Au, Elaine Y.L.

Chan, Eric

Lau, Chak Sing

Rosa Duque, Jaime S.

The Journal of Allergy and Clinical Immunology In Practice

English

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Clinical CommunicationsA patient with anaphylaxis todiphenhydramine withoutcross-reactivity to loratadineQ4Elaine Y.L. Au, MBBS, FHKAM (Medicine), FRCPA,FHKAM (Pathology), D (ABMLI)a,b,Jaime S. Rosa Duque, MD, PhD, DABPed, DABA&Ib,c,Chak Sing Lau, MBChB, MD (Hons), FRCP (Edin, Glasg,Lond), FHKCP, FHKAM (Medicine)b, andEric Chan, MBBS, PhD, FRCPath, FRCPA, FHKAM(Pathology)aClinical Implications Anaphylaxis to antihistamines is rare. In this case, thecausative antihistamine was confirmed by repeatedclinical reactions shortly after every exposure, as well asskin test and basophil activation tests, which were alsohelpful for identifying an alternative for the patient.TO THE EDITOR:Antihistamines are common over-the-counter medicationsused to alleviate symptoms of allergies, insomnia, nausea, andsymptoms of viral illnesses. It is exceedingly rare that these drugscause IgE-mediated, type I reactions. Previously, there were 2reported cases of anaphylaxis to diphenhydramine. Mur Gimenoet al1 reported a patient with suspected diphenhydramine-induced anaphylaxis and negative skin test, who developedrecurrent anaphylaxis on challenge with diphenhydramine.Nevertheless, she tolerated loratadine. Barranco et al2 reportedanother case of diphenhydramine anaphylaxis in a nonatopicpatient who had positive intradermal skin test and challenge butnegative prick test and specific IgE. This patient subsequentlytolerated terfenadine, cetirizine, loratadine, and dexchlorphenir-amine. Here we present the third case of anaphylaxis todiphenhydramine. This is the first case to be reported that in-volves the use of basophil activation test (BAT) in the diagnosisand management.A 42-year-old generally healthy man was referred for assess-ment of recurrent anaphylaxis after taking several medications toalleviate symptoms due to upper respiratory viral illnesses. Overthe course of many years, he experienced several episodes ofgeneralized, pruritic, urticarial eruption after using these medi-cations. He became more concerned when, 3 years before hisvisit to our allergy clinic, he suffered a severe reaction thatincluded diffuse urticaria, flushing, and angioedema, coupledwith shortness of breath and dizziness within 5 minutes after theapplication of the over-the-counter intranasal drops, Coldistan.His anaphylactic response was so intense that he was transferredto the intensive care unit and required an adrenaline infusion.Review of the packaging label of Coldistan revealed that theactive ingredients consisted of diphenhydramine and naphazolinewith no excipients listed. Serum tryptase during the event wassignificantly elevated compared with baseline (57.9 and 6.2 mg/L,respectively), supporting the diagnosis of anaphylaxis. Two yearslater, a similar reaction recurred after he took diphenhydramineorally for an upper respiratory illness. This time, he was stabilizedafter treatments for anaphylaxis in the emergency unit.Skin prick tests with diphenhydramine (50 mg/mL), cetirizine(10 mg/mL), and loratadine (10 mg/mL) were performed.1 Epi-cutaneous prick with preservative-free diphenhydramine yieldedpositive skin reactivity (wheal diameters: histamine 6  6 mm,saline 0 mm, diphenhydramine 13  19 mm with pseudopod),whereas loratadine and cetirizine prick results were negative(Figure 1). Diphenhydramine prick tests were negative in 6healthy subjects. We performed BAT with serial dilution of thedrugs from neat up to 10,000 fold (BAT reagents from FlowCAST BÜHLMANN Laboratories AG, Schönenbuch,Switzerland). The intravenous formulation of diphenhydramine(Omega Laboratories Q3) was used. The results showed positivereactivity for diphenhydramine (Figure 2) and cetirizine but werenegative for chlorpheniramine and loratadine. BATs for 4 healthycontrol subjects were tested negative for all 4 antihistamines.Based on these results, the patient agreed to an open challenge toloratadine, which he tolerated.This patient’s presentation was most consistent with an IgE-mediated process as evident by reproducibility of symptoms onself-challenge, an elevated serum tryptase level after exposure,and positive skin reactivity and BAT results.3,4 Anaphylaxis afterintranasal administration of a drug is rare, but it is possible. Apatient had even suffered cardiac arrest due to anaphylaxis afterapplying intranasal chlorhexidine.5 Diphenhydramine is a lowmolecular weight compound, and as such the underlyingmechanism leading to reaction is likely a hapten effect caused bythe drug itself or its metabolite(s). In the 2 previous reportedcases, one patient had a negative skin test result, whereas theprint&web4C=FPOFIGURE 1. Skin prick test results at 20 minutes.SCO 5.5.0 DTD  JAIP1389_proof  14 November 2017  9:11 pm  ce1123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122other demonstrated intradermal reactivity to diphenhydramine;our patient showed a positive skin prick test result. It is inter-esting to note the positive skin reactivity from an antihistamineepicutaneous prick. Histamine is an important but not the onlymediator involved in the induction of wheal and flare response.Other mediators also contribute, such as platelet-derived growthfactors, leukotrienes, and prostaglandins. Hence, it is likely thatthe skin reaction still occurred after degranulation of cutaneousmast cells with the antihistamine, diphenhydramine, as a stim-ulant in this unusual case. Although details of any potentialexcipient of the nasal drops and the oral formulation used duringthe anaphylaxis episodes were not available, the antihistamineswe used for skin and BATs were pure without mixtures withpreservatives. Therefore, the patient most likely has hypersensi-tivity to diphenhydramine.BAT, a flow-based assay, is increasingly used in drug allergyworkup.4,6-9 In general, the sensitivity of BAT is higher thanserum-specific IgE testing, but results can vary depending on thedifferent drug items under investigation.9 Drug preparation andoptimal dose for stimulation are the most crucial steps for BAT.Because there is no previously published protocol in the litera-ture, we performed the assay with serial concentrations of 5, 50,500, and 5000 mg/mL of diphenhydramine, and positive resultswere noted at 5 mg/mL, as well as 50 and 500 mg/mL.print&web4C=FPOFIGURE 2. Basophil activation test results: diphenhydramine Q5(top left); negative control without allergen (top right); loratadine (bottomright); and chlorphenamine (bottom left). A total of 69% of gated basophils (CCR3þ cells) showed upregulation of CD63 when stimulatedwith diphenhydramine (5 mg/mL), compared with only 0.73% in the negative control plot; 1.55% and 0.96% of gated basophils showedupregulation of CD63 when stimulated with loratadine (50 mg/mL) and chlorphenamine (4 mg/mL), respectively.SCO 5.5.0 DTD  JAIP1389_proof  14 November 2017  9:11 pm  ceJ ALLERGY CLIN IMMUNOL PRACTMONTH 20172 CLINICAL COMMUNICATIONS123124125126127128129130131132133134135136137138139140141142143144145146147148149150151152153154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184185186187188189190191192193194195196197198199200201202203204205206207208209210211212213214215216217218219220221222223224225226227228229230231232233234235236237238239240241242243244The chemical structure of antihistamines is quite differentbetween groups that are unlikely to share cross-reactivity. Indeed,including the previously reported cases, all 3 patients withdiphenhydramine allergy were successfully challenged with analternative antihistamine. In this