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Severe Anaphylactic Reaction to Ibuprofen in a Child With Recurrent Urticaria


An acute anaphylactic reaction after a conventional antipyretic dose of ibuprofen was diagnosed in a child with allergic rhinitis, recurrent idiopathic urticaria, and nonimmunologic cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs and acetaminophen. The patient reported several previous, mild (isolated cutaneous) hypersensitivity reactions after exposure to acetaminophen or ibuprofen. There was no evidence of an underlying inflammatory disease except as described above. Patients with chronic or recurrent idiopathic urticaria and those with atopic disease represent groups at increased risk of nonsteroidal antiinflammatory drug hypersensitivity. Mild hypersensitivity reactions to acetaminophen and/or ibuprofen may precede subsequent, more-severe adverse reactions. Risks and benefits of continued use of nonsteroidal antiinflammatory drugs in these children should be carefully considered.
DOI: 10.1542/peds.2006-2634
Yoke Hwee and Ng Kee Chong
Liew Woei Kang, Mona Iancovici Kidon, Chiang Wen Chin, Lim Siok Hoon, Chan
Severe Anaphylactic Reaction to Ibuprofen in a Child With Recurrent Urticaria
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Severe Anaphylactic Reaction to Ibuprofen in a Child
With Recurrent Urticaria
Liew Woei Kang, MBBS, MRCPCH, FAMS
, Mona Iancovici Kidon, MD
, Chiang Wen Chin, BMedSci, MBBS, MRCPCH
Lim Siok Hoon, MBBS, MRCPCH
, Chan Yoke Hwee, MBBS, MMed
, Ng Kee Chong, MBBS, MMed
Paediatric Allergy, Immunology and Rheumatology Service,
Children’s Intensive Care Unit, and
Children’s Emergency Department, KK Women’s and Children’s
Hospital, Singapore;
Children’s Health Centre, Clalit Health Services, Rishon LeZion, Israel
The authors have indicated they have no financial relationships relevant to this article to disclose.
An acute anaphylactic reaction after a conventional antipyretic dose of ibuprofen was diagnosed in a child with
allergic rhinitis, recurrent idiopathic urticaria, and nonimmunologic cross-reactive hypersensitivity to nonsteroidal
antiinflammatory drugs and acetaminophen. The patient reported several previous, mild (isolated cutaneous)
hypersensitivity reactions after exposure to acetaminophen or ibuprofen. There was no evidence of an underlying
inflammatory disease except as described above. Patients with chronic or recurrent idiopathic urticaria and those
with atopic disease represent groups at increased risk of nonsteroidal antiinflammatory drug hypersensitivity. Mild
hypersensitivity reactions to acetaminophen and/or ibuprofen may precede subsequent, more-severe adverse reac-
tions. Risks and benefits of continued use of nonsteroidal antiinflammatory drugs in these children should be
carefully considered.
BUPROFEN, A PROPIONIC-ACID derivative nonsteroidal
antiinflammatory drug (NSAID), is extensively used
in children for analgesia and fever control. Its mecha-
nism of action is the inhibition of prostaglandin produc-
tion by blocking the cyclooxygenase enzymes known as
COX-1 and COX-2, thus shunting arachidonic-acid me-
tabolism, toward the 5-lipoxigenase pathway, resulting
in increased production and release of cysteinyl leuko-
Hypersensitivity reactions to NSAIDs are classified ac-
cording to clinical reaction patterns
and divided into 2
major classification groups. The first group comprises
cross-reactive, most likely COX-inhibitor activity–related
clinical syndromes. These syndromes span the spectrum
from classical “aspirin triad” (aspirin-exacerbated respi-
ratory disease) to isolated urticaria and/or angioedema
reactions, which are more common in adults and chil-
dren with chronic urticaria
but also documented in
otherwise healthy children and adults. The second clas-
sification group contains drug-specific, most likely im-
munologically mediated reaction types, from cellular-
dependent delayed type hypersensitivity to classical type
I immunoglobulin E–mediated anaphylaxis.
The true incidence of NSAID-hypersensitivity reac-
tions in children is unknown and most likely shows a
marked variability in genetically distinct populations.
There is, however, a known increased incidence of the
cross-reactive type of reactions in children with allergic
respiratory disease.
