la secreción de agua y de albúmina a la luz intestinal, indicando un aumento de la actividad secretora y de la permeabilidad de forma mayoritaria en SII-D. Además se acompañaba de la liberación de quimiocinas proinflamatorias. Observamos también que en el yeyuno de pacientes con SII-D existe una sobreexpresión de CRF-R2. En resumen, la activación de los mastocitos secundaria al estrés en el yeyuno de pacientes con SII-D puede ser un factor relevante en la fisiopatología de la recaída del SII y de la inflamación intestinal producida por el estrés.Irritable Bowel Syndrome (IBS), classically considered a disease of the colon, is a highly prevalent disorder with significant impact on quality of life and few effective therapeutic options. Its etiology is unknown, but stress has been associated with the development and maintenance of IBS, based on the observation that affected patients suffer more chronic stress than the healthy population. Although the underlying pathophysiological mechanisms are not exactly known, a common finding related to symptomatology is the existence of an impaired intestinal barrier function along with the presence of intestinal mucosa microinflammation, especially in patients with subtypes diarrhea-predominant IBS (IBS- D). Diagnosis is based on clinical criteria and exclusion of other gastrointestinal pathologies with similar symptoms, due to the lack of useful diagnostic biomarkers. The mast cell in the intestine is involved in the regulation of motility, visceral sensitivity and intestinal epithelial function, so it meets all the requirements to be a candidate cell in modulating the pathophysiology of IBS. This thesis analyzes the role of the mast cell as a regulator of intestinal dysfunction caused by stress. To examine that, we have developed three different studies, two of them performed with patients with IBS- D and one experimental model in Wistar -Kyoto rats. In the first study, a jejunal biopsy was performed on 20 patients with IBS- D and 14 healthy volunteers and we observed that in the jejunum of patients with IBS- D there is an increase of intraepithelial lymphocytes, along with marked hyperplasia and activation mast cell. A common finding was that patients had more basal stress than healthy volunteers and since stress has been associated with the development and maintenance of IBS symptoms, we conducted an experimental model of chronic crowding stress in rats to test whether this was responsible of the intestinal changes observed in our patients and therefore, in the intestine of IBS. We observed that chronic psychosocial stress produces an intestinal inflammation, hyperplasia and activation of mast cells, which is accompanied by an increase in intestinal permeability. The latter is dependent on mast cells, because was reverted by ketotifen pretreatment. Therefore, this stress experimental model displayed pathophysiological characteristics of IBS and therefore represents a new experimental model for the study of its pathophysiology. Finally, in the third study, we conducted a segmental jejunal perfusion in 21 patients and 11 healthy volunteers to study the regulatory role of mast cells in the alteration of the intestinal barrier in the jejunum of IBS- D patients in response to acute stress. Intestinal effluents were collected at baseline, after the administration of placebo and after peripheral administration of CRF (corticotropin releasing factor), main neuromediator of the stress responses. We observed that acute stress produces increased luminal tryptase release, parallel to the secretion of water and albumin to the lumen, indicating an increase of the secretory activity and permeability predominantly in IBS-D. Addition was accompanied by the release of proinflammatory chemokines. Furthermore, in the jejunum of patients with IBS- D there is also a CRF- R2 overexpression. In summary, the activation of mast cells secondary to stress in the jejunum of patients with IBS- D may be a relevant factor in the pathophysiology and relapse of IBS and stress-induced IBS gut associated inflammation

El mastocito: célula clave en la microinflamación intestinal y en la regulación de la función barrera mediada por el estrés en el síndrome del intestino irritable con predominio de diarrea

