Hypersensitivity to antipyretics: pathogenesis, diagnosis, and management (2025)

DOI: 10.12809/hkmj166186

REVIEW ARTICLE

Hypersensitivity to antipyretics: pathogenesis, diagnosis, and management

QU Lee, MB, ChB, FHKAM (Paediatrics)

Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Laichikok, Hong Kong

Full paper in PDF

Introduction

Antipyretics (APs) are widely consumed drugs. In2013, the National Institute for Health and CareExcellence advised that paracetamol and ibuprofencan be prescribed for febrile children in distress.1In a national cross-sectional study in France, morethan 80% of health care professionals resorted to AP tomanage fever in children. Paracetamol was the first-choiceAP among 88% of health care professionals whileibuprofen, a non-steroidal anti-inflammatory drug(NSAID), was preferred by 11%.2 Diclofenac sodiumand mefenamic acid have also been advocated asAPs for children.3 4 What makes use of APs trulyubiquitous is their non-prescription, over-the-counteravailability. Widespread consumption oftenentails an increased chance of adverse drug reaction(ADR). Paracetamol and NSAIDs are two of themost common drugs to cause an allergic or pseudo-allergicreaction, secondary to general anaestheticagents and beta-lactam antibiotics.5 Prevalenceof NSAID hypersensitivity ranges from 0.1% to0.3%.6 Hypersensitivity reactions to ibuprofenoccur at 0.01%.7 The epidemiology of paracetamolhypersensitivity is unclear. This is understandablesince prescription data for over-the-counter drugsare difficult to obtain. Nevertheless between 1982and 1991, the Spanish Drug Monitoring Systemestimated the incidence of ADR to paracetamol tobe less than 1 per 100 000 inhabitants below the ageof 15 years. Among the reported ADRs, 30% wererelated to skin eruption, urticaria, or itchiness.8The real incidence might have been higher, hadunreported cases been included. This is a reviewof the pathogenesis, diagnosis, and management ofhypersensitivity to APs.

Types of hypersensitivity reactions to antipyretics

Hypersensitivity reactions to APs are idiosyncraticresponses of the body towards drugs given at atherapeutic dose. Around two thirds of patientswith NSAID or paracetamol hypersensitivity aresingle reactors, while one third are cross-reactors.9Reaction may either be to the active ingredient or to excipients. Hypersensitivity to APs can manifestas an immune-mediated reaction that stems froman immunoglobulin (Ig) E–mediated (immediate)reaction or a non–IgE-mediated (delayed) reaction.Unlike other drugs, hypersensitivity to APs can alsobe non–immune-mediated.

Immune-mediated hypersensitivity

Type I hypersensitivity

Type I hypersensitivity to APs, or an IgE-mediatedreaction, is selective in nature. It presents withsingle NSAID-induced urticaria/angioedema oranaphylaxis (SNIUAA) or hypersensitivity to NSAIDswith structural similarity but tolerance to NSAIDsfrom different classes. Ibuprofen and paracetamolare two common causes of SNIUAA.10Severity ranges from localised urticaria, mucosal swelling,and angioedema to anaphylaxis. Susceptible patientsbecome sensitised to an AP on first exposure, withthe production of drug-specific IgE. Specific IgEmolecules become attached to high-affinity IgEreceptors on mast cells or basophils. Re-exposure tothe same AP or cross-reacting drugs leads to cross-linkingof adjacent IgE receptors and subsequentdegranulation of vasoactive inflammatory mediatorslike histamine and tryptase.11 Patients with SNIUAAagainst ibuprofen produce IgE against specificantigen determinants of the drug. Hence they mayreact to arylpropionic acids with similar chemicalstructure but tolerate NSAIDs from other groups,such as acetic acids.7 Similarly, patients with selectivehypersensitivity to paracetamol confirmed by IgEtests or oral challenge can tolerate other NSAIDs.12