By and large, the most common
manifestations of NSAID hypersensitivity in children are
angioedema and urticaria, but respiratory symptoms
may appear as well.
Patients with chronic urticaria may have exacerba-
tions of their urticaria symptoms after exposure to
NSAIDs. In fact, in some cases, intolerance to NSAIDs is
reported to precede by years the onset of chronic urti-
However, most such reactions are confined to
symptoms of facial angioedema and urticaria exacerba-
tion, and most children with chronic urticaria can toler-
ate recommended doses of acetaminophen safely.
Here we report the case of a young Nepalese boy,
born in Singapore, who presented with a severe anaphy-
lactic reaction after ingestion of ibuprofen.
Key Words: nonsteroidal antiinflammatory drugs, acetaminophen, ibuprofen, child,
allergy, chronic urticaria
Abbreviations: NSAID; nonsteroidal antiinflammatory drug; COX; cyclooxygenase
Address correspondence to Liew Woei Kang, MBBS, MRCPCH, FAMS, Rheumatology, Immunology
and Allergy Service, Department of Pediatric Medicine, KK Women’s and Children’s Hospital, 100
Bukit Timah Rd, Singapore 229899. E-mail:
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2007 by the
American Academy of Pediatrics
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A Nepalese boy who was born in Singapore presented at
12 years of age. He had had a significant history of
recurrent urticaria/angioedema since the age of 5 years,
with a frequency of urticaria/angioedema bouts of once
or twice per month. The episodes were mostly unpro-
voked, but some reported triggers included egg inges-
tion, exercise, and acetaminophen ingestion. The patient
has previously taken egg and acetaminophen with no
apparent problems before the onset of these episodes.
With regards to the adverse drug reactions, there
were encounters with acetaminophen on 3 separate oc-
casions at 6, 8, and 12 years of age, with worsening of
urticaria/angioedema symptoms approximately 1 hour
postingestion of paracetamol. The child had also taken
ibuprofen on a few occasions with similar but more-
severe bilateral periorbital angioedema approximately 1
hour after ingestion.
In addition, the patient had had mild-persistent aller-
gic rhinitis since 2 years of age and was treated with
intermittent courses of nasal steroids. There was no his-
tory of previous bronchitis or wheezing episodes, and
there was no significant family history of allergic or
autoimmune disease or drug hypersensitivity.
Our patient presented to the KK Women’s and Chil-
dren’s Hospital emergency department with fever and
cough of 1 day’s duration after receiving a 150-mg dose
of ibuprofen (5 mg/kg) from his family physician. He
developed a generalized rash, facial angioedema, and
shortness of breath 1 hour after the ingestion.
The patient was noted to be tachypneic on presenta-
tion, with a respiratory rate of 54 breaths minute and an
oxygen saturation of 89%. He was also noted to be
bradycardic (heart rate from 40 to 60 beats per minute)
and hypotensive (blood pressure trough of 60/40
mm Hg). Other physical findings included generalized
urticaria and bilateral periorbital and perioral angio-
Resuscitation was commenced immediately, and his
vital signs stabilized after intravenous adrenaline, hydro-
cortisone, fluid boluses, nebulized salbutamol, and sup-
plemental oxygen. He was subsequently transferred to
our children’s ICU for additional management.
The patient’s subsequent progress was uneventful,
with no further progression or recurrence of symptoms.
The investigations performed included a full septic
workup, which was unremarkable. The results of inves-
tigations for chronic urticaria, including measuring the
erythrocyte sedimentation rate, running renal- and liv-
er-function tests, obtaining complement component 3
and 4 levels, performing mycoplasma serology, and
measuring levels of autoimmune antibodies, were nor-
mal. Results of an examination of a stool sample for ova,
cysts, and parasites were negative. His total immuno-
globulin E level was elevated at 1140 IU/L.
A skin-prick test (SPT) to food allergens, aeroaller-
gens, and ibuprofen was performed in our outpatient
clinic. The syrup ibuprofen solution consumed by the
patient was used in the SPT. We diluted 1 mL of the
syrup solution with 9 mL of normal saline 0.9% before
application to the skin. The patient had positive SPT
reactions to house dust mites (Der P and Der F mix, and
Blomia tropicalis) and cockroach mix. Results of the ibu-
profen SPT were negative, and results of the pulmonary-
function tests were normal.
