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    What 2012 drug allergy What 2012 drug allergy Presentation Transcript

    • WHAT YOU SHOULD HAVE READ BUT….2012  drug allergyAttilio BonerUniversity ofVerona, Italy
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:123Background Proven IgE or T-cell mediateddrug hypersensitivity reactions (DHRs) seemless common in children compared with adults.However, this has never been proved by data.Objective To determine and compareproven DHR prevalence in children and adults.
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:123 (Drug Allergy and Hypersensitivity Database) cohort. % of patients belonged to the A/A group Children with proven drug 100 – hypersensitivity reactions (DHRs) 90 – compared with adults. 80 – 4 groups: 74.5% 70 – - index reaction and test during 60 – childhood (C/C); 50 – - index reaction at childhood and test at adulthood (C/A); 40 – - index reactions at childhood and 30 – adulthood and test at adulthood (CA/A); 20 – - index reaction and test at adulthood 10 – (A/A). 0 3275 patients.
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:123 Prevalence of positive tests.25 – p<0.0001 p=0.00320 – 22.1%15 – 15.2%10 – 16.5% 10.6% 10.6%05 –0 All C/C C/A CA/A A/A Tested classes
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:123 Prevalence of positive tests.25 – p<0.0001 p=0.00320 – 22.1%15 – 15.2%10 – 16.5% 10.6% 10.6%05 – Significant differences were found for0 maculopapular exanthemas only, and not for All C/C C/A CA/A A/A urticaria/angioedema and anaphylaxis. Tested classes
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:123 Prevalence of positive tests.25 – p<0.0001 p=0.00320 – 22.1%15 – 15.2%10 – 16.5% 10.6% 10.6%05 – The difference was mainly observed0 with β-lactams andC/A for NSAIDs. not CA/A A/A All C/C Tested classes
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:1231) When the first reaction occurred during childhood, the prevalence rate of positive tested class was similar whether the test was during childhood (10.6%) or adulthood (10.6%); thus, one could argue that drug allergy in childhood does not resolve with time.2) Finally, the rate of positive tested classes was higher when several reactions to the same drug class were observed (22%).
    • Results of drug hypersensitivity evaluations in a large group of children and adults. Rubio, Clin Exp Allergy 2012;42:1233) In children, exanthems during antibiotic courses can be difficult to assess. Maculopapular eruptions that are not pruritic occur frequently, as has been observed in 3–7% of children taking ampicillin in one study. They emerge during antibiotic treatment and rarely after. These exanthems are very unlikely to be allergic and their mechanisms are not well studied.4) Furthermore, the immune response that a patient develops for a viral infection can alter the immune response to an antibiotic, resulting in an allergic-like reaction specifically to that antibiotic, which is highly unlikely to recur. Caubet, JACI 2011;127:218; Pichichero, Pediatrics 2005;115:1048.
    • Clinicalmanifestation
    • Recurrence and outcomes of Steven-Jhonson Syndrome and Toxic Epidermal Necrolysis in children Finkelstein Pediatrics 2011;128:723 Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening conditions that represent different intensities along a spectrum of severe cutaneous adverse reactions to drug therapy. Both conditions are associated with significant morbidity and mortality (up to 5% in SJS and 20% in TEN in adults).
    • Recurrence and outcomes of Steven-Jhonson Syndrome and Toxic Epidermal Necrolysis in children Finkelstein Pediatrics 2011;128:723 SJS is defined as epidermal detachment of 10% body surface area; TEN as 30% of Body Surface Area; Cases with skin involvement between 10% and 30% are classified as SJS/TEN overlap.
    • Recurrence and outcomes of Steven-Jhonson Syndrome and Toxic Epidermal Necrolysis in children Finkelstein Pediatrics 2011;128:723 60 – % cases due to 53% 50 – 55 cases of 40 – SJS 29/55 (n=47), 30 – TEN (n=5) or 22% SJS/TEN 20 – overlap syndrome (n=3). 10 – 9% 12/55 5/55 0 Drugs Acute Mycoplasma Herpes simplex Pneumoniae virus infection.
    • Recurrence and outcomes of Steven-Jhonson Syndrome and Toxic Epidermal Necrolysis in children Finkelstein Pediatrics 2011;128:723 60 – % cases due to 53% 50 – 55 cases of drugs Antiepileptic SJSwere the most 40 – 29/55 common agents (n=47), 30 – (n=16), followed by TEN (n=5) or sulfonamide 20 – 22% SJS/TEN antibiotics (n=7) and overlap syndrome chemotherapy drugs – (n=3). 10 9% (n=2). 12/55 5/55 0 Drugs Acute Mycoplasma Herpes simplex Pneumoniae virus infection.