Non–type I hypersensitivity

Maculopapular eruptions

According to the revised Gell and Coombsclassification, maculopapular eruption (MPE) is atype IV-c, T-cell–mediated delayed hypersensitivityreaction.13 It is said to be the most common delayeddrug rash due to an AP. Implicated drugs includeibuprofen, diclofenac, and paracetamol.14 Such MPEmanifests as a morbilliform or scarlatiniform rashthat starts on the trunk with subsequent spread tothe limbs. Onset of MPE ranges from within 7 to 14days of first consumption of the drug, but may takeonly 2 to 3 days in patients with prior sensitisation.The reaction of MPE involves skin-homing Tlymphocytes, drug-specific cells that expresscutaneous lymphocyte antigen. Around two thirdsof the T-cells are CD4+, while one third are CD8+.Having resided in the dermo-epidermal junction, thesecells release perforin and granzyme B, two mediatorsof keratinocyte apoptosis, via their ability to inducepore formation in the cell membrane.15 Histologicalchanges include intracellular, intercellular anddermal papilla oedema, dislodgment of epidermalbasal cells, hydropic degeneration, spongiosis ofthe lower epidermis, and dyskeratosis and necrosisof keratinocytes. Inflammatory infiltration byT-cells is seen at the dermo-epidermal junction andeosinophils in the perivascular region.16

Fixed drug eruption

Fixed drug eruption (FDE) is a peculiar type of T-cell–mediated delayed drug hypersensitivity. It startswith solitary, well-circumscribed macules that eruptanywhere on the skin or mucosa, usually over thelips, palms, soles, groins, or glans penis. With time,the lesions evolve into plaques that recur at the samesite on re-exposures to the same drug. The intervalbetween drug intake and FDE is around 30 minutesto 8 hours. The eruption resolves spontaneously aftercessation of the culprit, leaving hyperpigmentationat the affected site. Pathologically, migration andresidence of drug-specific effector-memory CD8+T-cells in the epidermal side of the dermo-epidermaljunction of the affected area account for therecurrence of eruption at the same site. Upon drugre-exposure, quiescent CD8+ cells become activatedand secrete interferon-γ and cytotoxic granules intothe local microenvironment.17 Paracetamol is one ofthe most common causes of FDE, as are mefenamicacid, ibuprofen, and aspirin.18

Drug reaction with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemicsymptoms (DRESS) is classified as a type IV-bdelayed hypersensitivity reaction with eosinophilinvolvement. It is characterised by fever, exfoliativedermatitis, lymphadenopathy, haematologicalabnormalities (hypereosinophilia, atypicallymphocytes), and organ dysfunction. The intervalbetween drug consumption and onset of symptomsis quite prolonged, ranging from 3 weeks to 3months. The pathophysiology of DRESS involvesviral reactivation (eg human herpes type 6) andT-cell activation, two determining factors with amutual causal relationship.19 FOXP3+ (forkheadbox P3) regulatory T-cells are activated early in thecourse of DRESS, but are subsequently deactivatedand become deficient, culminating in the emergenceof autoimmune diseases commonly seen in theaftermath of DRESS. Ibuprofen and paracetamolhave rarely been associated with DRESS.20 21

