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Epidemiology and risk factors for drug allergyBernard Y-H. Thong & Teck-Choon Tan

Department of Rheumatology,Allergy and Immunology, Tan Tock Seng Hospital, Singapore

CorrespondenceDr Bernard Yu-Hor Thong MBBS MRCP(UK),Department of Rheumatology,Allergy and Immunology, Tan Tock SengHospital, 11 Jalan Tan Tock Seng,308433Singapore. Tel.:+ 65 6357 7822

Fax: + 65 6357 2686E-mail: bernard_thong@ttsh.com.sg----------------------------------------------------------------------

Financial support for study: NoneInstitutional afliation and address foreach: Same as for corresponding authorabove----------------------------------------------------------------------

Keywordsadverse drug reaction, anaphylaxis,mortality, Stevens Johnson syndrome,toxic epidermal necrolysis----------------------------------------------------------------------

Received

09 December 2009Accepted19 July 2010

Accepted Article16 August 2010

The aim of this review was to describe the current evidence-based knowledge of the epidemiology,prevalence, incidence, risk factorsand genetic associations of drug allergy. Articles published between 1966 and 2010 were identied in MEDLINE using the key wordsadult,adverse drug reaction reporting systems,age factors,anaphylactoid, anaphylaxis, anaesthetics, antibiotics, child,drug allergy, drugeruptions,ethnic groups, hypersensitivity,neuromuscular depolarizing agents,neuromuscular nondepolarizing agents,sex factors, Stevens Johnson syndrome and toxic epidermal necrolysis . Additional studies were identied from article reference lists. Relevant,peer-reviewedoriginal research articles, case series and reviews were considered for review. Current epidemiological studies on adverse drug reactions(ADRs) have used different denitions for ADR-related terminology, often do not differentiate immunologically andnon-immunologically mediated drug hypersensitivity, study different study populations (different ethnicities, inpatients or outpatients,adults or children), utilize different methodologies (spontaneous vs. non-spontaneous reporting,cohort vs. case-control studies),different methods of assessing drug imputability and different methods of data analyses. Potentially life-threatening severe cutaneousadverse reactions (SCAR) are associated with a high risk of morbidity and mortality.HLA associations for SCAR associated withallopurinol, carbamazepine and abacavir have been reported with the potential for clinical use in screening prior to prescription.Identication of risk factors for drug allergy and appropriate genetic screening of at-risk ethnic groups may improve the outcomes of drug-specic SCAR. Research and collaboration are necessary for the generation of clinically-relevant, translationalpharmacoepidemiological and pharmacogenomic knowledge,and success of health outcomes research and policies on drug allergies.

Introduction

Adverse drug reactions (ADRs) which account for 3 to 6%of all hospital admissions and occur in 10 to 15% of hospi-talized patients, result in morbidity, prolonged hospitaliza-tion and risk of mortality. An ADR is dened by the WorldHealth Organization (WHO) as a response to a medicinewhich is noxious and unintended, and which occurs atdoses normally used in man [1]. Type A ADRs which arepredictable anddose dependent,comprise up to 80%of allADR, e.g.pharmacological side-effects like gastrointestinalbleeding following treatment with non-steroidal anti-inammatory drugs (NSAID). Type B ADRs are unpredict-able, dose independent and comprise 1520% of all ADRs. These may include immunologically mediated drug hyper-sensitivity (drug allergy) or non-immune mediated/ idio-

syncratic reactions [2].ADRs should be differentiated fromadverse drug events (ADEs) [3] as ADEs extend beyondADRs to include harm related to medication errors anddrug/food interactions.

The World Allergy Organization (WAO) in 2003 deneddrug allergy as an immunologically mediated drug hyper-sensitivity reaction.The mechanismof drug allergy may beeither IgE or non-IgE mediated, with T-cell mediated reac-tions largely represented in the latter [4].

Severe cutaneous adverse reactions (SCAR) includeStevens Johnson syndrome (SJS), toxic epidermal necroly-sis (TEN) [59], drug-induced hypersensitivity syndrome(DiHS) or drug rash with eosinophilia and systemic symp-toms (DRESS) [10].Acute generalized exanthematous pus-tulosis (AGEP) [11, 12] has recently been added to the listcomprising SCAR. Anaphylaxis is a severe, life-threatening,

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generalized or systemic hypersensitivity reaction [3,13] forwhich drugs are a common cause [14].

The true incidence of drug allergy is not known. Themajority of currently available epidemiologic studies havebeen on ADRs rather than drug allergy specically [15].Most studies focus only on select population groups, e.g.inpatients or outpatients at the emergency departments,general practice clinics or specialist allergy centres; chil-dren or adults; cutaneous or severe cutaneous adversereactions (SCAR) [16], or all causes of anaphylaxis alone.Diagnosis of ADRs and drug imputability in the majority of these studies used the WHO ADR terms. Denitions of dif-ferent types of SCAR were different in the earlier studiesfrom the 1980s and early 1990s, compared with laterstudies. In addition, the majority of studies that addresseddrug allergy per se relied heavily on a clinical history of thetemporal relationship between drug use and diseaseonset, and suggestive clinical features for the diagnosis of drugallergy,with few studies/datasets [17] usingstandard-

ized clinical questionnaires [18] and validated in vivo or invitro tests to conrm the diagnosis of drug allergy [1921].

Studies on hospital-basedinpatient populations

To date, there have only been a few studies that haveattempted to evaluate the prevalence and incidence of drug allergy in hospital-based populations. Most studies(summarized in Table 1), including the Boston Collabora-tive Drug Surveillance Programme, only monitored cuta-neous reactions [2227]. Others reported on only singleclasses of drugs. The incidence and prevalence of drugallergy were either unknown or estimated in most studies.Case-verication in most studies was based on chartreview and not formal patient examination during theepisode of reaction, although case-verication was con-ducted by dermatologists in two reports [25, 26]. Thereported cases were diagnosed based on probability,without rm evidence of drug allergy being the mainmechanismusing theWAO denitionof allergy and/orvali-dated allergological tests.

To date, only two prospective studies on cutaneousADRs have attempted to study the incidence or prevalence

of cutaneous ADRs or cutaneous drug allergy. In France in2003, a 6 month prospective study on the incidence of cutaneous allergic reactions from systemic drugs in aFrench hospital was carried out [29]. Each reported casewas physically examined by a dermatologist and reviewedwith a pharmacologist. Among 48 inpatients with cutane-ousdrug allergy, the prevalence of cutaneous allergic reac-tions was 3.6 per 1000 hospitalized patients.Among thesepatients, 57% had exanthematous reactions, 8% erythro-derma and 2% SJS/TEN.Beta-lactam antibioticswere impli-cated in 21% of cutaneous allergic reactions studied.Themost frequently associated disorders were human immu-

nodeciency virus (HIV) infection (19%), connective tissuedisease (10%) and viral or autoimmune hepatitis (12%). Athird of the cases had a previous history of drug allergy.

In Mexico in 2006,a 10 month prospective cohort studyof all hospitalized patients with cutaneous adverse drugreactions (CADR) [30] showed a prevalence of 35/4765(0.7% or 7 per 1000 hospitalized patients), and mortalityrate of 16.6% amongsixpatients with SCAR.Risk factors forCADR included systemic lupus erythematosus (SLE)(14.6%), human immunodeciency (HIV) infection (7.3%)and non-Hodgkins lymphoma (7.3%).

To our knowledge, two prospective studies from Sin-gapore and Korea published are the only to date thatspecically described both cutaneous and systemic mani-festation of drug allergy, where all cases were allergist-veried, and reporting was electronic.

In Singapore in 2002,an inpatient network-based elec-tronic drug allergy notication systemin a general hospital[28] showed that of 366 cases reported from a total of

90 910 admissions during the study period, 210 cases wereveried by an allergist to have drug allergy. Cutaneouseruptions were the most common clinical presentation(95.7%), systemic manifestations occurred in 30% andserious adverse reactions such as SJS/TEN and generalizedexfoliative dermatitis occurred in 11 (5.2%) patients. Themost common (75%) causative drugs among those withdrugallergieswereantimicrobialsand anti-epileptic drugs. The estimated incidence of drug allergy was 4.2 per 1000hospitalizations (95% condence interval [CI] 2.93, 5.46),and the estimated mortality attributable to drug allergywas 0.09 per 1000 hospitalizations (95% CI 0.06, 0.12).

In Korea, a mandatory reporting system forimmunologically-mediated drug hypersensitivity reac-tions monitored by an inpatient team of allergists in a uni-versity hospital was described [31]. There were 2682reported cases of ADE (4.84%) among 55 432 admissions.Following allergists review, 532 were identied as signi-cant drug hypersensitivity reactions, of which 100 werenew events.There were 70% of new drug hypersensitivityreactions presenting with cutaneous manifestations, of which 2% developed exfoliative dermatitis and 1% devel-oped SJS/TEN.Anaphylaxis occurred in 11% of allnew drughypersensitivity reactions.The most common culprit drugsamong new drug hypersensitivity reactions were antibiot-

ics (32%), radiocontrast media (26%) and antineoplasticdrugs (17%).The estimated incidence of drug hypersensi-tivity reactions was 0.18 per 100 hospital admissions.

