Luis Felipe Ensina

Drug-Induced Anaphylaxis in Latin American Countries

BACKGROUND Information regarding the clinical features and management of drug-induced anaphylaxis (DIA) in Latin America is lacking. OBJECTIVE The objective of this study was to assess implicated medications, demographics, and treatments received for DIA in Latin American patients referred to national specialty centers for evaluation. METHOD A database previously used to compile information on drug-induced allergic reactions in 11 Latin American countries was used to identify and characterize patients presenting specifically with a clinical diagnosis of DIA. Information regarding clinical presentation, causative agent(s), diagnostic studies performed, treatment, and contributing factors associated with increased reaction severity was analyzed. RESULTS There were 1005 patients evaluated for possible drug hypersensitivity reactions during the study interval, and 264 (26.3%) met criteria for DIA. DIA was more frequent in adults and in elderly females (N = 129 [76.6%] and N = 30 [75%], respectively) compared with children and/or adolescents (N = 21 [42.9%], P < .01). Severe DIA was less frequent with underlying asthma (N = 22 vs 35 [38.6% vs 61.4%], P < .05) or atopy (N = 62 vs 71 [43% vs 59% ], P < .01). Nonsteroidal anti-inflammatory drugs (NSAIDs) (N = 178 [57.8%]), beta-lactam antibiotics (N = 44 [14.3%]), and other antibiotics (N = 16 [5.2%]) were the most frequently implicated drug classes. Anaphylaxis was rated as severe in N = 133 (50.4%) and anaphylactic shock (AS) was present in N = 90 (34.1%). Epinephrine was only used in N = 73 (27.6%) overall, but in N = 70 (77.8%) of patients with AS. CONCLUSION In Latin American patients referred for evaluation of DIA, NSAIDs and antibiotics were implicated in approximately 80% of cases. Most of these reactions were treated in the emergency department. Epinephrine was administered in only 27.6% of all cases, although more frequently for anaphylactic shock. Dissemination of anaphylaxis guidelines among emergency department physicians should be encouraged to improve management of DIA.

Hypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy

Antibiotics are used extensively in the treatment of various infections. Consequently, they can be considered among the most important agents involved in adverse reactions to drugs, including both allergic and non-allergic drug hypersensitivity [J Allergy Clin Immunol 113:832–836, 2004]. Most studies published to date deal mainly with reactions to the beta-lactam group, and information on hypersensitivity to each of the other antimicrobial agents is scarce. The present document has been produced by the Special Committee on Drug Allergy of the World Allergy Organization to present the most relevant information on the incidence, clinical manifestations, diagnosis, possible mechanisms, and management of hypersensitivity reactions to non beta-lactam antimicrobials for use by practitioners worldwide.

Multinational experience with hypersensitivity drug reactions in Latin America

BACKGROUND Epidemiologic drug allergy data from Latin America are scarce, and there are no studies on specific procedures focusing on this topic in Latin America. OBJECTIVE To assess the clinical characteristics and management of hypersensitivity drug reactions in different Latin American countries. METHODS An European Network of Drug Allergy questionnaire survey was implemented in 22 allergy units in 11 Latin American countries to report on consecutive patients who presented with a suspected hypersensitivity drug reaction. Each unit used its own protocols to investigate patients. RESULTS Included were 868 hypersensitivity drug reactions in 862 patients (71% of adults and elderly patients were women and 51% of children were girls, P = .0001). Children presented with less severe reactions than adults and elderly patients (P < .0001). Urticaria and angioedema accounted for the most frequent clinical presentations (71%), whereas anaphylaxis was present in 27.3% of cases. There were no deaths reported. Nonsteroidal anti-inflammatory drugs (52.3%), β-lactam antibiotics (13.8%), and other antibiotics (10.1%) were the drugs used most frequently. Skin prick tests (16.7%) and provocation tests (34.2%) were the study procedures most commonly used. A large proportion of patients were treated in the emergency department (62%) with antihistamines (68%) and/or corticosteroids (53%). Only 22.8% of patients presenting with anaphylaxis received epinephrine. CONCLUSION Nonsteroidal anti-inflammatory drugs and antibiotics were the drugs used in at least 75% of patients. More than half the reactions were treated in the emergency department, whereas epinephrine was administered in fewer than 25% of patients with anaphylaxis. Dissemination of guidelines for anaphylaxis among primary and emergency department physicians should be encouraged.

