NSAID Hypersensitivity in the Pediatric Population: Classification and Diagnostic Strategies

Figures & data

Table 1 Nonsteroidal Anti-Inflammatuary Drugs According to Their Chemical Structures

Chemical Group & Drugs	Chemical Group & Drugs	Chemical Group & Drugs
Propionic acid derivatives	Fenamic acid derivatives	Indol-acetic acid derivatives
Ibuprofen	Mefenamic acid	Indomethacin
Naproxen	Meclofenamic acid	Sulindac
Loxoprofen	Flufenamic acid	Tolmetin
Flurbiprofen	Tolfenamic acid
Ketoprofen
Dexketoprofen	Salicylic acid derivatives	Naphthyl alkanone (non-acid derivative)
Fenoprofen	Aspirin (Acetylsalicylic acid)	Nabumetone
Indoprofen	Sodium Salicylate
Oxaprozin	Salsalate	Pyridinic Sulfonamide derivatives
Tiaprofenic acid	Diflunisal	Nimesulide
	Sulfasalazine
Phenyl-acetic acid derivatives	Enolic acid derivatives	Selective COX-II inhibitors (Diaryl heterocyclic acids)
Diclofenac	Piroxicam	Celecoxib
Etodolac	Meloxicam	Etoricoxib
Ketorolac	Lornoxicam	Rofecoxib
Aceclofenac	Tenoxicam	Valdecoxib
	Piroxicam	Paracoxib
		Lumiracoxib
Pyrazolones	Para-aminophenol	Benzethiazoline
Phenylbutazone	Paracetamol (acetaminophen)	Tiaramide
Dipyrone (Metamizole)
Propifenazone
Oxyphenylbutazone
Azapropazone

Table 2 Frequency of NSAID-H in Children

First Author/Date	N, Study Population	Age (Range or Mean (±SD))	Outcome of the Study	CI/ SR	Diagnostic Test	ASA/NSAID-H/ Paracetamol/ Ibuprofen
Settipane, 1980^Citation26	638 healthy	2–16 y	ASA-H	NA	Hx	0.32%
Ibero, 1982^Citation43	25 food allergic	25–153 mo	ASA-H	NA	OPT w ASA	7.8%
Botey, 1984^Citation45	1632 healthy	infants, children	ASA-induced recurrent U/AO	NA	OPT w ASA	0.55%
Bousetta, 2005^Citation44	25, Paracetamol-induced	8 mo–15 y	Paracetamol-H	1/0	OPT w Paracetamol and ASA	4%
Hassani, 2008^Citation25	164, NSAID-induced	7 mo-17.3 y	NSAID-H	2.2	OPT w culprit drug and hx	49%
Zambonino, 2013^Citation30	63, NSAID-induced	1–14 y	NSAID-H	1.4	OPT w culprit drug and ASA	68%
Yılmaz, 2013^Citation34	58, NSAID-induced	4 mo-18 y	NSAID-H	1.7	OPT w culprit drug	29%
Cavkaytar, 2015^Citation31	110, NSAID- induced	2–18 y	NSAID-H	1.1	OPT w culprit drug and ASA	27%
Guvenir, 2015^Citation32	115, NSAID-induced	2 mo-17 y	NSAID-H	0.25	OPT w culprit drug and ASA	17%
Ertoy Karagol, 2013^Citation39	95, AO w/o U	8 mo-17 y	NSAID-H	NA	OPT w culprit drug	6%
Cavkaytar, 2015^Citation40	68, CSU	2–18 y	ASA-H	NA	OPT w ASA	24%
Cousin, 2016^Citation37	635, NSAID-induced	2–13 y	NSAID-H	4.3	OPT w culprit drug and ASA & other NSAIDs	16.9%
Calvo Campoverde, 2016^Citation27	93, NSAID-induced	4–17 y	NSAID-H	1	OPT w culprit drug or hx in case of >1 rxn with the culprit NSAID & OPT w ASA	28%
Alves, 2017^Citation35	119, NSAID-induced	5–14 y	NSAID-H	NA	OPT w culprit and alternative drug	7.6%
Arikoglu, 2017^Citation36	106, NSAID-induced	1–18 y	NSAID-H	2	ST & OPT w culprit drug	29%
Blanca-Lopez, 2018^Citation38	116, NSAID-induced	6 mo-14 y	NSAID-H	4.9	OPT w ASA & culprit drug	26%
Guvenir, 2018^Citation46	2000 healthy	11.6 (3.5–14.5) y	NSAID-H	NA	OPT w culprit drug	0%
Eser Simsek 2019^Citation41	56, NSAID-induced	7.1 (1.2–18) y	NSAID-H	6	OPT w ASA & culprit drug	37.5%
Gaffar, 2020^Citation5	44, ibuprofen-induced	6.9 (±4.7) y	Ibuprofen-H	NA	OPT w ibuprofen	22.7%
Yılmaz Topal, 2020^Citation33	243, NSAID-induced	84.3 (50.7–139.2) mo	NSAID-H	1.45	OPT w culprit drug	20.3%
Sipahi Cimen, 2021^Citation42	60, Paracetamol-induced	2–18 y	Paracetamol-H	0.75	OPT w paracetamol and ibuprofen	13%