    • Recurrence and outcomes of Steven-Jhonson Syndrome and Toxic Epidermal Necrolysis in children Finkelstein Pediatrics 2011;128:723 10 children (18%) had recurrence of SJS up to 7 years after the index 60 – % cases due to episode,3 experienced multiple recurrences. 53% 50 – 55 cases of drugs Antiepileptic SJSwere the most 40 – 29/55 common agents (n=47), 30 – (n=16), followed by TEN (n=5) or sulfonamide 20 – 22% SJS/TEN antibiotics (n=7) and overlap syndrome chemotherapy drugs – (n=3). 10 9% (n=2). 12/55 5/55 0 Drugs Acute Mycoplasma Herpes simplex Pneumoniae virus infection.
    • Skin prick tests
    • Challenge
    • Diagnosis of drug hypersensitivity in children and adolescents: Discrepancy between physician-based assessment and results of testing Seitz Pediat Allergy Immunol 2011;22:405 Diagnosis of drug hypersensitivity is often based on history alone. To confirm or rule out drug Drug hypersensitivity was hypersensitivity, skin excluded in 40 patients testing, in vitro studies, and by tolerated oral challenge tests are challenge tests with the necessary. incriminated drug. 43 children and adolescents with a history of immediate or delayed hypersensitivity symptoms in temporal
    • Diagnosis of drug hypersensitivity in children and adolescents: Discrepancy between physician-based assessment and results of testing Seitz Pediat Allergy Immunol 2011;22:405 Diagnosis of drug Allergologic testing in hypersensitivity is often cases of suspected based on history alone. To drug hypersensitivity confirm or rule out drug Drug hypersensitivity was is of importance both hypersensitivity, skin testing, excluded in 40 patients in vitro studies, a correct to establish and challenge by tolerated oral tests diagnosis and to are necessary. challenge tests with the prevent unjustified 43 withholding of a drug children and adolescents incriminated drug. with a history of immediate or class of drugs. or delayed hypersensitivity symptoms in temporal relation to drug treatment.
    • basophilactivationtest (BAT)
    • The diagnostic value of basophil activation test inpatients with an immediate hypersensitivity reaction to radiocontrast media. Pinnobphun Ann Allergy Asthma Immunol 2011;106:387BackgroundNo available test diagnoses allergic reactions to radiocontrastmedia (RCM). The basophil activation test (BAT) has beenintroduced for the diagnosis of both IgE andnon-IgE–dependent mast cell degranulation, but its valueto diagnose immediate RCM reactions is still unknown.ObjectiveThis study aims to evaluate the diagnostic value of BAT inimmediate RCM hypersensitivity.
    • The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Pinnobphun Ann Allergy Asthma Immunol 2011;106:387 % activated basophil 26 patients with immediate 20 – allergic reactions to 19.2% radiocontrast media (RCM). 15 – p=0.001 43 healthy volunteers. 10 – Whole blood was incubated with the responsible RCM. 05 – % activated (CD63+/CCR3+) 3.73% 00 basophils were analyzed by Patients with a Normal flow cytometry. history of immediate controls RCM reactions
    • The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Pinnobphun Ann Allergy Asthma Immunol 2011;106:387 % activated basophil 26 patients with immediate 20 – allergic reactions to Our study demonstrated 19.2% radiocontrast media BAT the potential of (RCM). 15 – p=0.001 as a diagnostic tool 43 healthy volunteers. for an immediate RCM 10 – hypersensitivity, Whole blood was incubated particularly as a with the responsible RCM. 05 – confirmation test. % activated (CD63+/CCR3+) 3.73% 00 basophils were analyzed by Patients with a Normal flow cytometry. history of immediate controls RCM reactions
    • Cross-reactivity
    • Cow’s milk allergy as a cause of anaphylaxis to systemic corticosteroids Savvatianos, Siragakis, Allergy 2011;66:983 milk  Immediate IgE-mediated allergic reactions to corticosteroids are rather uncommon, whereas causative agents usually involve the native steroid molecule or a pharmaceutical excipient, in most cases as succinate ester bound to methyl-prednisolone or hydrocortisone;  We here report two cases of immediate reaction to methyl-prednisolone, attributed to milk allergen contamination.
