A. Romano

Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes.

BACKGROUNDnAlthough in some cases delayed hypersensitivity may be observed, beta-lactam antibiotics frequently induce immediate allergic IgE-mediated reactions with the specificity localized in the acyl-side chain structure. Generally, delayed immunologic reactions are related to sensitized T lymphocytes and major histocompatibility complex restricted.nnnOBJECTIVEnTo investigate the prevalence of HLA class I and II antigens in patients with delayed hypersensitivity to aminopenicillins in order to evaluate a relationship between major histocompatibility complex immune response genes and aminopenicillins hypersensitivity.nnnMETHODSnWe assessed 24 patients with history of delayed hypersensitivity to aminopenicillins using (1) skin test with penicilloyl polylysine, minor determinant mixture, benzylpenicillin, amoxicillin, and ampicillin; (2) patch tests with benzylpenicillin, amoxicillin, and ampicillin; (3) RAST for penicilloyls G and V; and (4) oral challenges with amoxicillin, ampicillin, and penicillin V in 18/24 patients. All patients were typed by microlymphotoxicity standard test for HLA class I and II antigens. Statistical analysis by chi2 test 2 x 2 contingency tables, according to Svejgaard, were used for comparison between patients and random Italian population (522 subjects).nnnRESULTSnIn the patients group we found higher prevalence of HLA A2 (12/24 = 50%, RR = 6.76 P < .001, EF = 0.425), DRw52 (20/24 = 83.3%, RR = 9.28, P < .001, EF = 0.74), and lower frequency of DR4 (3/24 = 12% ns).nnnCONCLUSIONSnThese data suggest that the immune mechanisms involved in adverse reactions to aminopenicillins in vivo are related to genetic markers of immune response and confirms that the presentation of penicillin-hapten determinants to lymphocyte is major histocompatibility complex restricted.

Selective immediate hypersensitivity to ceftriaxone

. CEFTRIAXONE is a third-generation cephalosporin used for serious infections. There have been very few reports of type I allergies (1), even though the frequency of hypersensitivity reactions to ceftriaxone is 3% (2). We studied a 68year-old man who had developed urticaria, dyspnea, shortness of breath, dizziness, tachycardia, and severe hypotension within 15 min after intramuscular administration of the ®rst gram of ceftriaxone as prophylaxis for a cataract operation. After treatment with subcutaneous epinephrine, 6-methylAnaphylactic shock presumed to be allergic. 2. OUE T, FUKUZAWA M, KUSAFUKA T, KOHMOTO Y, OKADA A, IMURA K. Transcatheter arterial chemoembolization in the treatment of hepatoblastoma. J Pediatr Surg 1998;33:1771±1775. 3. SAKAGUCHI M, NAKAYAMA T, INOUYE S. Food allergy to gelatin in children with systemic immediate-type reactions including anaphylaxis to vaccines. J Allergy Clin Immunol 1996;98:1058±1061. 4. SAKAGUCHI M, HIROSHI K, INOUYE S. A case of anaphylaxis to gelatin included in erythropoietin products. J Allergy Clin Immunol 1999;103:349±350. 5. ISHIKURA H, SOTOZAKI Y, ADACHI H, SATO M, YOSHIKI T. Granulomatous arteritis with massive eosinophilic leukocyte in®ltration and transient peripheral eosinophilia subsequent to transarterial embolization therapy with a gelatin sponge. Acta Pathol Jpn 1991;41:618±622. prednisolone, and chlorphenamine intravenously, symptoms resolved completely in 12 h. Ten months later, we skin-tested the patient with penicilloylpolylysine (Allergopen, Reinbek, Germany), minor determinant mixture (Allergopen), benzylpenicillin, ampicillin, and amoxicillin, as well as ceftriaxone, cefuroxime, cephalothin, ceftazidime, cefotaxime, and cefamandole, as previously described (1). All cephalosporins were used at a concentration of 2 mg/ml in 0.9% NaCl. The patient responded positively to prick testing with ceftriaxone (wheal 738 mm). Prick and intradermal histamine tests produced wheals with maximum diameters of 8 and 12 mm, respectively. Intradermal tests with the above cephalosporins were negative in 40 healthy control subjects, 10 of whom had previously tolerated ceftriaxone. Assays (UniCAP speci®c IgE; Pharmacia & Upjohn, Uppsala, Sweden) for speci®c IgE to penicilloyl G, penicilloyl V, ampicilloyl, amoxicilloyl, ceftriaxone, cefuroxime, cefaclor, cephalexin, cefotaxime, and cefatrizine were negative (,0.35 kU/l). All the cephalosporin assays except cefaclor were experimental prototypes. Single-blind, placebo-controlled oral challenges with penicillin V (1 000 000 IU), ampicillin (1 g), cephalexin (500 mg), cefaclor (500 mg), and ce®xime (400 mg) were also performed (each on a different day). Increasing amounts (0.01, 0.1, and 1.0) of the therapeutic doses, indicated in parentheses, were administered at 1-h intervals. No reactions were observed to the challenges. Our clinical ®ndings and the positive prick test with ceftriaxone suggest that the patient developed type-I hypersensitivity. We could not show speci®c IgE by RAST. It should be considered that we used experimental prototypes, and that cephalosporin allergenic determinants have not been fully identi®ed (3). Furthermore, in our case, the assays were performed 10 months after anaphylactic shock and it is possible that the IgE titer had meanwhile fallen below the cutoff value, as observed with penicilloyl IgE antibodies (4). We had previously diagnosed a case of immediate hypersensitivity to ceftriaxone (1). This subject showed skin-test and RAST positivity to both ceftriaxone and cefotaxime, which have identical (2-amino4-thiazolyl) (methoxyimino) acetyl sidechains; thus, his reaction was probably caused by selective sensitization to sidechain determinants, as con®rmed by skin tests and in vitro assays, as well as negative challenge results with other b-lactams. The present subject displayed skin-test and RAST negativity to cefotaxime as well as to the other drugs and tolerated challenges with other b-lactams. Thus, the patients reactivity could have been to the entire ceftriaxone molecule (Fig. 1), as previously demonstrated with cefaclor (3). To our knowledge, this is the ®rst case in

