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(a) Results of skin prick test. A positive reaction to 100 mg/ml acetaminophen (2þ). (b, c) Subsequent skin prick test. Positive reaction to 100 mg/ml acetaminophen (2þ), 10 mg/ml acetaminophen (2þ), and 1% histamine (arrow head). The reaction to 1 mg/ml acetaminophen was not considered clinically significant (1þ).
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Citations
... In the few cases described of selective hypersensitivity to paracetamol, the diagnosis is mostly based on the oral challenge test, which does not elucidate the underlying pathophysiological mechanism [6][7][8]. The IgEmediated mechanism was demonstrated by positive skin tests in only 10 reported cases [5,[12][13][14][15][16][17] ( Table 1). The authors describe two clinical cases of IgE-mediated hypersensitivity to paracetamol. ...
Paracetamol is one of the most commonly used analgesic and antipyretic agents worldwide, attributed in part to its excellent safety profile when administered at recommended doses. Paracetamol allergy is not common, and the majority of the reactions are related to the pharmacological action of cyclooxygenase 1 inhibition. Selective and Immunoglobulin E (IgE)-mediated hypersensitivity reactions are rare. In this article, the authors report two cases of paracetamol allergy in which the mechanism of IgE-mediated hypersensitivity was demonstrated by positive skin tests and basophil activation tests. We highlight the relevance of identifying the mechanism underlying the reaction since patients with IgE-mediated paracetamol allergies will be able to tolerate non-steroidal anti-inflammatory drugs.
... Several cases of allergic reactions to paracetamol have been reported in the literature including a recent report in Japan, which described an anaphylaxis to paracetamol diagnosed by skin prick test (SPT). [8] The patient developed urticarial and dyspnea and exhibited positive reaction to SPT after a few minutes of administering paracetamol. Based on the SPT results, IgE-mediated anaphylaxis due to paracetamol was diagnosed. ...
... Based on the SPT results, IgE-mediated anaphylaxis due to paracetamol was diagnosed. [8] In Turkey, a 51-year-old woman developed swelling and redness reactions more than 3 mm to prick test. [9] An allergic reaction associated with paracetamol was diagnosed as a result of the prick test. ...
Introduction: National Pharmaceutical Regulatory Agency, Ministry of Health Malaysia has received 1018 adverse drug reaction reports related to paracetamol with 1972 adverse events from the year 2000 to February 2015. Serious skin reactions including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis, and acute generalized exanthematous pustulosis may develop as a result of allergic reactions of paracetamol. This study aimed to develop and validate a questionnaire regarding Knowledge, Attitude, and Perception towards Allergic Reactions of Paracetamol (KAP-ARP) among the general population. Materials and Methods: Content and face validity of the KAP-ARP were determined by four experts and 20 respondents, respectively. A questionnaire with 36 items, consisting of 16 Knowledge, 9 Attitude, and 11 Perception items, was distributed to 177 respondents. Exploratory factor analysis (EFA) was performed for construct validity. Cronbach’s alpha was used to determine the reliability of the questionnaire. Results: EFA constructed 13 Knowledge, 8 Attitude, and 8 Perception items. The final KAP-ARP questionnaire is reliable based on its internal consistency reliability (Knowledge: α = 0.78; Attitude: α = 0.63; Perception: α = 0.70). Conclusion: A valid and reliable questionnaire that is useful for measuring KAP-ARP among the general population has been developed.
Keywords: Allergic reaction, development, paracetamol, questionnaire, validation
... There are numerous case reports and some case series describing anaphylaxis or anaphylactoid reactions to acetaminophen. [683][684][685][686][687][688][689][690][691][692][693][694][695][696] Acetaminophen is classified as an NSAID, but it is a weak cyclooxygenase inhibitor and does not provide any anti-inflammatory effects. 683 However, a number of patients who are aspirin intolerant can also be intolerant of acetaminophen, and some acetaminophen-specific reactions can also be either dependent on or independent of dose. ...
... However, in case reports citing skin prick and intradermal testing at various concentrations, all control subjects have been negative. 685,687,688,692,696,697 Of the skin testing protocols proposed, many are not feasible because the sterile forms required for intradermal testing do not exist in many countries. Currently, the only intravenous formulation of acetaminophen is a single concentration of 10 mg/mL. ...
