Clinical Allergy – Research Article

Int Arch Allergy Immunol Received: December 20, 2017

Accepted after revision: January 24, 2018
DOI: 10.1159/000487556 Published online: April 3, 2018

Prevalence of Hypersensitivity Reactions in

Children Associated with Acetaminophen:
A Systematic Review and Meta-Analysis
Sofianne Gabrielli Alexandra Langlois Moshe Ben-Shoshan
Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Centre,
Montreal, QC, Canada

Keywords ic epidermal necrolysis, fixed drug eruptions, and cross-in-

Acetaminophen · Allergy · Hypersensitivity · Paracetamol · tolerance reactions. Five pediatric studies were included in
Pediatrics our meta-analysis. The prevalence of acetaminophen hyper-
sensitivity reaction among children undergoing oral chal-
lenge was 10.1% (95% confidence interval 4.5–15.5). Conclu-
Abstract sion: Future studies assessing the risk of immediate and non-
Background: Acetaminophen is the most commonly used immediate hypersensitivity reactions to acetaminophen and
antipyretic in children. However, there are limited data as- elucidating the mechanism of acetaminophen hypersensi-
sessing hypersensitivity reactions related to acetaminophen tivity reactions are required. © 2018 S. Karger AG, Basel
usage. Objectives: To conduct a systematic review to char-
acterize reported reactions to acetaminophen in adults and
children, and perform a meta-analysis to assess the preva-
lence of acetaminophen hypersensitivity in children with a Introduction
suspected acetaminophen allergy. Methods: We performed
a systematic review of studies reporting hypersensitivity re- Acetaminophen is the most commonly used antipyret-
actions to acetaminophen by searching 2 electronic data- ic medication in children and is also often used to treat
bases. From the selected studies, we included those assess- pain [1]. Although hepatotoxicity related to acetamino-
ing the prevalence of acetaminophen hypersensitivity by phen overdosing has been well documented [2], acet-
performing oral challenge in our meta-analysis. Results: aminophen hypersensitivity is a rare event [3], and very
Eighty-five studies were included in the systematic review, little is known about the hypersensitivity reactions related
assessing a total of 1,030 participants. Immediate (within 1 h to appropriate dosing. Most reported cases of hypersen-
of exposure) hypersensitivity reactions were reported in sitivity reactions to acetaminophen involve the skin, in-
> 25% of the articles, while cutaneous nonimmediate reac-
tions were similarly reported in about 25% of the articles. The
remaining articles reported Steven-Johnson syndrome/tox- Edited by: H.-U. Simon, Bern.
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Univ. of California Santa Barbara

© 2018 S. Karger AG, Basel Correspondence to: Dr. Sofianne Gabrielli

McGill University Health Centre, Montreal Children’s Hospital
1001 Boulevard Decarie
E-Mail [email protected]
Montreal, QC H3A 3J1 (Canada)
www.karger.com/iaa
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E-Mail sofiannegabrielli @ gmail.com