Omalizumab in Chronic Spontaneous Urticaria: A Brazilian Real-Life Experience

Background: Current guidelines on chronic spontaneous urticaria (CSU) suggest a treatment based on a 3-step approach that aims at total symptom control, starting with H1-antihistamines. However, a significant number of patients present an antihistamine-resistant urticaria that must be treated with an alternative third-line therapy such as omalizumab. Methods: Patients with a history of CSU who did not respond to treatment with high doses of modern antihistamines were treated with 150 or 300 mg of omalizumab every 4 weeks. The response to treatment was recorded as complete (CR), partial (PR) or no response. A dose adjustment was proposed according to response. Results: We treated 47 CSU patients with omalizumab (40 females), of whom 39.5% had evidence of autoimmunity. The average number of treatments was 11.4 (range 2-87). All patients had been refractory to high-dose modern antihistamines. A CR was seen in 84.6% of patients who started with 300 mg and in 60% of those who started with 150 mg. Only 1 patient had no response to both the 150- and 300-mg doses. In 6 of the PR patients with 150 mg, a higher dose of 300 mg was proposed and 4 had a CR. Four patients discontinued the treatment. No severe adverse events were reported in the patients who finished the study. Discussion: Although good results were seen in both groups, CR rates were higher in those under a high-dose initial treatment. Our data strongly suggest that the therapy should be individualized.

Drug-induced anaphylaxis in children: Nonsteroidal anti-inflammatory drugs and drug provocation test

e, etoricoxib; neg, negative; pos, positive. *Drugs involved in the reaction that was evaluated and prior reactions: a, aspirin; dic, diclofenac; dip, dipyrone; i, ibuprofen; pa, paracetamol. TO THE EDITOR: In a recent publication, Aun et al demonstrated that 14.5% of drug hypersensitivity reactions (DHR) are anaphylactic in nature, and nonsteroidal anti-inflammatory drugs (NSAID) account for nearly half of these cases. In our practice, we observed a higher frequency of anaphylactic reactions in pediatric patients with DHR, which also highlights the importance of NSAIDs in this population. From June 2011 to May 2014, we evaluated 104 children (mean age, 10.4 years) with a history of DHR, from which 26 had anaphylaxis symptoms. Unlike adults, there was a predominance of male patients (n 1⁄4 16). Most reactions were classified as moderate (85%), with dyspnea (n 1⁄4 18), urticaria associated with angioedema (n 1⁄4 16), and angioedema alone (n 1⁄4 8) being the most frequent clinical manifestations. All the patients were seen in the emergency department, except one, who had not received medical attention. However, only 5 received epinephrine, whereas most received antihistamines (n 1⁄4 12) or corticosteroid injections (n 1⁄4 11). Twenty patients presented fever and/or viral infection symptoms at the time of reaction. NSAIDs were the main drug class involved in anaphylactic reactions (70.6%). Sixteen patients associated the reactions exclusively to NSAIDs, whereas 4 had used other drugs in combination (amoxicillin [2], azithromycin, and metoclopramide). Among those who presented reactions to NSAIDs alone, 12 reported 2 or more episodes with drugs of different chemical groups, with dipyrone being associated to all cases, followed by ibuprofen (75%) and paracetamol (acetaminophen) (50%). The other 4 patients reported only 1 episode of reaction (3 with dipyrone and 1 with paracetamol) (Table I). Eleven patients had atopy symptoms, and only 3 had a familial history of drug hypersensitivity. In our department, we prescribe the drug provocation test (DPT) with paracetamol for all patients with a suspected reaction to this drug because paracetamol is a weak inhibitor of COX and rarely triggers symptoms in subjects with nonselective hypersensitivity reaction to NSAIDs. In 5 patients tested, only 1 had a reaction. During the study, this patient took ibuprofen and dipyrone on his own, without the occurrence of symptoms, which characterized a selective hypersensitivity reaction to paracetamol, with a positive skin test (by using paracetamol drops at 50 mg/mL concentration and negative in 10 controls), suggesting an IgE-mediated mechanism. The DPT also is indicated in cases in which the patient had a single episode in an attempt to characterize it as a selective or nonselective NSAID reactor. We also performed DPT with acetylsalicylic acid with 2 patients who presented a single episode of anaphylaxis associated with dipyrone, both with positive results. Finally, 1 patient was challenged with etoricoxib. The test result was negative, and the drug was offered as a safe therapeutic option. We concluded that NSAIDs are the most important cause of DHR-related anaphylaxis also in children, with most reactions being related to dipyrone. We also emphasize the importance of the DPT, mainly to exclude paracetamol as a cause of anaphylaxis because this is one of the few safe options for these patients.

