What 2012 drug allergy

WHAT YOU SHOULD HAVE READ BUT….2012

 drug allergy
Attilio Boner
University of
Verona, Italy

Results of drug hypersensitivity evaluations
in a large group of children and adults.
Rubio, Clin Exp Allergy 2012;42:123

Background Proven IgE or T-cell mediated
drug hypersensitivity reactions (DHRs) seem
less common in children compared with adults.
However, this has never been proved by data.
Objective To determine and compare
proven DHR prevalence in children and adults.


 (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.

Prevalence of positive tests.
25 – p<0.0001
p=0.003
20 – 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

25 – p<0.0001
p=0.003
20 – 22.1%

15 –
15.2%
10 – 16.5%
10.6% 10.6%
05 –
Significant differences were found for
0 maculopapular exanthemas only, and not for
All C/C C/A CA/A A/A
urticaria/angioedema and anaphylaxis.
Tested classes

25 – p<0.0001
p=0.003
20 – 22.1%

15 –
15.2%
10 – 16.5%
10.6% 10.6%
05 –
The difference was mainly observed
0 with β-lactams andC/A for NSAIDs.
not CA/A A/A
All C/C

Tested classes


1) 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%).


3) 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.

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).


 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.

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.

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
Pneumoniae virus
infection.

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
Pneumoniae virus
infection.

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.

basophil
activation
test (BAT)

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

Background
No available test diagnoses allergic reactions to radiocontrast
media (RCM). The basophil activation test (BAT) has been
introduced for the diagnosis of both IgE and
non-IgE–dependent mast cell degranulation, but its value
to diagnose immediate RCM reactions is still unknown.

Objective
This study aims to evaluate the diagnostic value of BAT in
immediate RCM hypersensitivity.


% 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


% 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

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.

corticosteroids
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.

corticosteroids
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.

corticosteroids
milk

Skin testing results in both patients with acute
reaction to lactose-containing succinylated
methyl-prednisolone

corticosteroids
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

corticosteroids
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)

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 are
maculopapular or morbilliform rashes and
delayed-appearing urticaria/angioedema.
• There are studies suggesting that either
delayed-reading intradermal tests or patch tests,
or both can be an effective way of diagnosing a delayed
hypersensitivity.

Romano, JACI 2012;129:1166

• In the present study*, according to the diagnostic protocol
devised by the European Network for Drug Allergy, subjects with
histories of nonimmediate reactions to cephalosporins were
assessed by using both patch tests and delayed-reading (after >48
hours) skin tests and, in case of negative responses, by provocation
tests in an attempt to clarify the pathogenic mechanism involved.
• Skin prick and intradermal tests using penicilloyl-polylysine, minor
determinant mixture, and benzylpenicillin, as previously described.
In the second evaluation 2 days later, we used ampicillin and
amoxicillin at concentrations of 1 and 20 mg/mL, as well as the
suspect cephalosporins at a concentration of 2 mg/mL and any other
suspect penicillins at concentrations of 1 and 20 mg/mL.

*Romano A, Allergy 2004;39:1153-60

Romano, JACI 2012;129:1166

 Positive controls for skin prick and intradermal tests were
performed with histamine (at 10 and 1 mg/mL, respectively). As a
negative control for skin prick and intradermal tests, normal saline
was used.
 We used the suspect aminocephalosporins
(cephalexin, cefaclor, and cefatrizine) at concentrations of 2 and 20
mg/mL.
 Readings of late reactions to intradermal tests were done after
48 and 72 hours; any infiltrated erythema with a diameter larger
than 5 mm was considered a positive reaction.
 Patch tests with benzylpenicillin, ampicillin, and amoxicillin, as well
as with suspect cephalosporins and any other suspect penicillins
(5% in petrolatum), as previously described. Readings were made 15

Romano, JACI 2012;129:1166

Subjects with negative results in all of the above tests or who
displayed a doubtful response underwent challenges with the
suspect cephalosporin concerned: cephalexin (1 g), cefaclor
(500mg), cefixime (400 mg), ceftibuten (400 mg), cefatrizine (500
mg), cefprozil (500 mg), cefpodoxime (200 mg), and cefuroxime
axetil (500 mg) administered orally or
ceftriaxone, ceftazidime, cefotaxime, cefamandole, cefazolin, cefon
icid, and cefepime (1 g) administered intramuscularly.
We administered an initial dose of one hundredth of the
therapeutic one.
In patients with negative results, 1 week later, we administered a
dose of one tenth and, if the result was again negative, a full dose
after another week, as previously described.

