Allergenic significance of cephalosporin side chains

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6. Nassiri M, Babina M, D€ olle S, Edenharter G, Ru€eff F, Worm M. Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. J Allergy Clin Immunol 2015;135:491-9. Available online September 26, 2015. http://dx.doi.org/10.1016/j.jaci.2015.06.052

Reply To the Editor: The correspondence by Francuzik et al1 interrogates sex as a risk factor for anaphylaxis severity using an Anaphylaxis Registry database.2 They confirm the increased incidence of anaphylaxis in premenopausal women compared with men found in other epidemiological studies. These findings had prompted us to evaluate the effect of sex in anaphylaxis in a controlled mouse model3 because sex biases in other allergic and nonallergic human diseases have been reproduced in mice and it allows for testing sex in the absence of other confounding factors. We demonstrated more severe reactions in female mice that were dependent on estrogens.3 Even though our mouse data, we would argue, may relate to the increased incidence of anaphylaxis in women because severe reactions are more likely to be recognized, the actual effect of sex on the severity of anaphylaxis in humans is of interest. Francuzik et al1 report that unlike mice, males aged between 13 and 56 years have a slightly higher risk of severe anaphylaxis. As discussed below, we believe their registry cannot unequivocally address this question. The registry includes patients who presented at specialized medical centers with anaphylaxis, a situation that may itself skew the assessment of severity because it may be influenced by differences between men and women in the initial recognition of symptoms or willingness to seek medical help. In addition, the reference describing the Anaphylaxis Registry2 states that most patients received medical treatment, thus bringing into consideration the possibility that sex-related responses to therapy could affect assessment of severity grading. Furthermore, this registry does not appear to have included questions relating to the reproductive phase nor gathered data on diet and medications that influence sex hormone levels of individual patients. Rather, to address such issues, they selected ages 1 to 12 years as prepubertal and 57 years and above as postmenopausal, when the reported median age at menopause is 51.3 years.4,5 It would have been much preferable to obtain such information from each patient during the course of study because the possibility exists that these selected ages for onset of puberty and menapause do not accurately reflect the study population. In addition, the cases in the registry include a preponderance of anaphylaxis from insect venom,2 a proportion unlikely representative of the most common elicitors in the general population. Insect venom is reportedly an independent predictor of severity,6 and anaphylaxis elicited by insect stings has been recently associated with clonal mast cell disorders (diagnosed by bone marrow biopsy),7 thus possibly affecting the conclusion of this analysis. We do, however, much appreciate this effort to assess anaphylaxis severity related to sex and would encourage that future epidemiological studies on anaphylaxis prevalence and severity consider sex and be designed to consider life events, diet, and medications that influence the levels of estrogens and androgens. Valerie Hox, MD, PhD Dean D. Metcalfe, MD Ana Olivera, PhD

From the Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. E-mail: [email protected]. This work was supported by the Division of Intramural Research Program within the National Institute of Allergy and Infectious Diseases, National Institutes of Health and by the Research Foundation Flanders (Fonds voor Wetenschappelijk Onderzoek). V.H. was a research fellow and the recipient of a travel grant from Fonds voor Wetenschappelijk Onderzoek as well as a Gustave Bo€el – Sofina – Belgian American Educational Foundation fellow. Disclosure of potential conflict of interest: V. Hox has received research support from the Belgium American Education Foundation. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Francuzik W, Nassiri M, Babina M, Worm M. Impact of sex on anaphylaxis severity—data from the Anaphylaxis Registry. J Allergy Clin Immunol 2015; 136:1425-6. 2. Worm M, Edenharter G, Rueff F, Scherer K, Pfohler C, Mahler V, et al. Symptom profile and risk factors of anaphylaxis in Central Europe. Allergy 2012;67:691-8. 3. Hox V, Desai A, Bandara G, Gilfillan AM, Metcalfe DD, Olivera A. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. J Allergy Clin Immunol 2015;135:729-36.e5. 4. Kato I, Toniolo P, Akhmedkhanov A, Koenig KL, Shore R, Zeleniuch-Jacquotte A. Prospective study of factors influencing the onset of natural menopause. J Clin Epidemiol 1998;51:1271-6. 5. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 2008;61:4-16. 6. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371-6. 7. Zanotti R, Lombardo C, Passalacqua G, Caimmi C, Bonifacio M, De Matteis G, et al. Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels. J Allergy Clin Immunol 2015;136:135-9. Available online September 26, 2015. http://dx.doi.org/10.1016/j.jaci.2015.08.002

