Antonio Abilio Motta

Nonsteroidal Anti-Inflammatory Drugs are Major Causes of Drug-Induced Anaphylaxis

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.

Outcomes and safety of drug provocation tests.

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.

Classification of angioedema by endotypes

We congratulate Powell et al. for the development of the ‘BSACI guideline for the management of chronic urticaria and angioedema’, which is enlightening, and recognize the importance of NSAID as a trigger of angioedema. Recently, an international panel of HAE experts proposed a classification for ‘angioedema without wheals’. However, this classification did not include angioedema induced or exacerbated by NSAIDs, and the pathophysiological mechanisms of general angioedema were not completely addressed. Although NSAID-induced or NSAID-exacerbated angioedema usually is associated with urticaria, it can also present as the sole manifestation of NSAID intolerance. In our experience, NSAIDs are a major cause of drug-induced anaphylaxis and the major cause of angioedema without urticaria. We reviewed the records of 290 patients who sought medical assistance due to adverse drug reactions at the Adverse Drug Reaction Outpatient Facility of the ‘Hospital das Cl inicas’, University of S~ao Paulo School of Medicine, during 2013 and 2014. Patients who seek our hospital for chronic urticaria or aspirin-exacerbated respiratory disease were not included in the study. Forty-two percent of the patients (n = 122) had immediate hypersensitivity reactions (HSRs) to NSAIDs, with an average age of 40.8 years old, and 77.1% were female. Isolated cutaneous angioedema was observed in 27.9% (Fig. 1), and a ‘familiar form’ of HSRs to NSAIDs was observed in 11.5% of the cases. Patients presenting with simultaneous respiratory and cutaneous reactions, also called blended reactions, were counted as anaphylaxis cases. Two major pathophysiological mechanisms of angioedema have been described: one induced by the activation of mast cells and/or basophils, resulting in release of histamine and other mediators (histaminergic angioedema), and other due to an excess of bradykinin (bradykinin-mediated or non-histaminergic angioedema), as seen in hereditary angioedema, acquired angioedema with C1-INH deficiency (lymphoproliferative and autoimmune disorders) and in angioedema induced by angiotensin-converting enzyme inhibitors. HAE results from genetic mutations leading to C1-INH protein or function deficiency, or from the recently described mutations of factor XII. Based on ours’ and others’ observations, we propose a classification of Angioedema based on endotypes (Fig. 2). Classifications based on endotypes provide insight into the aetiology and/or pathophysiological mechanism of diseases. The paradigm of personalized medicine is based on the principle that external stimuli (environment) induce diverse clinical manifestations (phenotypes), mediated by distinct pathophysiological processes (endotypes) in different individuals (genotypes)’. This angioedema classification based on endotypes (Fig. 2) includes the main causes of angioedema and is in agreement with the new information on the pathophysiology of the disease. Furthermore, it is consistent with angioedema consensus, and the ‘hypersensitivity reactions to non-steroidal anti-inflammatory drugs’ consensus. The high rate of patients with HSRs to NSAIDs with isolated angioedema emphasizes the importance of including this type of angioedema in the classification. The understanding of angioedema subtypes and endotypes will allow the developing of new treatments for more effective disease management. Classification of angioedema by endotypes may identify patient groups that will benefit most from new and existing treatments

Thyroid dysfunction in patients with chronic urticaria

Methods A retrospective study of medical records evaluated 37 outpatients with chronic urticaria (CU), which means persistent symptoms lasting more than 6 weeks. Patients of both genders and aged over 18 years were included. Patients were classified according to the chronic urticaria in spontaneous, physical or autoimmune (positive autologous skin test). They were evaluated for the presence of any thyroid dysfunction or presence of antithyroid autoantibodies. We also evaluated the time of urticaria and age at diagnosis of thyroid dysfunction.

Increase of 10% in the Rate of Adverse Drug Reactions for Each Drug Administered in Hospitalized Patients

OBJECTIVE: To assess the risk factors, incidence and severity of adverse drug reactions in in-patients. METHODS: This prospective study evaluated 472 patients treated at a teaching hospital in Brazil between 2010 and 2013 by five medical specialties: Internal Medicine, General Surgery, Geriatrics, Neurology, and Clinical Immunology and Allergy. The following variables were assessed: patient age, gender, comorbidities, family history of hypersensitivity, personal and family history of atopy, number of prescribed drugs before and during hospitalization, hospital diagnoses, days of hospitalization. The patients were visited every other day, and medical records were reviewed by the investigators to detect adverse drug reactions. RESULTS: There were a total of 94 adverse drug reactions in 75 patients. Most reactions were predictable and of moderate severity. The incidence of adverse drug reactions was 16.2%, and the incidence varied, according to the medical specialty; it was higher in Internal Medicine (30%). Antibiotics were the most commonly involved medication. Chronic renal failure, longer hospital stay, greater number of diagnoses and greater number of medications upon admission were risk factors. For each medication introduced during hospitalization, there was a 10% increase in the rate of adverse drug reaction. In the present study, the probability of observing an adverse drug reaction was 1 in 104 patients per day. CONCLUSIONS: Adverse drug reactions are frequent and potentially serious and should be better monitored in patients with chronic renal failure or prolonged hospitalization and especially in those on ‘polypharmacy’ regimens. The rational use of medications plays an important role in preventing adverse drug reactions.