Stevens-Johnson syndrome/toxic epidermal necrolysis

Stevens-Johnson syndrome/toxic epidermalnecrolysis (SJS/TEN) is a type IV-c delayedhypersensitivity reaction to infections or drugsincluding APs. The interval between intake of theculprit drug and SJS/TEN is shorter than that ofDRESS, ranging from 1 to 21 days.22 Skin lesionsin SJS/TEN are typically target-like with centralnecrosis, bullae formation, or purpuric lesions.In SJS, less than 10% of the body surface areais involved, whereas in TEN, more than 30% isinvolved. Gentle rubbing of ‘normal’ skin causesseparation of the epidermis (Nikolsky sign). Mucosaland eye inflammation is present in 90% and 60%of cases, respectively. Severe cases culminate incorneal scarring, respiratory distress syndrome,pneumonia, and respiratory failure.23 A caveat in thediagnosis is that the prodromal phase of SJS/TENmay be mistaken as symptoms of a febrile illness,with consequent administration of APs. In the eventthat SJS/TEN occur secondary to other causes,subsequent appearance of skin and mucosal lesionsmay impart the wrong impression of AP as thecausative agent. In SJS/TEN, CD4 T-cells accumulatein the dermis while CD8 T-cells predominate inthe epidermis. T-cell infiltration causes massiveapoptosis of the keratinocytes via the toxic action ofperforin, granzyme, and Fas/Fas ligand interaction.24 Of note, SJS/TEN due to NSAIDs is exceedingly rare.The incidence for ibuprofen was 0.013 per 1 000 000as opposed to 0.032 per 1 000 000 for oxicams.25 Compared with controls, the relative risk ofparacetamol and ibuprofen for SJS/TEN in childrenranges from 5 to 11.26 It is also noteworthy that APsare often prescribed together with antibiotics totreat infection, with the latter two factors (antibiotics and infection) potentiallyrelated to SJS/TEN.27

Acute generalised exanthematous pustulosis

Acute generalised exanthematous pustulosis(AGEP) is a rare type IV-d drug hypersensitivitywith sterile subcorneal pustule formation. Onsetof pustules occurs around 1 day after drug intake.Most patients present with fever. Non-follicularsmall pustules with an erythematous base start onthe face or intertriginous area and subsequentlybecome generalised. The pustules, which areitchy or burning, persist for 4 to 30 days beforedesquamation.28 Histological characteristics includepapillary oedema, perivascular infiltration byneutrophils, and drug-specific T-cells and epidermalkeratinocyte necrosis. Interleukin-8, a neutrophilchemoattractant, is expressed by drug-specific T-cells.Presence of human leukocyte antigens (HLAs)-DR within the inflammatory infiltrate suggeststhe role of a major histocompatibility complexin causing this peculiar type of drug eruption.29 Among NSAIDs, only the oxicams are significantlyassociated with AGEP, with a multivariate odds ratioof 8.4. Paracetamol is not considered at an increasedrisk of causing AGEP.30

Organ-specific delayed hypersensitivity

Of note, NSAIDs can cause an allergic inflammatoryresponse in different organs. Cases of NSAID-inducedhepatitis, pneumonitis, nephritis, andaseptic meningitis have been reported.6

Non–immune-mediated hypersensitivity: cyclooxygenase inhibition

Three types of non-immune drug hypersensitivity toNSAIDs have been described: NSAID-exacerbatedrespiratory disease (NERD), NSAID-exacerbatedcutaneous disease (NECD), and NSAID-inducedurticaria/angioedema (NIUA). In NERD, patientsusually have asthma, rhinosinusitis, and/or nasalpolyps. Aspirin or other NSAIDs may precipitatenasal congestion, rhinorrhoea, bronchialobstruction, or dyspnoea within 30 to 180 minutesof ingestion. Urticaria, angioedema, and flushing ofthe upper thorax may occur. Patients with NECDusually have underlying chronic spontaneousurticaria. Aspirin or NSAIDs may cause flare-up ofurticaria and angioedema in 12% to 30% of patientswith chronic spontaneous urticaria. On the otherhand, NIUA occurs primarily in patients withoutunderlying disease. Immediate reactions that occurless than 15 minutes following consumption and latereactions that occur after several hours have beendescribed.10

Non-immune hypersensitivity to NSAIDs isthe result of cyclooxygenase (COX) inhibition, apharmacological property common to all NSAIDsthat accounts for their propensity to cause cross-reactivity.Three COXs—COX-1, COX-2, andCOX-3—have been identified, and NSAIDs likeibuprofen inhibit all three COXs. On the contrary,paracetamol is a weak inhibitor of COX-1 and COX-2, especially at a low dose, and preferentially inhibitsCOX-3.31 In susceptible patients, inhibition ofCOX leads to overproduction of pro-inflammatorycysteinyl leukotrienes by mast cells and eosinophilsbut depletion of the homeostatic and anti-inflammatoryprostaglandin E₂ (PGE₂).31 Imbalanceof leukotrienes and prostaglandins culminates ininflammation in the skin, nasal cavities, sinuses,and airway mucosa.32 Accumulation of leukotrienesin the skin results in urticaria and angioedemacharacterised by dermal oedema, and lymphaticdilation involving perivascular or interstitial cellularinfiltration.33