An acute anaphylactic reaction to ibuprofen was di-
agnosed in this child with nonimmunologic cross-reac-
tive hypersensitivity to NSAIDs and acetaminophen. An
oral provocation test with a selective COX-2 inhibitor is
currently being considered.
Here we have described a case of severe anaphylactic
reaction to ibuprofen in a Nepalese boy with recurrent
urticaria and angioedema, persistent allergic rhinitis, and
previous mild hypersensitivity reactions to acetamino-
phen and ibuprofen.
Acetaminophen, the most ubiquitously used antipy-
retic medication for children worldwide, has no signifi-
cant action on peripheral COX-1 and COX-2, but its
antipyretic effect is consistent with a central nervous
system–mediated activity on relatively recently discov-
ered COX-3, found only in the brain and spinal cord.
Thus, although acetaminophen has almost no antiin-
flammatory effects even at high doses and, therefore, is
not an NSAID, strictly speaking, it is an inhibitor of
prostaglandin synthesis, similar to aspirin and the
Our patient presented with a severe anaphylactic re-
action including hypotension, respiratory distress, and
cutaneous symptoms and required significant resuscita-
tion at the emergency department after a conventional
antipyretic dose of ibuprofen (5 mg/kg). This occurred in
the background of previously mild (isolated cutaneous)
but progressively more severe hypersensitivity reactions
to acetaminophen and ibuprofen. The drug-hypersensi-
tivity reactions developed after the onset of allergic rhi-
nitis and recurrent urticaria in our patient. Although
atopy is not considered a risk factor for most drug allergic
reactions, NSAID hypersensitivity seems to be directly
related to atopy and allergic disease.
An underlying autoimmune disease may be an addi-
tional risk factor. A severe anaphylactoid reaction with
ibuprofen has been reported as the first manifestation of
systemic lupus erythematosus in adolescence.
Our pa-
tient has a history of recurrent idiopathic urticaria that
may also be secondary to an as-yet-undiagnosed auto-
immune mechanism. Therefore, patients who present
with such severe reactions to NSAIDs may need an
evaluation for an autoimmune inflammatory disease.
A cross-reactive hypersensitivity reaction to NSAIDs
and acetaminophen is the likely explanation for our
PEDIATRICS Volume 120, Number 3, September 2007 e743
by guest on June 3, 2013pediatrics.aappublications.orgDownloaded from
patient. We have noted that NSAID cross-reactive hy-
persensitivity reactions are more common than previ-
ously reported, especially in Asian children who present
with facial angioedema and urticaria.
In addition, we
have observed that the majority of these children under
6 years of age with NSAID hypersensitivity have cross-
reactive hypersensitivity reactions to paracetamol.
We postulate that there may be increased susceptibil-
ity to prostaglandin inhibition in this population, and
genetic markers could possibly be identified and serve to
abrogate the need for diagnostic oral provocation tests in
the future. Selective COX-2–specific medications may be
appropriate alternatives for some of the older children.
There are many facets to NSAID hypersensitivity, and
patients with chronic or recurrent idiopathic urticaria
and those with atopic disease represent groups with
increased risk. Mild hypersensitivity reactions to acet-
aminophen and/or ibuprofen may precede subsequent,
more-severe adverse reactions. Continued use of
NSAIDs in patients with previous hypersensitive reac-
tions may result in increasingly severe responses includ-
ing systemic anaphylactoid reactions.
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DOI: 10.1542/peds.2006-2634
Yoke Hwee and Ng Kee Chong
Liew Woei Kang, Mona Iancovici Kidon, Chiang Wen Chin, Lim Siok Hoon, Chan
Severe Anaphylactic Reaction to Ibuprofen in a Child With Recurrent Urticaria
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and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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... The most prominent problems, antimicrobial resistance (AMR) and microbiome imbalance, are related to antibiotics, but there are also problems related to antipyretic use that have yet to be systematically investigated on a larger scale including their possible side effects on a short-term (e.g. hepatic injury [6], empyema [7][8][9], overdose [6], anaphylaxis [10,11], midterm (e.g. antimicrobial resistance because antibiotics may be less effective when combined with antipyretics [12], asthma [13,14]) and long-term (e.g. ...