Abbreviations: AO, Angioedema; ASA, Aspirin (acetylsalicylic acid) ASA-H, Aspirin (acetylsalicylic acid) hypersensitivity; CSU, Chronic spontaneous urticaria; Hx, Clear-cut history; Ibuprofen-H, ibuprofen hypersensitivity; L-ASA, Lysine aspirin; Mo, months; NSAID, Nonsteroidal anti-inflammatory drug; NSAID-H, Nonsteroidal anti-inflammatory drug hypersensitivity; NA, Not applicable; OPT, Oral provocation test; Paracetamol-H, Paracetamol hypersensitivity; SD, Standard deviation; ST, Skin test; U, Urticaria; w, with; w/o, without; Y, years.

Table 3 Frequency of NSAID-H in Asthmatic Children

First Author, Date	N, Study Population	Age (Range or Mean (±SD))	Outcome	Diagnostic Test	ASA/NSAID-H
Falliers, 1973^Citation57	1298, asthma	6–16 y	ASA-H	Hx & Medical records	1.9%
Rachelefsky, 1975^Citation47	50, asthma	6–18 y	ASA-H	OPT w ASA	28%
Vedanthan, 1977^Citation49	3, asthma	8–18 y	ASA-H	OPT w ASA	33%
Schuhl, 1979^Citation48	32, asthma	6–11 y	ASA-H	OPT w ASA	0
Fischer, 1983^Citation50	25, asthma	8–18 y	ASA-H	OPT w ASA	12%
Towns, 1984^Citation51	29, asthma	5.5–14 y	ASA-H	OPT w ASA	21%
Hussein, 1989^Citation52	70, asthma	6–17y	ASA-H	NPT w L-ASA	2.7%
Short, 2000^Citation53	70, asthma	6–15 y	Diclofenac-H	OPT w Diclofenac	0
Capriles-Behrens, 2000^Citation54	1007 asthma and rhinitis	0–21 y	NSAID-induced facial AO	History & confirmed with inadvertent re-exposure	4.1%
Debley, 2005^Citation55	100, asthma	6–18 y	Ibuprofen-H	OPT w ibuprofen	2%
Soferman, 2013^Citation56	42, asthma	12.4 ± 2.4	Paracetamol-H	OPT w Paracetamol	0%
Guvenir, 2018^Citation46	976 asthma	10.6 ± 4.2 y	NSAID-H	OPT w culprit drug and ASA	0.9%

Abbreviations: AO, Angioedema; AR, Allergic rhinitis; ASA-H, Aspirin (acetylsalicylic acid) hypersensitivity; L-ASA, Lysine-aspirin; H, Hypersensitivity; NSAID-H, Nonsteroidal anti-inflammatory drug hypersensitivity; OPT, Oral provocation test; SD, Standard deviation; W, With.

Table 4 Proposed Classification of Phenotypes of Pediatric NSAID-Hypersensitivity According to Recent Data*

Type of the Reaction	Phenotype	Timing of the Reaction	Underlying Disease	Clinical Manifestation
Selective responder	SNIUA/A MSIR	Usually immediate (within minutes up to 1 hour)	None	Urticaria/angioedema and/or anaphylaxis
	SNIDR	Usually more than 24 hours after exposure	None	Fixed drug eruption Maculopapular exanthema Severe bullous reactions Contact/photocontact dermatitis Pneumonitis, Nephritis Aseptic meningitis
Cross- intolerant	NIUA	Within one hour up to several hours	None	Urticaria/angioedema
	Blended (NIUAA)		± AR and/or Asthma	Angioedema + Asthma/Stridor/rhinosinusitis
	NECD		Chronic urticaria	Urticaria/angioedema
	NERD		Asthma/rhinosinusitis nasal polyposis	Asthma/rhinosinusitis

Notes: *Food Dependent NSAID-induced Hypersensitivity (FDNIH) is not included yet but would be with the emergence of further descriptive data.

