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.

Delayed postoperative reactions to metamizole: a diagnostic challenge.

Summary: Background. Metamizole, a non-steroidal anti-inflammatory drug from the pyrazolone group, is a frequent cause of immediate hypersensitivity reactions and, more rarely, of delayed drug hypersensitivity reactions. Due to its favorable pharmacokinetic characteristics, metamizole is widely used in the postoperative period for pain control. Methods. Retrospective study of patients referred for allergological study between January 2012 and June2022 for postoperative hypersensitivity reactions. Clinical and diagnostic data were collected through review of patients' medical records. Twenty patients with postoperative hypersensitivity reactions were referred, of which 10 presented delayed reactions. We analyzed the results of skin prick, intradermal and patch tests performed with an intravenous metamizole solution as well as provocation tests performed with metamizole and acetylsalicylic acid. Cross-reactivity to non-steroidal anti-inflammatory drugs was excluded by confirmation of clinical tolerance to non-steroidal anti-inflammatory drugs or by acetylsalicylic acid provocation test. Results. In 7 of the 10 patients a delayed reaction to metamizole was diagnosed. These reactions were characterized as maculopapular exanthema, occurring in multiple postoperative settings. Skin tests were negative, except in one patient with late mild erythema in the ipsilateral upper limb and no reaction at the site of intradermal injection. Delayed hypersensitivity was demonstrated by late positive metamizole provocation tests. Conclusions. This study demonstrated that for a correct diagnosis a high degree of suspicion about possible delayed hypersensitivity drug reactions to metamizole in the postoperative setting is needed. In the investigation, provocation test with metamizole was decisive for diagnostic confirmation.

Hereditary angioedema: 24 years of experience in a Portuguese Reference Center.

Summary: Hereditary angioedema (HAE) poses a high burden of disease, being its epidemiological and clinical data heterogeneous among countries, with no recent published studies concerning Portuguese patients. Therefore, we aimed to raise awareness of HAE and to contribute to clinical knowledge. An observational, descriptive, retrospective, and cross-sectional study was performed, that included a cohort of 126 patients followed in a single Portuguese Center. We observed a high prevalence of HAE-C1-INH type II (45.2% of patients). Most HAE patients (67.4%) presented the initial manifestations of the disease before adulthood, at a mean age of 12.6 ± 8.4 years. However, we found a long delay in HAE diagnosis, especially in those without family history (mean 20.7 ± 17.3 years). Stress was the most common trigger, followed by trauma and infection. Symptoms involving different systems were increasingly reported with increased disease duration. Cutaneous symptoms (95.0%) were more frequent, followed by gastrointestinal (80.7%), and respiratory symptoms (50.4%). HAE symptoms led to abdominal surgery in 22 (17.5%) patients and induced laryngeal edema requiring intubation/tracheostomy in 8 (6.3%) patients. Most patients were under long-term prophylaxis, mainly with attenuated androgens (62.7% of patients).The correct distinction between HAE and other common causes of angioedema is critical, allowing reduction of diagnostic delay, improvement of adequate management, and ultimately improving outcomes and quality of life of HAE patients.

Anaphylaxis: A Decade of a Nationwide Allergy Society Registry.

BACKGROUND AND OBJECTIVES: Anaphylaxis is an acute, life-threatening, multiorgan hypersensitivity reaction. Objective: The aim of this study was to identify the causes of anaphylaxis in Portugal in order to improve our knowledge of epidemiology and management. METHODS: We implemented a nationwide notification system for anaphylaxis over a 10-year period, with voluntary reporting by allergists. Data on 1783 patients with anaphylaxis were included. Etiopathogenesis, manifestations, and clinical management were characterized in detail for both children and adults. RESULTS: The mean age was 32.7 (20.3) years, and 30% were under 18 years of age; 58% were female. The mean age at the first anaphylaxis episode was 27.5 (20.4) years (ranging from 1 month to 88 years). The main culprits of anaphylaxis were foods (48%), drugs (37%) (main trigger in adults, 48%), and hymenoptera venom (7%). The main culprit foods were shellfish (27%), fresh fruit (17%), cow's milk (16%), tree nuts (15%), fish (8%), egg (7%), and peanut (7%). The main drugs were nonsteroidal anti-inflammatory drugs (43%), antibiotics (39%), and anesthetic agents (6%). Other causes included exercise (3%), latex (2%), cold-induced anaphylaxis (2%), and idiopathic anaphylaxis (2%). Most patients (80%) were admitted to the emergency department; only 43% received adrenaline. Anaphylaxis recurred in 41% of patients (21% with ≥3 anaphylactic episodes); 7% used an adrenaline autoinjector device. CONCLUSION: Food is the leading cause of anaphylaxis in Portugal, while drugs were the main elicitors in adults. We emphasize undertreatment with adrenaline and recurrent episodes, highlighting the need to improve diagnostic and therapeutic approaches to anaphylaxis.

