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.

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.

Analysis of adrenaline autoinjectors acquisition in Portugal over 15 years.

Summary: Background. The adrenaline autoinjector (AAi) is universally recommended as the first-line treatment for anaphylactic reactions occurring outside the medical setting. The quantification of its acquisition may help estimate the prevalence of patients at risk of anaphylaxis with an indication for AAi. Objective. Evaluation of the global and regional frequency of AAi purchases in Mainland Portugal between 2003-2017 and calculate the inherent costs in 2017. Methods. AAi acquisition distribution analysis along this period. The population was divided in two age groups according to the adrenaline dosage. Results. A total of 10,993 AAi units of 0.15mg/0.3mL and 28,619 of 0.3mg/0.3mL were acquired in these 15 years, with an annual average of 733 and 1908 units, respectively. In cumulative values terms, Lisbon showed the highest number of AAI acquired and higher prevalence per region/100,000 inhabitants in both groups. In 2017, the annual cost for each age group was 64,202.71 € 187,447.70 € for patients and € 37,706.35 / 110,113.30 € for the National Health System. Conclusions. In the last 15 years, there was a progressive increase in AAi acquisition. We estimate a rate of anaphylaxis occurrence in Portugal according to AAi aquisition of 0.165%.

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)

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.

Subcutaneous immunotherapy with aeroallergens: safety profile assessment.

SUMMARY: Introduction. Severe systemic reactions (SR) to allergen subcutaneous immunotherapy (SCIT) are rare but local reactions (LR) are common. We aimed to characterize the type of reactions and safety profile. Methods. Retrospective analysis of medical record from patients under SCIT between 2013-2016. Results. Total of 7372 SCIT injections in 323 patients: 52% female; mean age 30 years (SD 13); mean treatment time 19 months (SD 13). There were 57 patients (17.6% of population, 70% female) with at least one adverse reaction, for 93 reactions described (1.3% injections). There were 79 LR (1.1% injections) in 46(14.2%) patients: 36 in build-up, 43 in maintenance. There were 14 SR (0.19% injections) in 12(3.7%) patients: 12 in build-up, 2 in maintenance. All SR were grade 1. The majority of reactions were caused by mite SCIT (69.9%). Conclusions. SCIT is safe and well tolerated, with no report of SR grade > 1.

Molecular Profile of Sensitization to Dermatophagoides pteronyssinus Dust Mite in Portugal.

BACKGROUND AND OBJECTIVES: To analyze component-resolved diagnosis of sensitization to Dermatophagoides pteronyssinus (Der p) in patients with respiratory allergy and the association between diagnostic findings and clinical severity in different geographical areas. METHODS: The study population comprised 217 patients (mean age, 25.85 [12.7] years; 51.16% female) selected from 13 centers in Portugal (5 from the North, n=65). All had allergic rhinitis with or without asthma and positive skin prick test results to at least 1 dust mite. Specific IgE (sIgE) to Der p, Dermatophagoides farinae, Lepidoglyphus destructor, Der p 1, Der p 2, Der p 10, and Der p 23 was determined using ImmunoCAP. The Mann-Whitney test was applied for the following comparisons: rhinitis vs rhinitis and asthma; mild vs moderate-to-severe rhinitis; North vs South. RESULTS: The prevalence of sensitization was 98.2% for Der p, and 72.4%, 89.4%, 9.7%, and 77% for Der p 1, Der p 2, Der p 10, and Der p 23, respectively. The corresponding median sIgE levels were 8.56, 17.7, 0.01, and 3.95 kUA/L. sIgE to all allergens was higher in patients with moderate-to-severe rhinitis and rhinitis with asthma (nonsignficant). Concentrations of sIgE to Der p 2 were significantly higher in the South than in the North (P=.0496). CONCLUSION: The most common sensitization in Portugal was to Der p. The highest prevalence and median sIgE level were observed for Der p 2. All sIgE values for molecular components were higher in more symptomatic patients (nonsignificant). Concentrations of sIgE to Der p 2 were higher in the South, probably because of the warmer temperature and/or the larger sample size.

Subcutaneous immunotherapy with aeroallergens Evaluation of adherence in real life.

