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Patch Testing for Adverse Drug Reactions

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Patch Testing for Adverse Drug Reactions Patch Testing for Adverse Drug Reactions Sahil Sekhon, MD; Susan T. Nedorost, MD PRACTICE POINTS • Consider patch testing in suspected eczematous drug rashes and fixed drug eruption. • Patch test to inactive excipients as well as active ingredients. • Caution patients that sensitivity of patch testing for systemic drug reactions is unknown and likely lower than specificity. Adverse drug reactions result in a substantial suspicion of drugcopy allergy and were included in the number of hospital admissions and inpatient analysis. The excluded patients had pseudoallergic events. Diagnosis usually is made with clinical reactions, reactive exanthemas due to infection, his- judgment and circumstantiality without diagnostic topathologic exclusion of drug allergy, angioedema, testing. Furthermore, even in situations where or notother dermatological conditions such as contact diagnostic testing is performed, no safe gold dermatitis and eczema. Of the included patients, standard tests exist. Oral rechallenge is currently 107 were diagnosed with drug reactions, while the gold standard but carries the risk of recrudes- the remainder had non–drug-related exanthemas cence of severe allergic symptoms. Other testsDo or unknown etiology after testing. Identified culprit include skin prick tests, the lymphocyte trans- drugs were predominantly antibiotics (39.8%) and formation test, immunohistochemistry, and patch NSAIDs (21.2%); contrast media, anticoagulants, testing. This article provides a review of patch anticonvulsants, antimalarials, antifungals, glucocor- testing in cases of adverse drug reactions and ticoids, antihypertensives, and proton pump inhibi- presents new data on this topic. tors also were implicated. They were identified with Cutis. 2017;99:49-54. skin prick, intradermal, and patch tests (62.6%); lymphocyte transformation test (17.7%); oral rechal- CUTIS lenge (5.6%); or without skin testing (6.5%). One dverse drug reactions account for 3% to quarter of patients with a high suspicion for drug 6% of hospital admissions in the United allergy did not have a confirmed drug eruption in States and occur in 10% to 15% of hospi- this study. Another study found that 10% to 20% of A 1,2 talized patients. The most common culprits are patients with reported penicillin allergy had confir- antibiotics and nonsteroidal anti-inflammatory drugs mation via skin prick testing.14 These findings sug- (NSAIDs).3-12 In most cases, diagnoses are made gest that confirmation of suspected drug allergy may clinically without diagnostic testing. To identify require more than one diagnostic test. drug allergies associated with diagnostic testing, one center selected patients with suspected cutaneous Tests for Adverse Drug Reactions drug reactions (2006-2010) for further evaluation.13 The following tests have been shown to aid in the Of 612 patients who were evaluated, 141 had a high identification of cutaneous drug eruptions: (1) patch tests15-21; (2) intradermal tests14,15,19,20; (3) drug prov- ocation tests15,20; and (4) lymphocyte transformation From Case Western Reserve University School of Medicine and tests.20 Intradermal or skin prick tests are most use- University Hospitals Cleveland Medical Center, Ohio. The authors report no conflict of interest. ful in urticarial eruptions but can be considered in Correspondence: Sahil Sekhon, MD, 515 Spruce St, San Francisco, nonurticarial eruptions with delayed inspection of CA 94118 ([email protected]). test sites up to 1 week after testing. Drug provocation WWW.CUTIS.COM VOLUME 99, JANUARY 2017 49 Copyright Cutis 2017. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Patch Testing With Active Drugs tests are considered the gold standard but involve Patch test results of many drugs have been reported patient risk. Lymphocyte transformation tests use in the literature, with the highest frequencies of the principle that T lymphocytes proliferate in the positive results associated with anticonvulsants,26 presence of drugs to which the patient is sensitized. antibiotics, corticosteroids, calcium channel block- Patch tests will be discussed in greater detail below. ers, and benzodiazepines.21 Immunohistochemistry can determine immunologic Patch test placement affects the diagnostic value mechanisms of eruptions but cannot identify caus- of the test. Placing patch tests on previously involved ative agents.16,17,22 sites of fixed drug eruptions improves yield over A retrospective study of patients referred for placement on uninvolved skin.27 Placing patch tests evaluation of adverse drug reactions between 1996 on previously involved sites of other drug eruptions