Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children

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DOI: 10.1542/peds.2005-0969 · Source: PubMed
Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs), mainly ibuprofen, are used extensively among children as analgesic and antipyretic agents. Our initial survey in the Kendang Kerbau Children's Hospital in Singapore showed NSAIDs to be the second most common adverse drug reaction-causing medications among children of Asian descent. We attempted to characterize the clinical and epidemiologic profile of NSAID reactions in this group of patients. A retrospective case series from a hospital-based pediatric drug allergy clinic was studied. A diagnosis of NSAID hypersensitivity was made with a modified oral provocation test. Atopy was evaluated clinically and tested with a standard panel of skin-prick tests. We excluded from analysis patients with any unprovoked episodes of urticaria and/or angioedema, patients < 1 year of age, and patients who refused a diagnostic challenge test. Between March 1, 2003, and February 28, 2004, 24 patients, including 14 male patients (58%) and 18 Chinese patients (75%), with a mean age of 7.4 years (range: 1.4-14.4 years), were diagnosed as having cross-reactive NSAID hypersensitivity. A family history consistent with NSAID hypersensitivity was elicited for 17% of patients. None of the patients reported any episodes of angioedema/urticaria unrelated to NSAIDs. The median cumulative reaction-eliciting dose was 7.1 mg/kg. Facial angioedema developed for all patients (100%) and generalized urticaria for 38% of challenged patients, irrespective of age. There was no circulatory compromise, but respiratory symptoms of tachypnea, wheezing, and/or cough were documented for 42% of patients. A cross-reactive hypersensitivity response to acetaminophen was documented for 46% of our patients through their history and for 25% through diagnostic challenge. Compared with patients with suspected adverse drug reactions to antibiotics, patients in the NSAID group were older (7.4 vs 4.8 years) and more likely to have a diagnosis of asthma (odds ratio: 7.5; 95% confidence interval: 3.1-19). Early presentations of facial angioedema and urticaria are key features of dose- and potency-dependent, cross-reactive reactions to NSAIDs in a subpopulation of young, Asian, atopic children. Significant overlap with acetaminophen hypersensitivity, especially among very young patients, for whom the use of a cyclooxygenase-2-specific medication may not be feasible, severely limits options for medical antipyretic treatment.
DOI: 10.1542/peds.2005-0969
; originally published online October 17, 2005; 2005;116;e675Pediatrics
See, Anne Goh, Jenny Tang Poh Lin and Oh Moh Chay
Mona Iancovici Kidon, Liew Woei Kang, Chiang Wen Chin, Lim Siok Hoon, Yvonne
Atopic Children
Hypersensitivity to Nonsteroidal Antiinflammatory Drugs Among Young, Asian,
Early Presentation With Angioedema and Urticaria in Cross-reactive
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Early Presentation With Angioedema and Urticaria in Cross-reactive
Hypersensitivity to Nonsteroidal Antiinflammatory Drugs Among Young,
Asian, Atopic Children
Mona Iancovici Kidon, MD; Liew Woei Kang, MBBS; Chiang Wen Chin, MBBS; Lim Siok Hoon, MBBS;
Yvonne See, MBBS, MMed(Paeds), MRCP(Paeds), FAMS; Anne Goh, MBBS, MMed(Paeds), FAMS;
Jenny Tang Poh Lin, MBBS, MMed(Paeds), FAMS; and Oh Moh Chay, MBBS, MMed(Paeds), FAMS
ABSTRACT. Objective. Nonsteroidal antiinflamma-
tory drugs (NSAIDs), mainly ibuprofen, are used exten-
sively among children as analgesic and antipyretic
agents. Our initial survey in the Kendang Kerbau Chil-
dren’s Hospital in Singapore showed NSAIDs to be the
second most common adverse drug reaction-causing
medications among children of Asian descent. We at-
tempted to characterize the clinical and epidemiologic
profile of NSAID reactions in this group of patients.