Studies in children and adolescents

The overall incidence of ADRs, based on prospectivestudies in children and adolescents,was 10.9% in hospital-ized children,1.5% in outpatient children, and rate of hos-pital admission due to ADRs 2.1% [32, 33]. Community-based studies [34] have shown that there is generally an

Epidemiology and risk factors for drug allergy

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overestimation of the rates of ADRs/drug allergy amongchildren and adolescents, with parental self-reporting of ADRs of 2.510.2% compared with conrmed drug allergyof 6% following allergological tests.The majority of paedi-atric studies on ADRs looked at overall prevalence or inci-dence of ADRs without categorizing these into allergic andnon-allergic drughypersensitivity.There has onlybeenone10 year retrospective cohort study of paediatric patientswho experienced an ADR (pharmacist reviewed) at acommunity-based, tertiary care,childrens teaching hospi-tal in the United States [35] which showed that 51% weredeemed to be allergic/idiosyncratic in nature, and 24%of all ADRs were attributed to drug hypersensitivityreactions/SJS predominantly from phenytoin and carbam-azepine.Antibiotics were the most common cause of ADRs(33%), followed by narcotic analgesics (12%) and anticon-vulsants (11%). There were two deaths, neither of whichwas denitively due to drug allergy. Apart from this study,there are no other studies in children or adolescents

looking specically at the types and causes of paediatricdrug allergy.

Studies from outpatients

Most of the studies from allergy centres and clinics involveeither inpatients alone, outpatients or both and involveadults and/or children.These studies may not be reectiveof the true incidence/prevalence of drug allergy in thecommunity in view of referral bias. It is likely that only themore severe and/or complex cases would be referred to anallergy clinic. The comparator in these studies was oftenthe number of all cases referred to the allergy clinic/centreduring the study period.

The Spanish Alergolgica 2005 study was a descriptive,cross sectional, prospective observational epidemiologicstudy in Spain, involving 332 allergists across the country.Gamboa[36] reported 4991 adult patients consulting aller-gology services for the rst time. There were 732 patientconsultations for possible drug allergies. Among these,26.6% of cases were diagnosed to have drug allergies, 75%reported only cutaneous symptoms, 0.75% SJS and 10%anaphylaxis. Antibiotic allergy accounted for 47% of drugallergies, of which 73% were due to amoxicillin, 29% were

caused by NSAIDs and 10% by pyrazolones. The mostcommon diagnostic tests used were skin tests and oraldrug provocation tests. Ibanez & Garde [37] analysed thedata from patients younger than 14 years from the Aler-golgica 2005 study. A sub-group analysis of 69 patients(7.5% of total patient consults) younger than 14 years whoconsulted the allergology service for the rst time for sus-pected drug allergy, showed a 3% prevalence of drughypersensitivity with the majority of cases attributed toantibiotics and NSAIDs.

England et al . [38] reviewed a total of 1284 inpatientallergy/immunology consults from 1987 to 2001 from the

UnitedStates,where 36%of consults were forevaluationof ADRs. Dietrich et al . [39] followed up with a review of allergy/immunology consults in the same US centre fromJanuary to December 2006.A total of 1412 outpatient pae-diatric and adult consults were requested of which 4.7%were for suspected drug allergy.

Studies from emergencydepartment (ED) attendances

Emergency room attendances are often used to study theincidence and prevalence of severe types of allergic reac-tions requiring urgent attention, in particular anaphylacticreactions. In the United States National Electronic InjurySurveillance System: Co-operative Adverse Drug EventsSurveillance System (NEISS-CADES) [40], the estimatedincidence for ADRs between 200405 was 2.4 ED visits per1000 population (95% CI 1.7, 3.0 per 1000 persons). Drug

allergies comprised 33.5% of all ADR-related ED visits,with11.3% requiring hospitalization. Cohen et al . [41] subse-quently conducted a prospective cohort study on a paedi-atric population using data from the NEISS-CADES projectwhere the annual estimated population incidence forADRs in children 18 years old was 2 per 1000 persons(95% CI 1.5,2.6 per 1000 persons).Of these cases,35% wereattributed to drug allergy (based on historyalone) with themost common putative drug class being antimicrobialagents (60.8%).No deaths were reported.

The majority of the other studies on the prevalence of drug allergy in emergency departments were retrospec-tive. In Italy, a retrospective study over a 6 year period onthe incidence of allergic diseases in a Novaran hospitalemergency department showed that out of 6107 of 165 120 visit records for suspected allergic reactions, drugallergy was reported in 7.5% of adult patients and 6.1% of paediatric patients [42]. The other studies on ED atten-dances among adults and children, predominantly on allcauses of anaphylaxis, will be discussed in a later section.

Studies from pharmacovigilancedatabases

Pharmacovigilance databases may take the form of ADRscollated fromspontaneous reporting or intensive monitor-ing of prescriptions via electronic prescribing or dispens-ing systems,each with its inherent limitations [43].Severalattempts have been made to obtain epidemiological dataon drug allergies from such databases of ADRs.

From a retrospective case control study using an ADRdatabase of the Italian Interregional Group of Pharma-covigilance (GIF)which collectedspontaneous ADRreportsfrom seven regions in Italy, Salvo et al . investigated drugallergy associated with oral drug usage from the period1988 to 2006 [44].Drugallergy wasdenedas anaphylactic




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shock or anaphylactoid reaction; cutaneous or systemicreactions (involving at least two organs/systems involve-ment),with time to onset (not dened) suggesting an aller-gic reaction. Each case was reviewed by an ad hoc panelcomprising toxicologists, clinical pharmacologists andpharmacists.A totalof 27 175ADRs were analysed,of which3143 (11.6%) were deemed to be due to drug allergy. Thecausative drug classes with signicant reported odds ratio(ROR) were antibiotics (2.92, 95% CI 2.71,3.15) and NSAIDs(1.65, 95% CI 1.51, 1.81). The study showed that amongantibiotics, cinoxacin (6.88, 95% CI 4.19, 11.29) and moxi-oxacin (4.20, 95% CI 3.19, 5.55) were related with thehighest ROR values, while propionic acid derivatives (2.75,95% CI 2.30, 3.28) and, in particular, ibuprofen (4.2, 95% CI3.13,5.63) showed the highest ROR values among NSAIDs.

The French Pharmacovigilance database was estab-lished in 1985 to register spontaneous reporting of ADRs.By law, every prescriber in France must report serious orunexpectedADRs to their French Regional Pharmacovigi-

lance Centre. A recent study on allergic drug reactions tolocal anaesthetic agents using the French Pharmacovigi-lance database and the GERAP (Groupe dEtudes desReactions Anaphylactodes Peranesthesiques: studygroup of peranaesthetic anaphylactoid reactions) data-base over a 12 year period (19952006), identied 16reports (seven from the Pharmacovigilance database andnine from the GERAP database) [45]. Local anaestheticallergic reactions occurred mostly in young females(female : male sex ratio 14:2). An immediate-type allergicreaction was encountered in 11/16 cases. Lidocaine wasfound to be the local anaesthetic most often involved (11/16). Skin prick, intradermal and drug provocation testswere used to conrm the diagnosis. Cross-reactivitybetween the different amide type local anaesthetics wasfound in six cases (lidocaine-mepivacaine in all cases).

Collaborations similar to this and the Galenda project[17], comprising allergologists, toxicologists, pharmacolo-gists and pharmacists working through such pharma-covigilance databases, are very useful sources of information in dening the true incidence,prevalence andpatterns of allergic drug hypersensitivity.

Serious drug allergies

Drug-induced anaphylaxis The epidemiologyof all causes of anaphylaxis in the UnitedStates, United Kingdom, Europe, Australia, New Zealand,Korea, Singapore and Thailand has been described inseveral studies involving both adults and children [4668]and are summarized in Table 2.The population prevalenceor incidence of anaphylaxis has been difcult to quantifybecause of a lack of consensus on the denition of anaphy-laxis, analysis of different sample populations, and the useof varying methodologies for data collection. The esti-mated incidence or prevalence of anaphylaxis in western

countries is in the range of 850 per 100 000 person-years,with a lifetime prevalence of 0.052.0% [69]. However, thetrue incidence/prevalence and mortality due to drug-induced anaphylaxis is unknown. In these studies, drugs(penicillin, anaesthetic agents given during the peri-operative period) were a common cause of IgE-mediatedallergic anaphylaxis.NSAIDs and radiocontrast media werecommon causes of non-allergic anaphylaxis.Drug-inducedanaphylaxis was highest in the 5584 year age group (3.8/100 000 population) with a predominance of males in theless than 15 year age group in Australia [68], and were themost common cause of fatalities in the United Kingdom[52], New Zealand [63] and Australia [55].