... Other reviews published on acetaminophen allergy use solely SPTs up to concentrations of 200 mg/mL despite evidence elsewhere demonstrating that concentrations more than 10 mg/ mL can be known irritants leading to false positives for drugs. 688,692,696 Management. Of the studies identifying patients with a history concerning for acetaminophen hypersensitivity, the current recommendations for definitive evidence of a reaction are oral-based challenge tests. ...
... In the diagnostic workup of paracetamol hypersensitivity, skin tests are generally being used. [8][9][10][11] However, it is noteworthy to emphasize that OCT serves as the gold-standard method for definite diagnosis, as well as characterizing the reaction type. OCT is also crucial in finding out the alternative drug in these patients. ...
... 2,27,28 Such reactions involving at least two different organs may be considered as anaphylaxis since defined as NIUAA 12,26 There are few reports in which skin tests were used as a diagnostic tool in the evaluation of paracetamol hypersensitivity. [8][9][10][11] Rarely, skin tests and OCTs were concomitantly evaluated. In a study performed by Paramo et al, 4 OCT-proven paracetamol-hypersensitive adults were evaluated with SPTs with a concentration of 100mg/mL, and in only 2 of them, SPTs were found to be positive. ...
Background
Paracetamol, a non‐steroidal anti‐inflammatory drug, is commonly being used for fever and pain relief worldwide. The aim of this study was to evaluate children with a suspected history of paracetamol hypersensitivity.
Methods
Sixty patients who were referred to our clinic in between January 2015 and December 2018 with a suspected history of paracetamol hypersensitivity were included. Reactions were classified according to the European Network for Drug Allergy (ENDA)/Global Allergy and Asthma European Network classification and European Academy of Allergy and Clinical Immunology (EAACI)/ENDA Position Paper. Diagnoses were confirmed by skin tests and oral challenge tests (OCTs). In those with verified paracetamol hypersensitivity, an OCT with a strong COX‐1 inhibitor was performed to classify the type of the reaction to refer as either selective or cross‐intolerance hypersensitivity. A subsequent OCT with a selective COX‐2 inhibitor was performed in those cross‐intolerant patients to find out a safe alternative drug.
Results
Sixty OCTs with paracetamol were performed to patients with a median age of 8.5 years, and hypersensitivity to paracetamol was verified in 8 patients. Four children were classified as selective responders, and 3 were classified as cross‐intolerant after OCT with a COX‐1 inhibitor. Overall, skin test positivity for paracetamol was detected in only one patient, in whom OCT with paracetamol was negative. In all 3 cross‐intolerant patients, a safe alternative non‐steroidal anti‐inflammatory drug was identified after an OCT with a selective COX‐2 inhibitor.
Conclusion
OCT stands as the gold‐standard procedure in verifying the diagnosis of patients with paracetamol‐induced drug hypersensitivity, as well as, in defining the type of reactions and finding out safe alternative drugs.
... The mechanism of paracetamol hypersensitivity is not fully known but it is thought to be immunologically (IgE mediated/T cell-mediated) or nonimmunologically (cross-reactive type) mediated. 8 However, immunological reactions with paracetamol are rare and skin tests are usually negative. 8 The skin tests of our patient were also negative, which may be due to 3 reasons: First, sensitivity of skin tests with paracetamol is low. ...
... 8 However, immunological reactions with paracetamol are rare and skin tests are usually negative. 8 The skin tests of our patient were also negative, which may be due to 3 reasons: First, sensitivity of skin tests with paracetamol is low. 8 Second, we had to administer adrenalin intramuscularly immediately as soon as we observed anaphylaxis (1 min after the application of the 1/100 ID test with paracetamol) in our patient, which was well before the 15-min timeframe allotted before a normal ID test reading. ...
... 8 The skin tests of our patient were also negative, which may be due to 3 reasons: First, sensitivity of skin tests with paracetamol is low. 8 Second, we had to administer adrenalin intramuscularly immediately as soon as we observed anaphylaxis (1 min after the application of the 1/100 ID test with paracetamol) in our patient, which was well before the 15-min timeframe allotted before a normal ID test reading. 9 We think that this early mandatory adrenalin injection might have caused a false-negative ID test result. ...