Methods. A retrospective case series from a hospital-
based pediatric drug allergy clinic was studied. A diag-
nosis of NSAID hypersensitivity was made with a mod-
ified oral provocation test. Atopy was evaluated
clinically and tested with a standard panel of skin-prick
tests. We excluded from analysis patients with any un-
provoked episodes of urticaria and/or angioedema, pa-
tients <1 year of age, and patients who refused a diag-
nostic challenge test.
Results. Between March 1, 2003, and February 28,
2004, 24 patients, including 14 male patients (58%) and 18
Chinese patients (75%), with a mean age of 7.4 years
(range: 1.4–14.4 years), were diagnosed as having cross-
reactive NSAID hypersensitivity. A family history con-
sistent with NSAID hypersensitivity was elicited for 17%
of patients. None of the patients reported any episodes of
angioedema/urticaria unrelated to NSAIDs. The median
cumulative reaction-eliciting dose was 7.1 mg/kg. Facial
angioedema developed for all patients (100%) and gen-
eralized urticaria for 38% of challenged patients, irre-
spective of age. There was no circulatory compromise,
but respiratory symptoms of tachypnea, wheezing,
and/or cough were documented for 42% of patients. A
cross-reactive hypersensitivity response to acetamino-
phen was documented for 46% of our patients through
their history and for 25% through diagnostic challenge.
Compared with patients with suspected adverse drug
reactions to antibiotics, patients in the NSAID group
were older (7.4 vs 4.8 years) and more likely to have a
diagnosis of asthma (odds ratio: 7.5; 95% confidence in-
terval: 3.1–19).
Conclusions. Early presentations of facial angioedema
and urticaria are key features of dose- and potency-depen-
dent, cross-reactive reactions to NSAIDs in a subpopula-
tion of young, Asian, atopic children. Significant overlap
with acetaminophen hypersensitivity, especially among
very young patients, for whom the use of a cyclooxygenase-
2-specific medication may not be feasible, severely limits
options for medical antipyretic treatment. Pediatrics 2005;
116:e675–e680. URL: www.pediatrics.org/cgi/doi/10.1542/
peds.2005-0969; nonsteroidal antiinflammatory drug, chil-
dren, urticaria, atopy, angioedema.
ABBREVIATIONS. NSAID, nonsteroidal antiinflammatory drug;
COX, cyclooxygenase; ADR, adverse drug reaction; AERD,
aspirin-exacerbated respiratory disease.
A
spirin and other nonsteroidal antiinflamma-
tory drugs (NSAIDs) are a widely used group
of medications whose mechanism of action
involves inhibition of prostaglandin production
through blockade of the cyclooxygenase (COX) en-
zymes known as COX-1 and COX-2. This blockade
also results in the shunting of arachidonic acid me-
tabolism toward the 5-lipoxygenase pathway, result-
ing in increased production and release of cysteinyl
leukotrienes.
Acetaminophen, the most ubiquitously used anti-
pyretic medication for children worldwide, is an
“old” medication whose mechanism of action has
been defined recently. Acetaminophen has no signif-
icant action on peripheral COX-1 and COX-2, but its
antipyretic effect is consistent with a central nervous
system-mediated activity at a new, previously un-
known, enzyme, ie, COX-3, which is found in the
brain and spinal cord and is distinct from the 2
already known COX enzymes.
1
It is now thought
that this selective inhibition of the enzyme COX-3 in
the brain and spinal cord explains the effectiveness
of acetaminophen in relieving pain and reducing
fever without unwanted gastrointestinal side effects.
Although it has almost no antiinflammatory effects
(even at high doses) and thus is not a NSAID, acet-
aminophen, like aspirin and the NSAIDs, is an inhib-
itor of prostaglandin synthesis. This may explain the
published incidence of sensitivity to acetaminophen
among patients with cross-reactive NSAID hyper-
sensitivity, ie, an average of 7% (0–16%).
2
From the Department of Pediatric Medicine, Kendang Kerbau Children’s
Hospital, Singapore.
Accepted for publication May 31, 2005.
doi:10.1542/peds.2005-0969
No conflict of interest declared.
Address correspondence to Mona Iancovici Kidon, MD, Rheumatology,
Immunology, and Allergy Service, Department of Pediatric Medicine, Ken-
dang Kerbau Children’s Hospital, 100 Bukit Timah Rd, 229899 Singapore.