Romano, JACI 2012;129:1166

Subjects with negative results in all of the above tests or who
displayed a doubtful response underwent challenges with the
suspect cephalosporin concerned: cephalexin (1 g), cefaclor
(500mg), cefixime (400 mg), ceftibuten (400 mg), cefatrizine (500
Each patient was carefully monitored during
mg), cefprozil (500 mg), cefpodoxime (200 mg), and cefuroxime
axetil challenges until administered
(500 mg) 4 hours after the orally or
ceftriaxone, administration of thecefamandole, cefazolin, cefon
ceftazidime, cefotaxime, dose; complete
icid, and equipment g) administered intramuscularly.
cefepime (1 for cardiopulmonary resuscitation
We administered was initial dose of one hundredth of the
an immediately available.
therapeutic one.
In patients with negative results, 1 week later, we administered a
dose of one tenth and, if the result was again negative, a full dose
after another week, as previously described.

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

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.

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

Romano, JACI 2012;129:1166

• In the present study most delayed skin manifestations in temporal
correlation with cephalosporin treatments did not show a
sensitization on intradermal skin tests nor could they be reproduced
in a provocation test. Thus allergy alone does not seem to be a
sufficient explanation for them.
• It is interesting to note that the mean time for resolution of
generalized skin reactions was significantly longer in the patients
with sensitization than in the patients without sensitization (13.6 vs
3.31 days).

Romano, JACI 2012;129:1166

• Patch tests and delayed-reading intradermal tests are useful tools
in evaluating nonimmediate reactions to ß-lactams, particularly
maculopapular rashes.
• Concentration of 20 mg/mL used for intradermal tests with
aminocephalosporins might reduce the number of subjects with
false-negative results at the concentration of 2 mg/mL.
• In conclusion, intradermal tests are useful tools in identifying
the cephalosporins responsible for nonimmediate reactions.
However, considering the results of the present study, patch
testing is not indicated in subjects with mild nonimmediate
reactions to cephalosporins, such as maculopapular and urticarial
rashes.

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 diagnosis
of a delayed-type allergy.
• Romano et al* used weekly challenges with first one hundredth and
then one tenth and finally one single therapeutic daily dose.
• However, it is well documented that some nonimmediate reactions
appear only after a treatment of several days at full therapeutic
dosage.
•Furthermore, cofactors, such as concomitant viral infections, are
considered important, and these are normally not present during
challenge tests.
•Thus only a positive test result is conclusive, and even challenge
tests are not an unequivocal gold standard.
*Romano A, J Allergy Clin Immunol 2012;129:1166


• Sensitivity requires not only the detection of patients with drug
hypersensitivity in spite of negative skin test results (false-negative
results) but also the number of patients with positive skin test
results 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 result
has no allergy.
• However, the predictive value is not only dependent on test
accuracy but also on the pretest probability. Pretest probability
stands for the probability that a patient has an allergy before
testing. It is influenced inter alia by patient selection.


• Sensitivity requires not only the detection of patients with drug
hypersensitivity in spite of negative skin test results (false-negative
results) but also the number of patients with positive skin test
results 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 result
has no allergy.
• However, the predictive value is not only dependent on test
A low negative predictive value might be
accuracy but also on the pretest probability. Pretest probability
stands for the probability that alow pretest an allergy before
entirely due to a very patient has probability
testing. It is influenced inter alia by patient selection.


Avoiding further use of the incriminated drug without performing a
challenge 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 replace
and there is an urgent need for this treatment, a stepwise (graded)
challenge might be an option, hoping to eliminate those reactions
that are due to strong sensitizations.
Altogether, the situation is not yet satisfying, and improvements in
in vivo and in vitro evaluations of these reactions are urgently
needed.

Non-steroidal
anti-
inflammatory
drugs (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 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 % members with multiple drug
intolerance intolerance syndrome
syndrome (MDIS)
defined by 3 or more 4 –
3 –
“allergies”.
2 –
 2,375,424 health
plan members.
2.1%
1 –



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;
heavier, BMI 29.3;
“allergies”.
3 –
and likely to be
2 –
female,
 2,375,424 health 2.1%
84.9%
plan members. 1 –



•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.

What 2012 drug allergy

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