Alex Eustáquio de Lacerda

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

Tabaco na mídia: análise de matérias jornalísticas no ano de 2006

Aiming at understanding the relation among health, press and public policies on Tobacco in Brazil, this article analyses the texts about Tobacco published in the Brazilian press in 2006. In the clipping process of eight newspapers and magazines, the information about Tobacco were identified and then submitted to content analysis allowing categorization and classification of the texts. The frequency of the texts in 2006 was compared to that of in 2000 and 2003. We observed a higher prevalence of factual approach among the texts (46.7%). Most of the texts mentioned the negative consequences, such as physical health problems (44.2%), death (20%) and dependence (14.2%). The analysis of the headlines and lead-ins showed control policies, anti-smoking movements and spreading of results as the main categories observed. The frequency of the articles in 2006 was similar to that of in 2003 and lower to that of in 2000. The journalistic coverage on Tobacco in 2006 was restricted predominantly to harm to health and anti-smoking movements. The high proportion of the factual approach and the stabilization in the frequency of texts (2003-2006) might suggest an impoverishment of the discussion on this issue in the country.

Beta-lactam hypersensitivity: not always what it seems

Results One hundred and four children were evaluated with a suspected drug allergy history, with 28% reporting reactions to beta-lactam antibiotics. The mean age was 6.2 years and 52% were female. Cutaneous symptoms were the most frequent reported (89%), followed by respiratory (45%). Most of them had maculopapular exanthema (52%). Urticaria and/or angioedema were seen in 34% of patients. The majority of the reactions were mild/moderate (93%), occurring in the first 24 hours after drug intake (77%), and 48% presented associated fever. The suspected drugs were: amoxicilin (59%), cefalexin (16%), penicilin and ceftriaxone (8% each). Patients went to an Emergency Unit in 97% of the reactions and treated with anti-histaminic drugs and corticosteroids in 40% and 30% respectively. Epinephrine was used in just one patient. In almost half of the patients the clinical history was not consistent enough to submit them to an extensive investigation. Of those who were investigated, skin tests were performed in 48% (57% prick tests and 43% intradermal tests). Positive test was seen in only one patient (cefazolin). Drug provocation tests with amoxicilin were performed in 57% of patients and none was positive.

Hypersensitivity to non-steroidal anti-inflammatory drugs in pediatric patients

Results Medical records of 104 individuals with a history of hypersensitivity to drugs were analyzed. NSAIDs were the primarily suspected drug in 50% of the cases. The mean age was 10.9 years, with a predominance of males (57.7%). All patients had cutaneous manifestations and isolated angioedema was observed in the majority (53.8%); respiratory symptoms were reported in 44% of cases and gastrointestinal manifestations in 7.6%. Most of the patients reported reactions to more than one NSAID (71%) and dipyrone was the main drug reported in this group (34%), as in the group who had reactions to a single NSAID (73%). All reactions occurred in less than 24 hours after the drug use and 69.2% were of moderate severity. The ER was the main site searched for the treatment of the reactions (88%). During diagnostic investigation 38 oral provocation tests were performed, with positive results in 8 (5 ASA, 1 Ibuprofen, 1 Acetaminophen, 1 Dipyrone). Conclusions The reactions to NSAIDs in pediatric patients are more frequent in males. Angioedema alone was the main clinical manifestation and dipyrone the main drug involved in the reactions. The OPT proved to be an important tool to confirm or exclude the diagnosis of hypersensitivity, with the possibility of providing safer alternatives for those patients with proven reaction.

Drug hypersensitivity in children in Brazil

Results Ninety patients were evaluated, 54 male, with a median age of 6 years. Personal history of atopy was reported in 65 and previous DHR in 9. Cutaneous manifestations were observed in 86 – urticaria and/or angioedema in 71 and macular or maculopapular exanthema in 15. Other symptoms reported were: respiratory (25), gastrointestinal (8), cardiovascular (5). The interval between dose and reaction was less than 1 hour in 38 subjects. Mild reaction was observed in 32 patients and moderate in 55. Fever and/or viral infection were present in 61 patients during or just before the reaction. The majority of subjects were treated in emergency units (79). More than one drug was suspected as a trigger in 50 children (NSAIDs in 50%, beta-lactam antibiotics in 31% and other antibiotics in 8.5%). Sixteen skin tests (prick and intradermal) were performed and were all negative but one with amoxicilin. Drug provocation tests were positive in 4 of 51 tests NSAIDs 29 (4 positive), beta-lactam antibiotics 20 and others 4. Sixty-one reactions were possible or probable related with the suspected drug, but in 25 this relation was unlikely.