E-mail: drkidon@yahoo.com
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad-
emy of Pediatrics.
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NSAIDs are a common factor in adverse drug
reactions (ADRs) among adults.
3
The average rela
-
tive risk of urticaria/angioedema in a large cohort of
patients exposed to these agents was between 1.1%
(for those who used NSAIDs chronically) and 3.6%
(for those who took NSAIDs intermittently, for treat-
ment of acute pain). NSAID hypersensitivity reac-
tions are probably less common among children. In a
population-wide screen, the estimated incidence of
ADRs attributable to NSAIDs among children was
0.3%.
4
In fact, ibuprofen (a propionic acid-derivative
NSAID) suspension was approved in 1995 for non-
prescription use for children, after a thorough review
of a stellar safety profile in the United States.
5
Nev
-
ertheless, in their report from a survey of 36 years of
suspected ADR-associated fatalities among children
in the United Kingdom, Clarkson and Choonara
6
showed that NSAIDs were implicated in 3% (12
cases) of the 390 fatality cases reviewed.
There is a known increased incidence of ADRs
among patients with a history of drug hypersensitiv-
ity, with increased age, with the presence of an as-
sociated chronic disease, with the use of multiple
medications, and with female gender in the older age
group.
7
Traditionally, atopic patients are not at in
-
creased risk of developing ADRs, although, if a pen-
icillin allergy develops, then asthmatic individuals
are more likely to experience a severe or life-threat-
ening reaction.
8
NSAID hypersensitivity, however,
seems to be associated positively with the presence
of atopy.
4,9
Among highly selected children with
difficult-to-treat asthma, the incidence of aspirin-ex-
acerbated respiratory disease (AERD) is almost 30%,
mostly among female patients with associated sinus-
itis and early onset of disease
10
and in the context of
the triad of AERD, nasal polyps, and severe asth-
ma.
11
There is, however, significant controversy re
-
garding the importance of these challenge-derived
findings for selected patients in the routine treatment
of children with asthma. Lesko et al
12
showed a
decrease in outpatients visits for asthma exacerba-
tions among asthmatic children after short-term use
of ibuprofen and definitely no increase in the rate of
hospitalization for these children. A recent review of
the subject even suggested that ibuprofen, as an an-
tiinflammatory medication, may be of use in the
treatment of acute exacerbations among asthmatic
children
13
In recent years, a new classification of NSAID hy-
persensitivity has been proposed
14
and extended to
the pediatric age group.
15
Basically, reactions are
either dose dependent and likely related to the anti-
COX-1 effect of the medication (ie, AERD, urticaria/
angioedema among patients with chronic urticaria,
urticaria/angioedema among patients without
chronic urticaria, and mixed/anaphylactoid reac-
tions) or activity independent and most likely immu-
nologically mediated; the latter reactions are drug
specific and require a period of sensitization before
the reaction can be elicited.
AERD has been studied extensively, with ad-
vances being made in the understanding of the pu-
tative mechanism of first-exposure reactions to
chemically dissimilar drugs,
16,17
the genetic back
-
ground,
18–20
and the rationale for the relatively safe
use of specific COX-2 inhibitors among such pa-
tients.
21–23
Classically, patients with AERD and the
aspirin triad (asthma, nasal polyps, and aspirin hy-
persensitivity) are nonatopic adults with difficult-to-
control asthma, persistent sinusitis, and nasal polyps.
Protocols for oral and inhalational provocation tests
are in use for the diagnosis of AERD,
24
and the
incidence of AERD established with such tests was
21% among adults and 0% to 5% among nonse-
lected children with asthma.
2
The same systematic
review established that most patients with AERD
also reacted to ibuprofen, naproxen, and diclofenac,
whereas the incidence of cross-reactivity to acet-
aminophen among such patients was only 7% (range:
0–16%).
2
The likelihood of acetaminophen cross-re
-
activity seems to be related inversely to the reaction-
eliciting aspirin dose.