Among all causes of drug-induced anaphylaxis,penicil-lin in the 1960s and 1970s was purported to be the mostcommon cause of drug-induced anaphylaxis in the UnitedStates [70, 71]. Subsequently there has been little epide-miological evidence to show this to be true [72]. Drugsused during the peri-operative period are another impor-

tant cause of anaphylaxis in several studies worldwide.Theestimated incidence of all immune- and non immune-mediated immediate anaesthetic hypersensitivity reac-tions was 1 in 5000 to1 in 13 000 in Australia [73],1 in 4600in France [74], 1 in 5000 in Thailand [75], 1 in 1250 to 1 in5000 in New Zealand and 1 in 3500 in England [76]. Theestimated incidence of immune-mediated reactions was 1in 10 000 to 1 in 20 000 in Australia [73], 1 in 13 000 inFrance [74], 1 in 10 263 in Spain, 1 in 5500 in Thailand [75]and 1 in 1700 to 1 in 20 000 in Norway [77]. The mostcommon causes were neuromuscular blocking agents(NMBA) and antibiotics [78].

Severe cutaneous adverse reactions (SCAR) The reported incidence for SJS/TEN is between 1.4 and 6per million person-years [7981]. The estimated mortalityfrom SJS is 10%, SJS/TEN overlap 30% and TEN almost 50%[9].Various cohortson SCAR have been described since the1990s [7993] from Europe, United States, South Asia andthe Asia Pacic (Table 3). Most of these described cohortsincluded both adult and paediatric inpatients, with only alimited number describing organ and systemic manifesta-tions of SCAR. Antibiotics and anticonvulsants were theclasses of drugs most commonly implicated in most series.

Large multicentre collaborative European SCAR regis-

tries include the population-based registry of SCAR inGermany [86],the prospectively-ascertained studyof com-munity cases in the SCAR and case-control EuroSCARstudies [92], and the RegisSCAR study comprising bothcommunity- and hospital-onset SCAR with clear deni-tions of SCAR comprising SJS,TEN and overlap syndromes[5]. These studies have shown that the time to onset of SCAR was within 4 weeks, although this varies among dif-ferent drugs; certain drugs were high risk for SCAR (e.g.cotrimoxazole, allopurinol, carbamazepine, phenytoin,phenobarbital and oxicam-NSAIDs), and no signicant risk persisted beyond 8 weeks of use [92]. AGEP was recently

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T a b l e 2

S u m m a r y o f e p i d e m i o l o g i c a l s t u d i e s o n a n a p h y l a x i s i n c l u d i n g d r u g s a s a c a u s e

Y e a r

A u t h o r

T y p e o f s t u

d y

P e r i o d o f

s t u

d y

C o u n t r y

N u m b e r o f

c a s e s

A g e ( r a n g e )

S e x

F :

M

C a u s e s

O u t c o m e m e a s u r e s

1 9 9 4

Y o c u m e t a

l . [ 4 7 ]

R e t r o s p e c t i v e a l l e r g y

c l i n i c

3 y e a r s 6

m o n t h s

U n i t e d S t a t e s

1 7 9

M e a n 3 6 y e a r s

1 . 9 : 1

F o o d ( 3 3 % )

I d i o p a t h i c ( 1 9 % )

I n s e c t v e n o m ( 1 4 % )

D r u g s ( 1 3 % )

E x e r c i s e ( 7 % )

N i l

1 9 9 5

K e m p e t a

l . [ 4 8 ]


c l i n i c

1 4 y e a r s


2 6 6

P a e d i a t r i c a n d a d u l t

M e a n 3 8 y e a r s ( 1 2 7 5 )

1 . 4 : 1

I d i o p a t h i c ( 3 7 % )

F o o d ( 3 4 % ) :

D r u g s ( 2 0 % ) : N S A I D

E x e r c i s e ( 7 % )

L a t e x ( 0

. 8 % )

N i l

1 9 9 6

P u m p h r e y e t a

l . [ 4 9 ]


c l i n i c

U n k n o w n

U n i t e d K i n g d o m

1 7 2


5 m o n t h s

6 9 y e a r s

1 : 1

P e a n u t ( 4 2 )

T r e e n u t ( 2 3 )

O t h e r f o o d ( 2 0 )

F D E I A ( 5 )

V e n o m ( 6 b e e , 2 2 w a s p )

N M R B ( 7 )

N R L ( 6 )

I d i o p a t h i c ( 2 0 )

N i l

1 9 9 8

I n t e r n a t i o n a l

C o l l a b o r a t i v e S t u d y o f

S e v e r e A n a p h y l a x i s

[ 5 0 ]

P r o s p e c t i v e ,

m u l t i c e n t r e

3 y e a r s

H u n g a r y , S

p a i n , I n d i a ,

S w e d e n

1 2 3

U n k n o w n

U n k n o w n

U n k n o w n

M o r t a l i t y 2 %

1 9 9 8

N o v e m b r e e t a

l . [ 5 1 ]

R e t r o s p e c t i v e

p a e d i a t r i c a l l e r g y

c l i n i c

2 y e a r s

I t a l y

7 6

U n k n o w n

0 . 5 : 1

F o o d ( 5 7 % )

V e n o m ( 1 2 % )

D r u g s ( 1 1 % )

E x e r c i s e ( 9 % )

I d i o p a t h i c ( 6 % )

V a c c i n e s ( 2 % )

A d d i t i v e s ( 1 % )

S p e c i c i m m u n o t h e r a p y ( 1 % )

N R L ( 1 % )

N i l

2 0 0 0

P u m p h r e y & R o b e r t s [ 5 2 ]

R e t r o s p e c t i v e f a t a l

a n a p h y l a x i s

r e g i s t r y

8 y e a r s

U n i t e d K i n g d o m

5 6


M e d i a n 5 2 y e a r s ( 7 8 5 )

1 . 5 : 1

D r u g s ( 3 8 % )

V e n o m ( 3 4 % )

F o o d ( 2 8 % )

N i l

2 0 0 1

P a s t o r e l l o e t a

l . [ 5 3 ]


e m

e r g e n c y r o o m

a t t e n d a n c e s

2 y e a r s

I t a l y

1 4 0

U n k n o w n

F e m a l e

F o o d ( 3 9 % )

D r u g s ( 3 6 % )

I d i o p a t h i c ( 2 1 % )

V e n o m ( 2 % )

O t h e r s ( 2 % )

I n c i d e n c e 4 %

2 0 0 1

C i a n f e r o n i e t a

l . [ 5 4 ]


i n p a t i e n t

h o s p i t a l i z a t i o n s

1 1 y e a r s

I t a l y

1 0 7

A d u l t

M e a n 4 8

1 8 y e a r s

0 . 8 : 1

D r u g s ( 4 9 % )

V e n o m ( 2 9 % )

F o o d ( 8 % )

S p e c i c i m m u n o t h e r a p y ( 6 % )

I d i o p a t h i c ( 6 % )

E x e r c i s e ( 2 % )

N i l




7/17


8/17

2 0 0 6

L o w & S t a b l e s [ 6 3 ]

R e v i e w o f c o r o n i a l a u t o p s i e s 2 0 y e a r s

N e w Z e a l a n d

1 8

A d u l t

M e a n 5 2 y e a r s ( 3 3 7 6 )

1 : 1

D r u g s ( 5 5 . 5 % ) ( a n a e s t h e t i c

a g e n t s

, a n t i b i o t i c )

I n s e c t v e n o m ( 2 2 . 2 % )

F o o d ( 1 1 . 1 % )

I d i o p a t h i c ( 1 1 . 1 % )

N i l

2 0 0 7

J i r a p o n g s a n a n u - r u k e t a

l . [ 6 4 ] R e t r o s p e c t i v e r e v i e w o f

h o s p i t a l i z e d i n p a t i e n t s

6 y e a r s

T h a i l a n d

1 0 1


M e a n 2 4

2 2 y e a r s

P a e d : m o r e m a l e s

A d u l t : m o r e f e m a l e s

D r u g s ( 5 0 % )

F o o d ( 2 4 % )

I d i o p a t h i c ( 1 5 % )

I n s e c t v e n o m ( 1 1 % )

A n n u a l o c c u r r e n c e o f a n a p h y l a x i s

i n c r e a s e d f r o m 9 . 1 6 p e r

1 0 0 0 0 0 a d m i t t e d p e r s o n s i n

1 9 9 9 t o 5 5

. 4 5 p e r 1 0 0 0 0 0

a d m i t t e d p e r s o n s i n 2 0 0 4

.

C a s e f a t a l i t y r a t e w a s 0 . 1 9 p e r

1 0 0 0 0 0 a d m i t t e d p e r s o n s .