Evolution of Api m10 Specific IgE and IgG4 After One Year of Bee Venom Immunotherapy.

Summary: Background. Bee-venom (BV) anaphylaxis can be life-threatening, requiring treatment with BV immunotherapy (bVIT). Different molecular profiles may be associated with different outcomes after bVIT. Methods. In 19 patients with BV anaphylaxis, sensitized both to Api m1 and Api m10, we evaluated sIgE and sIgG4 Api m1 and Api m10 levels before and after 1 year bVIT.Results.7 patients (37%) had higher baseline Api m10 than Api m1 sIgE levels (Api m10 predominant). bVIT reduced sIgE to both components but sIgG4 levels were increased only for Api m1. 5 patients (2 in the Api m10 predominant group) were re-stung without anaphylaxis. Conclusions. Although there was no increase in Api m10 sIgG4 levels after 1 year bVIT, we did not observe relevant differences in other outcomes between patients with predominant Api m1 or Api m10 sensitization.

Severe bronchiectasis in a patient with common variable immunodeficiency.

BACKGROUND: Bronchiectasis are common in Common Variable Immunodeficiency. These patients are prone to infection, leading to progressive lung destruction and accelerated FEV1 decline. CLINICAL CASE: 40 year-old man, with recurrent respiratory infections, autoimmunity and diarrhea since age 7. At 17 CVID was diagnosed and IVIgG was started. During the following years, respiratory symptoms progressively worsened and bronchiectasis was found on thoracic computed tomography. Bronchoscopy revealed Pseudomonas aeruginosa in bronchoalveolar lavage and bronchial secretions cultures. Eradication therapy led to clinical improvement. DISCUSSION: This case report stresses the importance of regular microbiological screening and appropriate antibiotherapy. Early/aggressive treatment may significantly impact on patients' evolution.

Longitudinal study of the expression of FcεRI and IgE on basophils and dendritic cells in association with basophil function in two patients with severe allergic asthma treated with Omalizumab.

Severe asthma is a challenging disease, and omalizumab has been an important tool to help clinicians address more efficiently this problem. Besides reduction of free and total serum IgE levels, there are a number of other immunologic effects of omalizumab that may be of relevance in its therapeutic action. We report two mite-allergic severe asthmatic patients successfully treated with omalizumab for one year. Clinically, patients improved gradually, with no further need for systemic steroids or emergency department visits during that treatment period, and with Asthma Control Test (ACT) scores showing controlled disease, although pulmonary function didn't show any significant improvement. Immunologically, we observed marked down-regulation of surface IgE and FcεRI on basophils, plasmacytoid and myeloid dendritic cells, as well as a reduction of basophil activation after specific allergen stimulation. These effects were clearly evident immediately after one month but were enhanced at 3, 6 and 12 months of omalizumab treatment, suggesting an advantage to continuing this therapy, and raising the hypothesis of some markers being useful to assess immunological responses to omalizumab, which could assist in the clinician's decision to stop or to restart this treatment.

Prevalence and classification of rhinitis in preschool children in Portugal: a nationwide study.