Recent genetic studies have further elucidatedthe pathogenesis of NSAID hypersensitivity due toCOX inhibition, explaining why it only occurs insome patients. Candidate genes are responsible forvarious enzymes, receptors, or mediators involvedin dysregulation of arachidonic acid metabolism,initiation of immune response, dysfunction ofepithelial cells, biochemical signalling, effectorfunction in inflammatory cells, and aspirinmetabolism.34 Studies revealed that HLAs areassociated with NSAID hypersensitivity, for instance,subjects with HLA DPB1*0301 are at a higher risk ofdeveloping NERD.35 Aside from genes, methylationprofiles of DNA have been associated with NERD,underscoring the role of epigenetics.36

Hypersensitivity to excipients

Discussion of hypersensitivity to APs is incompletewithout mentioning the role of excipients that act asvehicles of drugs. It was thought that an excipient,being ostensibly inert, should not cause ADR. Recentreports of excipient hypersensitivity, however,have cast doubt on that.37 Common paracetamolpreparations come in the form of tablets, syrup, andsuppositories. As with other drugs, excipients inparacetamol contain preservatives, colouring, sugar,and ethanol. Parabens and benzoates, two potentialallergens, are preservatives widely used in variousparacetamol preparations.

Different excipients are added to producedifferent formulations. For instance, one type ofparacetamol syrup contains propylene glycol,methyl hydroxybenzoate, propyl hydroxybenzoate,xanthan gum, sorbitol solution 70%, sucrose,mango flavouring, and purified water.38 There arecurrently more than 90 registered manufacturersof generic paracetamol in Hong Kong, producing astunning inventory of more than 900 paracetamol-containingformulations in the drug registry of theDepartment of Health.39 Patients hypersensitive tothe excipient of one product (eg paracetamol tablet)may tolerate another form (eg paracetamol syrup)or the same form of another brand. Unfortunately,pharmaceutical companies may not discloseexcipient components of a drug in their entirety.This makes thorough comparison between differentproducts difficult.

Diagnosis of hypersensitivity to antipyretics

History and clinical scoring system

Prudent management of hypersensitivity to APsstarts with an attempt to confirm or exclude thediagnosis. As APs are usually prescribed for fever onan as-required basis, clinicians should concentrateon actual consumption rather than prescription.Reactions that appear within 1 to 2 hours of APconsumption constitute immediate hypersensitivity,while reactions that appear several hours or beyondare considered delayed hypersensitivity. Althoughsymptoms usually subside within 24 to 48 hours,some may persist for up to 1 to 2 weeks.40

The number of previous exposures to anAP should be noted. The same drug tolerated onmany occasions is unlikely to be the culprit. AnAP tolerated only once before may trigger an IgE-mediatedreaction the second time it is given to asusceptible patient. An AP given for the first time canstill trigger a reaction via T-cell activation or COXinhibition. Previous exposure may not be apparentin case of poor recall or if the AP is given in thecontext of polypharmacy. With details of the past andpresent drug treatment, clinicians should estimate theprobability of AP hypersensitivity before attachingthe label. A validated scoring system can help classifypatients as definite, probable, possible, or doubtfulcases of ADR.41 The next step is to differentiatebetween single-reactors and cross-reactors bythorough history taking and collation of data fromvarious sources, including written and electronicdrug records.