2 0 0 7

Y a n g e t a

l . [ 6 5 ]

R e t r o s p e c t i v e r e v i e w

i n p a t i e n t s ,

o u t p a t i e n t s a n d

e m e r g e n c y

d e p a r t m e n t

a t t e n d a n c e s

6 y e a r s 6

m o n t h s

S o u t h K o r e a

1 3 8

U n k n o w n

U n k n o w n

D r u g s ( 3 5 . 3 % ) : R C M m o s t

c o m m o n

F o o d ( 2 1 . 3 % ) : b u c k w h e a t m o s t

c o m m o n

F D E I A ( 1 3 . 2 % )

I n s e c t s t i n g s ( 1 1 . 8 % ) , E x e r c i s e

i n d u c e d ( 2

. 9 % )

B l o o d p r o d u c t s ( 1

. 5 % )

N R L ( 0

. 7 % ) .

P r e v a l e n c e 0 . 0 1 4 %

M o r t a l i t y r a t e 0 . 0 0 0 1 %

.

2 0 0 8

D e c k e r e t a

l . [ 6 6 ]

P o p u l a t i o n - b a s e d

i n c i d e n c e s t u d y

1 0 y e a r s

U n i t e d S t a t e s 2 1 1


M e a n a g e

2 9

1 8 y e a r s

( 0 . 8 7

8 . 2 )

1 . 3 : 1

F o o d ( 3 3 . 2 % )

I n s e c t v e n o m ( 1 8 . 5 % )

D r u g s ( 1 3 . 7 % )

I d i o p a t h i c ( 2 5 . 1 % )

O v e r a l l a g e - a n d s e x - a d j u s t e d

i n c i d e n c e r a t e w a s 4 9

. 8

( 9 5 %

C I 4 5 . 0 , 5 4

. 5 ) p e r

1 0 0 0 0 0 p e r s o n - y e a r s .

A g e - s p e c i c r a t e s w e r e

h i g h e s t f o r a g e s 0 t o 1 9

y e a r s ( 7 0 p e r 1 0 0 0 0 0

p e r s o n - y e a r s ) .

O v e r a l l i n c i d e n c e r a t e

4 9 . 8 p

e r 1 0 0 0 0 0

p e r s o n - y e a r s .

2 0 0 8

D e S i l v a e t a

l . [ 6 7 ]

R e t r o s p e c t i v e ,

p a e d i a t r i c

e m e r g e n c y

d e p a r t m e n t

5 y e a r s

A u s t r a l i a

1 2 3 e p i s o d e s i n

1 1 7 p a t i e n t s

P a e d i a t r i c

M e d i a n 2 . 4 y e a r s ( I Q R

1 . 4 6 . 6 )

U n k n o w n

F o o d ( 8 5 % )

I d i o p a t h i c ( 7 % )

D r u g s ( 6 % )

I n s e c t v e n o m ( 3 % )


2 0 0 9

L i e w e t a

l . [ 6 8 ]

R e t r o s p e c t i v e s t u d y

a l l a n a p h y l a x i s

f a t a l i t i e s f r o m

N a t i o n a l M o r t a l i t y

D a t a b a s e

9 y e a r s

A u s t r a l i a

1 1 2

A d u l t a n d p a e d i a t r i c

U n k n o w n

P r o b a b l e d r u g ( 3 8 % )

D r u g ( 2 2 % )

I n s e c t v e n o m ( 1 8 % )

I n d e t e r m i n a t e ( 1 3 % )

F o o d ( 6 % )

O t h e r s ( 5 % )

R e l a t i v e n u m b e r o f d e a t h s t o

a d m i s s i o n s w a s

1 : 1 0 0 0

f o r f o o d - i n

d u c e d

a n a p h y l a x i s a n d 1 1 : 1 0 0 0

f o r n o n -

f o o d - i n d u c e d a n a p h y l a x i s .

R a t e o f a n a p h y l a x i s

f a t a l i t y

i n A u s t r a l i a

0 . 6 4 d e a t h s p e r m i l l i o n

p o p u l a t i o n

p e r y e a r .

F D E I A

, f o o d d e p e n d e n t e x e r c i s e i n d u c e d a n a p h y l a x i s ; N M R B

, n e u r o m u s c u l a r r e c e p t o r b l o c k e r s ; N R L , n a t u r a l r u b b e r l a t e x .




9/17

T a b l e 3

S u m m a r y o f e p i d e m i o l o g i c a l s t u d i e s o n s e v e r e c u t a n e o u s a d v e r s e r e a c t i o n s ( S C A R )

Y e a r

A u t h o r

T y p e o f s t u

d y

P e r i o d o f

s t u

d y

C o u n t r y

N u m b e r o f

c a s e s

A g e ( r a n g e )

S e x

F :

M

S y s t e m

i c

m a n i f e s t a t i o n s

C a u s e s

O u

t c o m e m e a s u r e s

1 9 8 6

G u i l l a u m e e t a

l .

[ 6 ]

P r o s p e c t i v e , T E N

1 3 y e a r s

F r a n c e

8 7

U n k n o w n

U n k n o w n

U n k n o w n

S u l f o n a m i d e s ( 2 0 . 7 % )

s u l f a m e t h o x a z o l e / t r i m e t h o p r i m

( 6 7 % )

A n t i c o n v u l s a n t s ( 8 % )

b a r b i t u r a t e s a n d

c a r b a m a z e p i n e o n l y

N S A I D s ( 3 3 . 3 % ) - p h e n y l b u t a z o n e ,

o x i c a m d e r i v a t i v e s

A l l o p u r i n o l ( 3

. 4 % )

C h l o r m e z a n o n e ( 3

. 4 % )

U n k n o w n

1 9 9 0

C h a n e t a

l . [ 7 9 ]


E M / S J S / T E N

1 4 y e a r s


3 7 E M / S J S / T E N

U n k n o w n

U n k n o w n

U n k n o w n

4 3 % a t t r i b u t e d t o d r u g s

D r u g t h e r a p i e s w i t h r e a c t i o n r a t e s

i n e x c e s s o f 1 p e r 1 0 0 0 0 0

e x p o s e d i n d i v i d u a l s i n c l u d e

p h e n o b a r b i t a l ( 2 0 p e r

1 0 0 0 0 0 )

, n i t r o f u r a n t o i n ( 7 p e r

1 0 0 0 0 0 )

, s u l f a m e t h o x a z o l e

a n d t r i m e t h o p r i m

, a n d

a m p i c i l l i n ( b o t h 3 p e r 1 0 0 0 0 0 )

,

a n d a m o x i c i l l i n ( 2 p e r

1 0 0 0 0 0 )

.

I n c i d e n c e o f T E N a l o n e d u e

t o a l l c a u s e s w a s 0 . 5 p e r

1 0 6 p e r s o n - y e a r s .

I n c i d e n c e o f E M

, S J S

, o r T E N

a s s o c i a t e d w i t h d r u g u s e

w e r e 7 . 0 , 1 . 8 , a n d 9 . 0 p e r

1 0 6 p e r s o n - y e a r s ,

r e s p e c t i v e l y , f o r p e r s o n s

y o u n g e r t h a n 2 0 y e a r s o f

a g e , 2 0 t o 6 4 y e a r s o f a g e ,

a n d 6 5 y e a r s o f a g e a n d

o l d e r .

1 9 9 0

S c h o p f e t a

l .

[ 8 1 ]


S J S / T E N

5 y e a r s

G e r m a n y

2 5 9 T E N 3 1 5 S J S

M e a n a g e 6 3 y e a r s

( T E N ) ; 2 5 y e a r s

( S J S )

T E N : 2 : 1 ; S J S :

1 : 2

U n k n o w n

A n t i b i o t i c s ( T E N

, 4 0 % ; S J S

, 3 4 % )

A n a l g e s i c s ( T E N

, 2 3 % ; S J S

, 3 3 % )

T E N : A n n u a l r i s k o f 0 . 9 3 p e r

m i l l i o n , m o r t a l i t y 3 4 %

S J S : A n n u a l r i s k 1 . 1 p e r

m i l l i o n , m o r t a l i t y 1 %

1 9 9 0

R o u j e a u e t a

l .

[ 8 2 ]

R e t r o s p e c t i v e , T E N

5 y e a r s

F r a n c e

3 9 9 T E N

U n k n o w n

U n k n o w n

U n k n o w n

S u l f a d i a z i n e

I s o x i c a m

O x y p h e n b u t a z o n e

P h e n y t o i n

F e n b u f e n

C o t r i m o x a z o l e

I n c i d e n c e 1 . 2 c a s e s p e r

m i l l i o n p e r y e a r

1 9 9 3

L e e n u t a p h o n g

e t a

l . [ 8 4 ]

R e t r o s p e c t i v e , S J S

a n d T E N

9 y e a r s

T h a i l a n d

T o t a l = 7 8

5 8 S J S , 2 0 T E N

U n k n o w n

U n k n o w n

U n k n o w n

A n t i b i o t i c s ( 4 1 % ) p e n i c i l l i n ,

s u l f o n a m i d e s , t

e t r a c y c l i n e ,

e r y t h r o m y c i n

A n t i c o n v u l s a n t s ( 1 1 . 5 % )

p h e n y t o i n , c a r b a m a z e p i n e

b a r b i t u r a t e s

A n t i t u b e r c u l a r d r u g s ( 1 0 . 3 % )

t h i a c e t a z o n e

M o r t a l i t y r a t e 1 4 % ; 4 0 %

T E N

, 5 % S J S

1 9 9 5

R o u j e a u e t a

l .