BACKGROUND: Information on rhinitis epidemiology in preschool children is scarce. OBJECTIVES: To estimate, in children with 3-5 years of age, current rhinitis prevalence, to describe rhinitis symptoms and associated sociodemographic characteristics, and to report allergic rhinitis and its impact on asthma (ARIA) classification. METHODS: Cross-sectional, nationwide, population-based study including children aged 3-5 years. A multistep selection strategy was used to obtain a representative sample. Data were collected at kindergartens and parish centers by face-to-face interview to caregivers, using an adapted ISAAC questionnaire. 'Current rhinitis' (CR) was defined as the presence of ≥1 rhinitis symptom (repeated sneezing and/or itchy nose, blocked nose for >1 h, or runny nose without having a cold/flu) in the last year. Rhinitis lasting ≥4 days/week and ≥4 consecutive weeks was classified as persistent. Moderate-severe disease interfered 'a moderate amount' or 'a lot' in daily activities. RESULTS: Five thousand and eighteen children were included. CR prevalence was 43.4% [95% CI (42.0-44.8%); n = 2179] and that of physician-diagnosed rhinitis was 11.7% [95% CI (10.8-12.6%); n = 588]. Of children with CR, 67% reported blocked nose, 48% rhinorrhea, and 46% sneezing/itchy nose. Considering ARIA classification, 30% of the population had mild intermittent, 3% mild persistent, 7% moderate-severe intermittent, and 3% moderate-severe persistent rhinitis. Children with CR had more current wheezing, physician-diagnosed asthma, self-reported food allergy, and family history of allergic disease. These characteristics were also associated with persistent and moderate-severe rhinitis. CONCLUSIONS: This is the first nationwide population-based study reporting rhinitis prevalence and ARIA classification in preschool children. In this age-group, rhinitis is frequent and underdiagnosed. About 25% children with rhinitis presented moderate-severe disease.

Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma.

BACKGROUND AND AIM: The Control of Allergic Rhinitis and Asthma Test (CARAT) was developed to be used in the concurrent management of these diseases, as recommended by the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. However, it was necessary to statistically identify and remove redundant questions and to evaluate the new version's factor structure, internal consistency and concurrent validity. METHODS: In this cross-sectional study 193 adults with allergic rhinitis and asthma from 15 outpatient clinics in Portugal were included. The CARAT questionnaire was reduced using descriptive analysis, exploratory factor analysis and internal consistency. Spearman's correlations were used to compare the CARAT scores with a medical evaluation and other measures of control, including the Asthma Control Questionnaire and symptoms' visual analogue scales. The performance against physician rating of control was summarized using the area under the curve (AUC) from receiver operating characteristic analysis. In addition, CARAT was compared with the physician's decision to reduce, maintain or increase treatment. RESULTS: The reduced version has 10 questions and 2 factors (CARAT10). The Cronbach's alpha was 0.85. All correlation coefficients of CARAT10 and factors with the different measures of control met the a priori predictions, ranging from 0.58 to 0.79. The AUC was 0.82. For the physician's decision groups of reduce, maintain or increase treatment, the mean (IC95%) scores of CARAT10 were 24 (21.4;26.6), 21 (19.4;21.9) and 15 (13.6;16.5), respectively. CONCLUSION: CARAT10 has high internal consistency and good concurrent validity, making it useful to compare groups in clinical studies.

Monoid sublingual immunotherapy.

Sublingual monoid immunotherapy with monomeric allergoids has been largely used in Europe in the last few years. An open trial of allergoid in tablets has been done in rhinitic patients allergic to house dust mites, grass pollens and Parietaria with clear improvement in clinics and drug consumption scores. In a second phase a double blind placebo controlled trial of grass pollens allergoids have been done in hay fever patients with significant decrease on the scores of rhinorrea, sneezing and conjunctivitis nasal steroid consumption and clinical score after serial nasal challenges. Monomeric allergoids are an efficace and safe immunotherapy in allergic rhinitis.

Immunoblot studies in allergic patients to hymenoptera venom before and during immunotherapy.