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Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed medications globally. They act through inhibiting cyclooxygenase (COX)-1 and COX-2 enzymes. In contrast to other NSAIDs, anaphylaxis due to ibuprofen is quite rare, especially in adults. The management of anaphylaxis depends on early recognition of the symptoms, administering epinephrine, and avoidance of the causing allergen. Here, we report a case of a 23-year-old female who presented with anaphylactic shock after ingesting ibuprofen.
... We postulated that this was due to the adolescent's ability to communicate breathing discomfort and co-operate with a physical examination compared to the young child. Compared to the study by Rudders et al. [12] , our elicitors of adolescent anaphylaxis included a high proportion of shellfish anaphylaxis (13 vs. 5%) and NSAID drug anaphylaxis, reflecting the high incidence of locally published antipyretic drug allergy [13][14][15] . ...
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Background: The study objective was to compare age-related differences in the cause and clinical presentation of anaphylaxis. Methods: We conducted a prospective study of patients visiting the emergency department for anaphylaxis. Data were collected from 3 emergency departments from 1 April 2014 to 31 December 2015. Patient electronic records with the diagnoses of allergy, angioedema, urticaria, and anaphylaxis (ICD-9 codes 9953, 9951, 7080, 9950, 7089) were screened and cases fulfilling World Allergy Organisation criteria for anaphylaxis were included. Results: A total of 426 cases of anaphylaxis were identified with a median age of 23 years (range 3 months to 88 years and 9 months). The causes of anaphylaxis were food (n = 236, 55%), drugs (n = 85, 20%), idiopathic (n = 64, 15%), and insect bites or stings (n = 28, 7%). The most common food was shellfish (n = 58, 14%) and the most common drugs were non-steroidal anti-inflammatory drugs (n = 26, 6%). There were more cases of food anaphylaxis in children than in adults (72 vs. 42%, p < 0.001) and more cases of drug anaphylaxis in adults than in children (28 vs. 10%, p < 0.001). Compared to patients of other ages, infants and young children had more gastrointestinal symptoms (adjusted odds ratio [aOR] 2.1, 95% CI 1.1-3.9), while schoolchildren and adolescents had more respiratory symptoms (aOR 2.7, 95% CI 1.4-5.2). Adults had more cardiovascular symptoms (aOR 2.9, 95% CI 1.8-4.6) and hypotension (aOR 3.7, 95% CI 2.1-6.8) compared to children. However, 42% of the infants lacked blood pressure measurements. Conclusions: Knowledge of age-related variation in the cause and clinical presentation of anaphylaxis aids in diagnosis and acute management.
... This may explain the correlation between increased sales of ibuprofen for children and complicated pneumonia in France [133], although reverse causation is also possible. Further Evidence-Based Complementary and Alternative Medicine 7 risks associated with antipyretic use include systemic reactions, asthma (especially for paracetamol [69][70][71][72]), gastrointestinal complications and anorexia [138], low white blood cell count (ibuprofen) [139], hepatic injury (paracetamol) [140], overdose (paracetamol) [140], and, extremely rarely, anaphylaxis [141,142] (although sometimes the reaction may be due to other substances such as mannitol [143]). ...
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Objective . To conduct a scoping review to characterize how fever is viewed in anthroposophic medicine (AM) and discuss the scientific validity of these views. Methods . Systematic searches were run in Medline, Embase, CAMbase, and Google Scholar. Material from anthroposophic medical textbooks and articles was also used. Data was extracted and interpreted. Results . Most of the anthroposophic literature on this subject is in the German language. Anthroposophic physicians hold a beneficial view on fever, rarely suppress fever with antipyretics, and often use complementary means of alleviating discomfort. In AM, fever is considered to have the following potential benefits: promoting more complete recovery; preventing infection recurrences and atopic diseases; providing a unique opportunity for caregivers to provide loving care; facilitating individual development and resilience; protecting against cancer and boosting the anticancer effects of mistletoe products. These views are discussed with regard to the available scientific data. Conclusion . AM postulates that fever can be of short-term and long-term benefit in several ways; many of these opinions have become evidence-based (though still often not practiced) while others still need empirical studies to be validated, refuted, or modified.
... Although we have previously reported that APs also contribute to SRs (4), a substantial proportion of cases were diagnosed on the basis of repeated episodes to these drugs in individuals with good tolerance to ASA. In other studies reporting ibuprofen-induced anaphylaxis, tolerance to ASA was not verified (23) or the reaction belonged to another category (24). The aim of this work was to characterize patients with an unequivocal clinical history of an immediate hypersensitivity reaction after APs intake that was also confirmed by challenge. ...