Laronidase hypersensitivity and desensitization in type I mucopolysaccharidosis: a case report

To the Editor, Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disorder, resulting from the deficiency of lysosomal alpha-Liduronidase enzyme. It is a rare disorder, with an estimated prevalence ranging from 0.69 to 3.8 per 100,000 live births (1). The disorder affects independently the central nervous, skeletal, digestive, cardiac, upper and lower respiratory systems at different grades of severity (1). Untreated patients with MPS-I have a lower life expectancy and higher morbidity. The enzyme replacement therapy (ERT) with laronidase has been approved for MPS-I treatment since 2003 in the United States and 2005 in Brazil (2). We describe the first case of a MPS-I patient with hypersensitivity to laronidase, who was successfully treated with a three bags, 12 steps rapid desensitization protocol. An 11-yr-old female subject was referred to our allergy outpatient clinic for evaluation of hypersensitivity reactions during ERT with laronidase. The patient had a history of multiple surgeries and was diagnosed with MPS-I when she was 9 yr old. In January 2012, she started ERT with laronidase (20.3 mg/wk). She received four uneventful infusions and, during the fifth infusion, 90 min after starting the procedure (infusion rate 80 ml/h), she experienced hives in ears, neck, and back, lip swelling, increase in corporal body temperature (37.3°C) without respiratory, digestive, or cardiovascular symptoms. The infusion was stopped, and the patient was treated with hydroxyzine 0.5 mg/kg and methylprednisolone 2 mg/kg. The symptoms improved, and the infusion was restarted 1 h later (20 ml/h). After 3 min, she experienced a new episode of widespread hives, and the infusion was discontinued. Three weeks after the reaction, laronidase-specific IgG antibodies were detected (enzyme immunoassay/radioimmunoprecipitation test; Genzyme, Cambridge, MA, USA). On the other hand, in vitro specific IgE to laronidase (enzyme-linked immunosorbent assay – ELISA; Genzyme) was not found. A skin prick test with undiluted laronidase (0.58 mg/ml) was positive with a 3 mm-diameter wheal and flare as compared with the negative control. The test was negative in 10 disease-free controls and in one patient with MPS-I on ERT. Because laronidase was considered first line therapy, a three bags, 12-step laronidase desensitization protocol was elaborated based on previous chemotherapy protocols (3) (Tables 1 and 2), and informed consent was obtained. The patient was pre-medicated with ranitidine 35 mg, loratadine 10 mg, and montelukast 10 mg, 20 min before the procedure, and loratadine 10 mg and montelukast 10 mg before the 3rd bag. The desensitization was done in the intensive care unit, and no reaction occurred while the target dose of 20.3 mg was reached successfully. The patient was treated for 8 months weekly without any reactions. During 28th desensitization, after a dose adjustment for her weight, she experienced widespread urticaria at step 12. The protocol was amended by adding cetirizine 10 mg before step 9. The patient has been tolerating weekly infusions of laronidase adjusted to her weight for the last 2 months using the amended protocol without any reactions. Treatment with laronidase is the single best therapeutic option for patients over 18 months of age with MPS-I, and hypersensitivity reactions may prevent their continued treatment. Although the most frequent adverse events associated with ERT are mild and infusion-related (flushing, arthralgia, and headache), severe anaphylactic hypersensitivity reactions, requiring discontinuation of therapy, were described in 1/45 patients in a phase III clinical trial to evaluate the efficacy and safety of laronidase in the treatment of MPS-I (4). Our patient showed a mild (urticaria and angioedema) immediate hypersensitivity reaction during laronidase infusion. Due to the lack of any other factor or concomitant drugs that could account for the reaction observed, and the recurrence of symptoms when restarting the infusion, laronidase was considered the primary suspect drug. Immediate hypersensitivity reactions to drugs are those occurring up to 1 h after exposure, and, in most cases, are caused by IgE-mediated mechanism, that is,, mainly urticaria, angioedema, bronchoconstriction, rhinitis, and anaphylatic shock. As the symptoms were suggestive of IgE-mediated reaction, prick testing with undiluted laronidase was done with positive results. Because the predictive value and the potential for non-specific irritation were unknown, 10 controls and one patient on laronidase treatment were tested with negative results (5). In vitro IgG antibodies were found but not IgE. IgG levels in non-reactors vary and are present in 93%. The clinical