Positivity of patch tests in cutaneous reaction to diclofenac : two case reports

Immune‐mediated reactions to NSAIDs are unusual. We have observed two cases of maculopapular eruptions occurring 48–72 h after administration of diclofenac sodium. Patch tests performed with diclofenac were positive. The histopathologic findings resembled those of contact dermatitis with different degrees of dermal involvement. Clinical, allergologic, and histopathologic patterns strongly suggest a type IV mechanism of hypersensitivity. Patch tests play an important role in the assessment of possible immunologic mechanisms underlying cutaneous reactions to drugs.

Selective immediate hypersensitivity to ceftazidime

Cefepime is a fourth-generation cephalosporin with a broad antimicrobial spectrum and good activity against both gram-positive and gram-negative organisms. We present the case of a 61-year-old man who developed an immediate urticarial reaction after receiving a single dose of cefepime. Skin tests were positive to cefepime and negative to the other β-lactam antibiotics. Controlled administration of amoxicillin-clavulanic acid and ceftazidime was well tolerated by the patient. To the best of our knowledge, this is the fi rst report of selective hypersensitivity to cefepime demonstrated by skin and challenge tests. Complete allergological studies, including challenge tests with other β-lactam antibiotics that produce a negative result in skin tests, should be considered in these patients.

Omalizumab efficacy in a girl with atopic eczema.