Care is needed for proper drug identification, asAPs may have many trade names. Clinicians can referto the Drug Database of the Department of Healthfor a comprehensive list of registered drugs fromdifferent pharmaceutical companies.39 Over-the-counterdrugs should be carefully studied in historytaking. Patients should be encouraged to submit anyremaining drugs to hand for identification. Cliniciansshould try to differentiate between hypersensitivityto the active ingredients versus excipients. Patientswho react to different preparations of the same drugare likely hypersensitive to the active ingredient,while those who react only to some preparations maybe suffering from hypersensitivity to excipient(s).

A clinical history is valuable in predictinghypersensitivity to APs: 17% of children with suchhypersensitivity have a positive family history. Suchchildren are more than 5 times likely to have NSAIDhypersensitivity compared with controls.9 Emergenceof an ADR within an hour of administration and ahistory of hypersensitivity to multiple NSAIDs aretwo other stronger predictors of challenge-provenNSAID hypersensitivity.42

Clinicians should then differentiate betweenvarious clinical manifestations. Urticarial rash andangioedema are found in type I hypersensitivityand reactions due to COX inhibition; whereas MPEis erythematous, non-itchy, and flat lesions thatblanche on pressure (Fig 1). Isolated discoid lesionsrecurring at the same site are indicative of FDE (Fig 2). Presence of ‘red-flag signs’ signifies more sinisterdiseases. Mucosal inflammation and ulcerationsassociating with unremitting fever, intense skinpain, and Nikolsky sign should raise concern aboutpossible development of SJS/TEN. WidespreadMPE associating with persistent fever, peripheraleosinophilia, liver impairment but absence ofmucosal inflammation is suggestive of DRESS. InNERD, patients typically have underlying chronicrhinosinusitis, nasal polyps, and asthma complicatedby NSAID intolerance. Patients with NECD mayhave chronic spontaneous urticaria.10

Figure 1. Maculopapular rash due to sensitivity to non-steroidal anti-inflammatory drugs

Figure 2. Fixed drug eruption due to ibuprofen

Differential diagnoses of hypersensitivity toAPs include hypersensitivity to concomitant drugsand diseases with skin or mucosal manifestations,eg viral infections, chronic urticaria, or Kawasakidisease. On the other hand, SJS is related to infectionsuch as mycoplasma in 25% of affected children.27 As mentioned, AP may be given for fever control afterthe onset of other symptoms. The febrile illnessthat requires AP can also cause skin or mucosalsymptoms. One should also consider the possibilitythat the AP is a co-factor of other allergens. A co-factormay not cause allergy per se, but may lowerthe threshold for allergic reaction to anotherallergen. Common co-factors include exercise,infection, menstruation, stress, alcohol, angiotensin-convertingenzyme inhibitors, and NSAID. Possiblemechanisms of co-factors include tight junctiondysregulation, increased gastrointestinal absorptionof allergens, and COX inhibition. The prevalence ofco-factor–dependent anaphylaxis related to NSAIDranges from 1.2% to 4.7%.43

Workup for hypersensitivity to APs should becarried out 4 to 6 weeks after complete resolution ofsymptoms.44 A battery of in-vitro and in-vivo testscan confirm or exclude hypersensitivity to APs andascertain safe alternative drugs.

In-vivo tests

Aside from diagnosis of allergy to an aeroallergenin patients with NERD, the skin prick test for AP isprobably useful only in the context of IgE-mediated SNIUAA. A negative skin prick test, however,does not exclude hypersensitivity to APs as manyreactions are non–IgE-mediated. Moreover, with thepassage of time, even individuals with IgE-mediatedhypersensitivity may lose skin test positivity. Anintradermal test and atopic patch test may be helpful in diagnosing NSAID-induced delayedhypersensitivity. These tests are generally specific butnot sensitive for diagnosis. Lack of standardisationand a scarcity of available commercial reagents limittheir utility. Except for diagnosis of IgE-mediatedhypersensitivity to APs, skin tests seem to have littlediagnostic value.10