[ 8 5 ]


C a s e - c o n t r o l

s t u d y

4 y e a r s

F r a n c e ,

G e r m a n y , I t a l y ,

a n d P o r t u g a l

T o t a l = 2 4 5

S J S 8 9

S J S - T E N o v e r l a p

7 6

T E N 8 0

U n k n o w n

U n k n o w n

U n k n o w n

S u l f o n a m i d e s , t

r i m e t h o p r i m -

s u l f a m e t h o x a z o l e

C a r b a m a z e p i n e

O x i c a m N S A I D s

C h l o r m e z a n o n e

P h e n y t o i n

A l l o p u r i n o l

U n k n o w n




10/17

1 9 9 6

R z a n y e t a

l . [ 8 6 ]

R e t r o s p e c t i v e , d Z h

G e r m a n

p o p u l a t i o n - b a s e d

r e g i s t r y f o r

s e v e r e s k i n

r e a c t i o n s .

2 y e a r s 8

m o n t h s

G e r m a n y

S J S 1 3 9

S J S - T E N o v e r l a p 9 5

T E N 5 6

U n k n o w n

U n k n o w n

U n k n o w n

U n k n o w n

I n c i d e n c e o f S J S / T E N

U p t o 1 . 8 9 p e r 1 m i l l i o n

i n h a b i t a n t s p e r y e a r

1 9 9 8

K a m a l i a h e t a

l .

[ 8 7 ]


E M / S J S / T E N ( E M

e x c l u d e d i n t h i s

t a b l e )

8 y e a r s

E a s t M a l a y s i a

T o t a l = 2 5

2 2 S J S , 3 T E N

1 9 a d u l t a n d 6

p a e d i a t r i c

P a e d : 1 0 m o n t h 1

2

y e a r s

A d u l t : 1 5 6

5 y e a r s

0 . 7 3 : 1

F e v e r ( 6 2 . 1 %

)

L e u k o c y t o s i s ( 3 4 . 5 % )

H e p a t i t i s ( 3 1 % )

A n t i b i o t i c s ( 3 6 % )

C o t r i m o x a z o l e

A m p i c i l l i n / a m o x i c i l l i n

A n t i c o n v u l s a n t s ( 3 2 % )

A l l o p u r i n o l ( 4 % )

M o r t a l i t y : T E N 3 7

. 3 %

, S J S

4 . 5 %

1 9 9 9

W o n g e t a

l . [ 8 7 ] R e t r o s p e c t i v e ,

S J S / T E N

1 2 y e a r s

A u s t r a l i a

T o t a l = 1 7

1 0 S J S , 7 T E N

M e a n a g e 6 1

. 5 y e a r s 0 . 5 : 1

U n k n o w n

B e t a l a c t a m a n t i b i o t i c s ( 5 2 . 9 % )

M o r t a l i t y : 2 8

. 6 % T E N 1 0 %

S J S

2 0 0 7

G e r d t s e t a

l . [ 8 9 ] R e t r o s p e c t i v e

1 5 y e a r s

T h e N e t h e r l a n d s 1 9

A d u l t a n d p a e d i a t r i c

M e a n a g e

4 5 . 6

2 3 . 9

y e a r s

( 5 7

0 )

1 . 6 : 1

U n k n o w n

A n t i c o n v u l s a n t s p h e n y t o i n /

c a r b a m a z e p i n e ( 3 6 . 8 % )

A m o x i c i l l i n ( 1 0 . 5 % )

M o r t a l i t y ( 1 5 . 8 % )

2 0 0 7

Y a m a n e e t a

l .

[ 9 0 ]

R e t r o s p e c t i v e , a l l

c a s e s p u b l i s h e d

f r o m J a p a n

6 y e a r s

J a p a n

T o t a l = 1 1 7

5 2 S J S , 6 5 T E N

S J S : m e a n 4 5

. 2 y e a r s

T E N : m e a n 4 5

. 7

y e a r s

S J S 1 . 7 : 1 T E N

H e p a t i t i s ( 5 5 . 6 % )

R e s p i r a t o r y ( 2 5 . 6 % )

R e n a l d y s f u n c t i o n ( 1 9 . 7 % )


A n t i b i o t i c s ( 1 7 . 1 % )

N S A I D s ( 1 2 . 8 % )

M o r t a l i t y : S J S 1 . 9 % T E N

6 . 2 %

2 0 0 8

S h a r m a e t a

l .

[ 9 1 ]


3 y e a r s

I n d i a

T o t a l = 3 0

1 5 T E N

, 9 S J S - T E N

o v e r l a p a n d 6 S J S


M e a n a g e

2 2 . 3

1 5 . 4

y e a r s

( 4 6

5 )

1 . 2 : 1

H a e m a t o l o g i c a l ( 8 6 . 7 % )

H e p a t i t i s ( 3 6 . 7 % )

R e n a l ( 1 3

. 3 % )

P n e m o n i t i s ( 1 0 % )


p h e n y t o i n 4 5 %

,

c a r b a m a z e p i n e 3 0 %

A n t i b i o t i c s ( 3 3 . 3 % )

c e p h a l o s p o r i n s 2 6 %

N S A I D S ( 2 4 . 6 % ) .

M o r t a l i t y 1 6

. 7 %

1 3 . 3

% T E N

, 3 . 3

% S J S - T E N

o v e r l a p

2 0 0 8

M o c k e n h a u p t

e t a

l . [ 9 2 ]


c a s e - c o n t r o l

( E u r o S C A R )

U n k n o w n E u r o p e

T o t a l = 3 7 9

1 3 4 S J S , 1 3 6

S J S / T E N - o v e r l a p ,

1 0 9 T E N


M e d i a n 5 0 y e a r s

( I Q R 2 8 6

8 )

( 1 9

5 )

1 . 6 : 1

U n k n o w n

N e v i r a p i n e

L a m o t r i g i n e

C a r b a m a z e p i n e

P h e n y t o i n

P h e n o b a r b i t a l

C o t r i m o x a z o l e a n d o t h e r

a n t i - i n f e c t i v e s u l f o n a m i d e s

S u l f a s a l a z i n e

A l l o p u r i n o l

O x i c a m - N

S A I D s

U n k n o w n

2 0 1 0

W e t t e r e t a

l . [ 9 3 ] R e t r o s p e c t i v e

8 y e a r s


2 7 S J S


M e a n 2 8

. 1

2 2 . 3

y e a r s

0 . 7 : 1

F e v e r ( 7 0 % )

H e p a t i t i s ( 3 7 % )

L e u k o c y t o s i s ( 2 2 % )

7 4 % d r u g r e l a t e d

A n t i b i o t i c s ( 3 5 % ) c o t r i m o x a z o l e

A n t i c o n v u l s a n t s ( 3 5 % )

p h e n y t o i n , l a m o t r i g i n e

N S A I D ( 1 0 % )





11/17

included as one of the SCAR in the EuroSCAR studies [94].Medications associated with AGEP (aminopenicillins,pristinamycin, quinolones, hydroxychloroquine, diltiazem)were different from those associated with SJS/TEN. Differ-ent latent periods from drug intake to reaction onset wereobserved for different drugs (e.g. median treatment dura-tion of 1 day for antibiotics vs. 11 days for non-antibiotics),shorter than the overall time to onset for most SJS/TENreactions.

Hospital-based studies from a district in China [95]showed an overall prevalence of 0.32 per 1000 hospitaliza-tions, 0.15 per 1000 hospitalizations for SJS, 0.04 per 1000for TEN, and 0.07 per 1000 for DRESS. Antibiotics were themost common putative drug followed by anti-epilepticdrugs and traditional Chinese medicines. The risk of SCARfrom systemic drugs among hospitalized patients was0.03/1000 (0.02/1000 for SJS, and 0.01/1000 for ED andDRESS).The reported incidence of SCAR in the Haidian dis-trict was not less than 1.8 per million person-years. The

reported incidence of erythema multiforme, SJS, TEN andDRESS in the Haidian district was not less than 0.6,0.8, 0.05and 0.4 per million person-years, respectively. The mostcommon underlying disorders were infection, pain-relateddiseases and epilepsy.

Risk factors for drug allergy

Drug related factors Drug related factors that affect its immunogenicity includeits ability to act as a hapten, a prohapten or to bindcovalently to immune receptors (Pi concept) [96]. Thus,certain classes of drugs tend to be associated with a higherfrequency of drug allergies compared with others [97].Although it is believed that intermittent and repeatedadministrations appear to be more sensitizing than un-interrupted treatment, and parenteral administrationappears to be more sensitizing than the oral route, rigor-ous studies to support these are lacking.

