Branimir Nestorovic

Immediate allergic reactions to cephalosporins and penicillins and their cross‐reactivity in children

Penicillins and cephalosporins are the most important betalactams inducing IgE‐mediated reactions. The safety of administering cephalosporins to penicillin‐allergic children is a particular problem, because cephalosporin allergenic determinants have not been properly identified. A study was undertaken to evaluate the frequency of anaphylactic reactions to cephalosporins and penicillins and their cross‐reactivity in a pediatric population. A prospective survey was conducted in a group of 1170 children with suspected immediate allergic reactions to cephalosporins and/or penicillins, which were examined during a period of 8 yr. In vivo (skin tests and challenges) and in vitro tests (for specific IgE) were performed with standard concentration of penicillins and cephalosporins. When 1170 children with a clinical history of allergy to penicillins and/or cephalosporins were tested in vivo for immediate hypersensitivity to betalactams, 58.3% cases overall were found to be skin or challenge test positive. Among them, 94.4% patients were positive to penicillins and 35.3% to cephalosporins. The frequency of positive reactions in the in vivo testing was in the range from 36.4% to 88.1% for penicillins and from 0.3% to 29.2% for cephalosporins. However, 31.5% of the penicillin allergic children cross‐reacted to some cephalosporin. If a child was allergic to a cephalosporin, the frequency of positive reactions to penicillin was 84.2%. The cross‐reactivity between cephalosporins and penicillins varied between 0.3% and 23.9%. The cross‐reactivity among different generations of cephalosporins varied between 0% and 68.8%, being the highest for first and second‐generation cephalosporins and 0% for third generation cephalosporins. The frequency of immediate allergic reactions to cephalosporins is considerably lower compared to penicillins, and the degree of cross‐reactivity between cephalosporins and penicillins depends on the generation of cephalosporins, being higher with earlier generation cephalosporins. The cross‐reactivity among cephalosporins is lower compared to cross‐reactivity between penicillins and cephalosporins.

Stevens–Johnson syndrome and toxic epidermal necrolysis in children

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the most severe forms of hypersensitivity reactions affecting the skin. Current terminology is based on maximal extent of epidermal detachment. SJS indicates cases with epidermal necrolysis that involve less than 10% of the body surface area, TEN with more than 30%, and overlap of SJS/TEN in between (1). Clinically, SJS/TEN are characterized by polymorphic lesions like erythematous macules, papules, plaque, vesicles, and bullae with Nikolsky’s sign positive. Oral, genital, and conjunctival mucosae are often involved in the form of erosion or ulceration (2). Fever and malaise are the first symptoms of the disease (3). Incidence of SJS/TEN is 0.05–3 persons per million populations per year (2, 4). Several drugs are highly suspected to cause SJS/TEN in adults, such as anti-epileptics, anti-infective sulfonamides, nonsteroidal anti-inflammatory drugs, nevirapin, allopurinol, and antimicrobials (cephalosporins, aminopenicillins, quinolones, tetracyclines, and imidazole antifungals) (4–12). The list of causative drugs may vary from country to country (4). In children, anti-infective sulfonamides, phenobarbital, carbamazepine, lamotrigine, and acetaminophen are frequently associated with SJS/TEN (12). However, SJS/TEN are rare in children with mortality rate of 7.5% (12). In this article, evaluation of children with SJS/TEN, investigation of causative drug/drugs, treatment, clinical outcome, and complications are presented in three cases.

A case of selective IgE‐mediated hypersensitivity to ceftibuten

Besides penicillins, cephalosporins represent the most commonly prescribed betalactam antibiotics, and is able to induce severe and sometimes life-threatening IgE-mediated reactions.Ceftibuten is a third-generation cephalosporin used for treating serious infections. Side-effects from ceftibuten consumption are not common and they can occur as a mild or severe skin rash, itching, hive, difficulty in breathing or swallowing (swelling of the lips, tongue or face) and wheezing. Until now, there are no documented reports of IgE-mediated hypersensitivity reactions to ceftibuten. We report a 3-year-old girl who had an anaphylactic reaction within 20 min after oral administration of the second dose of Cedax (ceftibuten) (135 mg) given for ear infection, which she had tolerated 6 months before. Symptoms included facial flush with intensive itching in the throat and eyes, swelling of the lip, and urticarial rash on her trunk, which progressed to generalized urticaria, dyspnea, shortness of breath and wheezing. After treatment with anti-shock therapy, her symptoms were considerably reduced within 1 h and completely resolved after 6 h. The patient had no other medical history, in particular no other drug allergy, and no family history of allergic desease. Ten months later the child was referred to our department in order to study the drug reactions and to determine safe alternative drugs for the future. The child underwent prick and intradermal skin tests with standard concentration of penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, cephalexin, cefaclor, cefotaxime, ceftriaxone and ceftibuten diluted in 0.9% sodium chloride and administered at increasing concentrations every 15–20 min, as previously described (1–3). Commercially available assays for specific IgE (UniCAP System; Pharmacia, Uppsala, Sweden) were performed for penicilloyl G and penicilloyl V, amoxicilloyl, ampicilloyl, and cefaclor. Levels of specific IgE >0.35 kU/l were considered positive. When in vivo tests were negative, independently of the results of in vitro tests, single-blind, placebo-controlled challenges with progressively increasing amounts (0.01, 0.1 and 1.0) of the respective therapeutic doses of drugs were performed at 1 h intervals (each on a different day), as previously described (1–3). The patient responded positively to prick testing with ceftibuten (wheal 15 · 25 mm) at a concentration of 2 mg/ml, 10 min after application. Urticarial rash appeared on her arm, face and neck, which required antihistamine administration immediately. Prick and intradermal histamine test produced wheals with maximum diameters 5 and 10 mm respectively. Intradermal test with the above cephalosporins and semysintetic penicillins were negative in 10 healthy control subjects, who had previously tolerated those drugs. All assays for specific IgE and challenges were negative. Therefore, it should be emphasized that assays for specific IgE for third-generation cephalosporins are not yet commercially available. Clinical findings and positive skin tests with ceftibuten imply that the child developed type-I hypersensitivity. The lack of cross-reactivity with other betalactams, emphasizes the role of the IgE epitop present on R1 side chain of ceftibuten molecule in inducing immediate hypersensitivity. To the best of our knowledge, this is the first documented case of selective immediate hypersensitivity to ceftibuten with good tolerance to other betalactams.