Background: Although ibuprofen and other arylpropionic acid derivatives (APs) are the most common medicines involved in hypersensitivity drug reactions (HDRs) to NSAIDs, no patient series studies have been performed regarding immediate selective reactions (SRs) to these drugs. Objective: To characterise patients with immediate selective HDRs to ibuprofen and other APs through clinical history and challenge. Methods: Subjects who developed an HDR to APs less than one hour after drug intake were included. Tolerance to aspirin was assessed and challenge was performed with ibuprofen in all cases, and additionally with the culprit drug (if different) in those patients that tolerated ibuprofen. Serum tryptase levels and tryptase immunohistochemical staining in skin biopsies were also assessed in some patients with a positive DPT to ibuprofen. Results: From a total of 245 patients with a confirmed history of HDRs to APs, 17% were classified as selective immediate hypersensitivity reactors by both clinical history and challenge. A selective response to naproxen and dexketoprofen with tolerance to ibuprofen was found in 16 out of 20 cases. Significant differences in serum tryptase levels were observed between 2 and 24 hours in the 11 cases that were studied further. Conclusions: Within the group of patients with HDRs to NSAIDs, APs can induce immediate SRs. Within this group, selective responses to a single drug or responders to several APs may exist, suggesting potential immunological cross-reactivity. This article is protected by copyright. All rights reserved.
Purpose of review: NSAIDs are the drugs most frequently involved in hypersensitivity reactions (HSR). These are frequently prescribed at all ages. HSR are of great concern and can affect people at any age. These drugs can induce reactions by stimulating the adaptive immune system (IgE or T cell), known as selective responders or more frequently by abnormalities in biochemical pathways related with prostaglandin metabolism. These are known as cross-intolerant. With some exceptions, skin testing and in-vitro studies are of little value in selective responders. Recent findings: In the last years, several classifications have been provided based on clinical symptoms, time interval between drug intake and appearance of symptoms, response to other nonchemically related NSAIDs and the diseases. Based on this classification, several well differentiated categories within each group of entities cross-intolerant and selective responders are now recognized. The most complex groups for evaluation are cross-intolerant in which three major groups exist: NSAIDs exacerbated respiratory disease, NSAIDs exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema in the absence of chronic spontaneous urticaria. Within the selective responders, there are two mechanisms involved: drug-specific IgE or T-cell effector responses. New entities have been added to this classification like mixed reactions within the cross-intolerant category, that must manifest as anaphylaxis and multiple immediate selective reactions. Summary: The precise evaluation of patients with NSAIDs hypersensitivity following established guidelines will improve not only our understanding but also the management of these entices. As the number of patients affected with NSAIDs is important, further studies are warranted.
Background: Acetaminophen is the most commonly used antipyretic in children. However, there are limited data assessing hypersensitivity reactions related to acetaminophen usage. Objectives: To conduct a systematic review to characterize reported reactions to acetaminophen in adults and children, and perform a meta-analysis to assess the prevalence of acetaminophen hypersensitivity in children with a suspected acetaminophen allergy. Methods: We performed a systematic review of studies reporting hypersensitivity reactions to acetaminophen by searching 2 electronic databases. From the selected studies, we included those assessing the prevalence of acetaminophen hypersensitivity by performing oral challenge in our meta-analysis. Results: Eighty-five studies were included in the systematic review, assessing a total of 1,030 participants. Immediate (within 1 h of exposure) hypersensitivity reactions were reported in > 25% of the articles, while cutaneous nonimmediate reactions were similarly reported in about 25% of the articles. The remaining articles reported Steven-Johnson syndrome/toxic epidermal necrolysis, fixed drug eruptions, and cross-intolerance reactions. Five pediatric studies were included in our meta-analysis. The prevalence of acetaminophen hypersensitivity reaction among children undergoing oral challenge was 10.1% (95% confidence interval 4.5-15.5). Conclusion: Future studies assessing the risk of immediate and nonimmediate hypersensitivity reactions to acetaminophen and elucidating the mechanism of acetaminophen hypersensitivity reactions are required.
Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently involved in drug hypersensitivity reactions (DHR). NSAIDs are prescribed for different processes and some NSAIDs can be obtained over the counter. Areas covered: We analyse the practical approaches for managing and treating NSAID-DHR considering the five major groups of entities recognised, divided into two categories: those responding to strong COX-1 inhibitors and possibly weak COX-1 or selective COX-2 inhibitors named cross-intolerant (CI), and those induced by a single drug or drug group with good tolerance to strong COX-1 inhibitors, known as allergic reactions (SR). An analysis of the recent literature indicates that two approaches can be followed for CI: to give acetyl salicylic acid to confirm NSAID hypersensitivity or to give alternative drugs to provide a solution for the treatment of pain, fever, inflammation or other conditions. Desensitisation approaches have been undertaken, but mainly for CI cases with respiratory airway involvement and they are very rarely used for CI with cutaneous involvement or SR. Expert commentary: DHR to NSAIDs are now recognised as one of the most important problems in the evaluation and management of drug allergy. Because no diagnostic tests exist, important resources are needed to evaluate these patients.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used classes of medications in children. Despite a reported positive safety profile, NSAIDs have been associated with toxicities in both overdose and routine use. Most children with NSAID overdoses are asymptomatic and should be managed conservatively, whereas a small number may present with severe symptoms. We review NSAID exposures in children and strategies for their clinical evaluation and management.
Drugs may cause allergic or non-allergic hypersensitivity reactions. In many cases of hypersensitivity reactions, no specific macroscopic findings are present at autopsy. Therefore, postmortem diagnosis of such conditions becomes a difficult task in forensic practice. Paracetamol is relatively a safe drug which is consumed as an analgesic and antipyretic agent. Herein, a case of fatal angioedema due to ingestion of paracetamol is described. © 2011 South India Medico-Legal Association. All rights reserved.
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Allergic reactions to drugs are considered rare in the paediatric population. Host genetic and environmental factors influence the reported incidence and characteristics of adverse drug reactions (ADRs), and cause significant variation according to the population described and case definition used. We aimed to define the prevalence and characteristics of reported drug allergies in hospitalised children in Singapore. A retrospective case control study was performed through the hospital's inpatient electronic medical record (EMR) for the period of August 2002 to December 2002. The EMR was used to identify children with a previously reported ADR. The control group was randomly selected from patients hospitalised during the same period. Of the 8437 patients hospitalised during the study period, reports of previous ADRs were found in the records of 222 patients. The mean age of the patients was 7.4 years, range 2 months to 17 years (95 percent confidence interval [CI] 6.3 - 8.4). There were 146 males and 160 Chinese. The most commonly-involved medications were betalactam antibiotics (45 percent) and non steroidal anti-inflammatory drug (18.5 percent). Compared to the control group, children with a reported ADR were more likely to be older, with a mean age of 7.4 years versus 4.6 years (p-value less than 0.001), male (odds ratio [OR] 1.7, 95 percent CI 1.2-2.4), of Chinese descent (OR 1.8, 95 percent CI 1.5-5), have an associated chronic illness (OR 3.5, 95 percent CI 2.5-5), and a diagnosis of asthma (OR 2.7, 95 percent CI 1.7-4.5). In our paediatric inpatient population, the risk of reported ADRs increases with age, male gender, Chinese descent and the presence of chronic disease. The major drugs involved are betalactam antibiotics and non-steroidal anti inflammatory drugs.
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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.
The term "aspirin intolerance" is defined as acute urticaria-angioedema, bronchospasm, severe rhinitis, or shock occurring within three hours of aspirin ingestion. Aspirin intolerance occurs most commonly in patients with chronic urticaria (23%), in whom it is mostly manifested by the urticaria type of aspirin tolerance, and in asthmatic individuals (4%), in whom it is mostly manifested by the bronchospastic type. There is no definite evidence that aspirin intolerance is mediated by an immunologic reaction. In the bronchospastic type, an association between prostaglandins and the slow-reacting substance of anaphylaxis (SRS-A) seems likely. It is possible that aspirin causes a preponderance of prostaglandin F2 alpha (PGF2 alpha), resulting in bronchospasm. The effect of aspirin on blood histamine is controversial. The two major types of aspirin intolerance seem to be mediated by different mechanisms.