El Síndrome del Intestino Irritable (SII), clásicamente considerada una enfermedad del colon, es un trastorno altamente prevalente, con gran impacto en la calidad de vida y pocas opciones terapéuticas eficaces. Se desconoce cuál es su etiología, pero el estrés se ha asociado al desarrollo y mantenimiento del SII, en base a que los pacientes afectos padecen más estrés crónico que la población sana. Los mecanismos fisiopatológicos subyacentes no se conocen con exactitud, pero destaca, como hallazgo común relacionado con la sintomatología, la alteración de la función barrera intestinal, junto con la presencia de microinflamación de la mucosa intestinal más pronunciada en los pacientes con el subtipo SII con predominio de diarrea (SII-D). Su diagnóstico se basa en criterios clínicos y en la exclusión de otras patologías gastrointestinales que cursan con síntomas similares, debido a la carencia de biomarcadores diagnósticos útiles. El mastocito a nivel intestinal interviene en la regulación de la motilidad, sensibilidad visceral y la función epitelial intestinal, por lo que cumple los requisitos para ser la célula candidata en modular la fisiopatología del SII. Este trabajo analiza la función del mastocito como regulador de la disfunción intestinal producida por el estrés. Para ello se han desarrollado tres trabajos, dos realizados con pacientes afectos de SII-D y un modelo experimental en ratas Wistar-Kyoto. En el primer trabajo, se realizó una biopsia de yeyuno a 20 pacientes con SII-D y a 14 voluntarios sanos, y se objetivó que en el yeyuno de pacientes con SII-D existe un incremento de linfocitos intraepiteliales, junto con una marcada hiperplasia y activación mastocitaria. Un hallazgo común fue que los pacientes presentaban más estrés basal que los voluntarios, y dado que el estrés se ha asociado al desarrollo y mantenimiento de los síntomas del SII, realizamos un modelo experimental de estrés crónico por aglomeración en ratas para comprobar si este era responsable de los cambios intestinales observados en nuestros pacientes y por ende, en el intestino del SII. Observamos que el estrés crónico psicosocial produce una inflamación intestinal, una hiperplasia y activación de mastocitos, que se acompaña de un aumento de la permeabilidad intestinal. Este último es dependiente del mastocito, ya que se revierte tras el tratamiento con ketotifeno, un estabilizador de la membrana del mastocito. Por lo tanto este modelo de estrés experimental, reproduce características fisiopatológicas del SII y representa un nuevo modelo experimental para el estudio de su fisiopatología. Por último, en el tercer trabajo, para estudiar el papel regulador del mastocito en la alteración de la barrera intestinal en el yeyuno de pacientes con SII-D en respuesta al estrés agudo, realizamos una perfusión yeyunal segmentaria a 21 pacientes y a 11 voluntarios sanos y recogimos los efluentes intestinales de forma basal, tras la administración de placebo y tras la administración periférica de CRF (factor liberador de corticotropina), principal neuromediador del estrés. Observamos que el estrés agudo producía un aumento de la liberación luminal de triptasa, de forma paralela a la secreción de agua y de albúmina a la luz intestinal, indicando un aumento de la actividad secretora y de la permeabilidad de forma mayoritaria en SII-D. Además se acompañaba de la liberación de quimiocinas proinflamatorias. Observamos también que en el yeyuno de pacientes con SII-D existe una sobreexpresión de CRF-R2. En resumen, la activación de los mastocitos secundaria al estrés en el yeyuno de pacientes con SII-D puede ser un factor relevante en la fisiopatología de la recaída del SII y de la inflamación intestinal producida por el estrés.Irritable Bowel Syndrome (IBS), classically considered a disease of the colon, is a highly prevalent disorder with significant impact on quality of life and few effective therapeutic options. Its etiology is unknown, but stress has been associated with the development and maintenance of IBS, based on the observation that affected patients suffer more chronic stress than the healthy population. Although the underlying pathophysiological mechanisms are not exactly known, a common finding related to symptomatology is the existence of an impaired intestinal barrier function along with the presence of intestinal mucosa microinflammation, especially in patients with subtypes diarrhea-predominant IBS (IBS- D). Diagnosis is based on clinical criteria and exclusion of other gastrointestinal pathologies with similar symptoms, due to the lack of useful diagnostic biomarkers. The mast cell in the intestine is involved in the regulation of motility, visceral sensitivity and intestinal epithelial function, so it meets all the requirements to be a candidate cell in modulating the pathophysiology of IBS. This thesis analyzes the role of the mast cell as a regulator of intestinal dysfunction caused by stress. To examine that, we have developed three different studies, two of them performed with patients with IBS- D and one experimental model in Wistar -Kyoto rats. In the first study, a jejunal biopsy was performed on 20 patients with IBS- D and 14 healthy volunteers and we observed that in the jejunum of patients with IBS- D there is an increase of intraepithelial lymphocytes, along with marked hyperplasia and activation mast cell. A common finding was that patients had more basal stress than healthy volunteers and since stress has been associated with the development and maintenance of IBS symptoms, we conducted an experimental model of chronic crowding stress in rats to test whether this was responsible of the intestinal changes observed in our patients and therefore, in the intestine of IBS. We observed that chronic psychosocial stress produces an intestinal inflammation, hyperplasia and activation of mast cells, which is accompanied by an increase in intestinal permeability. The latter is dependent on mast cells, because was reverted by ketotifen pretreatment. Therefore, this stress experimental model displayed pathophysiological characteristics of IBS and therefore represents a new experimental model for the study of its pathophysiology. Finally, in the third study, we conducted a segmental jejunal perfusion in 21 patients and 11 healthy volunteers to study the regulatory role of mast cells in the alteration of the intestinal barrier in the jejunum of IBS- D patients in response to acute stress. Intestinal effluents were collected at baseline, after the administration of placebo and after peripheral administration of CRF (corticotropin releasing factor), main neuromediator of the stress responses. We observed that acute stress produces increased luminal tryptase release, parallel to the secretion of water and albumin to the lumen, indicating an increase of the secretory activity and permeability predominantly in IBS-D. Addition was accompanied by the release of proinflammatory chemokines. Furthermore, in the jejunum of patients with IBS- D there is also a CRF- R2 overexpression. In summary, the activation of mast cells secondary to stress in the jejunum of patients with IBS- D may be a relevant factor in the pathophysiology and relapse of IBS and stress-induced IBS gut associated inflammation

Allergic diseases in the elderly

Demographic distribution of the population is progressively changing with the proportion of elderly persons increasing in most societies. This entails that there is a need to evaluate the impact of common diseases, such as asthma and other allergic conditions, in this age segment. Frailty, comorbidities and polymedication are some of the factors that condition management in geriatric patients. The objective of this review is to highlight the characteristics of allergic diseases in older age groups, from the influence of immunosenescence, to particular clinical implications and management issues, such as drug interactions or age-related side effects