Novel cftr gene sequence variation in Serbian patient with idiopathic disseminated bronchiectasis.

This paper reports a novel Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variant, 1811+1G→T, detected in a 5-year-old girl diagnosed with idiopathic disseminated bronchiectasis and negative sweat chloride test (17 mmol/L). The performed CFTR gene mutation analysis included detection of the F508del mutation, analysis of Tn polymorphism and screening of CFTR exons 3, 10 and 11. The CFTR gene screening has shown the altered band pattern in exon 11. The DNA sequencing of CFTR exon 11 revealed the presence of the novel sequence variation 1811+1G→T in heterozygous state. This sequence variation was not found in any of 100 control alleles, analyzed by polymerase chain reaction – restriction fragment length polymorphism method. The novel sequence variation 1811+1G→T is located at the splicing site at the boundary of exon 11 and intron 11 and might be either a sequence variation or a splicing site defect.

Anaphylaxis followed by unilateral lung opacity and hypocomplementemia in a young female

A 36-year-old woman was stung in the right wrist by a bee, suffered typical anaphylaxis, and was transferred to a local hospital. After a few hours, which corresponded to late-onset reaction, she developed shortness of breath and weakness and was transferred to the emergency department, where the diagnosis of anaphylaxis was confirmed. Serum complement levels, components C3 and C4, were undetectable. Flexible bronchoscopy excluded lung hemorrhage. She was on the ventilator for 4 days and was fully awake during that time. After the treatment, her improvement was rapid, and she fully recovered. Three weeks after she had been stung by a bee, skin prick tests to bee, wasp, and yellow jacket venom were done, and all tests came back negative as well as IgE and IgG4 antibodies to the same venoms. Coagulation factors and the complement, including C1q inhibitor, were normal. Occurrence of complement activation and consumption could point to the immune complexes as basis of pathophysiological mechanism. It remains unclear why such a reaction would involve only the right lung and why no detectable immune complexes were discovered. The clinical picture in the presented case resembled acute respiratory distress syndrome, but the exact nature of lung consolidation remains puzzling. The most likely explanation is a very rare case of airway obstruction. To our knowledge, this is the only reported case of anaphylaxis associated with undetectable serum complement levels. The potential role and diagnostic significance of hypocomplementemia in cases of anaphylaxis should be further investigated.

Authors reply to beta-lactam allergy in children.

Editor, We thank you for the opportunity to answer to the interesting remarks made by colleagues Perez-Rodrigues et al. (1) on our recent paper published in Pediatric Allergy and Immmunology on betalactam allergies in children. We found the comments very useful to clarify a few issues that a critical reading of our paper could actually raise. In our study, a group of 1170 children with already suspected immediate allergic reactions to penicillins and/or cephalosporins was evaluated. There were no self-reported allergies in the studied population. We agree that the percentage of betalactam (BL) allergic children found in our study is very high, particularly if compared with literature data. However, such percentage can be explained by the fact that penicillins, including benzyl penicillin, are the most frequently prescribed drugs for children in our country and by the characteristics of the sample assessed, which might be unique for genetic reasons. We used PPL and MDM produced by the Institute of Immunology and Virology of Torlak (Serbia). The highest concentrations for all tested drugs were given in the Methods section, and were the same proposed by Torres et al. (2) in the position paper of the European Network for Drug Allergy (ENDA). The testing was done in accordance with the ENDA position paper on diagnosis of immediate allergic reactions to BLs. As far as re-evaluation is concerned, we are aware of its importance in patients who suffered immediate reactions to BLs and display negative results in the first allergologic exam, including challenges. However, at the time we started this study, we did not include re-evaluations in our diagnostic protocol, as we have been doing since 2003. The skin testing results presented in the paper were obtained by both skin prick and intradermal testing (mentioned as skin tests at the beginning of Methods section). We did not show separately the results obtained by each of the two in vivo methods, as it was not the scope of the paper. We showed the separate data only for the challenge test, to emphasize the low percentage of positive responses to it, in case the skin test was negative. In parts of the Results section and in the Table 1, the in vivo tests were marked as skin prick tests, but they should have been marked as skin tests, as we did not show any separate data on the percentages of the results obtained by skin prick testing. We also want to underline that the Ethical Committee of the University Children’s Hospital in Belgrade approved the study. For the control group of 100 children without drug allergies the informed consent was obtained, and the testing was carried out according to a request on the part of parents because of a family history of drug hypersensitity. Only those children constituted the control group. We do agree that performing the testing without an informed consent would be unethical. With regard to the diagnosis of selective sensitizations, we performed provocation tests only with suspect BLs; therefore, such diagnosis actually was based only on responses to skin tests. However, in patients with immediate reactions to penicillins, the negative predictive value of skin tests with compounds other than the culprit ones is very high (3, 4).