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Hereditary angioedema (HAE) encompasses a group of diseases characterized by recurrent, genetically mediated angioedema associated with increased vascular permeability primarily due to bradykinin. The disease poses diagnostic challenges, leading to underdiagnosis and delayed therapy. Severe manifestations include laryngeal and intestinal angioedema, contributing to significant morbidity and mortality. If left undiagnosed, the estimated mortality rate of the disease ranges from 25% to 40% due to asphyxiation caused by laryngeal angioedema. There is a pressing need to enhance awareness of hereditary angioedema and its warning signs. The acronym "H4AE" may facilitate the memorization of these signs. This study comprehensively reviews clinical, laboratory, and physiopathological features of documented HAE subtypes. The study advocates for an improved HAE classification based on endotypes, building on the knowledge of angioedema pathophysiology. The proposed endotype classification of HAE offers a clear and applicable framework, encouraging advancements in disease understanding and classification., (© 2024 The Authors.)

Objectives: The study describes a case series of hereditary angioedema with C1 Inhibitor Deficiency (C1INH-HAE) in order to corroborate six clinical warning signs "HAAAAE (H4AE)" to enable early identification of this disease., Methods: The authors analyzed the C1INH-HAE cohort to analyze the clinical aspects of the present study's patients and corroborate the six clinical warning signs of the Hereditary Angioedema Brazilian Guidelines. Data regarding demographics, the onset of disease, time to diagnosis, frequency of attacks per year, organs involved, triggers, crisis duration and their outcomes, and disease treatment were collected. Then the authors developed an acronym, H4AE, to help healthcare professionals remember the warning signs., Results: The authors included 98 patients in the study, with a mean age of 38.1 years, 67.3% being female, and 75.3% with a family history of HAE. HAE diagnosis was delayed, on average, 13.7 years after its initial manifestation. Exploratory laparotomy was reported by 26.9%, and orotracheal intubation by 21.3% of the present study's patients; 61.3% and 30.3% of them were admitted at least once in the hospital and in the intensive care unit, respectively. The authors constructed an acronym "H4AE" with the six warning signs of HAE: Hereditary, recurrent Angioedema, Abdominal pain, Absence of urticaria, Absence of response to antihistamines, Estrogen association., Conclusion: C1INH-HAE is still underdiagnosed and associated with high morbidity. The study showed clinical features of this disease, corroborating the warning signs, which may be useful in raising awareness and improving the diagnosis of C1INH-HAE. The authors suggest the acronym "H4AE" to remind the warning signs., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Gestational syphilis is underdiagnosed and undertreated, leading to stillbirth, prematurity, low birthweight, neonatal death, and congenital syphilis. Most patients who label as allergic to penicillin are misdiagnosed., Objective: To assess the efficacy and safety of an algorithm to guide re-exposure to penicillin in pregnant women with syphilis and reporting allergy to the antibiotic., Methods: We performed a prospective study assessing pregnant women with syphilis and labeled as allergic to penicillin. Based on clinical history, patients were divided in two groups: high-risk and low-risk to penicillin allergy. Low-risk patients with negative skin testing and negative serum specific IgE to penicillin underwent drug provocation test. The remaining patients underwent desensitization., Results: Ninety-one patients were enrolled. Allergy to penicillin was confirmed in 7.69% of pregnant women with syphilis and clinical history of allergy to penicillin; in all cases the diagnosis was made through intradermal testing, which predicted 100% of the breakthrough reactions observed during rapid drug desensitization (p < 0.001). Risk stratification based on the initial clinical reaction and skin testing to guide penicillin re-introduction through drug challenge or desensitization was safe (97.8%) and effective (97.8%)., Conclusion: We developed and showed the efficacy and safety of an algorithm to guide re-exposure to penicillin in pregnant women with syphilis and labeled as allergic to this drug. Intradermal test is an excellent biomarker in the diagnosis of immediate hypersensitivity reaction to penicillin and to predict breakthrough reaction during rapid drug desensitization. Further studies may confirm the greater safety of the intravenous protocol compared to the oral protocol., Competing Interests: The authors have no financial or conflicts of interest to disclosure. All authors participated in the design of the present study and in the analysis of its results. Juliana F. B. Garcia and Pedro Giavina-Bianchi collected the data and wrote the manuscript. All authors read, approved and consented to the publication of this manuscript., (© 2021 The Authors.)

Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

Objective To evaluate the positivity of challenge tests of patients suspected of chronic inducible urticaria and the response to treatment. Methods A retrospective study of electronic medical records of patients suspected of chronic inducible urticaria. All patients were submitted to challenge tests with triggering stimuli, according to the clinical history and, subsequently, the response to drug treatment was evaluated. Results A total of 191 patients with suspected chronic inducible urticaria were included. It was confirmed in 118 patients and 122 positive tests (4 patients with 2 different positive tests). Most had dermographic urticaria (70.3%), followed by cholinergic urticaria (17.8%). Regarding treatment, 28% responded to antihistamine in licensed doses, 34.7% with increased doses, 9.3% responded to the addition of another medication. The concomitance of chronic inducible urticaria and chronic spontaneous urticaria was found in 35.3% of patients, being more frequent in females, with longer time to control symptoms and higher frequency of cholinergic urticaria. Conclusion The confirmation of chronic inducible urticaria in patients with this suspicion, after challenge tests, was high. There was a good response to antihistamine. In the concomitance of chronic spontaneous urticaria, longer time to control symptoms and higher frequency of cholinergic urticaria were observed.