Summary: Introduction. Adherence in allergen immunotherapy is crucial for its efficacy. At least 3 years of treatment are recommended for achieving a long-term modifying effect. Objectives. To assess patient's adherence and to identify determinant factors for allergen subcutaneous immunotherapy (SCIT) suspension in patients with respiratory allergy. Methods. Retrospective analysis of the medical record of patients submitted to SCIT between January 2013 and December 2016 in our Department. Results. 323 patients were included: 52% female; mean age 30±13 years; average treatment time 19±13 months. 52 patients (16%) stopped SCIT: 54% female; mean age 30±9 years; average treatment time 12±6 months; 67% dropped the treatment during the 1st year, 27% in the 2nd and 6% during the 3rd year of treatment. Adherence rate determined was 77%. The most frequent reasons for withdrawal were due to economic reasons (47.9%), followed by patients' perception of no clinical improvement (23%) and change to sublingual immunotherapy (11.6%). Conclusion. Adherence rate in our study was 77%. Economic reasons were the main cause of abandonment in the first year, while the perception of non improvement was the main reason for abandonment in subsequent years. Adequate information on SCIT prescribing and rigorous monitoring of patients during the treatment can improve adherence.

Venom Immunotherapy: a 20-year experience with an ultra-rush protocol (210-min).

SUMMARY: Background. Ultra-rush (UR) are induction protocols used in venom immunotherapy (VIT). Objectives: To evaluate the adverse reactions during a 210-minutes UR and determine possible risk factors. Methods: Retrospective study of 129 patients submitted to UR with VIT in the last 20 years. Results: In 114 (88.4%) patients the 101.1 µg maintenance dose was reached in 210 minutes. Systemic reactions (SR) occurred in 22% of patients (71% mild). There were no severe SR, late reactions or fatalities. Adrenaline was administered in 10% of all UR. The SR were more frequent with honey bee VIT and had greater severity in the patients with a previous severe systemic sting reaction. No significant difference in the risk of SR was found with other demographic, clinical or laboratory factors. There were 5% of large local reactions (LLR), these being more frequent in females. Conclusion: Most SR during UR were mild with no need for adrenaline treatment. The honey bee venom and the severity of the anaphylaxis during the field sting were the only SR´s risk factors for systemic adverse reactions during the UR.

Salmon roe as an emerging allergen in western countries

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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.

Efficacy and safety of specific immunotherapy with a modified mite extract.

BACKGROUND: In specific immunotherapy (SIT), modified extracts have been used to allow safe administration of higher allergen doses. Schedules reaching maintenance doses in approximately 1 month, which may have greater efficacy, have even been proposed. AIMS: To assess the safety and efficacy of SIT with modified (depigmented and polymerized) Dermatophagoides pteronyssinus extract in the treatment of allergic rhinitis. MATERIAL AND METHODS: Fifty patients with moderate-to-severe persistent allergic rhinitis and who were monosensitized to Dermatophagoides were included in this controlled, pragmatic, 1-year open study. The patients were randomly allocated to receive treatment with a Dermatophagoides pteronyssinus 100 % modified allergen vaccine (active group, n = 25) or pharmacological treatment only (control group, n = 25). All SIT-related adverse reactions were recorded. Efficacy was assessed primarily through the results of nasal allergen challenges, through visual analog scale (VAS) and symptom scores. RESULTS: In SIT-treated patients, significant improvements were found in symptom scores (mean reduction > 40 %), VAS scores (mean improvement > 20 %) and nasal challenges (mean increase in allergen concentration threshold > 500 %). For symptom and VAS scores, statistically significant differences between control and SIT-treated patients were recorded at 12 months. In nasal challenges statistically significant differences were observed as early as at 6 months. Control patients showed no significant differences during the study period. Local reactions were observed in 28 % of SIT-treated patients (total 24 reactions). There was only one immediate grade I systemic reaction, which was successfully treated with an antihistamine. CONCLUSIONS: SIT with this modified extract appears to be a relatively safe treatment, which can rapidly improve nasal allergenic tolerance, reduce symptom scores and improve subjective self-evaluation measured through VAS, reflecting a general improvement in patients' well-being.

Effect of allergen immunotherapy on soluble adhesion molecules.