    • Cow’s milk allergy as a cause of anaphylaxis to systemic corticosteroids Savvatianos, Siragakis, Allergy 2011;66:983 milk 1) A 9 yrs old boy with severe persistent cow’s milk allergy (CMA) was seen for asthma exacerbation; 2) The boy was administered 40 mg of methyl-prednisolone by intravenous injection; 3) Paradoxically, wheezing deteriorated; 4) The boy was given another course of the same medication on assumption of clinical under-responsiveness; 5) Within a few minutes the patient acutely collapsed.
    • Cow’s milk allergy as a cause of anaphylaxis to systemic corticosteroids Savvatianos, Siragakis, Allergy 2011;66:983 milk a) Another patient, a 7-year-old boy with severe CMA was similarly treated with intravenous administration of 40 mg methyl-prednisolone; b) The therapeutic intervention resulted in a full-blown anaphylactic reaction; c) Both children were evaluated within the next 6 months for assumed IgE-mediated reactivity to methyl-prednisolone.
    • Cow’s milk allergy as a cause of anaphylaxis to systemic corticosteroids Savvatianos, Siragakis, Allergy 2011;66:983 milk Skin testing results in both patients with acute reaction to lactose-containing succinylated methyl-prednisolone
    • Cow’s milk allergy as a cause of anaphylaxis to systemic corticosteroids Savvatianos, Siragakis, Allergy 2011;66:983 milk Sensitization to theresultssteroid molecule andwith acute Skin testing native in both patients to the succinate reaction to lactose-containing succinylated ester was ruled out by negative skin tests, while both patients exhibited positive skin response exclusively to lactose-containing preparations. methyl-prednisolone
    • Cow’s milk allergy as a cause of anaphylaxis to systemic corticosteroids Savvatianos, Siragakis, Allergy 2011;66:983 milk Subsequent drug provocation tests were negative in both patients Skin a full therapeuticboth patients with acute reaction for testing results in dose (125 mg) of non-lactose to lactose-containing succinylated methyl-prednisolone containing, otherwise identical to the one that elicited the reaction, succinylated methyl-prednisolone preparation (Solu-Medrol 125 mg, Pfizer)
    • Antibioticsensitivity
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166• Like penicillins, cephalosporins can cause nonimmediate reactions(occurring >1 hour and within 7 days after the last administration).• The main nonimmediate reactions aremaculopapular or morbilliform rashes anddelayed-appearing urticaria/angioedema.• There are studies suggesting that eitherdelayed-reading intradermal tests or patch tests,or both can be an effective way of diagnosing a delayedhypersensitivity.
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166• In the present study*, according to the diagnostic protocoldevised by the European Network for Drug Allergy, subjects withhistories of nonimmediate reactions to cephalosporins wereassessed by using both patch tests and delayed-reading (after >48hours) skin tests and, in case of negative responses, by provocationtests in an attempt to clarify the pathogenic mechanism involved.• Skin prick and intradermal tests using penicilloyl-polylysine, minordeterminant mixture, and benzylpenicillin, as previously described.In the second evaluation 2 days later, we used ampicillin andamoxicillin at concentrations of 1 and 20 mg/mL, as well as thesuspect cephalosporins at a concentration of 2 mg/mL and any othersuspect penicillins at concentrations of 1 and 20 mg/mL. *Romano A, Allergy 2004;39:1153-60
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166 Positive controls for skin prick and intradermal tests wereperformed with histamine (at 10 and 1 mg/mL, respectively). As anegative control for skin prick and intradermal tests, normal salinewas used. We used the suspect aminocephalosporins(cephalexin, cefaclor, and cefatrizine) at concentrations of 2 and 20mg/mL. Readings of late reactions to intradermal tests were done after48 and 72 hours; any infiltrated erythema with a diameter largerthan 5 mm was considered a positive reaction. Patch tests with benzylpenicillin, ampicillin, and amoxicillin, as wellas with suspect cephalosporins and any other suspect penicillins(5% in petrolatum), as previously described. Readings were made 15
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166Subjects with negative results in all of the above tests or whodisplayed a doubtful response underwent challenges with thesuspect cephalosporin concerned: cephalexin (1 g), cefaclor(500mg), cefixime (400 mg), ceftibuten (400 mg), cefatrizine (500mg), cefprozil (500 mg), cefpodoxime (200 mg), and cefuroximeaxetil (500 mg) administered orally orceftriaxone, ceftazidime, cefotaxime, cefamandole, cefazolin, cefonicid, and cefepime (1 g) administered intramuscularly.We administered an initial dose of one hundredth of thetherapeutic one.In patients with negative results, 1 week later, we administered adose of one tenth and, if the result was again negative, a full doseafter another week, as previously described.