Background: Hereditary angioedema (HAE) is a rare genetic disorder mainly caused by mutations in the SERPING1 gene, determining a deficit of C1 inhibitor (C1-INH). In approximately 10% of the cases, HAE with C1-INH deficiency (C1-INH-HAE) is caused by large gene rearrangements, which are not detected by Sanger sequencing. Here we present the exon quantification technique (EQT), a molecular diagnostic test for the detection of large genetic rearrangements in SERPING1, mapping the exact size and location of the deletion caused by the recombination of Alu elements. EQT analysis was performed on total DNA extracted from blood of patients belonging to two Brazilian families with a medical history of HAE, low plasma levels of C4 and C1-INH and no pathogenic alteration in SERPING1 analyzed by Sanger sequencing., Results: Two large deletions were found, one of 1356 pb and one of 1804 pb, which resulted from recombination of two Alu elements present in introns 3 and 4 of the gene., Conclusion: These results showed that the EQT could be used as a simple, rapid, and efficient diagnosis test for analysis of large deletions and insertions involving SERPING1, otherwise not detected by Sanger sequencing, serving as a support technique for molecular diagnosis of HAE., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Importance: Hereditary angioedema (HAE) is a rare but severe disease, with high risk of death, and attacks have been associated to high estrogen levels. Polycystic ovary syndrome (PCOS) is a common hyperandrogenic condition, which is frequently treated with combined oral contraceptives., Objective: The aim of this study was to describe 2 clinical cases of young women diagnosed as having PCOS who developed HAE attacks after the introduction of combined estrogen-progestin pills to treat PCOS symptoms., Evidence Acquisition: Literature review of sex hormones' role in genesis of HAE attacks and possible mechanisms involved., Results: In the cases reported, after initiation of combined contraceptives, patients presented with facial swelling with airway involvement (laryngeal edema) and abdominal pain. They had a familial history of angioedema and normal C1 inhibitor (C1-INH) levels, leading to the diagnosis of HAE with normal C1-INH (HAEnC1-INH) or HAE type III. After suspension of exogenous estrogen, patients remained asymptomatic from HAE., Conclusions and Relevance: HAEnC1-INH is an estrogen-dependent form of HAE. It is well established that exogenous estrogen triggers attacks of all types of HAE. However, this is the first description of the association between PCOS and HAE, in which PCOS could be masking HAE symptoms. We propose that PCOS might have a protective role regarding HAE attacks, because of its particular hormonal features, that is, hyperandrogenism and relative stable levels of estradiol. The use of combined estrogen-progestin compounds in women with PCOS and HAE must be avoided, and treatment must be individualized.

Background: Drugs are responsible for 40% to 60% of anaphylactic reactions treated in the emergency department. A global research agenda to address uncertainties in anaphylaxis includes studies that identify factors associated with morbidity and mortality., Objective: The present study investigated drug-induced anaphylaxis, etiologies, aggravating factors, and treatment., Methods: A total of 806 patients with adverse drug reactions were screened, and those who had a clinical diagnosis of anaphylaxis were included in the study. Clinical and demographic characteristics of anaphylaxis were described, including etiologies, pathophysiologic mechanisms involved in the reactions, and a personal history of atopy and asthma. Factors associated with disease severity also were identified., Results: Anaphylaxis was diagnosed in 117 patients (14.5%). The etiologies were defined in 76% of the cases, nonsteroidal anti-inflammatory drugs being the most frequent. Seventy-eight patients (66.7%) reported a previous reaction to the drug involved in the current reaction or to a drug from the same class and/or group. Epinephrine was used to treat 34.2% of patients who presented with anaphylaxis, and 40.8% of those with anaphylactic reactions with cardiovascular involvement. IgE-mediated reactions were associated with greater severity, manifested by the rates of cardiovascular dysfunction, hospitalization, and use of epinephrine., Conclusions: The prevalence of anaphylaxis is high in patients who seek medical assistance for drug reactions, but its diagnosis is missed in emergency services, and adrenaline is underused. Drugs were prescribed to many patients despite a history of previous reaction. Nonsteroidal anti-inflammatory drugs were implicated in most cases of anaphylaxis induced by drugs, and IgE-mediated reactions were less frequent but more severe., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of a single intravitreal bevacizumab injection on visual acuity, contrast sensitivity and optical coherence tomography-measured central macular thickness in eyes with macular edema from branch retinal vein occlusion., Methods: Seventeen eyes of 17 patients with macular edema from unilateral branch retinal vein occlusion were treated with a single bevacizumab injection. Patients were submitted to a complete evaluation including best corrected visual acuity, contrast sensitivity and optical coherence tomography measurements before treatment and one and three months after injection. Visual acuity, contrast sensitivity and optical coherence tomography measurements were compared to baseline values., Results: Mean visual acuity measurement improved from 0.77 logMAR at baseline to 0.613 logMAR one month after injection (P=0.0001) but worsened to 0.75 logMAR after three months. Contrast sensitivity test demonstrated significant improvement at spatial frequencies of 3, 6, 12 and 18 cycles/degree one month after injection and at the spatial frequency of 12 cycles/degree three months after treatment. Mean ± standard deviation baseline central macular thickness (552 ± 150 µm) reduced significantly one month (322 ± 127 µm, P=0.0001) and three months (439 ± 179 µm, P=0.01) after treatment., Conclusions: Bevacizumab injection improves visual acuity and contrast sensitivity and reduces central macular thickness one month after treatment. Visual acuity returns to baseline levels at the 3-month follow-up, but some beneficial effect of the treatment is still present at that time, as evidenced by optical coherence tomography-measured central macular thickness and contrast sensitivity measurements.