The data on perioperative anaphylaxis (PA) in children is limited and usually reported with neuromuscular blocking agents and antibiotics. However we present a first pediatric case who developed PA with paracetamol unlike the literature.
... Because of the fact that prescription data for over-the-counter drugs are difficult to obtain, the epidemiology of paracetamol hypersensitivity is poorly recognized [18]. Anaphylactic reactions to acetaminophen are thought to be immunologically or non-immunologically mediated [19,20]. Paracetamol functions as a weak inhibitor of cyclooxygenase-1 and it can induce reaction analogous to nonsteroidal anti-inflammatory drugs (NSAIDs) [20,21]. ...
... Anaphylactic reactions to acetaminophen are thought to be immunologically or non-immunologically mediated [19,20]. Paracetamol functions as a weak inhibitor of cyclooxygenase-1 and it can induce reaction analogous to nonsteroidal anti-inflammatory drugs (NSAIDs) [20,21]. Cross-sensitivity between aspirin and acetaminophen in aspirin-sensitive asthmatic patients has been reported with frequencies ranging from 0-29% [21]. ...
... Cross-sensitivity between aspirin and acetaminophen in aspirin-sensitive asthmatic patients has been reported with frequencies ranging from 0-29% [21]. On the other hand, IgE-mediated acetaminophen-induced hypersensitivity is extremely rare [20]. The most common hypersensitivity reactions to analgesic are those caused by NSAIDs. ...
Paracetamol is a popular and easily available drug which is used world-wide as analgesic, antipyretic agent. Hypersensitivity reactions to this drug involve a wide range of symptoms of various importance for patient management. The EudraVigilance (EV) database serves as a system for monitoring adverse events (AE) due to drug intake. We retrospectively recorded AE reports for “paracetamol” reported from 1 January 2007 to 1 October 2018 which fulfilled the category of “serious” in EV. For further analysis the retrieved AE reports were selected according to the keywords corresponding to hypersensitivity symptoms. We included in the study 4589 AE reports with 9489 particular AEs. 24.2% of all the AE reports concerned children. The most often reported symptoms were “angioedema,” “rash” and “urticaria” (each of them with a frequency of >10% in the AE reports). An important group of AEs were oedema reported as being located in the head, neck or respiratory tract. We recorded 58 AE reports with fatal outcomes, including 9 Stevens-Johnson syndrome/toxic epidermal necrolysis cases (SJS/TEN), 10 anaphylactic reactions, 21 cases of hepatic failure and a further 18 cases which occurred for other reasons. SJS/TEN, acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms were reported 129, 42 and 25 times, respectively. Prodromes and symptoms of potentially life-threating SJS/TEN appeared in 286 of the AE reports. 380 AE reports pointed to a diagnosis of anaphylaxis. To improve patient safety, healthcare professionals, including pharmacists, can identify warning signs of severe hypersensitivity reactions to paracetamol.
The detailed mechanism of acetaminophen hypersensitivity remains unclear, but two sets of immunological and pharmacological mechanisms have been assumed. In addition, there are no reports of remission in cases in which an immunological mechanism is assumed without complications of hypersensitivity to other NSAIDs. Herein, we describe two cases of acetaminophen hypersensitivity, with immunological assessment. The first case was a 15-year-old girl. She had developed nausea, vomiting, and high fever after taking 8.5 mg/kg of acetaminophen. The skin test was unevaluable and other tests were negative; however, the drug provocation test (DPT) produced generalized flushing, nausea, and peripheral cold extremities at a total dose of 10 mg/kg, which necessitated an intramuscular adrenaline injection. The other case was an 8-year-old boy who had developed cough and wheals for the first time despite having taken acetaminophen several times before. The skin test was negative, but the DPT produced nasal obstruction, eyelid swelling, and multiple wheals at a total dose of 0.9 mg/kg. Twenty-two months later, he had a negative DPT at a total dose of 14 mg/kg. Even in patients with previously diagnosed acetaminophen hypersensitivity, the DPT should be considered after some time due to the possibility of remission.