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166Subjects with negative results in all of the above tests or whodisplayed a doubtful response underwent challenges with thesuspect cephalosporin concerned: cephalexin (1 g), cefaclor(500mg), cefixime (400 mg), ceftibuten (400 mg), cefatrizine (500 Each patient was carefully monitored duringmg), cefprozil (500 mg), cefpodoxime (200 mg), and cefuroximeaxetil challenges until administered (500 mg) 4 hours after the orally orceftriaxone, administration of thecefamandole, cefazolin, cefon ceftazidime, cefotaxime, dose; completeicid, and equipment g) administered intramuscularly. cefepime (1 for cardiopulmonary resuscitationWe administered was initial dose of one hundredth of the an immediately available.therapeutic one.In patients with negative results, 1 week later, we administered adose of one tenth and, if the result was again negative, a full doseafter another week, as previously described.
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166 105 subjects with 3 subjects showed both positive histories of patch test and positive delayed nonimmediate intradermal test results to the reactions to culprit cephalosporins, cephalosporins whereas Patients had a total 2 presented only a delayed of 144 reactive positive intradermal test result to episodes these cephalosporins
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166 105 subjects with 1 patient experienced a histories of maculopapular rash with diffuse nonimmediate angioedema during cephalexin reactions to therapy, had negative patch test cephalosporins results, and displayed a doubtful response (an infiltrated erythema Patients had a total with a diameter of 3 mm) to the of 144 reactive delayed-reading intradermal test episodes with cephalexin at 2 mg/mL.
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166 Another patient a local reaction (infiltrated 105 subjects witha diameter erythema with 1 patient experienced a histories oflasting 4 days) 3 of 11 cm maculopapular rash with diffuse nonimmediate the second hours after angioedema during cephalexin reactions to intramuscular injection of therapy, had negative patch test cephalosporins cefodizime. She presented results, and displayed a doubtful response (an infiltrated erythema Patients had aresponses to immediate total with a diameter of 3 mm) to the intradermal tests of 144 reactive with cefodizime, as well delayed-reading intradermal test episodes with cephalexin at 2 mg/mL. as patch test
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166• In the present study most delayed skin manifestations in temporalcorrelation with cephalosporin treatments did not show asensitization on intradermal skin tests nor could they be reproducedin a provocation test. Thus allergy alone does not seem to be asufficient explanation for them.• It is interesting to note that the mean time for resolution ofgeneralized skin reactions was significantly longer in the patientswith sensitization than in the patients without sensitization (13.6 vs3.31 days).
    • Diagnosing nonimmediate reactions to cephalosporins Romano, JACI 2012;129:1166• Patch tests and delayed-reading intradermal tests are useful toolsin evaluating nonimmediate reactions to ß-lactams, particularlymaculopapular rashes.• Concentration of 20 mg/mL used for intradermal tests withaminocephalosporins might reduce the number of subjects withfalse-negative results at the concentration of 2 mg/mL.• In conclusion, intradermal tests are useful tools in identifyingthe cephalosporins responsible for nonimmediate reactions.However, considering the results of the present study, patchtesting is not indicated in subjects with mild nonimmediatereactions to cephalosporins, such as maculopapular and urticarialrashes.
    • Nonimmediate drug allergy: diagnostic benefit of skin testing and practical approach. Editorial Schnyder, JACI 2012;129:1170• There is currently no established gold standard for the diagnosisof a delayed-type allergy.• Romano et al* used weekly challenges with first one hundredth andthen one tenth and finally one single therapeutic daily dose.• However, it is well documented that some nonimmediate reactionsappear only after a treatment of several days at full therapeuticdosage.•Furthermore, cofactors, such as concomitant viral infections, areconsidered important, and these are normally not present duringchallenge tests.•Thus only a positive test result is conclusive, and even challengetests are not an unequivocal gold standard. *Romano A, J Allergy Clin Immunol 2012;129:1166
    • Nonimmediate drug allergy: diagnostic benefit of skin testing and practical approach. Editorial Schnyder, JACI 2012;129:1170• Sensitivity requires not only the detection of patients with drughypersensitivity in spite of negative skin test results (false-negativeresults) but also the number of patients with positive skin testresults who really have drug hypersensitivity (true-positive results).• The negative predictive value (or negative posttest probability)stands for the probability that a patient with a negative test resulthas no allergy.• However, the predictive value is not only dependent on testaccuracy but also on the pretest probability. Pretest probabilitystands for the probability that a patient has an allergy beforetesting. It is influenced inter alia by patient selection.