Urticaria and angioedema have been documented
as associated reactions among patients with
AERD,
25,26
but they are not the hallmarks of these
reactions. Urticaria and angioedema with multiple
NSAIDs are observed among patients with chronic
urticaria, but usually these are not associated with
respiratory disease. The incidence of facial angio-
edema and NSAID hypersensitivity among atopic
children was studied by Capriles-Behrens, et al
27
in a
10-year, retrospective, random chart review of pa-
tients attending an allergy clinic for treatment of
asthma and/or allergic rhinitis. In this group of chil-
dren, 41 of 1007 (4.1%) experienced documented fa-
cial angioedema in response to NSAIDs, with the
incidence increasing significantly with age, ie, 2% at
5 years of age, compared with 21% (7 of 32 pa-
tients) in the 16- to 21-year-old group. The exact
mechanism of aspirin-induced urticaria and angio-
edema is unknown,
28
but the difference between pa
-
tients who develop AERD and those who develop
urticaria is not explained easily by metabolic differ-
ences in the production of different eicosanoids.
29
To date, there have been no publications regarding
the incidence and reaction profile of aspirin or
NSAID hypersensitivity among Asian children but,
interestingly, 5-lipoxygenase-related genetic markers
associated strongly with AERD in a Korean popula-
tion
19,20
were not found to be significant in a study
performed in the United States.
30
In our population,
2.7% of pediatric patients admitted to the Kendang
Kerbau Children’s Hospital in Singapore reported
histories of ADRs, mostly cutaneous.
31
The most fre
-
quently involved drugs in this patient group were
-lactam antibiotics. In this same survey, NSAIDs
were the second most common ADR-causing medi-
cations among children of Asian descent. To define
more clearly the clinical characteristics and associ-
ated risk factors for NSAID hypersensitivity in our
population, we performed a retrospective review of
data for patients from our drug allergy outpatient
clinic from March 2003 to February 2004. We report
on a group of 24 young children with cross-reactive
urticaria/angioedema anaphylactoid reactions to
multiple NSAIDs who were examined within 1 year
in the pediatric allergy clinic of the Kendang Kerbau
Children’s Hospital in Singapore.
e676 CROSS-REACTIVE HYPERSENSITIVITY TO NSAIDs
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METHODS
Patients
The study involved a retrospective case series from the pediat-
ric drug allergy clinic at Kendang Kerbau Children’s Hospital in
Singapore. Between March 2003 and February 2004, all patients
referred to the pediatric allergy outpatient clinic at Kendang Ker-
bau Children’s Hospital in Singapore with suspected hypersensi-
tivity to NSAIDs were evaluated by an experienced pediatric
allergist and offered an oral provocation test as needed. Informa-
tion on early birth and exposure data, social, economic, and ma-
ternal factors, additional diagnoses and medication usage, family
history of allergic disease, and exposure to house pets and passive
smoking was recorded in each patient’s chart.
Patients were included in the analysis if they had confirmed
hypersensitivity to NSAIDs. Diagnosis of NSAID hypersensitivity
was made either with a clear history of recurrent reactions to
multiple NSAIDs or with a modified oral provocation test. Atopy
was confirmed with skin-prick tests with a standard panel of
respiratory allergens. Additional provocation tests with COX-2-
specific NSAIDs were performed as needed. Demographic and
clinical data were compared with those for a group of patients
referred in the same time period because of ADRs to a
-lactam
antibiotic. We excluded from analysis patients with any unpro-
voked episodes of urticaria and/or angioedema, patients 1 year
of age, and patients who refused a diagnostic challenge test.
