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Drug Hypersensitivity

Article #1

Sloane D, Govindarajulu U, Harrow-Mortelliti J, Barry W, Hsu FI, Hong D, et al.
Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies. J Allergy Clin Immunol Pract. 2016 May-Jun;4(3):497-504.

BACKGROUND: Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined.

OBJECTIVE: We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD.

METHODS: We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group.

RESULTS: RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls.

CONCLUSIONS: RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy. This study confirms that rapid drug desensitization (RDD) is safe and effective. It demonstrates that the efficacy of a drug administered by RDD is maintained and that  patients treated with RDD do not incur greater costs than those treated by standard administration. Therefore, patients with hypersensitivity reactions to chemo-therapeutics or monoclonal antibodies should be evaluated by an allergist and preferentially treated with first line therapy through RDD.

Article #2

Mayorga C, Celik G, Rouzaire P, Whitaker P, Bonadonna P, Rodrigues-Cernadas J, et al.
In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2016 Aug;71(8):1103-34.

ABSTRACT: Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis.

CONCLUSIONS: This European position paper provides useful information on indications and limits of in vitro tests for evaluating subjects with hypersensitivity reactions to drugs. In particular, there are many in vitro tests that can help in the diagnosis and identification of the culprit drug, but only a few of them show enough evidence for at least a grade B recommendation.

Article #3

Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D.
Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016 Jul;138(1):179-86.

BACKGROUND: The few studies performed in adults with T cell-mediated hypersensitivity to penicillins have found a rate of cross-reactivity with cephalosporins ranging from 2.8% to 31.2% and an absence of cross-reactivity with aztreonam.

OBJECTIVE: We sought to evaluate the possibility of using cephalosporins and aztreonam in subjects with documented delayedhypersensitivity to penicillins who especially require them.

METHODS: We conducted a prospective study of 214 consecutive subjects who had 307 nonimmediate reactions to penicillins (almost exclusively aminopenicillins) and had positive patch test and/or delayed-reading skin test responses to at least 1 penicillin reagent. To assess cross-reactivity with cephalosporins and aztreonam and the tolerability of such alternative β-lactams, all subjects underwent skin tests with cephalexin, cefaclor, cefadroxil, cefuroxime, ceftriaxone, and aztreonam. Subjects with negative responses were challenged with the alternative β-lactams concerned.

RESULTS: All subjects had negative skin test results to cefuroxime, ceftriaxone, and aztreonam and tolerated challenges. Forty (18.7%) of the 214 subjects had positive skin test responses to at least 1 aminocephalosporin. Of the 174 subjects with negative responses, 170 underwent challenges; 1 reacted to cefaclor.

CONCLUSIONS: These data demonstrate a rate of cross-reactivity between aminopenicillins and aminocephalosporins (ie, cephalexin, cefaclor, and cefadroxil) of around 20%, as well as the absence of cross-reactivity between penicillins and cefuroxime, ceftriaxone, and aztreonam in all subjects with T cell-mediated hypersensitivity to penicillins, almost exclusively aminopenicillins. Therefore these subjects could be treated with cefuroxime, ceftriaxone, and aztreonam. In those who especially require cephalosporin or aztreonam treatment, however, we recommend pretreatment skin tests because negative responses indicate tolerability.

This study demonstrates a rate of cross-reactivity between aminopenicillins and aminocephalosporins of around 20%, as well as the tolerability of aztreonam, cefuroxime, and ceftriaxone in 214 subjects with a T-cell-mediated hypersensitivity to penicillins. Therefore, these subjects could be treatedwith aztreonamand ceph-alosporins, which have side-chain determinants different from those of the responsible compounds and elicit negative re-sponses on pretreatment skin tests.

Article #4

Lerondeau B, Trechot P, Waton J, Poreaux C, Luc A, Schmutz JL, et al.
Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions. J Allergy Clin Immunol. 2016 Feb;137(2):633-635.e4.

BACKGROUND: This retrospective study evaluated patients who had skin tests with 9 radiocontrat media (RCM), after a hypersensitivity reaction to a radiocontrast medium, followed by a substitution test with another compound. The authors identified 3 groups of RCM in which cross-reactions were frequent: group A (iodixanol, iopamidol, iomeprol, iohexol, ioversol, and ioxitalamate), the members of which share 2 identical N-(2,3-dihydroxypropyl) carbamoyl side chains (except for ioxitalamate); group B (ioxaglate and iobitridol); and group C with an isolated radiocontrast medium (amidotrizoate). This classification was based primarily on the scarcity of RCM cross-reactivity among these 3 groups and the frequency of cross-reactivity among RCM belonging to group A and between the two RCM of group B. The results were statistically significant among patients belonging to the “delayed reactions” (>1 hour after RCM administration) group, but less robust for those in the ‘‘immediate reactions’’ (onset ≤1 hour after RCM administration) group.

To assess more quantitatively the preceding findings, a logistic regression within the groups with immediate and delayed reactions separately was conducted. This allowed the authors to express the ‘‘risk’’ of positive cross-reactions among the RCM. For delayed reactions, and using a positive reaction to iomeprol as reference, the ‘‘risk’’ of a positive cross-reaction was 19.8 for iodixanol and 33.5 for ioversol. For ioxaglate and iobitridol, the risk was 3. For immediate reactions, taking iopremol as reference, the risk of a positive cross-reaction was 4.6 for amidotrizoate and 10.5 for ioxitalamate. The risk was between 9 and 10 for ioversol, ioxaglate, and iodixanol, using a positive reaction to iopamidol as reference.

CONCLUSIONS: This study demonstrates that cross-reactions among RCM do not follow the current chemical classification. It also demonstrates that reactions to RCM frequently occur on first exposure. Thus, reactivity to RCM might be induced by earlier exposure to molecules containing carbamoyl side chains, which is found in other molecules such as buzepide metiodure and cefuroxime.