case, cetirizine showed a posi-tive result in BAT. It would be interesting to test whether pos-itivity in BAT correlates with cetirizine intolerance. However,the patient declined cetirizine challenge after he toleratedloratadine.Although severe allergic reactions to a drug commonly usedfor allergy treatment are rare, one should remain vigilant of thispossibility. Skin testing and BATs showed some promise forconfirming the diagnosis of diphenhydramine allergy and iden-tifying an alternative, although more research will be needed tovalidate the methodology. Moreover, because neither skin testnor BAT is an absolute proof of an IgE-mediated process, onehas to interpret investigation findings along with clinical pre-sentation carefully.aDepartment of Pathology, Queen Mary Hospital, Hong KongQ1bDepartment of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine,The University of Hong Kong, Hong KongcDepartment of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong KongNo funding was received for this workQ2 .Conflicts of interest: The authors declare that they have no relevant conflicts ofinterest.Received for publication September 12, 2017; revised October 10, 2017; acceptedfor publication October 24, 2017.Available online --Corresponding author: Elaine Y.L. Au, MBBS, FHKAM (Medicine), FRCPA,FHKAM (Pathology), D (ABMLI), Division of Clinical Immunology, Departmentof Pathology, Room 511, Clinical Pathology Building, Queen Mary Hospital, 102Pokfulam Road, Hong Kong. E-mail: elaineauyl@gmail.com.2213-2198 2017 American Academy of Allergy, Asthma & Immunologyhttps://doi.org/10.1016/j.jaip.2017.10.032REFERENCES1. Mur Gimeno P, Alfaya Arias T, Iglesias Aranzazu M, Lombardero Vega M,Sastre B. Anaphylactic shock caused by antihistamines. J Investig Allergol ClinImmunol 2011;21:321-2.2. Barranco P, Lopez-Serrano MC, Moreno-Ancillo A. Anaphylactic reaction due todiphenhydramine. Allergy 1998;53:814.3. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as anindicator of mast-cell activation in systemic anaphylaxis and mastocytosis.N Engl J Med 1987;316:1622-6.4. Decuyper II, Mangodt EA, Van Gasse AL, Claesen K, Uyttebroek A, Faber M,et al. In vitro diagnosis of immediate drug hypersensitivity anno 2017: potentialsand limitations. Drugs R D 2017;17:265-78.5. Chisholm DG, Calder I, Peterson D, Powell M, Moult P. Intranasal chlorhexidineresulting in anaphylactic circulatory arrest. BMJ 1997;315:785.6. Sanz ML, Gamboa PM, Antepara I, Uasuf C, Vila L, Garcia-Aviles C, et al. Flowcytometric basophil activation test by detection of CD63 expression in patientswith immediate-type reactions to beta lactam antibiotics. Clin Exp Allergy 2002;32:277-86.7. Mangodt EA, Van Gasse AL, Bastiaensen A, Decuyper II, Uyttebroek A,Faber M, et al. Flow-assisted basophil activation tests in immediate drug hyper-sensitivity: two decades of Antwerp experience. Acta Clin Belg 2016;71:19-25.8. Ebo DG, Sainte-Laudy J, Bridts CH, Mertens CH, Hagendorens MM,Schuerwegh AJ, et al. Flow-assisted allergy diagnosis: current applications andfuture perspectives. Allergy 2006;61:1028-39.9. Hamilton RG, Franklin Adkinson N Jr. In vitro assays for the diagnosis of IgE-mediated disorders. J Allergy Clin Immunol 2004;114:213-25.SCO 5.5.0 DTD  JAIP1389_proof  14 November 2017  9:11 pm  ceJ ALLERGY CLIN IMMUNOL PRACTVOLUME -, NUMBER -CLINICAL COMMUNICATIONS 3245246247248249250251252253254255256257258259260261262263264265266267268269270271272273274275276277278279280281282283284285286287288289290291292293294295296297298299300301302303304305306307308309310311312

A patient with anaphylaxis to diphenhydramine without cross-reactivity to loratadine

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A patient with anaphylaxis to diphenhydramine without cross-reactivity to loratadine

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