Evolution of Guidelines for the Management of Hereditary Angioedema due to C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients' needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients' lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as "first-line") and the introduction of patient-reported outcome measures to assess patients' perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified.

Evolution of Guidelines for the Management of Hereditary Angioedema due to C1 Inhibitor Deficiency

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients’ needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients’ lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as “first-line”) and the introduction of patient-reported outcome measures to assess patients’ perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified (AU)

El angioedema hereditario (AEH) es una enfermedad grave e incapacitante, caracterizada por episodios recurrentes de edema subcutáneo en la piel o en las mucosas de los tractos respiratorio y gastrointestinal. El AEH por déficit del C1-inhibidor (AEH-C1-INH) es el subtipo más prevalente. En el presente estudio ibérico se han comparado las guías/recomendaciones de tratamiento del AEH-INH-C1, publicadas entre 2010 y 2022 para identificar las principales diferencias en cuanto a los enfoques terapéuticos para el tratamiento a demanda y la profilaxis a corto y largo plazo (PLP). A nivel mundial, las directrices sobre el AEH evolucionaron con la disponibilidad de nuevos tratamientos y con un cambio en el paradigma de gestión hacia un enfoque individualizado y centrado en el paciente en el que la calidad de vida (CdV) es fundamental. En consonancia con ello, se observó una tendencia creciente hacia el tratamiento domiciliario, ya que facilita potencialmente las intervenciones precoces, proporciona mayor flexibilidad y comodidad, y se asocia a una mayor calidad de vida, permitiendo a los pacientes llevar una vida normal. La PLP es el indicador que más innovaciones ha experimentado a lo largo de los años, paralelamente a la disponibilidad de nuevas terapias y a la toma de conciencia de las necesidades de los pacientes. Se dispone de varias terapias profilácticas con un alto nivel de evidencia, aunque faltan estudios específicos de comparaciones directas entre ellas. Los objetivos del tratamiento se han ido haciendo más ambiciosos, desde la reducción de la frecuencia, gravedad y duración de los ataques, hasta lograr el control total de la enfermedad y la normalización de la vida de los pacientes en la actualidad (AU)

Management of Pregnancy and Delivery in Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency.

BACKGROUND AND OBJECTIVE: There is little information on pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency (C1INH-HAE). The aim of this study was to describe the effect of pregnancy and deliveries on symptoms of C1INH-HAE and review the need for and safety of treatments available during the study period. METHODS: Retrospective review using a purpose-designed questionnaire of 61 C1INH-HAE patients from 5 hospitals specialized in the management of HAE in Spain. The outcomes measured were number of pregnancies, changes in symptoms during pregnancy and delivery, mode of delivery, type of anesthesia during delivery, treatments received, and tolerance of treatments. RESULTS: We reviewed 125 full-term pregnancies (89 without a prior diagnosis of C1INH-HAE), 14 miscarriages, and 4 induced abortions. Patients reported an increased frequency of C1INH-HAE symptoms in 59.2% of pregnancies (74/125) and the presence of symptoms throughout pregnancy in 40% (50/125). Prophylactic C1INH-HAE therapy was used during 9 (7.2%) of the 125 pregnancies. Nine patients--in 11 pregnancies (8.8 %)--received treatment for acute attacks. Most deliveries (n=110, 88%) were vaginal. A cesarean section was necessary in 15 cases (12%). Short-term prophylaxis with pdhC1INH was administered before 14 deliveries (11.2 %); 111 deliveries (88.8 %) were performed without premedication and were well tolerated. Anesthesia was used in 51 deliveries (40.8%). CONCLUSIONS: Pregnancy has a variable influence on the clinical expression of C1INH-HAE. Attacks tend to occur more frequently but not to increase in severity. Vaginal delivery was mostly well tolerated. pdhC1INH prophylaxis should be administered prior to cesarean delivery and is also recommended before vaginal delivery if there are additional risk factors. pdhC1INH should always be available in the delivery room.

Anaphylaxis in Adolescent/Adult Patients Treated in the Emergency Department: Differences Between Initial Impressions and the Definitive Diagnosis.