There is scarce information in the literature about a possible association between atopy and certain clinical manifestations of NSAID sensitivity. (1) To evaluate the prevalence of atopy in patients proved to be sensitive to cyclooxygenase inhibitors. (2) To assess cross-reactivity to two alternative NSAIDs, paracetamol (acetaminophen) and nimesulide. NSAID-sensitive patients attending an allergy clinic and unselected controls were prick tested with inhalant allergens. Oral challenges with NSAIDs were carried out by the single-blinded (SBOC) method. Clinical data about personal and family history of allergic and atopic diseases were obtained by a careful review of the medical records and by direct questioning by experienced allergists. Fifty patients had positive SBOCs to the suspected NSAID and only these were studied. A personal history of atopic diseases was present in 41 patients (82%) and 7 controls (14.5%), and a family history in 24 patients (48%) and 6 controls (12.5%). Prick skin tests with aeroallergens were positive in 39 of 45 patients tested (86.6%) and in 14 of 48 controls (29.1%), (P = .0001). Skin test positivity rates were higher in patients with cutaneous challenge reactions who responded to only one NSAID (single reactors) in comparison to cross-reactors (P = .04). The most frequent clinical manifestations of NSAID sensitivity were (1) cutaneous (angioedema, urticaria) in 34 patients, (2) blended (cutaneous plus respiratory) in 12, (3) respiratory in 3, and (4) anaphylactoid in 1. Aspirin, pyrazolone, paracetamol, and ibuprofen were the drugs more frequently implicated in these reactions. Cross-sensitivity with paracetamol and nimesulide were 32% and 25%, respectively. The prevalence of atopy is increased in challenge-proven NSAID-intolerant patients. The atopic condition may represent an important risk factor for developing reactions to these drugs. Paracetamol and nimesulide are relatively safe alternative choices in those patients, although their use still carries some risk of unwanted reactions.
Epidemiological data for drug reactions in pediatric medical literature as well as in specialized periodicals are scarce. A relationship between nonsteroidal antiinflammatory drugs (NSAIDs), facial angioedema and atopic status has been described in adults. A 10-year retrospective random review of 1,007 charts of atopic children (60.9% male) attending an allergy clinic for management of asthma and/or rhinitis was carried out. Careful attention was given to the written history of NSAID facial angioedema reactions (41 out of 1007, 4.07%) and atopy was confirmed if the patient had a family history and at least one positive skin prick test (>3 mm wheal compared to glycerosaline control) to aeroallergens. Telephone recall was performed when available. Patients were classified into four age groups as follows: a) 0-5 years old; b) 6-10 years old; c) 11-15 years old; and d) 16-21 years old. NSAID facial angioedema rates were as follows: group a 10/493 (2.0%), group b 14/361 (3.8%), group c 10/121 (8.2%), and group d 7/32 (21.8%). Aspirin was the most commonly reported NSAID, and less common were pyrazolones and ibuprofen. Of the 41 patient with chart-reported reactions, 27 (66%) could be contacted by telephone. Of these, 17 patients confirmed the facial angioedema NSAID reaction occurring once or more due to inadvertent exposure. No reactions were reported in the remaining 10 patients since no other NSAID, except acetaminophen, had been used for fever or pain. In conclusion, our data show the age dependency of these reactions and its rather frequent occurrence in such selected pediatric atopic populations. Since NSAIDs are used more frequently in younger children, exposure would not be a plausible explanation for these observations.
Aspirin can provoke reactions ranging from respiratory to cutaneous in susceptible individuals. There has been particular attention looking at the role of cyclo-oxygenase enzymes 1 and 2 and their role in aspirin-exacerbated respiratory disease. Patients who present with a spectrum of allergic and pseudoallergic reactions to aspirin pose a special challenge for the physician. This article discusses proposed classification system, clinical manifestations, pathogenesis of disease, and current treatment options of aspirin-related disease. Relevant articles in the medical literature were derived from searching the MEDLINE database with key terms aspirin-sensitive asthma, cyclo-oxygenase enzymes 1 and 2. Sources also include review articles, randomized control trials, and standard textbooks of allergy and immunology. Aspirin-exacerbated respiratory disease remains a complex, heterogenous disease with varied clinical presentations. There have been many advances in trying to elucidate the pathogenesis of this disease. The classification system presented will provide greater ease when reading the literature and communicating with one another. Oral aspirin challenge remains the diagnostic test of choice for both respiratory and cutaneous reactions. Aspirin desensitization is an option for those with refractory respiratory disease or who require aspirin for other medical conditions. This review discusses the challenges in classification, diagnosis, and treatment of those patients with a sensitivity to aspirin. Special attention is made to the possible mechanisms mediating disease progression and how specific therapies, such as leukotriene modifiers, may be helpful.