BACKGROUND: Hymenoptera venom immunotherapy (VIT) is immunologically effective in patients with systemic allergic reactions after hymenoptera stings. OBJECTIVE: To evaluate the effect of VIT on specific IgE and IgG4 immunoblotting bands in VIT-treated patients. MATERIAL AND METHODS: Specific IgE and IgG4 immunoblotting bands for hymenoptera venom were performed with ALABLOT in sera of 17 patients (8 allergic to honeybee venom, 8 to wasp and 1 to polistes venom) before and during successful VIT (1 and 3 years). Before immunotherapy, all patients had experienced moderate/severe systemic reactions to a hymenoptera sting, with positive skin tests and venom-specific IgE. During immunotherapy all patients suffered field stings, without any systemic reaction. RESULTS: Before VIT we detected several immunoglobulin-binding bands in different regions, with different individual patterns. After VIT, we observed in some patients (5/8 for honeybee venom, 6/8 for wasp and 1/1 for polistes) complete disappearance of some IgE-binding bands, mainly the 15 kDa region (honeybee) and 23 and 44 kDa regions (wasp and polistes). All patients showed decreased intensity of IgE-binding bands, most pronounced in regions 16, 44 and 52 kDa (honeybee); 44 and 35 kDa bands (wasp) and 23 kDa (polistes). Some patients showed de novo appearance of IgG4-binding bands (4/8 for honeybee and 8/8 for wasp venom), mainly in 52 kDa (honeybee) and in 23 and 44 kDa regions (wasp). All patients showed increased intensity of IgG4 bands that were already present before VIT, more pronounced in 52 and 44 kDa (honeybee) and in 44 and 35 kDa regions (wasp). CONCLUSIONS: During successful VIT there are changes in intensity and number of IgE and IgG4 binding bands, which could reflect the immunological improvement induced by VIT. These changes are more pronounced/frequent in wasp VIT, a fact that could explain the best results usually seen in these patients.

Nasal provocation and immunotherapy.

Nasal mucosa is heavily exposed to inflammatory and allergic stimuli, rhinitis being the most common form of allergic respiratory disease. The nose is an easily accessible organ and a good model for the study of allergies as it makes it possible to monitor the effects of specific challenges as well as therapeutic interventions, namely specific immunotherapy (SIT). Injectable, nasal or sublingual SIT are useful therapeutic strategies in the management of allergic rhinitis patients. Monitoring the evolution of parameters such as clinical scores, nasal peak flow variation or drug requirements during SIT provides important information on its clinical efficacy. Laboratory measurement of tryptase and eosinophil cationic protein in the target organ after specific nasal provocation makes it possible to record changes in the release of mast cell and eosinophil mediators, thus providing objective evidence of the immunological efficacy of this therapy on these cell populations and providing data which eventually will contribute to a better understanding of the multiple mechanisms of action of allergen desensitization therapy.

Latex and chickpea (Cicer arietinum) allergy: first description of a new association.

In this paper we describe the existence of cross-reactivity between allergens from latex and chickpea, a food from the Leguminosae family, which is common in the Mediterranean diet. We present the case report of a spina bifida boy with a clinical relevant food allergy to chickpea (oral syndrome + dysphonia), developing after the appearance of latex allergy symptoms (lip angioedema + intraoperative anaphylaxis). Specific IgE to latex and chickpea was demonstrated by skin prick tests, measurement of patient's serum specific IgE and IgE-immunoblotting. Cross-reactivity was studied by means of EAST-inhibition and western blotting-inhibition. A strong inhibition was observed in several IgE-binding bands when latex extract was used in solid phase and patient serum was preincubated with chickpea extract (chickpea extract as inhibitor phase). As far as we know, this is the first report of cross-reactivity between latex and chickpea, a food which should therefore be added to the extensive list of latex cross-reactive foods.

Allergic rhinitis and asthma: more similarities than differences.

Clinical epidemiological and pathophysiological studies suggest a strong functional and immunological relationship between the nose and the bronchi. Nasal stimulation, can induce bronchoconstriction by a proposed rhinobronchial reflex and inflammatory mediators originating from the nose could be inhaled and trigger bronchial inflammation. Bronchial provocation in sensitised subjects results in nasal inflammation through systemic circulation. There is an increased prevalence of asthma in patients with rhinitis relatively to patients without nasal complaints and allergic rhinitis patients have an increased risk to develop asthma. Nasal and bronchial co-morbidity is high, 75% of asthmatics have rhinitis and 20% to 40% of rhinitic patient suffer from asthma. In the World Health Initiative on Allergic Rhinitis and its effect on Asthma (ARIA) it is quoted that asthma and rhinitis are common co-morbidities suggesting the concept of one airway one disease. The term allergy rhinobronchitis has been proposed to link the association between asthma and rhinitis. The treatment of rhinitis and sinusitis is important for management of asthma. Treatment of chronic rhinitis not only reduces nasal inflammation obstruction and discharge but also can reduce lower airway hyperesponsiveness and symptoms of asthma. Treating nasal inflammation is a key point in asthma control. These data strength the functional and allergologial link between nose and bronchi. Nasal inflammation induced by nasal challenge in patients with rhinitis has the ability to also induce bronchial changes in some asthmatic patients.