Long-term omalizumab therapy for refractory chronic spontaneous urticaria: a real-life experience

Omalizumab is an anti-IgE drug that has proved to be effective in concerned about changing her treatment regimen and preferred to the treatment of recalcitrant chronic urticaria (CU). It has recently been approved in many countries for CU treatment, but there are few data on its long-term effectiveness and safety. Har et al1 reported the outcomes of using omalizumab for more than 1 year in 10 patients with refractory CU in the United States. We retrospectively analyzed data from CU patients treated with omalizumab for more than 1 year from June 2012 to June 2015. Treatment started with 150-mg or 300-mg doses (according to its availability for each patient) every 4 weeks. After 6 months of treatment, doses were increased to 300 mg for those with no response or partial response (improvement on urticaria but still with symptoms or additionally taking antihistamine) or decreased to 150 mg for the complete responders (total absence of symptoms). When a complete response was maintained with a 150-mg dose for more than 6 months, an additional progressive 2-week interval was added between injections. Nine patients (7 women; mean age, 39 years) were treated with omalizumab for a long term (mean, 23 months; range, 12e61 months) for CU. All these patients were resistant to high-dose second-generation H1-antihistamines and depended on oral corticosteroids to control their symptoms. Autoimmunity, as defined by the presence of a positive autologous skin test result and/or the presence of antithyroid or antinuclear antibodies, was investigated in 7 of the 9 patients, and 43% of them had evidence of autoimmunity. Two patients started the treatment with a 150-mg dose. One had a complete response (CR) and is currently taking omalizumab every 6 weeks, and the other had a partial response (slightly improved with a higher dose of 300 mg). Five of 7 patients who started with a 300-mg dose had a CR. Two maintained a CR when stepped down to 150 mg and are currently being treated at 4and 12-week intervals. The other 2 had a relapse with the lower dose and are still taking 300 mg every 4 weeks. One patient was

Registries as useful tools in characterization of allergic manifestations.

Purpose of reviewRegistries are useful to discover the applicability of data generated from randomized clinical trials (RCTs) into daily practice, and to search for real-life data usually not covered by them. Recent findingsIn allergy, registry research brought clues to important epidemiological and clinical problems hardly accessible with other methods. The increase in the asthma prevalence in Sweden in contrast with stabilization in Denmark; the association of the prevalence of asthma and environmental factors; the knowledge of existing rhinitis international guidelines, but the poorly complacence of some of their recommendations; the low epinephrine use in anaphylaxis and the difference among European and Latin American elicitors; the predominance of &bgr; lactams or NSAIDs as drug hypersensitivity reactions inducers in different regions; the fact that most of the hereditary angioedema patients were receiving long-term prophylaxis with attenuated androgens; all the mentioned are clear examples of relevant and important data provided by current registries. SummaryRegistries in allergy enlighten knowledge in areas not covered by classical investigational methods. As the number and importance of registries is growing, its contribution to the knowledge and management of allergic diseases will increase in the near future.

Chronic urticaria: the first visit in a specialized unit

Results Among the 50 CU patients, 70% were female. The mean age at the consultation was 33 years, but the mean age of symptoms onset was 15.3 years. Fifty one percent referred only urticaria, 44% referred urticaria associated with angioedema and 5% presented isolated angioedema. Besides itching, 6 patients complained of burning (12%) and 2 of pain (4%). Frequency of wheals was daily in 33%, weekly in 36% and monthly in 31%. At first visit, Urticaria Activity Score was verified in 24 patients, resulting > 3 in half of them. The most associated atopic disease was rhinitis (45%). Many patients mentioned triggers as medicines (33%), food (23%), stress (17%), viral infection (8%) and physical agents (16%). Only 6% had thyroidopathy. As previous treatment a significant amount of patients received sedating antihistamines (AH) (36%) or oral corticosteroids (24%), with partial improvement in 65% and complete improvement in 29%. Dermographism was positive in 91% of the patients tested (20/22). One of them was diagnosed with cholinergic urticaria and another one with delayed pressure urticaria.

Erratum to: The Burden of Chronic Urticaria from Brazilian Patients’ Perspective

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