Specific questionnaire detects a high incidence of intra-operative hypersensitivity reactions

OBJECTIVE: To assess the incidence of intra-operative immediate hypersensitivity reactions and anaphylaxis. METHODS: A cross-sectional observational study was conducted at the Department of Anesthesiology, University of São Paulo School of Medicine, Hospital das Clínicas, São Paulo, Brazil, from January to December 2010. We developed a specific questionnaire to be completed by anesthesiologists. This tool included questions about hypersensitivity reactions during anesthesia and provided treatments. We included patients with clinical signs compatible with immediate hypersensitivity reactions. Hhypersensitivity reactions were categorized according to severity (grades I-V). American Society of Anesthesiologists physical status classification (ASA 1-6) was analyzed and associated with the severity of hypersensitivity reactions. RESULTS: In 2010, 21,464 surgeries were performed under general anesthesia. Anesthesiologists answered questionnaires on 5,414 procedures (25.2%). Sixty cases of intra-operative hypersensitivity reactions were reported. The majority patients (45, 75%) had hypersensitivity reactions grade I reactions (incidence of 27.9:10,000). Fifteen patients (25%) had grade II, III or IV reactions (intra-operative anaphylaxis) (incidence of 7:10,000). No patients had grade V reactions. Thirty patients (50%) were classified as ASA 1. The frequency of cardiovascular shock was higher in patients classified as ASA 3 than in patients classified as ASA 1 or ASA 2. Epinephrine was administered in 20% of patients with grade III hypersensitivity reactions and in 50% of patients with grade II hypersensitivity reactions. CONCLUSIONS: The majority of patients had hypersensitivity reactions grade I reactions; however, the incidence of intra-operative anaphylaxis was higher than that previously reported in the literature. Patients with ASA 3 had more severe anaphylaxis; however, the use of epinephrine was not prescribed in all of these cases. Allergists and anesthesiologists should implement preventive measures to reduce the occurrence of anaphylaxis.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis

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.

Anafilaxia a morfina e tramadol: relato de caso

RESUMO 1. Disciplina de Imunologia Clínica e Alergia da FMUSP. 283 A investigação diagnóstica de reações anafiláticas durante a anestesia é difícil, uma vez que vários medicamentos são administrados. O diagnóstico é necessário para evitar uma reexposição ao medicamento potencialmente ofensivo. Os opioides raramente causam anafilaxia. A incidência total de reação de hipersensibilidade imediata aos opiáceos é desconhecida, e as incidências diferenciais de reações alérgicas e não alérgicas aos opiáceos também. Os dados sobre a sensibilidade cruzada entre as classes de medicamentos são limitados pela ocorrência rara destas alergias, e qualquer uso de opioide em um paciente com alergia relatada deve ser feito com cautela. O valor dos testes cutâneos de leitura imediata nos indivíduos sensíveis aos opiáceos é incerto, por poderem causar desgranulação direta dos mastócitos, e o teste de IgE sérico para opiáceos não está disponível comercialmente. O objetivo dos autores é relatar um caso de anafilaxia perioperatória, tendo como agente causal um opioide e discorrer sobre a investigação e implicações decorrentes do uso destes medicamentos. Estudos bem desenhados e adequadamente controlados sobre o assunto ainda são necessários para melhor entendimento das reações e maior segurança para o uso destes medicamentos. Descritores: Anafilaxia, morfina, tramadol. Diagnostic investigation of anaphylactic reactions during anesthesia is difficult, since several drugs are administered simultaneously. However, diagnosis is necessary to avoid reexposure to potentially harmful drugs. Opioids rarely cause anaphylaxis. The overall incidence of immediate hypersensitivity reactions to opiates is unknown, as are the differential incidences of allergic and non-allergic reactions. Data on cross-sensitivity between different classes of drugs are limited by the rare occurrence of these allergies, and any use of opioids in a patient with a reported history of allergy should be made with caution. The value of immediate-reading skin tests in opiate-sensitive individuals is uncertain, as they may cause direct degranulation of mast cells; serum-specific IgE testing for opiates, in turn, is not commercially available. The objective of this study was to report a case of perioperative anaphylaxis to opioid and to discuss the diagnostic investigation and implications of the use of these drugs. Well-designed and adequately controlled studies are needed to improve our understanding of reactions to these drugs and to make their use safer.

Erythema multiforme induced by clindamycin diagnosed by patch test

Results A 17 years of age male was admitted in a University Hospital In Sao Paulo, Brazil, because he had been a victim of a car accident in May 2012. He suffered a tibia open fracture and was submitted to a surgical treatment. Three days after the procedure he developed face rash, cutaneous itching, target lesions in oropharynx and lower limbs peeling. He was being treated with Clindamycin, Ciprofloxacin, Dipyrone, Ketoprofen and Tramadol. The patient evolved with fever and leucocytosis, without eosinophilia. This reaction was diagnosed as EM major by Dermatology Unit and he was successfully treated with antihistamines and corticosteroids, besides suspected drugs substitution. After been discharged the patient was referred to the Allergy Unit to perform a drug hypersensitivity investigation. He was submitted to patch test with all the suspected drugs diluted in petrolatum 10%. Only the clindamycin patch test was positive, which was confirmed with a second patch test. The patient also presented reactivation of previous lesions. Conclusions As far as we know, this is the first patient who had developed erythema multiforme due to clindamycin. The patch test was essential to confirm the diagnosis and the use of all other drugs which were present at the time of the reaction could be released.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE): two atypical case reports

Background The symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a delayed-type hypersensitivity drug reaction (HDR) that causes symmetrical erythematous lesions in flexural areas, including buttocks and groin, which arise following exposure to drugs, especially beta-lactams. The involvement of palms and soles is rare and, until now, it has only been described after exposure of amoxicillin. We hereby report a patient with SDRIFE and involvement of the palms and soles after taking cephalexin and another patient who developed SDRIFE after exposure to doxycyclin.