Antihistamines and serum adhesion molecule levels.

BACKGROUND: Some antihistamines are capable of inducing decreased expression of adhesion molecules in nasal and conjunctival tissues of allergic rhinoconjunctivitis patients. This study aimed to determine if one month of therapy with loratadine 10 mg once daily would also induce any decrease in serum levels of soluble ICAM-1 (sICAM-1) or VCAM-1 (sVCAM-1). MATERIAL AND METHODS: 40 monosensitized House Dust Mite (HDM) mild-to-moderate allergic rhinitis patients were included in the study. During the study, twenty patients randomly received 10 mg loratadine daily, the other twenty did not take any antihistamine. All patients were treated with nasal budesonide daily and sodium cromoglycate nasal spray when needed. Serum soluble ICAM-1 and VCAM-1 levels were determined by immunoenzimatic assay before and in the end of the study period. RESULTS: After one month of loratadine sVCAM-1 levels had a significant decrease (from 724.8 to 625 ng/ml) while sICAM-1 levels had a slight but not significant increase. Control patients did not have significant variations in sVCAM-1 or sICAM-1 serum levels. During regular antihistamine therapy patients improved their clinical scores. CONCLUSIONS: Loratadine 10 mg daily during one month induced a decrease in sVCAM-1 but not in sICAM-1 levels in HDM allergic rhinitis patients.

Development of immunoglobulins to venoms during specific immunotherapy.

Immunotherapy against venoms (itv) is an efficacious treatment for most subjects who are allergic to hymnenoptera venoms. The authors studied 8 patients: 7 who were allergic to honey been venom and 1 who was allergic to wasp venom, followed for two years during immunotherapy with an aqueous extract of pure venoms from ALBAY Dome Hollister Stier. Specific IgE and IgG4 were evaluated by the Elisa Cap Technique of Pharmacia at different times: T0 before immunotherapy, T1 (one year after) and T2 (2 years after). A significant fall of specific IgE (p < 0.02) and a significant increase in specific IgG4 (p < 0.008) were seen during the two years in all patients. Four of the patients were re-stung and none had systemic reactions. These results suggest that increase in specific IgG4 is correlated with the protective effect of immunotherapy.

Nasal allergen challenge and immunotherapy control.

Nasal allergen challenges, despite not reproducing exactly natural allergen exposure, are a very useful method to understand the complex cellular kinetics and cellular interactions that occur in allergic rhinitis. Cell-specific soluble mediator measurements can give useful diagnosis information as well as complementary information regarding the monitoring of specific immunotherapy. In this article we present data concerning eosinophil cationic protein and tryptase measurements after nasal allergen and the influence of specific immunotherapy on nasal peak flow before and 1, 2 and 3 years after starting immunotherapy.

Kinetics of eosinophil cationic protein release in mite-allergic rhinitis after specific nasal provocation.

Nasal allergen challenges, despite not reproducing exactly natural allergen exposures, are a useful method to try to understand the complex mediator and cellular kinetics as well as the cellular interactions triggered by allergen exposure in allergic rhinitis. In this article we evaluated the kinetics of Eosinophil Cationic Protein (ECP) release into nasal lavage fluid after nasal allergen challenge. Our results have shown heterogeneity in ECP kinetics, probably due to heterogeneous activation of the eosinophils already present in the nasal mucosa of perennial allergic rhinitis patients. More studies in this field are needed to evaluate the effect of specific immunotherapy and/or prolonged topical steroid therapy on the kinetics of ECP liberation after allergen challenge. These studies will ultimately lead to a more clear definition of the clinical usefulness of this procedure.