and 2006 found the collective negative predic- such as toxic epidermal necrolysis also may aid in tive value (NPV)—the percentage of truly nega- diagnosis, though the literature is sparse.25,26,28 tive skin tests based on provocation or substitution testing—of cutaneous drug tests including patch, Patch Testing in Drug Eruptions prick, and intradermal tests to be 89.6% (95% confi- Morbilliform eruptions account for 48% to 91% of dence interval, 85.9%-93.3%).23 The NPVs of each patients with adverse drug reactions.4-6 Other drug test were not reported. Patients with negative cutane- eruptions include urticarial eruptions, acute gen- ous tests had subsequent oral rechallenge or substitu- eralized exanthematous pustulosis (AGEP), drug tion testing with medication from the same drug reaction with eosinophilia and systemic symptoms class.23 Another study16 found the NPV of patch (DRESS) syndrome, toxic epidermal necrolysis, testing to be at least 79% after review of data from Stevens-Johnson syndrome, lichenoid drug eruption, other studies using patch and provocation test- symmetric drug-relatedcopy intertriginous and flexural ing.16,24 These studies suggest that cutaneous testing exanthema (SDRIFE), erythema multiforme (EM), can be useful, albeit imperfect, in the evaluation and and systemic contact dermatitis. The Table sum- diagnosis of drug allergy. marizes reports of positive patch tests with various medicationsnot for these drug eruptions. Review of the Patch Test In general, antimicrobials and NSAIDs were Patch tests can be helpful in diagnosis of delayed the most implicated drugs with positive patch test hypersensitivities.18 Patch testing is most commonly results in AGEP, DRESS syndrome, EM, fixed drug and effectively used to diagnose allergic contactDo der- eruptions, and morbilliform eruptions. In AGEP, matitis, but its utility in other applications, such as positive results also were reported for other drugs, diagnosis of cutaneous drug eruptions, has not been including terbinafine and morphine.29-38 In fixed extensively studied. drug eruptions, patch testing on involved skin The development of patch tests to diagnose sys- showed positive results to NSAIDs, analgesics, plate- temic drug allergies is inhibited by the uncertainty let inhibitors, and antimicrobials.27,52-55 Patch test- of percutaneous drug penetration, a dearth of studies ing in DRESS syndrome has shown many positive to determine the best test concentrations of active reactions to antiepileptics and antipsychotics.39-43 drug in the patch test, andCUTIS the potential for nonim - One study used patch tests in SDRIFE, reporting munologic contact urticaria upon skin exposure. positive results with antimicrobials, antineoplastics, Furthermore, cutaneous metabolism of many anti- decongestants, and glucocorticoids.61 Nonsteroidal gens is well documented, but correlation to systemic anti-inflammatory drugs, antimicrobials, calcium metabolism often is unknown, which can confound channel blockers, and histamine antagonists were patch test results and lead to false-negative results implicated in EM.47-51 Positive patch tests were seen when the skin’s metabolic capacity does not match in morbilliform eruptions with selective serotonin the body’s capacity to generate antigens capable reuptake inhibitors, antiepileptics/benzodiazepines, of eliciting immunogenic responses.21 Additionally, NSAIDs, and antimicrobials.28,57-60 In toxic epider- the method used to suspend and disperse drugs in mal necrolysis, diagnosis with patch testing was patch test vehicles is unfamiliar to most pharmacists, made using patches placed on previously involved and standardized concentrations and vehicles are skin with sulfamethoxazole.62 available only for some medications.25 Studies suf- ficient to obtain US Food and Drug Administration Systemic Contact Dermatitis approval of patch tests for systemic drug eruptions Drugs historically recognized as causing allergic con- would be costly and therefore prohibitive to inves- tact dermatitis (eg, topical gentamycin) can cause sys- tigators. The majority of the literature consists of temic contact dermatitis, which can be patch tested. case reports and data extrapolated from reviews. In these situations, systemic contact dermatitis may 50 CUTIS® WWW.CUTIS.COM Copyright Cutis 2017. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Patch Testing With Active Drugs Positive Patch Test Results for Adverse Drug Reactions Class of Drug(s) Patch-Tested Medication(s) AGEP Anticonvulsants Carbamazepine,29 phenobarbital29 Antimicrobials/antifungals Amoxicillin,29 amoxicillin–clavulanic acid,30 ampicillin-cloxacillin,31 cefotaxime,32 ciprofloxacin,33 erythromycin,34 spiramycin,29,34 terbinafine35 Calcium channel blocker Diltiazem29
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