Recent studies have found that most otherwise normal subjects with a history of acute urticaria induced by several nonsteroidal anti-inflammatory drugs (NSAIDs) show a wheal-and-flare reaction on intradermal injection of autologous serum. This phenomenon has been previously observed in patients with chronic urticaria (CU) and suggests a possible common background in CU and NSAID-induced urticaria. A relationship between these 2 conditions is further suggested by the fact that up to 30% of patients with CU have a worsening of their skin disorders after the ingestion of chemically unrelated NSAIDs. I sought to assess whether otherwise normal subjects with multiple or single NSAID intolerance show a propensity to have CU. Two hundred eighty otherwise normal patients with an unequivocal history of acute urticaria induced by NSAIDs seen during the last 10 years were studied. On the basis of both clinical history and oral challenge tests with at least 2 alternative NSAIDs, the patients were classified as having single or multiple NSAID intolerance. All the patients were re-evaluated within the end of 2002, 1 to 10 years after the first visit, to assess the onset of CU. One hundred allergic adults without a history of CU and of drug allergy followed up for 1 to 10 years were used as control subjects. One hundred fifty-nine and 121 patients were finally considered as having single or multiple NSAID intolerance, respectively. At the follow-up visit, 93 (33%) of 280 patients had CU. The prevalence of CU was very similar in subjects with single or multiple NSAID intolerance (48/159 [30%] vs 45/121 [37%], respectively; P = not significant). Only 1 (1%) of 100 atopic control subjects had CU during the follow-up period (P <.001). Among single NSAID reactors, patients who had CU had a significantly higher prevalence of intolerance to aspirin than those who did not have CU (36/48 [75%] vs 41/111 [37%], P <.001), whereas the latter had a markedly higher prevalence of intolerance to pyrazolone drugs (52/111 [47%] vs 10/48 [21%], P <.01). Altogether, only 12 (15%) of 82 patients intolerant to drugs other than aspirin versus 36 (47%) of 77 aspirin reactors had CU (P <.001). NSAID intolerance might precede the onset of CU by years. Both multiple and single NSAID reactors with a history of aspirin-induced urticaria seem at higher risk for CU than patients with a history of single intolerance to NSAIDs other than aspirin.
Although largely investigated in adults, the issue of hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) in childhood is unsettled due to lack of sufficient data. The purpose of this study is to examine the clinical syndromes of hypersensitivity to NSAIDs in children and adolescents. We performed a review of relevant papers on cutaneous and respiratory adverse reactions triggered by NSAIDs in pediatric patients, and a recount of our own experience in 43 well-characterized NSAID-sensitive children with cutaneous reactions who were submitted to controlled oral challenges with NSAIDs and the new inhibitors of the enzyme isoform cyclooxygenase-2 (COX-2). Although it has been suggested that allergic and pseudoallergic reactions to NSAIDs in children occur rarely, their prevalence remains largely unknown due to the scarcity of studies. About 23% of NSAID-sensitive patients seen in our institutions are young patients aged 8-18 yr who more frequently develop facial angioedema as their main clinical manifestation. Most patients are atopic and show reactions to more than one drug (cross-reactors). Drugs that inhibit COX-2 with higher specificity than classic NSAIDs are better tolerated in young NSAID-hypersensitive patients.
We describe the first severe systemic hypersensitivity reaction to ibuprofen in a pediatric patient with previously undiagnosed systemic lupus erythematosus (SLE). An 11-year-old Thai male presented with fever, rash, altered mental status, and hypotension after oral administration of ibuprofen leading to the diagnosis of SLE. Re-dosing with ibuprofen resulted in recurrence of presenting symptoms. Severe hypersensitivity with hypotension can be a rare consequence of the use of ibuprofen in children with collagen vascular disease. When encountered in an otherwise healthy child, a high index of suspicion must be maintained for the diagnosis of SLE.