Atopic eczema (AE) is a chronic, relapsing form of skin inflammation characterized by a disturbance of the epidermalbarrier function, which culminates in dry skin, as well as by an IgEmediated sensitization to food and environmental allergens (1). Elevated levels of serum IgE to environmental allergens are generally found in about 80% of patients with AE (2). Atopic eczema often precedes the occurrence of food allergy, allergic rhinitis, and asthma. In the last few years, a number of studies have shown the efficacy of omalizumab in the treatment of AE either in monotherapy (3) or in combination with other therapies (e.g., topical steroids, tacrolimus, antihistamines, antileukotrienes, oral corticosteroids, and UV treatment) (4–7). In the aforementioned studies (4–7), some patients suffered only from AE (3, 5), while the great majority also suffered from asthma (4, 6, 7). Omalizumab, (Xolair; Novartis, Nürnberg, Germany) a recombinant humanized IgG1 monoclonal antibody is derived from the murine antibody MAE11. It specifically binds to the high-affinity FceRI domain of free circulating IgE, and thus prevents binding of free serum IgE to mast cells and other effector cells. We present the case of a 15-year-old girl with severe AE, according to the criteria of Hanifin and Rajka (8), as well as with rhinoconjunctivitis and asthma due to sensitization to parietaria judaica, birch, and hazel [a FEV1 and a peak expiratory flow (PEF) lower than 70% of the predicted value]. At the time of the first evaluation, she was under treatment with budesonide/formoterol (100/6 lg twice daily), montelukast (10 mg daily), and desloratadine (5 mg daily). Our patient had a 6-year-long history of severe generalized AE, treated with a standard therapy (topical corticosteroids, topical pimecrolimus, systemic corticosteroids, UV treatment, and oral antihistamines), without long-lasting and satisfactory relief from symptoms. The patient had also been treated with cyclosporine A, with a good clinical response. However, this therapy was withdrawn because of an increase in blood creatinine levels (from 0.8 to 1.9 g/l). Taking into account the literature data (4–6), and her total IgE, we decided to treat our patient with 300 mg of omalizumab subcutaneously for a month. The therapeutic protocol was approved by the institutional review board. To evaluate the clinical efficacy of omalizumab therapy, we monitored the eczema area and severity index (EASI) (9), as well as the Scoring Atopic Dermatitis (SCORAD) (4), at each visit; moreover, a detailed photo documentation was taken. In addition, we monitored total and allergen-specific IgE serum levels, as well as inflammatory cells and cytokine expression in the peripheral blood before and after therapy (Table 1). The patient tolerated the eight omalizumab doses we administered. In the first evaluation, the SCORAD was 55. After 2 months of therapy, the patient displayed a very good clinical response (SCORAD reduction of more than 50%), and after 5 months she showed a significant total SCORAD decrease of about 80% (Table 1). The EASI evaluation demonstrated reasonably good overall reliability (EASI score at baseline was 44, after 5 months of therapy it was eight). Five months after the start-up of the therapy, total and allergen-specific IgE serum levels showed no reduction, while the CD4/ CD8 antibodies ratio was lower (Table 1). The patient also experienced good relief of rhinoconjunctivitis and asthma symptoms (a FEV1 and a PEF of about 90%). We should emphasize that our patient experienced much improvement (1) in monotherapy, (2) with low-dose anti-IgE therapy, and (3) from the very beginning of the treatment. It is interesting to note that the patients with AE described in the study by Forman et al. (3), who successfully responded to omalizumab, had actually been treated during the first Success of omalizumab as monotherapy in a young girl with severe atopic eczema.

Practical Management of Antibiotic Hypersensitivity in 2017

Antibiotics are the most common class of medications that individuals report allergy or intolerance to. Adverse reactions are reported at a predictable rate with all antibiotic use that vary by antibiotic. Antibiotic allergy incidence rates are sex dependent, higher in females than in males. Most of these events are not reproducible or immunologically mediated. Antibiotic allergy prevalence increases with increasing age and is more common in hospitalized populations and in populations that use more antibiotics. Determining potential mechanisms for the observed symptoms of the adverse reactions is the starting point for effective management of antibiotic hypersensitivity. Skin testing and direct challenges are the primary tools used to determine acute tolerance in 2017. Commercially available inxa0vitro testing is not currently clinically useful in determining antibiotic hypersensitivity, with rare exceptions. Desensitization can be used when acute-onset immunologically mediated hypersensitivity is confirmed to safely administer a needed antibiotic. Desensitization is not possible when clinically significant T-cell-mediated delayed-type hypersensitivity is present. Effective management of antibiotic allergy is an important part of a comprehensive antibiotic stewardship program.

Delayed hypersensitivity to cefotetan

(2+) to cherry, garlic, onion, orange, pea, kiwi, wheat, and barley on SPT with commercial food extracts. A very strong reactivity (4+) to both apple peel and peach peel extracts, as well as to fresh fennel, apple, hazelnut, and peach was observed. SPT with fresh string bean induced a slight wheal (2+), whereas the cooked bean induced a much stronger reaction (4+). No sensitivity to cross-reactive birch pollen allergens was found. Serum showed a moderate reactivity to peach peel LTP (OD 557) that was reduced by 96%, 95%, 31%, 71%, 73%, 77%, 69%, and 81% by preabsorption with peach, apple, walnut, hazelnut, peanut, corn, rice, and fennel extracts, respectively, and by 19% by preabsorption with ovalbumin. Peach immunoblot showed an IgE reactivity to a 10-kDa protein (LTP) and a broad reactivity at high molecular mass (Fig. 1). String bean immunoblot showed a single band at about 35 kDa and a broad reactivity at high molecular mass, but no reactivity at low molecular mass (Fig. 1). This patient was hypersensitive to two distinct vegetable food allergens, namely, LTP in several plant-derived foods and a 35kDa protein in string bean. The lack of reactivity at 10 kDa on bean immunoblot indicates the heat lability of LTP. Boiled string bean mantained a strong allergenicity, as previously described for other legumes (3). Interestingly, it induced a much stronger reaction than the raw bean, suggesting a possible increase in allergenicity of this food with heat treatment. This has been observed in other allergies to vegetable foods (4). In contrast to most previous studies of legume food allergy, our patient showed IgE reactivity to a single protein at about 35 kDa and a smear at high molecular mass. The heat stability of our allergen suggests that it differs from the heat-labile 32-kDa class I chitinase recently described in green beans (5) and that it might represent a novel allergen.