OBJECTIVES: To contrast the initial suspected etiology of anaphylaxis with the postworkup diagnosis in patients attended at the emergency department (ED) of a tertiary-level hospital in Spain and to investigate the incidence, causes, and management of anaphylaxis. METHODS: We performed an observational study of patients aged more than 15 years who came to the ED with anaphylaxis between 2009 and 2010. All clinical records from the ED were reviewed. We recorded data on clinical management, the etiology proposed by the attending emergency physician, and the cause reported by the patient. The findings were compared with the diagnosis reached after the allergy workup. RESULTS: The incidence of anaphylaxis was 0.08%. The most common manifestation was skin-mucosal symptoms (98.3%). Anaphylaxis was diagnosed in the ED in only 44% of the cases, regardless of severity. Only 39.7% received epinephrine, which was administered more frequently when the ED physician diagnosed anaphylaxis, regardless of severity. A total of 60 patients were subsequently seen at the allergy department. The final etiology differed from the initial suspicion in the ED in 45% of cases. The frequency of anaphylaxis of uncertain origin decreased from 33.3% to 13.3%. After the allergy workup, drugs (41.7%) were considered the main cause of anaphylaxis, followed by food (25%). CONCLUSIONS: The incidence of anaphylaxis (0.08%) was double that estimated in the ED. Anaphylaxis is underdiagnosed. A correct diagnosis conditions the administration of epinephrine, regardless of the severity of symptoms. The real etiology of anaphylaxis should only be proposed after an allergy workup, which is recommended in all cases, as the real cause can differ considerably from the initial impression in the ED.

Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations.

BACKGROUND: There are no previous Spanish guidelines or consensus statements on bradykinin-induced angioedema. AIM: To draft a consensus statement on the management and treatment of angioedema mediated by bradykinin in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals. METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema, a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings were held to reach the consensus. RESULTS: Treatment approaches are discussed, and the consensus reached is described. Specific situations are addressed, namely, pregnancy, contraception, travelling, blood donation, and organ transplantation. CONCLUSIONS: A review of and consensus on treatment of bradykinin-induced angioedema is presented.

Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis.

BACKGROUND: There are no Spanish guidelines or consensus statement on bradykinin-induced angioedema. AIM: To review the pathophysiology, genetics, and clinical symptoms of the different types of bradykinin-induced angioedema and to draft a consensus statement in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals. METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings of the SGBA were held in Madrid to reach the consensus. RESULTS: The pathophysiology, genetics, and clinical symptoms of the different types of angioedema are reviewed. Diagnostic approaches are discussed and the consensus reached is described. CONCLUSIONS: A review of bradykinin-induced angioedema and a consensus on diagnosis are presented.

Recurrent anaphylaxis due to lupin flour: primary sensitization through inhalation.

Allergic reactions to lupin have increased in parallel with the growing use of lupin flour by food manufacturers. We studied a patient with recurrent anaphylaxis to manufactured foods and a history of rhinitis-asthma related to lupin inhalation and legume tolerance. Skin prick tests with airborne and food allergens, specific immunoglobulin (Ig) E determinations, and an inhalation exposure test to ground lupin were carried out. Lupin allergens and cross-reactivity with other legumes were also studied using sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting/immunoblotting inhibition. The skin tests and specific IgE were positive for lupin and vetchling and negative for other legumes. The presence of lupin flour in the implicated foods was confirmed. Immunoblotting showed multiple IgE-binding bands (10-40 kDa) for lupin and vetchling but not for peanut, pea, or soy extracts. Immunoblotting inhibition demonstrated intense lupin-vetchling cross-reactivity. We present a case of recurrent anaphylaxis due to lupin flour as a hidden food allergen with primary sensitization due to exposure to ground lupin via inhalation. We found cross-reactivity between lupin and vetchling but not other legumes.

Assessment of airway distribution of transnasal solutions in mice by PET/CT imaging.

PURPOSE: Transnasal administration is one of the most common routes for allergen challenge in mouse models of airway diseases. Although this technique is widely used, neither the amount of allergen that reaches the lung nor its airway distribution has been well established. We used positron emission tomography (PET) and computed tomography (CT) to examine the anatomical distribution of a solution containing a tracer immediately after transnasal delivery and to determine the possible influence of age and administered volume. PROCEDURES: Forty-six female BALB/c mice were divided into three groups according to instillation volume and age: (A) 15 microl, 8-10 weeks old (N = 10), (B) 30 microl, 8-10 weeks old (N = 20), and (C) 30 microl, 32 weeks old (N = 16). Anesthetized animals underwent a dynamic scan in a dedicated small-animal PET scanner immediately after transnasal administration of a solution containing (18)FDG. Regions of interest were used to obtain quantitative data. Animals were also imaged with a small-animal CT scanner to obtain complementary anatomical information. RESULTS: Mean +/- SD (5.69 +/- 4.51%) of the solution administered reached the lungs in group A, 41.84 +/- 8.03% in group B, and 36.65 +/- 16.15% in group C. A comparable percentage was delivered to the left and right lungs in all the groups. Analysis of variance revealed a significant difference between the groups in the proportion of the solution that reached the lungs depending on the injection volume (P < 0.001), but not depending on animal age. CONCLUSIONS: In this first report on quantitative imaging by PET and CT in small animals, we confirmed the suitability of the transnasal route with an instilled volume of 30 microl delivering fluids into the lower airways, although only about 40% of the dose reaches the lungs.