cluding nonimmediate cutaneous eruptions [4], fixed Methods
drug eruptions [5], Steven-Johnson syndrome (SJS) and
Data Sources and Searches
toxic epidermal necrolysis (TEN) [6, 7], and anaphylaxis We conducted a systematic review and meta-analysis of studies
[8]. A type I hypersensitivity reaction, or immediate hy- that reported the prevalence of hypersensitivity among patients
persensitivity reaction, occurs within <1 h after drug ex- reporting a reaction to acetaminophen. The review was conducted
posure, and includes symptoms of urticaria, angioedema, using the PubMed and Embase databases of work published in
wheezing, hypotension, abdominal pain, and diarrhea English and French in the past 10 years, i.e., from January 2007 to
January 2017, inclusively.
[9]. Type IV hypersensitivity reactions are the most com-
mon type of nonimmediate reactions, developing 6 h to Inclusion and Exclusion Criteria
10 days after exposure. The reaction is T cell-mediated We included relevant studies on both children and adults for
and usually manifests as a delayed cutaneous reaction, the systematic review. We focused on studies evaluating both im-
but may have various clinical presentations [9]. Reactions mediate and nonimmediate reactions to acetaminophen. To select
the appropriate studies from the search results, the general topic
to acetaminophen are reported mostly in association with of each article was assessed from the abstract. In certain countries,
suspected reactions to nonsteroidal anti-inflammatory acetaminophen is best known under the name paracetamol. We
drugs (NSAIDs) [3, 4]. Given that there are no validated therefore included this nomenclature into our research. Studies
skin tests, establishing the diagnosis of acetaminophen not pertaining to acetaminophen hypersensitivity were immedi-
hypersensitivity relies completely on conducting oral ately rejected. The articles were then read completely, and were
rejected if they were not original articles or had no history consis-
challenges [10, 11]. tent with acetaminophen hypersensitivity.
In studies assessing tolerance for both NSAIDs and For the meta-analysis, studies were only eligible if the sample
acetaminophen, it is reported that the prevalence of acet- size was ≥10, and if they had established the prevalence of acet-
aminophen hypersensitivity in children reporting allergy aminophen hypersensitivity by skin testing or oral challenge. Ad-
to NSAIDS is 4–25% [10, 12]. However, despite the wide- ditionally, studies evaluating cross-intolerance to acetaminophen
in patients reporting NSAID hypersensitivity were excluded from
spread use of acetaminophen in pediatrics, there are lim- the meta-analysis.
ited data regarding the true risk of acetaminophen hyper-
sensitivity in children suspected to have sensitivity to this Quality Assessment
drug. We aimed to review studies on acetaminophen al- The quality of the remaining articles was then assessed (Table
lergy in adults and children, and to define the prevalence 1). The quality assessment process for each article included meth-
ods for identifying sampling biases, testing, and data collection
of acetaminophen hypersensitivity in cases with suspect- methods, and the population’s composition, in compliance with
ed reactions to acetaminophen in children. We will pres- the PRISMA guidelines for systematic reviews. The leading author
ent a pediatric case of an established acetaminophen hy- (S.G.) and two coauthors (M.B.-S. and A.L.) independently evalu-
persensitivity, and conduct a systematic review to charac- ated each paper’s quality.
terize these reactions in children.
Statistical Analysis
Using STATA v12 software, a meta-analysis was conducted to
compile the data obtained from the systematic review. The author,
Case Report year, country, and design of the study, the diagnostic allergy test
performed, and the authors’ definition of a positive skin test and/
A 6-year-old boy was referred to our allergy clinic for the inves- or oral challenge were also collected. For each study, the sample
tigation of a possible hypersensitivity to acetaminophen. At the age size was collected as the total number of patients undergoing an
of 5 years, the patient was treated at home with acetaminophen for oral challenge to acetaminophen, and the numerator was defined
fever, and developed pancorporal urticaria with swelling and pruri- to be the number of patients with a positive result.
tus of the eyes 45 min after ingestion. The reaction was treated with
oral antihistamines, and resolved completely in 1.5 h. This was not
his first exposure to the drug, with at least 1 previous episode of ur-
ticaria after acetaminophen exposure reported. The patient has a
known allergy to cats. We conducted a graded oral challenge to Results
acetaminophen (Tempra; 50 mg and 20 min later, 500 mg) at the
allergy clinic. Three hours after the 500-mg dose, while at home, the Search Results
patient experienced mild urticaria and angioedema, was treated The initial PubMed and Embase searches yielded 415
with oral antihistamines, and returned to the emergency depart- and 407 results, respectively, and 631 records were ex-
ment. At the emergency department, he was prescribed another oral
antihistamine (cetirizine) and instructed to avoid acetaminophen. cluded because they were not relevant. Of the remaining
The symptoms resolved after 24 h. The patient returned to our clin- 189 records, 88 were rejected as they were conference ab-
ic 1 week later for oral challenge with ibuprofen, which was negative. stracts, 11 as they were reviews, 1 as it was a question-and-
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2 Int Arch Allergy Immunol Gabrielli/Langlois/Ben-Shoshan

DOI: 10.1159/000487556
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 Table 1. Methodological quality of studies included in the meta-analysis

First author, year External validity Internal validity Detection

Review of Acetaminophen
patients presented patients STs tested with a positive a positive OC considered OC protocol differences assessed type of study
with suspected presented with conducted OC when ST reaction OC reaction positive based between NSAID-H to
acetaminophen suspected ST negative? was clearly was clearly on objective sexes ensure no
hypersensitivity NSAID-H defined defined signs assessed coreactivity

