Miguel Blanca

HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping

BACKGROUNDnImmediate reactions to β-lactams are the most common causes of anaphylactic reactions and can be life-threatening. The few known genetic factors influencing these reactions suggest a link with atopy and inflammation.nnnOBJECTIVEnWe performed a fine-mapping genome-wide association study of the genetic predictors of β-lactam allergy to better understand the underlying mechanisms.nnnMETHODSnWe studied 387 patients with immediate allergic reactions to β-lactams and 1124 paired control subjects from Spain. We replicated the results in 299 patients and 362 paired control subjects from Italy.nnnRESULTSnWe found significant associations with the single nucleotide polymorphisms rs4958427 of ZNF300 (c.64-471G>A, P = 9.9 × 10(-9)), rs17612 of C5 (c.4311A>C [p.Glu1437Asp], P = 7.5 × 10(-7)), rs7754768 and rs9268832 of the HLA-DRA | HLA-DRB5 interregion (P = 1.6 × 10(-6) and 4.9 × 10(-6)), and rs7192 of HLA-DRA (c.724T>G [p.Leu242Val], P = 7.4 × 10(-6)) in an allelic model, with similar results in an additive model. Single nucleotide polymorphisms of HLA-DRA and ZNF300 predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block in HLA-DRA and the HLA-DRA | HLA-DRB5 interregion encompassed a motif involved in balanced expression of the α- and β-chains of MHC class II, whereas rs7192 was predicted to influence α-chain conformation. HLA-DRA rs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin (P = 6.0 × 10(-4) and P = 4.0 × 10(-4), respectively) but not to cephalosporins in the replication study.nnnCONCLUSIONSnGene variants of HLA-DRA and the HLA-DRA | HLA-DRB5 interregion were significant predictors of allergy to penicillins but not to cephalosporins. These data suggest complex gene-environment interactions in which genetic susceptibility of HLA type 2 antigen presentation plays a central role.

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.

Urticaria and Anaphylaxis due to Betalactams (Penicillins and Cephalosporins)

Anaphylaxis and urticaria are the main clinical entities associated nwith betalactam allergy. They usually occur within n1 h of drug exposure, although urticaria may occasionally nappear later. The sh

Reply to J. Leysen et al.

Dear Editor, We thank J. Leysen et al. for their interest in reading our article ‘Prevalence of IgE against neuromuscular blocking agents in hairdressers and bakers’ [1]. In a former survey by Dong et al. [2], assay of specific IgE against quaternary/tertiary ammoniums was performed in 303 patients having experienced neuromuscular blocking agents (NMBA) anaphylaxis. Results were positive in 251 cases (82.8%). As noticed by J. Leysen et al., 12 patients had positive IgE assay and negative skin tests (ST). This positive IgE assay had to be considered in the context of the anaphylaxis. Another recent retrospective study evaluated 114 patients who reacted during anaesthesia, including 57 cases with positive ST to the administered NMBA and 57 reactors with negative ST to NMBAs [3]. Fourteen of the patients with negative skin tests had positive serum IgE against quaternary/tertiary ammonium compounds. Ten of them reacted less than 5 min after NMBA injection. These data show therefore that both ST and assay of IgE against quaternary/tertiary ammoniums may produce false-negative results and should be used in association for improving the diagnosis of NMBA anaphylaxis in patients who undergo an adverse reaction during anaesthesia. In contrast, in the general population, it may be expected that few of sensitized subjects with IgE against quaternary/tertiary ammoniums are at risk of allergic reactions, considering the contrast between the relatively high frequency of positive assay of IgE against quaternary/tertiary ammoniums and the low prevalence of peri-operative NMBA anaphylaxis [1–4]. This explains that it is not recommended to do a systematic pre-operative screening with either ST or serum-specific IgE against quaternary/tertiary ammonium compounds, in the guidelines for clinical practice published by the interest group on drug hypersensitivity of the European Academy of Allergy and Clinical Immunology (ENDA) [4]. This policy is also justified by the absence of sufficient information on the respective positive and negative predictive values of these tests. Indeed, false-negative results and/or false-positive results could inappropriately contraindicate the use of NMBAs in numerous patients who could otherwise benefit from these drugs [4]. In contrast to the above-mentioned retrospective studies of reactors, the present study was performed in subjects who had no previous anaesthesia and no previous allergic manifestation. We observed a 4.6-fold increased rate of IgE sensitization to NMBAs in hairdressing apprentices exposed to quaternary ammonium compounds, compared to baker/ pastry makers and control groups. The sensitization was established by the cross-reactivity of specific IgE against choline with quaternary ammonium compounds used in hairdressing. These results show that occupational exposure to quaternary ammonium compounds plays a role in the sensitization against NMBAs, but the study cannot predict an increased risk of NMBA anaphylaxis. In contrast, our results suggest designing epidemiological studies with adapted questionnaires to evaluate the predictive risk of hairdressing occupational exposure in patients who experienced NMBA anaphylaxis.

Other NSAIDs Reactions

Nonsteroidal antiinflammatory drugs (NSAIDs), the drugs most frequently taken all over the world, are also the drugs most frequently involved in drug hypersensitivity reactions. Five major groups of entities are presently considered: respiratory manifestations, now recognized as NSAID-exacerbated respiratory disease (NERD); chronic spontaneous urticaria that is aggravated after the intake of an NSAID, designated as NSAID-exacerbated cutaneous disease (NECD); and urticaria and angioedema that appears in the absence of chronic urticaria, recognized as NSAID-induced urticaria and angioedema (NIUA). These reactions are included within the cross-intolerant category because patients can respond to nonchemically related NSAIDs. The other two groups belong to a different category, concerning selective responders where an immunologic mechanism is involved: either immediate allergic reactions that include a single NSAID-induced urticaria, angioedema, and anaphylaxis or reactions where a T cell mechanism is involved, leading to a single NSAID-induced delayed hypersensitivity reaction.