Allergic respiratory diseases and environmental pollution : experience in the printing/paper-manufacturing industry

Several studies have shown a correlation between airborne pollutants and respiratory disorders. To determine whether professional exposure to industrial pollution might represent a risk factor for allergic respiratory diseases, we administered allergologic tests to 275 workers employed in a paper‐making/printing factory and to a control population composed of 160 office workers from the same urban area. All subjects were evaluated on the basis of personal and family histories, the results of prick tests with common airborne allergens, specific serum IgE levels, pulmonary function test, and standard chest radiography. The percentage of subjects with allergies in the factory‐worker group (67/275; 24.4%) was significantly higher than that observed among the office workers (20/160; 12.5%) (chi‐square test: 8.17; P<0.01). Of the 67 factory workers with allergies, 94% had histories of daily exposure to aliphatic hydrocarbons. The results of this study indicate that exposure to the latter type of industrial pollutants is associated with a significantly higher prevalence of allergic respiratory diseases.

Delayed hypersensitivity to acylureidopenicillins: a case report

syndrome. Dermatology 1993;187:84– 85. 8. Bocquet H, Bagot M, Roujeau JC. Druginduced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg 1996;15:250–257. 9. Kardaun SH, Sidoroff A, ValeyrieAllanore L, Halevy S, Davidovici BB, Mockenhaupt M et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007;156:609–611. 10. Kanny G, Marie B, Hoen B, Trechot P, Moneret-Vautrin DA. Delayed adverse reaction to sodium ioxaglic acidmeglumine. Eur J Dermatol 2001;11:134– 137. 11. Kanny G, Pichler W, Morisset M, Franck P, Marie B, Kohler C et al. T cell-mediated reactions to iodinated contrast media: evaluation by skin and lymphocyte activation tests. J Allergy Clin Immunol 2005;115:179–185. 12. Vaillant L, Pengloan J, Blanchier D, De Muret A, Lorette G. Iododerma and acute respiratory distress with leucocytoclastic vasculitis following the intravenous injection of contrast medium. Clin Exp Dermatol 1990;15:232–233.

Same‐patient allergy to ampicillin and human insulin

clinically justified threshold . This study describes the effect of sublingual immunotherapy (SLIT) on well days in a randomized, double-blind, placebo-controlled, multicentre trial with the high-dose sublingual 6-grass pollen preparation AllerSlit forte. For details of study design, patient characteristics, primary results of SMS and safety, see (3). Well days are defined as days without intake of rescue medication and a symptom score £ 4. The definition is based on an inclusion criterion of the study. Recruited patients had to have a minimum symptom score of 4 on each day during the week after the grass pollen peak. Therefore, well days were correlated with a real improvement in patients symptoms and no need of rescue medication. The number of well days were analysed in 89 patients [active 41; placebo 48; Per Protocol Set (PP)]. After baseline observation during the 2003 grass pollen season, patients received SLIT for 1.5 years until the end of the 2005 pollen season. During the grass pollen season, patients rated 10 different symptoms (four nasal, three ocular, three bronchial) on a scale from 0 to 3 and documented intake of medication in a diary. Data for a 42-day period in the grass pollen season (highest grass pollen count) were evaluated. Differences between treatment groups were checked by using Wilcoxon–Mann–Whitney U-test. The median number of well days in the active and placebo groups did not differ in the baseline year 2003 (P = 0.9538), i.e. patients randomized to active treatment had 4/42 well days (9.5%), and placebo patients 7.5/42 well days (17.9%). After 1.5 years of SLIT in 2005, actively treated patients had a significantly higher median number of well days (22/42; 52.4%) than placebo patients (4.5/42; 10.7%) (P = 0.0007) (Fig. 1). The SMS also significantly improved after 1.5 years of SLIT in comparisonwith placebo [median area under the curve of SMSat baseline: active group 501, placebo group 430; after 1.5 years of SLIT: active 197, placebo 453 (PP; P = 0.0005)] (3). Therefore, the increase in number of well days corresponds well to the results in SMS. Hence, the above-defined well days are an additional variable to measure the efficacy of SIT. Well days confirm the excellent efficacy of the high-dose sublingual grass pollen preparation AllerSlit forte.