Drug provocation tests (DPTs) are considered the gold standard for identifying adverse drug reactions (ADRs). The aim of this study was to analyze DPT results and discuss severe systemic reactions associated with them. This was a retrospective analysis of 500 patients with ADRs who sought treatment and were submitted to DPTs when indicated between 2006 and 2010. We performed DPTs according to the European Network for Drug Allergy recommendations. Single-blind, placebo-controlled DPTs were performed with antibiotics, local anesthetics, and nonsteroidal anti-inflammatory drugs, as well as with other drugs. Patient characteristics, DPT results, and reactions were analyzed. The sample comprised 198 patients (80.8% of whom were female patients) submitted to 243 DPTs. Ages ranged from 9 to 84 years (mean, 39.9 years). The 243 DPTs were performed with local anesthetics (n = 93), antibiotics (n = 19), acetaminophen (n = 44), benzydamine (n = 33), COX-2 inhibitors (n = 26), dipyrone (n = 7), aspirin (n = 4), or other drugs (n = 17). The results of 4 tests (1.6%) were inconclusive, whereas those of 10 (4.1%) revealed positive reactions to antibiotics (2/19), COX-2 inhibitors (2/26), acetaminophen (3/44), and local anesthetics (3/93). Two severe reactions were observed: cephalexin-induced anaphylactic shock and bupivacaine-induced anaphylaxis without shock. Four patients (2.0%) reacted to the placebo before administration of the drug. Drug provocation tests are safe for use in clinical practice but they should be placebo-controlled and should be performed under the supervision of an allergist. To confirm a presumptive diagnosis and to manage allergies appropriately, it is crucial to perform DPTs.

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Insulin allergy was not uncommon in the past, but has lowered with the introduction of human recombinant insulin. Human recombinant insulin allergy is a rare condition, now reported in less than 1% of treated patients. However, it is a serious condition that requires an immediate allergological work-up. In this study, we describe 4 cases of IgE-mediated reaction to human recombinant insulin, emphasizing some practical aspects in diagnosis and treatment.

Purpose: To investigate whether the time interval between type 2 diabetes mellitus (DM) diagnosis and the first fundoscopic examination is related with the presence and the severity of diabetic retinopathy (DR) observed., Methods: A survey of 105 type 2 DM patients referred to ophthalmologic evaluation in the "Hospital das Clinicas" (HC), University of São Paulo Medical School (USPMS)., Results: Regarding classification of DR in the 105 patients, 15 (14.28%) did not show signs of DR, and 90 (85.72%) exhibited them on fundoscopy. Sixty patients underwent laser therapy, and 46.66% reported poor control of DM. Only 15.23% of DM patients were adequately screened for DR on the first year of their DM diagnosis. Among the 36 patients (34.30%) examined within five years of DM diagnosis, 58.33% did not present or demonstrate signs of mild DR and 22.20% of proliferative DR; 30 patients underwent an ophthalmologic examination after more than eleven years of DM diagnosis, 21.62% did not exhibit signs of DR and 59.46% were classified as proliferative DR., Conclusion: This study showed a statistically significant relationship between the time interval from the diagnosis of type 2 DM and the first fundoscopic examination with the severity of DR.

We report case of a female patient who during months presented pulmonary manifestation associated with nonspecific systemic symptoms resulting in several hospitalizations with the diagnostic hypothesis of pulmonary fibrosis. The echocardiographic study showed a great pedunculated left atrial myxoma prolapsing through the mitral valve for the left ventricle. In quite unfavorable clinical conditions the patient was sent to our Service for surgical treatment, evolving during the preparation for surgery with acute pulmonary edema and hemodynamic instability being submitted to a successfully surgery of emergency for resection of the tumor. The patient is asymptomatic.