Host related factors Females appear more likely to develop drug allergies thanmales, but this may be attributable to the overall femalepredominance in ADRs.In the Alergolgica 2005 study [36],

the female : male ratioof rst time consults fordrug allergywas approximately 2:1.The incidence of self reported drugallergy was also generally higher in females than in males[98]. Other studies have also shown that overall womenappear to be more affected than men [99, 100]. In ourregistry of hospitalized patients with drugallergy,hospital-ized females were statistically signicantly more likely todevelop drug allergy than males, although there were nosignicant differences in the clinical manifestations andmortality between both genders [101].

With regards to age groups, it is unclear at this point if the incidence of drug allergy is indeed lower in children

[33, 102]. Although children are less likely to be exposedrepeatedly to drugs necessary for sensitization to occur,widespread prescribing of certain drugs may theoreticallyincrease the risk for sensitization in certain groups of children, for instance antibiotic sensitization in childrenwith chronic diseases. The incidence of ADRs and ADR-associated hospitalization increaseswith age,but the asso-ciation of age with drug allergy is less well studied [102].Manifestations and outcome of drug allergy in elderly hos-pitalized patients appear to be similar to the non-elderly,but serious reactions (anaphylaxis, SJS,TEN, DiHS) are lesscommon [103].

Concomitant disease states may predispose to thedevelopment of allergic drug reactions by altering meta-bolicpathways andinducingvariations in the immunologicresponses to drugs. The apparent increased risk for drugallergy in patients with SLE has not been consistently con-rmed [104]. Drug allergies are frequently encountered inpatients with HIV infection, particularly to certain drugs

includingcotrimoxazole,abacavir and nevirapine.It is likelythat a complex interaction between theunderlying state of immune-reconstitution and genetic host factors predis-poses to these allergic drug reactions [105].Similarly, reac-tivation of herpes virus [Ebstein-Barr virus, human herpesvirus (HHV) 6 and7,cytomegalovirus] appears to be associ-ated with the pathogenesis of DiHS [106]. Atopy does notappeartobeamajorriskfactorformostdrugallergies[100].

Ethnicity andgenetics appear to be increasingly impor-tant in the predisposition to certain types of drug allergywith specic examples discussed below.

Genetics of drug allergy The study of medical genetics in recent years has focusedon the area of HLA genotypes and their association withsevere drug hypersensitivity.To generate an immune reac-tion, HLA molecules function as antigen presenters toimmune T-cells via the T cell receptor (TCR). HLA class I(HLA A, HLA B, HLA C) molecules are ubiquitous and arefound on all nucleated cell surfaces.They present intracel-lular antigens to CD8 + cytotoxic T-cells. HLA class II (HLADP, HLA DQ, HLA DR) molecules are found on the immunecells and they present extracellular antigens to CD4 +

helper T-cells. It has been suggested that MHC presenta-tion of drug derived antigen plays a key role in the devel-opment of drug hypersensitivity.

HLA associations that have been described in severecutaneous adverse reactions include:

HLA B*1502 associated with carbamazepine induced SJS/ TEN in Han Chinese in Taiwan [odds ratio,OR 1357 (95% CI193, 8838) - 2504 (95% CI 126, 49 522)] [106] and HongKong (OR 71.9) [107],Thais [OR 25.5 (95% CI 2.68,242.61)][108] and Indians [109] but neither in Japanese [110] norEuropeans of non-Asian ancestry [111]. There was no




12/17

association seen with maculopapular exanthema (MPE)in Han Chinese from Hong Kong and Thais.

HLA B*1502 associated with phenytoin induced SJS inHan Chinese in Hong Kong (OR 71.9) [107] and Thais [OR18.5 (95% CI 1.82, 188.4)] [108],but not with MPE amongHan Chinese from Hong Kong.

HLA B*5801 and allopurinol induced SJS/TEN in HanChinese from Taiwan [OR 580.3 (95% CI 34.4, 9780.9)][112], Thais [OR 348.3 (95%CI 19.2, 6336.9)] [113], Japa-nese [110] and Europeans [111];

HLA B*5701 and abacavir drug hypersensitivity in Cauca-sians [OR 117 (95% CI 29,481)] [114, 115],but not amongBlacks [116].This haplotype has been found to be uncom-mon in Taiwanese Chinese [117] and Korean populations[118].

A multi-national double-blind prospective randomizedstudy has shown that HLA B*5701 screening prior to theuse of abacavir inWhite populations is useful in preventing

abacavir hypersensitivity reactions [119]. Although theUnited States Food and Drug Administration and HealthCanada have also recommended testing for the HLAB*1502 allele in at-risk populations (e.g. South-east Asianancestry) prior to the prescription of carbamazepine, mostregulatory authorities in Asia have not made this manda-tory at the moment. Given the strong association of HLA-B*5801 with hypersensitivity to allopurinol across differentethnic populations (i.e. Southeast Asian, Japanese, Euro-pean), screening all patients before initiating allopurinolmay also appear to be prudent in future. However, severalfactors need to be considered before such screening pro-cedures canbe considered cost-effective in the populationat risk including: the population prevalence of that specicHLA allele, the prevalence of the condition for which thedrug is used,the utilization rate of that particular drug,andlastly, rapid methods of detection, as for HLA-B*5701 andHLA-B*1502, need to be readily available [120, 121].

Apart from HLA associations with serious drug aller-gies, various other genetic associations have also beenreported for:

IgE mediated penicillin allergy: E237G variant of Fc eR1b(high afnity IgE receptor b chain) gene, IL-4Ra Q576Rpolymorphism, IL-4 Il-13-SNP polymorphisms in Chinese

[122, 123, 124]; Immediate allergic reactions to beta-lactams:Il-13 (R130Q

and - 1055C > T variants) and IL-4RA (150V, S478P, andQ551R variants) polymorphisms in Italians [125]; lle75Valvariant of IL-4Ra gene two linked Il-10 promotor genepolymorphisms (-819C > T and - 592C > A) in Causasians[126].

Antituberculous drug induced hepatitis: CYP2E1 in theChinese [127] (but not in Korean and British), NAT2 (N-acetyltransferase) in Koreans [128] and GST (glutathione-S-transferase) genotypes in Caucasians [129].

A recent update on genetic and ethnic associationswith drug hypersensitivity to different drugs has beenreviewed in detail elsewhere [130].

Conclusion

Epidemiologists study the factors affecting the health andillness of populations,enablinginterventions to be made inthe interest of public health andpreventive medicine.Phar-macoepidemiology is the study of the use andeffects (out-comes) of drugs (exposure) in large populations of people.Current epidemiological data on ADRs often do notdifferentiate immunologically and non-immunologicallymediated drug hypersensitivity, study different studypopulations (different ethnicities,inpatientsor outpatients,adults or children),utilize different methodologies (sponta-neous vs. non-spontaneous reporting), different methodsof assessing drug imputability and different methods of

data analyses.Standardization of denitions of terminology used indrug allergy will ensure better comparability amongstudies, facilitate the validation of in vivo and in vitro aller-gological tests, and improve our understanding of theimmunological mechanisms underlying different types of drug allergies.Identication of risk factors for drug allergyand appropriate genetic screening of at-risk ethnic groupsmay improve the outcomes of drug-specic SCAR.

Research and collaboration among epidemiologists,allergists, pharmacologists, pharmacists, toxicologists,geneticists and immunologists, should be advocated assuch partnerships will contribute signicantly to the gen-eration of clinically-relevant, translational pharmacoepide-miological and pharmacogenomic knowledge, and hencethe success of health outcomes research and policies ondrug allergies.

Competing interests

There are no competing interests to declare.

REFERENCES1 World Health Organization. International drug monitoring:

the role of national centres.World Health Organ Tech RepSer 1972; 498: 125.

2 Rawlins MD, Thompson JV.Pathogenesis of adverse drugreactions. In: Textbook of Adverse Drug Reactions, ed.Davies DM. Oxford: Oxford University Press, 1977; 10.

3 Morimoto T,Gandhi TK, Seger AC, Hsieh TC, Bates DW.Adverse drug events and medication errors: detection andclassication methods. Qual Saf Health Care 2004; 13:30614.




13/17

4 Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ,Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA,Ring J, Thien F, Van Cauwenberge P, Williams HC. Revisednomenclature for allergy for global use: report of thenomenclature review committee of the World AllergyOrganization, October 2003. J Allergy Clin Immunol 2004;113: 8326.

5 Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L,Roujeau JC.Clinical classication of cases of toxicepidermal necrolysis, Stevens-Johnson syndrome, anderythema multiforme. Arch Dermatol 1993; 129: 926.

6 Guillaume JC,Rojeau JC, Revuz J, Penso D, Touraine R. Theculprit drugs in 87 cases of toxic epidermal necrolysis(Lyells syndrome). Arch Dermatol 1987;123: 116670.

7 Rzany B, Hering O, Mockenhaupt M, Schrder W,Goerttler E, Ring J, Schpf E. Histopathological andepidemiological characteristics of patients with erythemaexudativum multiforme major, Stevens-Johnson syndromeand toxic epidermal necrolysis. Br J Dermatol 1996; 135:611.