Résumé
Bien que les études épidémiologiques indiquent que la prévalence des réactions présumées allergiques aux antalgiques non-opiacés, antipyrétiques et anti-inflammatoires non stéroïdiens (AINS) est faible chez les enfants et adolescents, ces médicaments représentent la seconde cause d’hypersensibilité (HS) médicamenteuse présumée dans cette tranche d’âge, après les médicaments anti-infectieux. Les réactions les plus fréquemment rapportées sont des urticaires et/ou angio-œdèmes. Viennent ensuite des réactions respiratoires (rhinite et/ou asthme) et, beaucoup plus rarement, des réactions anaphylactiques ou des toxidermies (potentiellement) sévères, même si les AINS représentent la 1re ou 2e famille de médicaments inducteurs de réactions anaphylactiques et la 3e famille de médicaments inducteurs de toxidermies sévères, que ce soit chez l’enfant ou l’adulte. Les réactions peuvent résulter d’une HS allergique (spécifique d’un médicament ou des médicaments d’une même famille chimique). Le diagnostic de ces réactions, qui peuvent être immédiates ou très rapides (IgE-médiées) ou plus tardives (médiées par des lymphocytes T), repose essentiellement sur l’histoire clinique des patients et/ou la positivité des tests de réintroduction/provocation médicamenteuse (TPM) avec le médicament suspect et les médicaments proches, et la tolérance des AINS des autres familles chimiques. Si, aux concentrations non irritantes, les tests cutanés (TC) à lecture immédiate ou retardée ont une bonne spécificité, leur sensibilité est très faible (usuellement ≤ 25–30 %), et ces tests ne sont pas validés. Les réactions peuvent aussi résulter d’une hypersensibilité non-spécifique/non-allergique (« intolérance » pharmacologique), avec des réactivités croisées fréquentes entre les divers antalgiques, antipyrétiques et AINS, paracétamol inclus. Ces réactions aux AINS peuvent se développer chez des patients sans prédisposition particulière (réactions induites par les AINS), mais peuvent aussi s’inscrire dans le cadre de pathologies pré-existantes (urticaire/œdème chronique/récidivant ; rhinite et/ou asthme ± polypose nasosinusienne : réactions exacerbées par les AINS). Le diagnostic de ces réactions d’HS non-allergique, souvent moins graves que celles résultant d’une HS allergique, ne repose bien évidemment pas sur les TC, mais sur une histoire clinique convaincante et/ou les résultats des TPM. Les bilans effectués chez les patients, rapportant des réactions (de type) allergique aux antalgiques, antipyrétiques et AINS, montrent que 13 à 50 % de ces patients sont réellement atteints d’une HS (allergique ou non allergique) à ces médicaments, les principaux facteurs de risque étant une atopie personnelle et l’âge. Si, chez les adultes, les réactions d’HS non-allergique semblent être les plus fréquentes (≈ 70–75 %), diverses études plus ou moins récentes, dont certaines ayant porté sur plusieurs centaines d’enfants, suggèrent que, chez ces derniers, les réactions d’HS allergique seraient plus fréquentes (≈ 50–70 %) que les réactions d’HS non-allergique. Chez les enfants atteints d’HS allergique aux antalgiques, antipyrétiques et AINS, comme chez les adultes, la prévention des récidives repose sur l’administration de substances d’autres familles chimiques. Chez les patients atteints d’HS non-allergique, elle repose sur l’administration de médicaments faiblement inhibiteurs de la cyclo-oxygénase-1, sous réserve que leur tolérance ait été vérifiée sur la base de l’histoire clinique des enfants ou des TPM. Les méthodes d’accoutumance (induction de tolérance), plutôt efficaces chez les patients rapportant des réactions respiratoires, paraissent moins efficaces chez ceux qui rapportent des réactions cutanéo-muqueuses et anaphylactiques. Enfin, les résultats d’une étude récente menée chez des adultes suggèrent fortement que les réactions d’HS non-allergique aux AINS pourraient guérir spontanément en quelques années, notamment chez les patients rapportant des réactions initiales peu graves.
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.