Hypersensitivity Reactions in Children

Choi [13], ✓ n.a. ✓1 n.a. ✓ ✓ divided doses every 30–60 min until ✓ retrospective
2016 cumulative dose close to the daily dose
was reached

Topal [14], ✓ ✓ ✓ ✓ ✓ ✓ ✓ 4 or 5 escalating doses administered at ✓ ✓ retrospective

2016 60-min intervals until maximum
weight-adjusted single dose was reached

Guvenir ✓ ✓ ✓ ✓ ✓ ✓ divided doses every 30 min until ✓ prospective

[15], 2015 cumulative dose close to the age- and
weight-adjusted daily dose was reached

Loh [16], ✓ ✓ n.a. ✓1 n.a. ✓ ✓ 4 doses of 25% of the age-appropriate ✓ retrospective

2015 daily dose administered every 60 min

Rojas-Perez- ✓ ✓ ✓ ✓ single-blind placebo step followed by 3 ✓ prospective

Ezquerra [17], increasing doses (250, 500, and 1,000
2014 mg) at 60-min intervals

Renaudin [18], ✓ ✓ ✓ ✓ ✓ ✓ not described ✓ retrospective

2013

Thalayasingam ✓ ✓ ✓ ✓ ✓ ✓ administered in incremental doses ✓ retrospective

[19], 2013 (1:100, 1:10, and remaining therapeutic
dose) at 20-min intervals

DOI: 10.1159/000487556
Int Arch Allergy Immunol
Rutkowski ✓ ✓ ✓ ✓ ✓ ✓ starting dose determined by severity of ✓ retrospective
[3], 2012 the index reaction (range 50–1,000 mg)
was doubled at 60-min intervals until
1,000 mg reached

Chalabianloo ✓ ✓ ✓ ✓ ✓ ✓ gradually increasing doses ✓ retrospective

[20], 2011 (a quarter, a half, and the whole single
therapeutic dose) at 30-min intervals

Hassani ✓ ✓ n.a. ✓1 n.a. ✓ ✓ received a first dose of 1 or 10 mg, ✓ ✓ prospective

[21], 2008 depending on the severity of the
reaction; gradually increased at
20-min intervals until the appropriate
age- and weight-adjusted daily
cumulative dose was reached; for the
next 2 days, half the therapeutic dose at
9 a.m., half at 12 p.m., and then observed

NSAID-H, nonsteroidal anti-inflammatory drug hypersensitivity; ST, skin test; OC, oral challenge; n.a., not applicable.
1 OC was performed with no prior ST.

3
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 415 records identified through 407 records identified through
database searching PubMed database searching Embase

820 records after duplicates 631 records removed as

removed not relevant

1 record removed as it was 189 records assessed 88 records removed as they

a Q&A for eligibility were conference abstracts

1 article removed as the history 11 records removed as they

was not consistent with allergy were reviews

3 articles removed since the

full-texts were unable to be found
despite contacting authors

4 articles excluded as diagnostic 85 articles included in 63 articles excluded as there were

testing was not performed the qualitative analysis >10 patients in the cohort

1 article excluded as sample size 7 articles excluded as only cross-

not mentioned allergy was assessed

10 articles included in
meta-analysis

Fig. 1. Flow diagram illustrating study selection process.

Study No. ES (95% CI) Weight, %

1 33.33 (6.66–60.01) 4.35

2 8.33 (–2.72 to 19.39) 25.31

3 7.55 (0.44–14.66) 61.20

4 33.33 (–4.39 to 71.05) 2.18

5 16.67 (–4.42 to 37.75) 4.35

OS (I2 = 25.1%, p = 0.254) 10.06 (4.50–15.63) 100.00

–71.1 0 71.1

Fig. 2. Prevalence of established hypersensitivity to acetaminophen in children among those undergoing oral
challenge with the drug. OS, overall survival; ES, effect size.
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Table 2. Prevalence of acetaminophen hypersensitivity among those undergoing oral challenge to acetaminophen

First author, year Country Population Hypersensitivity Patients that Confirmed SE Prevalence Confidence
reaction type underwent by OC, n interval
OC, n