8 French LE. Toxic epidermal necrolysis and Stevens Johnsonsyndrome:our current understanding. Allergol Int 2006; 55:916.

9 Borchers AT,Lee JL, Naguwa SM, Cheema GS, Gershwin ME.Stevens-Johnson syndrome and toxic epidermal necrolysis.Autoimmun Rev 2008; 7: 598605.

10 Shiohara T, Inaoka M,Kano Y. Drug-inducedhypersensitivity syndrome (DIHS): a reaction induced by acomplex interplay among herpes viruses and antiviral andantidrug immune responses. Allergol Int 2006; 55: 18.

11 Sidoroff A, Halevy S, Bavinck JN, Vaillant L,Roujeau JC.Acute generalized exanthematous pustulosis (AGEP) a

clinical reaction pattern. J Cutan Pathol 2001; 28: 1139.12 Halevy S. Acute generalized exanthematous pustulosis.

Curr Opin Allergy Clin Immunol 2009;9: 3228.

13 Sampson HA, Muoz-Furlong A,Campbell RL,Adkinson NF Jr,Bock SA,Branum A, Brown SG,Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS,Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL,Metcalfe DD, OConnor R,Muraro A, Rudman A, Schmitt C,Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW.Second symposium on the denition and management of anaphylaxis: summary report Second National Institute of Allergy and Infectious Disease/Food Allergy andAnaphylaxis Network Symposium. J Allergy Clin Immunol2006; 117: 3917.

14 Lieberman P. Epidemiology of anaphylaxis.Curr OpinAllergy Clin Immunol 2008; 8: 31620.

15 Demoly P, Viola M,Gomes ER, Romano A. Epidemiologyand causes of drug hypersensitivity. In: DrugHypersensitivity, ed. Pichler WJ. Basel: Karger, 2007; 217.

16 Mockenhaupt M. Epidemiology and causes of severecutaneous adverse reactions to drugs. In: DrugHypersensitivity, ed. Pichler WJ.Basel: Karger, 2007; 1831.

17 Bousquet PJ,Demoly P, Romano A, Aberer W, Bircher A,Blanca M, Brockow K, Pichler W, Torres MJ, Terreehorst I,

Arnoux B, Atanaskovic-Markovic M, Barbaud A, Bijl A,Bonadonna P, Burney PG, Caimmi S, Canonica GW,Cernadas J, Dahlen B, Daures JP, Fernandez J, Gomes E,Gueant JL, Kowalski ML, Kvedariene V, Mertes PM,Martins P,Nizankowska-Mogilnicka E, Papadopoulos N,Ponvert C, Pirmohamed M, Ring J, Salapatas M, Sanz ML,Szczeklik A, Van Ganse E, De Weck AL,Zuberbier T, Merk HF,Sachs B, Sidoroff A, Global Allergy, Asthma EuropeanNetwork (GALEN) and Drug Allergy and HypersensitivityDatabase (DAHD) and the European Network for DrugAllergy (ENDA).Pharmacovigilance of drug allergy andhypersensitivity using the ENDA-DAHD database and theGALEN platform. The Galenda project. Allergy 2009; 64:194203.

18 Demoly P, Kropf R, Bircher A,Pichler WJ. Drughypersensitivity: questionnaire. EAACI interest group ondrug hypersensitivity. Allergy 1999; 54: 9991003.

19 Torres MJ,Blanca M, Fernandez J, Romano A, Weck A,Aberer W, Brockow K,Pichler WJ, Demoly P, ENDA,EAACIInterest Group on Drug Hypersensitivity. Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy 2003; 58: 96172.

20 Romano A, Blanca M, Torres MJ, Bircher A, Aberer W,Brockow K, Pichler WJ, Demoly P, ENDA, EAACI. Diagnosis of non-immediate reactions to beta-lactam antibiotics.Allergy 2004; 59: 115360.

21 Aberer W, Bircher A,Romano A, Blanca M, Campi P,Fernandez J, Brockow K, Pichler WJ, Demoly P, EuropeanNetwork for Drug Allergy (ENDA), EAACI interest group ondrug hypersensitivity. Drug provocation testing in thediagnosis of drug hypersensitivity reactions: generalconsiderations. Allergy 2003; 58: 85463.

22 Allain H, Chevrant-Breton J, Beneton C, Bousser AM,

Bentue-Ferrer D,Mazeas D, Van der Driessche J.Undesirable dermatologic results of drugs. Results of adrug monitoring survey (French). Ann Med Interne (Paris)1983; 134: 5306.

23 Bigby M, Jick S, Jick H,Arndt K.Drug-induced cutaneousreactions.A report from the Boston Collaborative DrugSurveillance Programme on 15 438 consecutive patients,1975 to 1982. JAMA 1986; 256: 3358 63.

24 Classen DC, Pestonik SL, Evans RS, Burke JP.Computerizedsurveillance of adverse drug events in hospitalizedpatients. JAMA 1991;266: 284751.

25 Rademaker M, Oakley A, Dull MB. Cutaneous adverse drugreactions in a hospital setting.N Z Med J 1995; 108: 1656.

26 Hunziker T, Kunzi UP, Braunschweig S, Zehnder D,Hoigne R. Comprehensive hospital drug monitoring(CHDM): adverse skin reactions, a 20-year survey. Allergy1997; 52:38893.

27 Sharma VK, Sethuraman G, Kumar B. Cutaneous adversedrug reactions:clinical pattern and causative agents a 6year series from Chandigarh, India. J Postgrad Med 2001;47:959.

28 Thong BY, Leong KP, Tang CY, Chng HH. Drug allergy in ageneral hospital: results of a novel prospective inpatientreporting system. Ann Allergy Asthma Immunol 2003; 90:34247.




14/17


15/17

58 Bohlke K, Davis RL, DeStefano F, Marcy SM, Braun MM, Thompson RS. Vaccine Safety Datalink Team. Epidemiologyof anaphylaxis among children and adolescents enrolled ina health maintenance organization. J Allergy Clin Immunol2004; 113: 53642.

59 Cianferoni A, Novembre E, Pucci N, Lombardi E,Bernardini R, Vierucci A. Anaphylaxis: a 7-year follow-up

survey of 46 children. Ann Allergy Asthma Immunol 2004;92:4648.

60 Thong BY, Cheng YK, Leong KP,Tang CY,Chng HH.Anaphylaxis in adults referred to a clinicalimmunology/allergy centre in Singapore.Singapore Med J2005; 46: 52934.

61 Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases.Ann Allergy Asthma Immunol 2006; 97: 3943.

62 Braganza SC, Acworth JP, Mckinnon DR, Peake JE,Brown AF. Paediatric emergency department anaphylaxis:different patterns from adults.Arch Dis Child 2006; 91:15963.

63 Low I, Stables S. Anaphylactic deaths in Auckland, NewZealand: a review of coronial autopsies from 1985 to 2005.Pathology 2006; 38: 32832.

64 Jirapongsananuruk O,Bunsawansong W, Piyaphanee N,Visitsunthorn N, Thongngarm T, Vichyanond P. Features of patients with anaphylaxis admitted to a university hospital.Ann Allergy Asthma Immunol 2007; 98: 15762.

65 Yang MS, Lee SH, Kim TW,Kwon JW,Lee SM, Kim SH,Kwon HS,Park CH,Park HW,Kim SS, Cho SH, Min KU,Kim YY, Chang YS.Epidemiologic and clinical features of anaphylaxis in Korea.Ann Allergy Asthma Immunol 2008;100: 316.

66 Decker WW,Campbell RL, Manivannan V,Luke A,St Sauver JL,Weaver A, Bellolio MF, Bergstralh EJ, Stead LG,Li JT. The etiology and incidence of anaphylaxis inRochester, Minnesota: a report from the RochesterEpidemiology Project. J Allergy Clin Immunol 2008; 122:11615.

67 de Silva IL, Mehr SS,Tey D, Tang ML. Paediatric anaphylaxis:a 5 year retrospective review. Allergy 2008; 63: 10716.

68 Liew WK,Williamson E, Tang ML. Anaphylaxis fatalities andadmissions in Australia. J Allergy Clin Immunol 2009; 123:43442.

69 Tang ML, Osborne N, Allen K. Epidemiology of anaphylaxis.Curr Opin Allergy Clin Immunol 2009;9: 3516.

70 Idsoe O, Guthe T, Willcox RR, DeWeck AL.Nature and extentof penicillin side-reactions,with particular reference tofatalities from anaphylactic shock.Bull World Health Organ1968; 38: 15988.

71 Valentine M, Frank M, Friedland L. Allergic emergencies. In:Asthma and Other Allergic Diseases, NIAID Task ForceReport. ed. Drause RM. Bethesda,MD: National Institutes of Health, 1979; 467507.

72 Joint Task Force on Practice Parameters,AmericanAcademy of Allergy, Asthma and Immunology, American

College of Allergy,Asthma and Immunology, Joint Councilof Allergy, Asthma and Immunology. The diagnosis andmanagement of anaphylaxis: an updated practiceparameter. J Allergy Clin Immunol 2005; 115: (Suppl 2):S483523.