    • Nonimmediate drug allergy: diagnostic benefit of skin testing and practical approach. Editorial Schnyder, JACI 2012;129:1170• Sensitivity requires not only the detection of patients with drughypersensitivity in spite of negative skin test results (false-negativeresults) but also the number of patients with positive skin testresults who really have drug hypersensitivity (true-positive results).• The negative predictive value (or negative posttest probability)stands for the probability that a patient with a negative test resulthas no allergy.• However, the predictive value is not only dependent on test A low negative predictive value might beaccuracy but also on the pretest probability. Pretest probabilitystands for the probability that alow pretest an allergy before entirely due to a very patient has probabilitytesting. It is influenced inter alia by patient selection.
    • Nonimmediate drug allergy: diagnostic benefit of skin testing and practical approach. Editorial Schnyder, JACI 2012;129:1170Avoiding further use of the incriminated drug without performing achallenge test might be a pragmatic and widely used approach,especially if the incriminated drug is easy to replace.When the incriminated drug (or drug class) is difficult to replaceand there is an urgent need for this treatment, a stepwise (graded)challenge might be an option, hoping to eliminate those reactionsthat are due to strong sensitizations.Altogether, the situation is not yet satisfying, and improvements inin vivo and in vitro evaluations of these reactions are urgentlyneeded.
    • Steroids sensitivity
    • Non-steroidalanti-inflammatorydrugs (NSAIDs)
    • Response to a selective COX-2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti-inflammatory drugs. Doña, Allergy 2011;66:1428 % patients intolerant to etoricoxib 252 patients with urticaria 30 – and/or angioedema caused by hypersensitivity owing to cross-intolerance to 25% 20 – NSAIDs; (A) patients with intolerance to paracetamol; 10 – (B) patients with tolerance to paracetamol. 6% 0 GROUP A GROUP B
    • Response to a selective COX-2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti-inflammatory drugs. Doña, Allergy 2011;66:1428 % patients intolerant to etoricoxib 252 Selective with urticaria patients COX-2 30 – and/or angioedemabe inhibitors may caused by hypersensitivity owing unsafe in subjects to with urticaria and/or cross-intolerance to 25% 20 – angioedema caused by NSAIDs; hypersensitivity (A) patientsto NSAIDs reactions with intolerance to paracetamol; 10 – with cross-intolerance to paracetamol. (B) patients with tolerance to paracetamol. 6% 0 GROUP A GROUP B
    • Multiple drug sensitivity
    • Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management Macy, Ann Allergy Asthma Immunol 2012;108:88 Multiple drug % members with at least 1 allergy intolerance syndrome (MDIS) 30 – defined by 3 or more unrelated drug class “allergies”. 20 – 20.1% 2,375,424 health 10 – plan members. Drug “allergy”. 0
    • Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management Macy, Ann Allergy Asthma Immunol 2012;108:88 Multiple drug % members with multiple drug intolerance intolerance syndrome syndrome (MDIS) defined by 3 or more 4 – unrelated drug class 3 – “allergies”. 2 – 2,375,424 health plan members. 2.1% 1 – Drug “allergy”. 00
    • Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management Macy, Ann Allergy Asthma Immunol 2012;108:88 The MDIS Multiple drug % members with multiple drug intolerance were cases intolerance syndrome syndrome (MDIS) significantly 4 – older, 62.4or more defined by 3 years; unrelated drug class heavier, BMI 29.3; “allergies”. 3 – and likely to be 2 – female, 2,375,424 health 2.1% 84.9% plan members. 1 – Drug “allergy”. 00
    • Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management Macy, Ann Allergy Asthma Immunol 2012;108:88 •Multiple drug intolerance syndrome is in part iatrogenic. It is associated with overweight elderly women who have high rates of health care and medication usage. Urticarial syndromes only explain a small fraction of MDIS cases. •Multiple drug intolerance syndrome is associated with anxiety, but not predominately with immunoglobulin E (IgE)-mediated allergy or life-threatening illness. •Multiple drug intolerance syndrome can be managed by medication avoidance and judicious rechallenge.
    • Takehome
    • Takehome