Choi [13], 2016 Korea pediatric unknown 12 4 13.61 33.30% 6.66 to 60.01
Topal [14], 2016 Turkey pediatric immediate 24 2 5.64 8.33% –2.72 to 19.39
Guvenir [15], 2015 Turkey pediatric immediate and 53 4 3.63 7.55% 0.436 to 14.66
nonimmediate
(fixed drug eruption)
Loh [16], 2015 Singapore pediatric immediate 6 2 19.25 33.33% –4.39 to 71.05
Rojas-Perez-Ezquerra Spain pediatric/ immediate and 10 10 0.00 100.00%
[17], 2014 adult nonimmediate
(fixed drug eruption, other)
Renaudin [18], 2013 France pediatric/ immediate 10 5 15.81 50.00% 19.01 to 80.99
adult
Thalayasingam [19], 2013 Singapore adult unknown 8 0 0.00 0.00%
Rutkowski [3], 2012 UK pediatric/ immediate and 31 15 8.98 48.39% 32.79 to 65.98
adult nonimmediate (other)
Chalabianloo [20], 2011 Norway pediatric/ immediate and 30 1 3.28 3.33% –3.09 to 9.76
adult nonimmediate (other)
Hassani [21], 2008 France pediatric immediate 12 2 10.76 16.67% –4.42 to 37.75

OC, oral challenge; SE, standard error.

answer article, 3 since the full-text articles could not be articles were included in the meta-analysis since they had
found despite contacting the authors, and 1 because the acceptable methods and they were assessed for their qual-
history was not consistent with acetaminophen hyper- ity (Table 1). This represents a total of 259 patients evalu-
sensitivity (Fig. 1). The 85 remaining articles [3, 9, 13–21, ated for a suspicion of acetaminophen hypersensitivity.
24–97] were included in the qualitative analysis (online
suppl. Table S1; for all online suppl. material, see www. Prevalence of Hypersensitivity to Acetaminophen in
karger.com/doi/10.1159/000487556). Patients with a Positive Oral Challenge Result
For both adult and pediatric patients, the meta-analy-
Systematic Review sis of patients positive on oral challenge to acetamino-
The 85 articles included in the systematic review rep- phen resulted in a pooled estimate for the prevalence of
resented 1,030 adult and pediatric patients with both im- hypersensitivity to acetaminophen of 10.1% (95% confi-
mediately and nonimmediately reported hypersensitivity dence interval [CI] 6.0–14.2; Table 2; online suppl. Fig.
reactions to acetaminophen. Over one-quarter of the ar- S1). The pooled estimate for the prevalence of hypersen-
ticles reported immediate reactions, including anaphy- sitivity to acetaminophen for only the pediatric patients
laxis. Almost 25% of the articles reported nonimmediate, was 10.1% (95% CI 4.5–15.6; Fig. 2).
cutaneous reactions, which excluded SJS/TEN and fixed
drug eruption reactions. The other 50% of articles de-
scribed SJS/TEN, fixed drug eruptions, cross-intolerance Discussion
reactions, and unknown reactions.
This is the first study to provide a pooled estimate of
Meta-Analysis acetaminophen hypersensitivity among children with
For the meta-analysis, 63 of the 85 articles were ex- suspected reactions. Our findings revealed that 10% of the
cluded, as they did not have a sample size ≥10. Of the re- children who underwent an oral challenge to acetamino-
maining articles, 7 were excluded as they only assessed phen had a true hypersensitivity. Due to its widespread
patients reporting NSAID hypersensitivity, 4 because di- use in children, pediatricians should be made aware of the
agnostic allergy testing was not performed, and 1 as the potential for hypersensitivity to acetaminophen in chil-
sample size was not reported (Fig. 1). The remaining 10 dren. By conducting a systematic review of 85 articles, our
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Review of Acetaminophen Int Arch Allergy Immunol 5