UNLABELLED: The level of soluble adhesion molecules in the serum reflects the degree of systemic inflammation but the dynamics of these molecules in the pathogenesis of allergic diseases and their evolution during treatment, remains to be established. OBJECTIVE: To determine the evolution of the levels of soluble forms of serum intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) during immunotherapy to Dermatophagoides pteronyssinus in patients with allergic rhinitis and/or asthma. POPULATION: We included in this study 23 patients with perennial allergic rhinitis and/or asthma to Dermatophogoides pteronyssinus. 17 patients (6 males, 11 females, 13-48 years; mean: 27.2 years) were treated for one year with specific immunotherapy using standardized slow-release D. pteronyssinus extract (Lofarma, Milan, Italy). The other 6 patients (control group; 2 males, 4 females, 20-37 years; mean: 26.5 years) received only symptomatic treatment. METHODS: Serum sICAM-1 and sVCAM-1 were measured by ELISA method (R&D system). Blood samples were collected from each immunotherapy-treated patient at two timings: before immunotherapy (T0) and after one year of immunotherapy (T1). The two blood samples from each control patient (T0 and T1) were also collected one year apart. RESULTS: Before Immunotherapy (T0), the mean serum level of sICAM-1 was 336.0 ng/ml. After one year of immunotherapy (T1) it decreased to 325.2 ng/ml but this difference was not statistically significant. Mean serum level of sVCAM-1 was 655.5 ng/ml before immunotherapy (T0), decreasing significantly (p < 0.05) to 568.2 ng/ml (T1). In the control group both sICAM-1 and sVCAM-1 had no significant changes (sICAM-1: 363.1 ng/ml (T0) and 374.7 ng/ml (T1); sVCAM-1: 611.5 ng/ml (T0) and 649.8 ng/ml (T1). CONCLUSIONS: These results suggest that specific immunotherapy with D. pteronyssinus induces a decrease in serum sVCAM-1 but not in sICAM-1 levels. The decreased expression of sVCAM-1 after immunotherapy is probably related to a decrease in the inflammatory reactions.

Immunotherapy in allergic rhinitis.

Allergen specific immunotherapy (IT) represents a cornerstone of allergic rhinitis treatment and his efficacy has been confirmed, through open and double blind trials and meta-analysis. In the last few years non invasive routs for IT (oromucosal, nasal) were developed gained general acceptation mainly in children and were validated by WHO. The efficacy of IT could be markers, the pattern of specific antibody response or by the effect on sequential nasal challenges. We have evaluated the effect of IT in allergic rhinitis by different methods. Nasal IT decreased mean symptoms and pharmacological scores as well as in seasonal as in perennial rhinitis. The same decrease has been observed after oromucosal IT. The effect of IT in allergic inflammation has been confirmed by a decrease in the level of soluble adhesion molecule sVCAM-1 which is related to eosinophilic inflammation but not statistically for sICAM-1. We have also evaluated the immunoblotting pattern or specific IgE after oromucosal IT for house dust mites. For D. pteronyssinus in 4 patients the bands intensity decreased and in 3 patients the bands decreased and in 10 disappeared. IT decreases tryptase and ECP in nasal lavage after sequential nasal challenges. Therefore IT decreases clinical scores, inflammation markers, specific IgE immunoblotting bands and response to allergen challenge. These different results confirm his efficacy and usefulness in allergic rhinitis.

Local and systemic immunotherapy in nasal allergy.

Two assays have been done to evaluate the effect of immunotherapy in nasal allergy. First, a trial of nasal immunotherapy and second, the study of mediator release after vaccines. Local immunotherapy, applied directly, triggers different response mechanisms. Specific nasal immunotherapy started before seasonal or perennial symptoms peak, has been done by increasing the doses of allergen three times a week during a 3-month period and a manutention period of a weekly nasal puff of the same allergen. Symptom scores and drug consumption have been registered. The results have been compared with the scores obtained in the same patients over the same period of the same year before immunotherapy. In perennial rhinitis blockage, rhinorrea, sneezing and itching scores all decreased. In seasonal rhinitis, a similar score decrease was obtained for blockage, rhinorrea, sneezing and itching. Pharmacological scores also decreased. These data point to a short-term effect of nasal immunotherapy. Tryptase release has been evaluated in nasal washings after nasal challenge with a Parietaria (Pellitory wall) extract before and after specific systemic immunotherapy, in order to evaluate changes in mast cells reactivity. Eight patients were studied, all allergic to Parietaria. Nasal provocation tests have been done before the season with increasing doses of 10, 100 and 1000 PNU and tryptase assayed in nasal washings at 10, 20 and 30 min after provocation. Immunotherapy decreased tryptase release after nasal challenge. The data point to the effect of systemic specific immunotherapy on mast cell reactivity.