Allergenic significance of cephalosporin side chains To the Editor: At the clinical level, structural similarities and differences between individual cephalosporins appear to be frequently overlooked in selecting drugs for allergy avoidance. In their study of IgE-mediated hypersensitivity to cephalosporins, Romano et al1 rightly draw attention to the need to consider structural features in addition to skin and provocation test results when selecting alternative cephalosporins. From their assembled data showing the many reaction patterns detected, and in the absence of any significant adjunct testing (only 8 patients had IgE antibodies to cefaclor, the only specificity tested), attempts are made to interpret the findings in terms of likely R1 sidechain structures, especially the presence of the methoxyimino group found on a number of third- and fourth-generation cephalosporins. Possible recognition of R2 side chains is suggested for 1 patient. There is ample evidence that the R1 side chains of cephalosporins can be involved in allergic recognition,2,3 and current thinking seems to be that it is the predominant, if not the only, allergenic structure on cephalosporins. This conclusion appears to have been influenced by the known lability of the dihydrothiazine ring; clear allergenic involvement of the aminobenzyl R1 group in some allergic patients; the lack of testing (especially in vitro) aimed at detecting R2 side-chain recognition by IgE; and the lack of appreciation of the extent of heterogeneity of the IgE response to cephalosporins.3 Despite published evidence of IgE antibody recognition of R2 side-chain structures, preoccupation with R1 group recognition prevails, often because of the failure to consider the

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H

R1 CO NH

S

7

6

8

N

5

1

2 3

4

O

R2

COOH

R1

Cefodizime

H2 N

N OCH3

CH3

S

CH2-COOH

CH2 O CO CH3

C S

N CH2 S C

Cefotaxime N

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Ceftriaxone

O

CH2 S C N O CH2 N+

Cefepime

H 3C

O

C

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N OCH3

FIG 1. General structure of cephalosporins and structures of cephalosporins used in the study1 showing the R1 methoxyimino group (magenta) and the R2 ester and thioether groups (blue and red, respectively). Space-filling models show that, compared with cefodizime, the thioether group of ceftriaxone is at least partially hindered by the adjacent ring N-methyl group, perhaps impeding IgE binding.

possible involvement of more than 1 population of drug-reactive antibodies of different specificities in the same patient.2,3 In the present data, even a brief analysis of the observed reactions with different cephalosporins reveals obvious inconsistencies. For example, although 32 patients had positive skin test results to either cefotaxime or ceftriaxone or both, more than half of the patients had negative skin test results to cefepime and cefuroxime. These differences occur despite the presence of an identical R1 side chain in ceftriaxone, cefotaxime, and cefepime and a methoxyimino sequence in all the 4 drugs (Fig 1). Clearly, the common R1 structure is not the sole explanation for the allergic recognition in all 32 patients. For patient 79, recognition of the R2 ester group of cefuroxime and cefotaxime, perhaps together with the R1 methoxyimino, is the likely basis of the sensitivity (Fig 1). Skin test reaction patterns in patient 92 indicate that rather than recognition of the R1 side chain, it is the entire R1 side chain and the 2-ring structure with the attached R2 ester/ether linkage (with sterically unhindered O or S) that

account for the patient’s sensitivity (Fig 1). Presented data indicate other examples of R2 and/or whole molecule recognition. Close analyses of skin test reactivity patterns supplemented with IgE antibody tests (especially inhibitions) superior in performance to the currently used cefaclor assay are likely to reveal further examples of cephalosporin allergies mediated by recognition of structures other than, or in addition to, the R1 side chains. In substituting cephalosporins to avoid allergy, similarities and differences between R1 groups need to be noted but failure to do likewise for R2 groups may lead to serious consequences for the occasional patient. Brian A. Baldo, PhDa,b Nghia H. Pham, PhDa,b From athe Molecular Immunology Unit, Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney and bthe Department of Medicine, University of Sydney, Sydney, Australia. E-mail: [email protected]. Both authors are now retired. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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REFERENCES 1. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Zaffiro A, Caruso C, et al. IgE-mediated hypersensitivity to cephalosporins: cross-reactivity and tolerability of alternative cephalosporins. J Allergy Clin Immunol 2015;136:685-91. 2. Pham NH, Baldo BA. b-Lactam drug allergens: fine structural recognition patterns of cephalosporin-reactive IgE antibodies. J Molec Recogn 1996;9:287-96. 3. Baldo BA, Pham NH. Drug allergy: clinical aspects, diagnosis, mechanisms, structure-activity relationships. New York: Springer; 2013. pp. 159-75. Available online September 18, 2015. http://dx.doi.org/10.1016/j.jaci.2015.06.051