Hypersensitivity Reactions in Children DOI: 10.1159/000487556
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results suggest that the percentage of reported reactions to both acetaminophen and NSAIDs. However, in our
were similar for immediate and nonimmediate hypersen- meta-analysis, we included only studies in which acet-
sitivity reactions to acetaminophen. The majority of the aminophen hypersensitivity reactions were reported and
articles about pediatric patients included in our meta- assessed by oral challenge. To ensure no cross-intoler-
analysis report immediate-type reactions (Table 2), con- ance, the majority of these studies also assessed hypersen-
sistent with other studies reporting that acetaminophen sitivity to NSAIDs. A potential within-study bias could
and ibuprofen are the most common elicitors of immedi- have been introduced because some reports in our meta-
ate-type reactions in children [22]. While the mechanism analysis did not clearly indicate the number of patients
underlying acetaminophen allergy is not yet fully under- undergoing oral challenge to acetaminophen, and not all
stood, we can hypothesize that immediate reactions are patients underwent the oral challenge. Another limita-
likely IgE-mediated, as described by de Paramo et al. [23]. tion of this study is that articles reporting positive oral
Studies also report a high risk of hypersensitivity to acet- challenge did not distinguish between immediate and
aminophen in patients who experience ibuprofen-in- nonimmediate hypersensitivity reactions. Hence, at this
duced anaphylaxis [24], so it is important to assess cross- point, we are unable to report the risk of immediate ver-
intolerance to acetaminophen in such patients. sus nonimmediate hypersensitivity reactions to acet-
Our systematic review revealed that in almost half of aminophen. Another potential limitation relates to the
the articles, an oral challenge to acetaminophen was used, fact that the studies reviewed did not mention the brand
rather than skin tests, to evaluate and diagnose a con- of acetaminophen used for oral challenge or assess hyper-
firmed hypersensitivity reaction. Due to the absence of sensitivity to acetaminophen versus other active and in-
standardized skin tests for acetaminophen [12], it is not active ingredients in the acetaminophen preparation, e.g.,
surprising that the diagnostic approach relies mainly on mannitol.
oral challenge. Our data reinforce the safety of oral chal- Future studies are required to develop biomarkers to
lenge to determine acetaminophen hypersensitivity [25], diagnose true acetaminophen hypersensitivity and devel-
given that the reactions reported were all mild (online op safe and appropriate oral challenge protocols. Genetic
suppl. Table S1) and that skin tests are not standardized. markers associated with an increased risk of acetamino-
Given that the majority of those suspected have negative phen hypersensitivity could provide screening tools for
challenges, all reported cases should be appropriately individuals suspected to be at an increased risk, e.g., those
evaluated in order to correctly establish the diagnosis of with previous reactions to NSAIDs.
acetaminophen hypersensitivity.
Given the overlap in 95% CIs of prevalence in adult
and pediatric patients and in pediatric patients only, our Disclosure Statement
analysis did not actually establish a higher risk of acet-
The authors have no conflicts of interest to declare.
aminophen hypersensitivity in the pediatric population.
Upon analysis of the 5 articles assessing pediatric patients
only, the pooled estimate for the prevalence of acetamin-
Funding Sources
ophen hypersensitivity did not change significantly; how-
ever, the I2 value fell to < 50% indicating less variation There was no funding.
across the studies (Fig. 2). Factors such as the age of pa-
tients, failing to control for gender effect, and the differ-
ent definitions of the term “hypersensitivity reactions” Author Contributions
could account for the high heterogeneity found when
conducting a meta-analysis of all patients (online suppl. Sofianne Gabrielli contributed to the conceptualization, meth-
Fig. S1). The managing physicians should, appropriately, odology, and investigation. She curated the data, performed for-
mal analysis, wrote the initial manuscript, and edited the manu-
assess all cases of suspected hypersensitivity to acetamin- script. Moshe Ben-Shoshan was involved in the supervision and
ophen in order to avoid mislabeling of patients as allergic oversight, and contributed to the methodology, data curation, and
to acetaminophen. formal analysis. He was involved in reviewing and editing the man-
Our study has potential limitations. A selection bias uscript. Alexandra Langlois contributed to data curation and for-
could be found in studies included in our systematic re- mal analysis. She was involved in editing and reviewing the manu-
script.
view, i.e., some reports assessed acetaminophen hyper-
sensitivity in patients reporting hypersensitivity reactions
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6 Int Arch Allergy Immunol Gabrielli/Langlois/Ben-Shoshan

DOI: 10.1159/000487556
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Review of Acetaminophen Int Arch Allergy Immunol 7

Hypersensitivity Reactions in Children DOI: 10.1159/000487556
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Review of Acetaminophen Int Arch Allergy Immunol 9

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