73 Fisher MM,Baldo BA. The incidence and clinical features of anaphylactic reactions during anesthesia in Australia.Ann

Fr Anesth Reanim 1993; 12: 97104.74 Mertes PM, Laxenaire MC, GERAP. Anaphylactic and

anaphylactoid reactions occurring during anaesthesia inFrance. Seventh epidemiologic survey (January2001-December 2002). Ann Fr Anesth Reanim 2004; 23:113343.

75 Thienthong S, Hintong T, Pulnitiporn A. The Thai AnesthesiaIncidents Study (THAI Study) of perioperative allergicreactions. J Med Assoc Thai 2005; 88: (Suppl 7): S12833.

76 Watkins J. Adverse anaesthetic reactions: an update from aproposed national reporting and advisory service.Anaesthesia 1985; 40: 797800.

77 Harboe T,Guttormsen AB, Irgens A, Dybendal T, Florvaag E.Anaphylaxis during anesthesia in Norway: a 6-yearsingle-center follow-up study.Anesthesiology 2005; 102:897903.

78 Mertes PM, Lambert M,Guant-Rodriguez RM,Aimone-Gastin I,Mouton-Faivre C, Moneret-Vautrin DA,Guant JL, Malinovsky JM, Demoly P. Perioperativeanaphylaxis. Immunol Allergy Clin North Am 2009; 29:42951.

79 Chan HL, Stern RS, Arndt KA, Langlois J, Jick SS, Jick H,Walker AM. The incidence of erythema multiforme,Stevens-Johnson syndrome, and toxic epidermal necrolysis.

A population-based study with particular reference toreactions caused by drugs among outpatients. ArchDermatol 1990; 126: 437.

80 Naldi L, Locati F, Marchesi L, Cainelli T. Incidence of toxicepidermal necrolysis in Italy. Arch Dermatol 1990;126:11034.

81 Schopf E, Stuhmer A,Rzany B, Victor N, Zentgraft R,Kapp JF. Toxic epidermal necrolysis and Stevens JohnsonSyndrome: an epidemiologic study from West Germany.Arch Dermatol 1991; 127: 83942.

82 Roujeau JC, Guillaume JC, Fabre JP, Penso Dominique P,Flechet ML,Girre JP. Toxic epidermal necrolysis (LyellSyndrome). Arch Dermatol 1990; 126: 3742.

83 Strom BL, Carson JL, Halpern AC, Schinnar R, Snyder ES,Shaw M, Tilson HH, Joseph M, Dai WS,Chen D et al . Apopulation-based study of Stevens-Johnson syndrome.Incidence and antecedent drug exposures. Arch Dermatol1991; 127: 8318.

84 Leenutaphong V, Sivayathorn A, Suthipinittharm P,Sunthonpalin P. Stevens-Johnson syndrome and toxicepidermal necrolysis in Thailand. Int J Dermatol 1993; 32:42831.

85 Roujeau JC,Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T,Auquier A, Bastuji-Garin S, Correia O, Locati F,




16/17

Mockenhaupt M, Paoletti C, Shapiro S, Neil Shear N,Schpf E, Kaufman DW. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.NEngl J Med 1995; 333: 16007.

86 Rzany B, Mockenhaupt M, Baur S,Schrder W, Stocker U,Mueller J, Hollnder N, Bruppacher R, Schpf E.Epidemiology of erythema exsudativum multiforme majus,

Stevens-Johnson syndrome, and toxic epidermal necrolysisin Germany (19901992): structure and results of apopulation-based registry. J Clin Epidemiol 1996; 49:76973.

87 Kamaliah MD, Zaimal D, Mokhtar N, Nazmi N. Erythemamultiforme, Steven Johnson Syndrome and toxic epidermalnecrolysis in North East Malaysia. Int J Dermatol 1998; 37:5203.

88 Wong KC, Kennedy PJ, Lee S. Clinical manifestations andoutcomes in 17 cases of Stevens Johnson Syndrome andtoxic epidermal necrolysis. Australas J Dermatol 1999; 40:1314.

89 Gerdts B, Vloemans AF, Kreis RW. Toxic epidermalnecrolysis; 15 years experience in a Dutch burns centre.JEur Acad Dermatol Venereol 2007; 21: 7818.

90 Yamane Y, Aihara M, Ikezawa Z. Analysis of Stevens-Johnson syndrome and toxic epidermal necrolysisin Japan from 2000 to 2006. Allergol Int 2007; 56: 41925.

91 Sharma VK, Sethuraman G, Minz A. Stevens Johnsonsyndrome, toxic epidermal necrolysis and SJS-TEN overlap:a retrospective study of causative drugs and clinicaloutcome. Indian J Dermatol Venereol Leprol 2008; 74:23840.

92 Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S,Bouwes Bavinck JN, Sidoroff A, Schneck J, Roujeau JC,Flahault A. Stevens-Johnson syndrome and toxic epidermalnecrolysis: assessment of medication risks with emphasison recently marketed drugs.The EuroSCAR-study. J InvestDermatol 2008; 128: 3544.

93 Wetter DA, Camilleri MJ. Clinical, etiologic, andhistopathologic features of Stevens-Johnson syndromeduring an 8-year period at Mayo Clinic. Mayo Clin Proc2010; 85: 1318.

94 Sidoroff A,Dunant A, Viboud C, Halevy S, Bavinck JN,Naldi L, Mockenhaupt M, Fagot JP,Roujeau JC. Risk factorsfor acute generalized exanthematous pustulosis(AGEP)-results of a multinational case-control study(EuroSCAR).Br J Dermatol 2007; 157: 98996.

95 Li LF, Ma C. Epidemiological study of severe cutaneousadverse drug reactions in a city district of China. Clin ExpDermatol 2006; 31: 6427.

96 Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC,Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis:a retrospective study on patients included in theprospective EuroSCAR Study. J Am Acad Dermatol 2008;58:3340.

97 Pichler WJ. Delayed drug hypersensitivity reactions. AnnIntern Med 2003; 139: 68393.

98 Gomes E, Cardoso MF, Praa F, Gomes L, Mario E,Demoly P. Self-reported drug allergy in a general adultPortuguese population. Clin Exp Allergy 2004; 34:1597601.

99 Barranco P, Lopez-Serrano MC.General andepidemiological aspects of allergic drug reactions. Clin ExpAllergy 1998; 28: (Suppl 4): S61S62.

100 Haddi E, Charpin D, Tafforeau M, Kulling G, Lanteaume A,Kleisbauer JP,Vervloet D. Atopy and systemic reactions todrugs. Allergy 1990;45: 2369.

101 Leong KP, Thong BY, Cheng YK, Tang CY, Chng HH. Arethere differences in drug allergy between the sexes? AnnAcad Med Singapore 2003; 32: 151.

102 Demoly P, Bousquet J. Epidemiology of drug allergy. CurrOpin Allergy Clin Immunol 2001; 1: 30510.

103 Chng HH, Leong KP,Cheng YK, Tang CY,Chia FL, Tan JW, Thong BY. Elderly inpatients have drug allergymanifestations and outcome similar to the non-elderly butserious reactions are less common: results of a 9-yearprospective study. Allergy 2008; 63: (Suppl 88): 379.

104 Pope J, Jerome D,Fenlon D, Krizova A, Ouimet J. Frequencyof adverse drug reactions in patients with systemic lupuserythematosus. J Rheumatol 2003; 30: 4804.

105 Phillips E, Mallal S. Drug hypersensitivity in HIV. Curr OpinAllergy Clin Immunol 2007; 7: 32430.

106 Chung WH,Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC,Wu JY, Chen YT. Medical genetics: a marker forStevens-Johnson syndrome. Nature 2004; 428: 486.

107 Man CB,Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH.Association between HLA-B*1502 allele and antiepileptic

drug-induced cutaneous reactions in Han Chinese.Epilepsia 2007; 48: 10158.

108 Locharernkul C, Loplumlert J, Limotai C, Korkij W,Desudchit T, Tongkobpetch S, Kangwanshiratada O,Hirankarn N, Suphapeetiporn K, Shotelersuk V.Carbamazepine and phenytoin induced Stevens-Johnsonsyndrome is associated with the HLA-B*1502 allele in a Thai population. Epilepsia 2008; 49: 208791.

109 Mehta TY, Prajapati LM, Mittal B, Joshi CG, Sheth JJ,Patel DB, Dave DM, Goyal RK. Association of HLA-B*1502allele and carbamazepine-induced Stevens-Johnsonsyndrome among Indians. Indian J Dermatol VenereolLeprol 2009; 75: 57982.

110 Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M,Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M,Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M,Sotozono C, Ikezawa Z, Hasegawa R, JSAR research group.HLA B locus in Japaneses patients treated withantiepileptic or antimicrobial agents. Pharmacogenomics2008; 9: 161722.

111 Lonjou C, Thomas L, Borot N, Ledger N, de Toma C,

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