Abbreviations: AR, Allergic rhinitis; MSIR, Multiple selective immediate reactor; NECD, NSAID-exacerbated cutaneous disease; NERD, NSAID-exacerbated respiratory disease; NIUA, NSAID-induced urticaria and/or angioedema; NIUAA, NSAID-induced urticaria and/or angioedema and/or anaphylaxis; NSAID, Nonsteroidal anti-inflammatory drug; SNIDR, Selective NSAID-induced delayed reaction; SNIUA/A, Selective NSAID-induced urticaria angioedema or anaphylaxis.

Table 5 Examples of NSAID Doses Utilized During Oral Provocation Tests in children^{29–31,39,62,146,147}

Drug	Dose (mg/kg)	Dose (mg)	Interval btw. Doses	Additional Doses at Home
ASA	10 mg/kg	10, 17, 44, 117, 312 mg	1.5h	–
ASA	20 mg/kg	1st day: ¼, ¼, ¼ of TCD 2nd day: ½, ½ of TCD	1h	+ (2 days)
Ibuprofen	10 mg/kg	¼, ¼, ½ of TCD	1h	+ (2 days)
	10 mg/kg	10, 30, 50, 100, 200 mg	1.5h	–
Diclofenac	25 mg/dose	1, 5, 25 mg	1.5h	–
Flurbiprofen	100 mg/dose	5, 15, 30, 50 mg	1.5h	–
Ketoprofen	0.5 mg/kg	1, 5, 20.80 mg	1.5h	–
Dexketoprofen	25 mg	1, 3, 7, 14 mg	1.5h	–
Paracetamol	15 mg/kg	¼, ¼, ¼ and ¼ of TCD	1h	–
	15 mg/kg	Single dose	1h	+ (2 days)
	20 mg/kg	Single dose	1h	–
Metamizol	20 mg/kg	¼, ¼, ½ of TCD	1h	+ (2 days)
	20 mg/kg	10, 50, 125, 250	1.5h	–
Meloxicam	7.5 mg/dose	¼, ½, ½ of TCD	1h	+ (2 days)
	15 mg/dose	2.5–5–7.5 mg	1h	–
Tolmetin	160 mg/dose	10–50–100 mg		–
Etoricoxib	60 mg/dose	¼, ¼, ½ of TCD	1h	+ (2 days)
	60 mg (<60kg) 90 mg (>60 kg)	Single dose	–	–
Nimesulide	100 mg/dose	25–75–100 mg	1h	–
Culprit NSAID^a		1/10, 2/10, 7/10 of TCD	30–90 min	1 or 2 or 3 days
		¼, ¾ of TCD	30–90 min	1 day

Notes: ^aIn case of anaphylaxis in the history; 1/100, 1/10 and full dose are given. In 2 or 3 day OPT performing centers, the NSAID is given as single dose on days following the first day.

Abbreviations: ASA, Aspirin (acetylsalicylic acid); min, minute; NSAID, Nonsteroidal anti-inflammatory drug; TCD, total cumulative dose.

Table 6 NSAID Classes According to Their Potency on COX Enzyme Inhibition

Strong COX-I inhibitors
Aspirin, ibuprofen, ketoprofen, flurbiprofen, ketorolac, diclofenac, sulindac, fenoprofen, piroxicam, indomethacin, naproxen, oxazoprin, mefenamic acid, diflunisal
Preferential COX-I inhibitors at low dose and weak COX-I inhibitors at high dose
Nimesulid, meloxicam, tolmetin, etodolac, nabumeton
Weak COX-I inhibitors
Paracetamol and salsalate
Selective COX-II inhibitors
Celecoxib, etoricoxib and parecoxib

Abbreviations: COX, Cyclo-oxygenase; NSAID, Nonsteroidal anti-inflammatory drug.

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