Oral Provocation Tests
Aspirin oral provocation tests were performed in the outpatient
clinic of the Kendang Kerbau Children’s Hospital. Before test
administration, patients were examined and interviewed and vital
signs, including heart rate, respiratory rate, systolic and diastolic
blood pressure, oxygen saturation, and peak flow measurement,
were recorded. All patients with a prior diagnosis of asthma
underwent a pulmonary function test, and challenge was per-
formed only if the forced expiratory volume in 1 second was
80% of the predicted value. Asthmatic patients continued to use
all inhaled medications in their scheduled regimen. Challenge was
not performed if the patient required orally administered steroids
or other orally administered medications. Administration of all
antihistamines was stopped 1 week before testing. The recom-
mended schedule (to be used in patients with nonspecific NSAID-
induced urticaria and angioedema without evidence of chronic
urticaria) of doubling the initial 30-mg dose every 30 minutes
27
caused quite severe reactions to develop, mostly after the end of
the challenge. Therefore, we modified the regimen so that the
initial dose was 50 mg of orally administered aspirin and subse-
quent doses of 50 mg each were administered at hourly intervals,
after monitoring of listed vital signs, if no clinical signs of an ADR
appeared. The maximal cumulative dose was 10 mg/kg body
weight. Patients were monitored in the clinic for 2 hours after
the last ingested dose.
Oral provocation tests with ibuprofen and/or acetaminophen
were performed as needed for diagnostic purposes, with similar
protocols. Oral provocation tests with COX-2-specific inhibitors
(12.5 mg of rofecoxib or 10 mg of valdecoxib) were administered
with 1 dose, with similar follow-up and evaluation protocols.
Patients remained under observation for 4 hours after challenge.
Skin-prick Tests
All tests were performed in the respiratory laboratory by an
experienced technician, with commercial allergen extracts and the
GreerPick skin-prick test device (Greer Laboratories, Lenoir, NC),
and were evaluated by an experienced pediatric allergist. A wheal
diameter of 3 mm, in excess of the negative control finding, was
considered a positive test result. The allergens included in our
panel were produced commercially by Greer Laboratories, except
for the Blomia tropicalis extract, which was produced by the Al-
lergy and Molecular Immunology Laboratory, National Univer-
sity of Singapore. The standard skin-prick test panel included
house dust mite mixture (Dermatophagoides farinae, 5000 allergic
units/mL, plus Dermatophagoides pteronyssinus, 5000 allergic
units/mL, standardized), Blomia tropicalis (0.2 mg protein/mL,
50%, vol/vol, glycerol), cockroach mixture (Periplaneta americana
and Blattella germanica), mixed feathers (chicken, duck, and goose),
canary feathers (Serinus canaria), kapok seeds, Alternaria alternata,
Curvularia spicifera, Cladosporium herbarum, Aspergillus fumigatus,
Candida albicans, cat hair (standardized cat hair, Felis catus [domes-
ticus], 10 000 biological allergic units/mL), dog epithelia (Canis
familiaris), grass mixture (9-grass mixture, standardized), acacia,
melaleuca, beefwood (Australian pine), oil palm, mango blossom,
sage mixture, and weed mixture.
Statistical Analyses
Simple analysis of variance was used for comparison of con-
tinuous data such as age and blood pressure. Logistic regression
analysis was used for comparison of dichotomous values such as
the presence or absence of associated allergic rhinitis and asthma,
and nonparametric tests (Kruskal-Wallis and Mann-Whitney tests)
were used for comparisons between small groups of patients.
SPSS for Windows, version 11.5 (SPSS, Chicago, IL), was used for
all statistical computations.
RESULTS
Between March 1, 2003, and February 28, 2004, 24
patients, including 14 male patients (58%), 18 Chi-
nese patients (75%), and 6 Malay patients, with a
mean age of 7.4 years (range: 1.4 –14.4 years; first
quartile: 4.9 years) were diagnosed in the pediatric
allergy clinic with cross-reactive NSAID hypersensi-
tivity. Clinically significant allergic disease was as-
sociated for 83% of patients; 58% had allergic rhinitis,
46% had asthma, and 29% had atopic dermatitis. A
diagnosis of asthma was more likely in the older age
group. A positive family history of atopy-related
disease was present for 83% of patients, whereas 17%
reported cross-reactive NSAID hypersensitivity
among closely related family members. Skin-prick
tests were positive for 1 aeroallergen for 88% of
patients, mostly for the house dust mites. The clinical
and demographic data for the patients according to
age group are detailed in Table 1. The clinical sever-
TABLE 1. Demographic and Clinical Data for the Patient Cohort
No. of Patients (%) (N 24) P
5y(n 7) 5–10 y (n 11) 10y(n 6)
Male/fe