A drug provocation test (DPT), which worksindependently of the underlying mechanism,remains the gold standard for diagnosis ofhypersensitivity to APs and establishment of cross-reactivity.As usual formulations are used, DPT ismore feasible than skin tests for AP. In a Turkishpaediatric study, only five (14%) of 36 children witha history of single NSAID hypersensitivity reactedpositively to a DPT using the culprit drug. For 18children with an alleged history of multiple NSAIDhypersensitivity, DPT was positive in eight (44%).Among patients with NSAID hypersensitivity,50% also reacted to paracetamol.9 Conversely, only25% of patients with paracetamol hypersensitivitydevelop cross-intolerance to NSAID.12 The negativepredictive value of DPT in children reaches 100% forNSAIDs, so patients who pass a DPT can be safelygiven the NSAID in future.45 A DPT is generallynot recommended during pregnancy, intercurrentillness, or in patients with co-morbidities such ascardiac, hepatic or renal disease, or uncontrolledasthma. Contra-indications to DPT include a historyof SJS/TEN, DRESS, AGEP, systemic vasculitis,drug-induced autoimmune diseases, and severeanaphylaxis.46

A typical protocol for DPT starts with 1/50 to1/20 of a single maximum dose of an AP, followedby four to five incremental doses given at regularintervals (eg 60 minutes) until the single maximumdose is reached.9 Patients who pass a DPT on day1 can be given a 2-day course on day 2 to ensurefull tolerance to the test drug. In case symptomsor signs of ADR appear, DPT should be abortedand anti-allergic treatment immediately given. Thethreshold cumulative dose can then be determined.For paracetamol, this ranges from 75 mg to 325 mg.47The same procedure can be repeated at least 1week later, using another AP from a structurallyunrelated class to determine cross-reactivity.48 Forinstance, patients who fail a DPT for ibuprofen, anarylpropionic acid, can undergo a subsequent DPTfor diclofenac, an acetic acid. A DPT should becarried out in the hospital setting with resuscitationfacilities available and supervised by cliniciansexperienced in managing drug hypersensitivity andanaphylactic reaction.

In-vitro tests

Most in-vitro tests to date have not been validated orstandardised. Aside from research purposes they arenot routinely recommended for clinical use.

Serum specific immunoglobulin E test

Demonstration of specific IgE (sIgE) against aNSAID in the serum theoretically aids diagnosis ofSNIUAA. Serum sIgE against paracetamol has beendemonstrated by some researchers.49 Comparedwith skin prick test, however, serum sIgE againstNSAID is less useful. Sensitivity and specificity ofsIgE are not known.14

Basophil activation test

Detection of CD63 signifies activation of basophilsand forms the basis of the basophil activation test.As a diagnostic tool for NIUA, basophil activationtest is relatively sensitive but not specific.50

Lymphocyte transformation test

As drug-specific T-lymphocytes are frequentlyinvolved in NSAID hypersensitivity, a lymphocytetransformation test (LTT) has been advocated as adiagnostic tool. The test is based on measurementof ³H-thymidine uptake by dividing T-cells. TheNSAIDs considered suitable for LTT includediclofenac, mefenamic acid, and paracetamol.Sensitivity of the LTT ranges from 60% to 70% withspecificity of approximately 85%. A positive LTTis useful for diagnosis, but a negative test does notexclude hypersensitivity. Involvement of a stringentprotocol and need for expert interpretation meansthat LTT can be performed only by specialisedlaboratories.51

Management of hypersensitivity to antipyretics

Acute management

The offending AP should be stopped andantihistamine given. In case of anaphylactic reaction,emergent treatment and resuscitation should beperformed. Oxygen, intramuscular adrenaline, andantihistamine should be given. A severe cutaneousadverse reaction should be managed in the intensivecare unit. Standard treatment includes intravenousfluids, corticosteroid, intravenous Ig, and otherimmunosuppressants.23

Follow-up

Management of suspected AP hypersensitivity startswith thorough discussion with patients or caretakersof the pros and cons of the AP as opposed to avoidance.The aims of investigation include confirmation ofhypersensitivity and cross-reactivity, differentiationbetween hypersensitivity to the active ingredientversus excipients, and trial of safe alternatives.Detailed review of drug history is of paramountimportance. Above all, DPT is pivotal to achieving theaims of investigation. A combination of drug historyand DPT culminates in six alternative approaches todeal with hypersensitivity to APs (Fig 3).