Pollen-induced airway inflammation, hyper-responsiveness and apoptosis in a murine model of allergy.

BACKGROUND: Previous studies indicate that murine models are useful tools for studying the allergic diseases, including certain aspects of bronchial asthma such as cellular tissue inflammation and pulmonary function. OBJECTIVE: To develop an experimental model of allergic lung inflammation based on a relevant human allergen, olive pollen, and to establish the immunological, cellular and functional airway features of the allergic response in this model. METHODS: Induction of systemic allergic response was achieved by the subcutaneous administration of Olea europaea extract in BALB/c mice. Olea-specific Igs (IgG1, IgG2a and IgE) and cytokines from splenocyte cultures IL-4, IL-5 IL-10, IL-13 and IFN-gamma were measured. Allergic airway response was generated by transnasal instillation of the allergens. Airway responsiveness was monitored by non-invasive methacholine inhalation challenge. Lungs were paraffin embedded and histologically analysed. Apoptosis was studied by the TUNEL technique in the lung tissue and through cell cycle analysis by flow cytometry in splenocytes. RESULTS: Our results demonstrate that Olea-sensitized mice develop a specific allergic antibody (IgG1 and IgE) and cytokine (IL-4, IL-5, IL-10 and IL-13) response. After transnasal Olea instillation, they show inflammatory infiltration of lung tissue, mucus secretion and non-specific hyper-responsiveness in the airway. Concomitantly, differences in the rate of apoptosis are observed in the lung cells as well as a significant reduction of spontaneous apoptosis in the splenocytes of allergic mice. CONCLUSION: We present a novel animal model of olive pollen-allergic disease. This model presents traits associated with human allergic asthma and could be an interesting tool in the study of underlying molecular mechanisms and in exploring the therapeutic approaches to this disease.

Diagnosis and management of hypersensitivity reactions caused by oxaliplatin.

Hypersensitivity reactions to oxaliplatin have been increasing since its introduction at the end of the 1990s, but allergy tests with antineoplastic drugs are rarely used to aid diagnosis. We describe 5 cases in which hypersensitivity reactions to oxaliplatin after several courses of chemotherapy were managed by allergy testing and desensitization. Skin prick tests were negative at 1 mg/mL in all patients, positive at 10 mg/mL in 2 tested patients, and negative in 10 control subjects. Intradermal tests were positive and not irritant at 0.01 to 0.001 mg/mL concentrations. A desensitization protocol with increasing concentrations and flow rates was successfully completed in all patients. We conclude that prick and intradermal skin tests are useful in the diagnosis of hypersensitivity reactions to oxaliplatin and that the desensitization protocol performed avoided discontinuation of chemotherapy in all patients.

Allergy to chironomid larvae (red migde larvae) in non professional handlers of fish food.

UNLABELLED: Chironomids are insects which inhabit wetlands. In countries such as Sudan, The United States. Egypt and Japan they are the cause of serious environmental allergy. In Europe, and particularly in Spain, allergy to Chironomids is infrequent and has only been described in patients who handle Chironomid larvae which form part of certain fish foods. MATERIALS AND METHODS: We report a case of hypersensitivity to the Chironomid Midge (Chironomus thummi thummi) in a 23-year-old patient who on two occasions, after being in contact with fishfood, suffered rash, rhinoconjunctivitis, dyspnea and dysphagia. A Prick test was carried out with the habitual pneumoallergens, Chironomid Midge extract (PBS: 1.3 mg/ml), Common Mosquito (Culex pipiens), Squid, Mussel, Prawn and Anisakis. Conjunctival provocation was also carried out with Chironomid Midge extract; detection of specific IgE for Chironomid Midge, Common Mosquito (Aedes comunis), Mussel, Squid, Shrimp, Anisakis, house dust and house mites by means of the CAP technique; detection of IgE by means of ELISA in response to Chironomid Midge, Aedes mosquito, Squid, Prawn, Mussel and Anisakis; ELISA-inhibition and Immunoblott-inhibition. RESULTS: The positive results of the cutaneous tests, the detection of specific IgE and conjunctival provocation confirmed the existence of an IgE-mediated mechanism. In our patient, the in vitro techniques demonstrated cross reactivity with the Common Mosquito. CONCLUSIONS: We report on a patient with a case history of rhinoconjunctivitis, rash, dyspnea, and dysphagia after handling fish food. The etiological agent was the Chironomid larvae. The sensitization of our patient has been demonstrated by means of in vivo and in vitro techniques.