Reply To the Editor: We read with great interest Baldo and Pham’s observations1 on our article2 and specifically their final claim that in selecting alternative cephalosporins in cephalosporin-allergic subjects, ‘‘similarities and differences between R1 groups need to be noted but failure to do likewise for the R2 groups may lead to serious consequences for the occasional patient.’’ Actually, our study2 aimed to evaluate the possibility of using alternative cephalosporins in cephalosporin-allergic patients who especially require these b-lactams. As stated in the clinical implications,2 we demonstrated that these subjects might be treated with alternative cephalosporins that have side-chain determinants different from those of the responsible compounds and elicit negative pretreatment skin test responses. Here, ‘‘side-chain determinants’’ refer to determinants of both R1 and R2 side chains. Indeed, even though literature data3-5 indicate that cross-reactivity among cephalosporins is mainly connected with their R1 side chains, cases of cross-reactivity related to the R2 side chain, such as subject 5 of our study,2 are possible. In this study,2 we used skin tests, challenges, and the only commercially available in vitro test, the assay of serum-specific IgE for cefaclor (ImmunoCAP). We agree that performing additional in vitro tests, including RAST inhibition studies, would have allowed us to detect ‘‘more than one population of drug-reactive antibodies of different specificities’’ in each patient and thus, better classify the responsible cephalosporins. In the study by Antunez et al,4 however, RAST and RAST inhibition studies demonstrated that the side chain at the R1 position is crucial for recognition and cross-reactivity among cephalosporins, such as cefotaxime, ceftriaxone, cefuroxime, and ceftazidime, which have been classified by us as group A. Moreover, patients 79 and 92 of our study,2 in whom, according to the information provided by Baldo and Pham,1 recognition of R2 side-chain determinants contributed to their sensitivity, were in any case positive to cephalosporins with a methoxyimino group, such as cefuroxime, cefotaxime,

and cefodizime, belonging to group A. Therefore, according to our approach,2 these 2 subjects would not have been exposed to risky challenges with such alternative cephalosporins. In our study,2 the correctness of the cephalosporin classification and the consequent choice of alternative compounds is demonstrated by statistical analysis and the fact that our 102 subjects tolerated a total of 323 challenges. In this study,2 the limited number of subjects sensitive to cephalosporins other than those in groups A and B did not allow us to identify further groups. On the basis of the case of subject 5, however, one could hypothesize additional groups, such as one consisting of cephalosporins such as cefamandole, cefoperazone, and cefotetan that share an identical R2 side chain with an Nmethyl-tetrazole-thiol group. Therefore, we agree with Baldo and Pham that one should take into account the antigenic determinants of both R1 and R2 side chains before administering alternative cephalosporins to subjects allergic to these b-lactams. Antonino Romano, MDa,b Francesco Gaeta, MD, PhDa Rocco Luigi Valluzzi, MDa Michela Maggioletti, MDa Alessandra Zaffiro, MDc Cristiano Caruso, MDa Donato Quaratino, MDc From athe Allergy Unit, Complesso Integrato Columbus, Rome, Italy; bIRCCS Oasi Maria S.S., Troina, Italy; and cAmbulatorio di Allergologia, IDI-IRCCS, Capranica, Italy. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. REFERENCES 1. Baldo BA, Pham NH. Allergenic significance of cephalosporin side chains. J Allergy Clin Immunol 2015;136:1426-8. 2. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Zaffiro A, Caruso C, et al. IgEmediated hypersensitivity to cephalosporins: cross-reactivity and tolerability of alternative cephalosporins. J Allergy Clin Immunol 2015;136:685-91. 3. Romano A, Gueant-Rodriguez RM, Viola M, Amoghly F, Gaeta F, Nicolas JP, et al. Diagnosing immediate reactions to cephalosporins. Clin Exp Allergy 2005; 35:1234-42. 4. Antunez C, Blanca-Lopez N, Torres MJ, Mayorga C, Perez-Inestrosa E, Monta~nez MI, et al. Immediate allergic reactions to cephalosporins: evaluation of crossreactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol 2006;117:404-10. 5. Romano A, Gaeta F, Valluzzi RL, Zaffiro A, Caruso C, Quaratino D. Natural evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity to cephalosporins. Allergy 2014;69:806-9. Available online September 18, 2015. http://dx.doi.org/10.1016/j.jaci.2015.06.053