Figure 3. Suggested pragmatic management algorithm for hypersensitivity to antipyretics

Patients allergic to excipients in one AP maytolerate a different brand or different formulation ofthe same drug (approach 1). Detailed comparison ofconstituents may reveal the excipient in question.In case of doubt, DPT can be performed on thealternative brand or formulation to confirmtolerance. In case the patient reacts to differentformulations and brands of the same AP, a trial of APwith unrelated structure can be considered (approach5). A common example is to try ibuprofen in patientswith paracetamol hypersensitivity. As mentionedbefore, three quarters of patients with paracetamolhypersensitivity tolerate NSAIDs. Patientshypersensitive to ibuprofen, an arylpropionic acid,can consider DPT using paracetamol or an aceticacid such as diclofenac.

Patients with cross-intolerance to paracetamoland NSAIDs pose a management dilemma.Avoidance of all APs seems logical (approach 2),especially if the feverish patient is not ‘distressed’.Nonetheless whether a patient is in distress or notis a matter of subjective judgement. For culturalreasons, it is exceedingly difficult to persuade HongKong parents not to give APs to a child with a highfever. In case fever control is deemed desirable byeither parents or physicians, viable solutions shouldbe sought. Desensitisation (approach 3) is anotherviable option. A standard desensitisation protocolhas been established for aspirin.52 Desensitisation isapplicable to patients having NERD or NIUA.10 It iscontra-indicated in patients with a history of severe,life-threatening drug reactions such as SJS/TENS orDRESS. Nonetheless desensitisation should only becarried out in medical facilities with resuscitationequipment and expertise in drug allergy. Alternativetheoretical choices (approach 4) include subthresholdor low-dose paracetamol,47 53 COX-2 inhibitors,54 pre-medication with antihistamines with or withoutleukotriene receptor antagonist,55 co-administrationof a PGE₂ analogue,56 and traditional Chinesemedicine.57 Future studies are needed to definethe safety and efficacy of these unconventionaltreatments.

Patients with a mild or doubtful reaction toan AP can consider a DPT, the gold standard todiagnose or exclude hypersensitivity to the culpritdrug. Patients who react to the culprit AP duringDPT can either try a structurally unrelated AP(approach 5) or try a different brand/formulation(approach 1). Finally, patients who pass the DPT canbe given the culprit drug in future (approach 6), asthe test has a very high negative predictive value.10

Conclusion

It is arguable that APs may not be indicated inthe first place and should be avoided in patientswith hypersensitivity. Although APs should notbe prescribed simply for the sake of ‘temperaturecontrol’, the need to mitigate patient discomfortshould not be disregarded.58 Patients with illnessessuch as heart failure, head injury, or sepsis presentspecial problems. Their limited reserve to withstandthe hypermetabolic state associated with febrileepisodes puts them at particular risk.59 For thesepatients, APs seem beneficial. In case they havehypersensitivity to APs, viable options should besought. Attempts to predict such hypersensitivityare daunting. Disappointingly, prediction of severecutaneous adverse reactions to APs is virtuallyimpossible. However, the presence of a positive familyhistory, reaction within 1 hour of consumption, andhistory of multiple NSAID hypersensitivities maysound an alarm for the increased risk of genuineimmediate hypersensitivity to APs. Cliniciansneed to strike a balance between ‘hypersensitivityphobia’ for the sake of drug safety and liberal useof APs to uphold patients’ rights. Knowledge of thepathogenesis of AP hypersensitivity and meticulousdiagnostics are key to judicious management.

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