| Arikoglu et al. [25], 2024, Turkey | Prospective observational study of patients with a history of NSAID-H reactions using a standardized diagnostic protocol according to EAACI/ENDA recommendations. Comparison of EAACI 2013 and paediatric EAACI/ENDA 2028 classification | 232 patients (4–11 years). Children with a history of nonsteroidal anti-inflammatory drug HSR | Primarily cutaneous (urticaria, angioedema), some respiratory reactions (mild-moderate), no anaphylaxis. | NSAID hypersensitivity was confirmed in 52/232 (22.4%) on diagnostic testing. 36/52 (69.2%) were classified as having cross intolerance. 16/52 (30.8%) were classified as selective responders. 11/52 (21.2%) unclassified using ENDA/EEACI protocols. EAACI 2013 vs. EAACI/ENDA 2018 classifications showed discordance. Children with underlying allergic diseases could form a separate classification subgroup as not fitting in well with current classifications.
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| Dogan et al. [12], 2024, Turkey | Observational retrospective clinical evaluation using ENDA/EAACI classification and drug provocation testings (DPTs) | 67 children with suspected NSAID hypersensitivity (age categories < 10 and > 10 included) | NSAID-H confirmed HSR: mainly NSAID-induced urticaria/angioedema (NIUA); classification into cross-intolerant and selective responders based on DPT outcomes | NSAID hypersensitivity was confirmed in 20 patients (≈ 29.9%) out of 67 tested. Among confirmed, 80% were cross-intolerant, 20% selective responders. Hypersensitivity was confirmed in 10.8% of < 10-year vs. 53.3% of > 10-year (statistically significant). Ibuprofen was the most common culprit; NIUA was the most frequent reaction. DPT was highlighted as the main diagnostic tool, but difficult to perform multiple tests clinically.
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| Aytekin Güvenir et al. [16], 2024, Turkey | Retrospective observational study; OPT/DPT with alternative drugs stratified by phenotype | 91 patients underwent testing with 109 alternative drugs, median age 15 years (Jan 2015–Feb 2023) | NSAID-H reactions, primarily cutaneous reactions (urticaria, angioedema), and less commonly GIT reactions (nausea). | 91 underwent DPTs with 109 alternative drugs 3/73 (4.1%) reactions were noted to paracetamol after DPT. 2/44 (4.5%) to meloxicam. 2/5 (40%) nimesulide, but later tolerated celecoxib. Paracetamol, meloxicam, and nimesulide were safe alternatives for most children with NSAID hypersensitivity. If not tolerated, selective COX-2 inhibitors (e.g., celecoxib) were an alternative option.
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| Hadley et al. [19], 2023, United States | Cross-sectional survey-based study | 100 paediatric patients with severe asthma, aged 6–18 years | Reported history of NSAID hypersensitivity based on survey (self-reported reactions to NSAIDs) | 19% reported at least one NSAID HSR. Ibuprofen is most implicated (16%). Common symptoms were respiratory (dyspnoea, wheezing, coughing) and GI (light-headedness, abdominal pain). Associated factors included other medication triggers, nasal polyps, ageusia, cold-triggered asthma, and family history of sinusitis. Highlights the importance of a thorough history in asthma patients who may be at higher risk for NSAID hypersensitivity.
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| Li et al. [15], 2022, USA | Retrospective observational cohort study of outpatient two-step NSAID challenge procedures | 249 patients with reported NSAID allergy (mean age 51.6 years, range 5–87; 63.5% female) undergoing 262 two-step NSAID challenges; individuals with aspirin-exacerbated respiratory disease were excluded | HSR during challenge: immediate reactions (within ~3 h) and delayed reactions following a two-step NSAID challenge protocol | 224/262 (85.5%) of challenges were negative (no reaction), allowing continued NSAID use. 30 challenges (11.5%) resulted in immediate reactions, 8 (3.1%) in delayed reactions. 3 immediate reactions required intramuscular epinephrine; reactions were generally mild. Factors associated with positive challenge: a prior reaction within 5 years, a prior immediate reaction (< 3 h), cross-reactive NSAID hypersensitivity, and chronic spontaneous urticaria. 60% of patients had their NSAID allergy label removed after evaluation. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.
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| Metbulut et al. [20], 2025, Turkey | Multicentre retrospective study | 265 children with 293 drug-related anaphylactic episodes; ages 1 month to 18 years (median 107 months) | Drug-related anaphylaxis (including NSAIDs, antibiotics, others) | Most common implicated drugs: antibiotics (56.7%), NSAIDs (25.7%), chemotherapeutics (3.4%). Common agents: cephalosporins (especially ceftriaxone) among antibiotics; ibuprofen among NSAIDs. Clinical setting: 62.1% reactions in hospital, 34.1% at home; 59.7% parenteral, 40.3% oral. Severity: 39.6% severe, 54.9% moderate; 5 biphasic events; no fatalities. Management: 72% received adrenaline. Of 64 positive tests (skin prick, intradermal, drug provocation), skin prick 23.4%, intradermal 17.2%, provocation 20.3%, overall confirmed 39 cases; 4 underwent desensitization. Paediatric drug-related anaphylaxis often involves antibiotics and NSAIDs. Algorithmic evaluation is crucial for diagnosis, preventing recurrence, and finding safe alternatives.
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| González Moreno et al. [22], 2025, Spain | Mixed retrospective and prospective observational study; retrospective focus on patients < 18 years old with cross-intolerance to NSAIDs through DPT 1999–2019, prospective reassessment in 2021–2022 in visit 2 | 46 children aged 1–17 years with confirmed cross-intolerance | Primarily cutaneous (urticaria, angioedema), some respiratory symptoms (bronchorrhea, bronchospasm) | 78.9% outgrew hypersensitivity over time (median 2–6 years) during re-challenge or real-world use. 21.1% remained cross-intolerant. 29/46 (63%) were male. Median age 10 years old. Half of the patients had a history of atopy, mainly to pollens. 40–60% of paediatric patients develop tolerance over 1–5 years, especially with cutaneous-only reactions (NIUA type). Cross-intolerance often resolves faster in adults. Recommends consideration of supervised re-evaluation in selected patients.
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| Mori et al. [17], 2020; multicentre European (Belgrade, Florence, Geneva, Madrid, Porto, Rome) | Multicentre retrospective study | 693 children with a history of NSAID reactions; ages 0–18 years; 526 drug provocation tests performed | HSR to NSAIDs in paediatric patients | 103/526 (19.6%) confirmed hypersensitivity via DPT. Most reactions were cutaneous (rashes, urticaria, angioedema). Ibuprofen is most commonly implicated. Cross-intolerance reactions are more frequent than selective NSAID reactions. Diagnostic approaches varied across centres, including limited use of skin tests and aspirin challenge. Highlights the importance of DPT to confirm or rule out NSAID hypersensitivity and guide safe drug selection.
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| Podlecka et al. [13], 2023, Poland | Observational clinical diagnostic study with drug challenge tests (oral provocation) in children | 56 children aged 4–18 years referred for suspected drug allergy to NSAIDs; skin prick tests and provocation tests performed | NSAID HSR: acute urticaria and angioedema; immediate (≤ 1 h) and delayed/late reactions (after 1 h) following NSAID | NSAID hypersensitivity was confirmed in 17/56 (30.1%) of children. 47/56 (84.9%) had clinical manifestations of angioedema and urticaria. Ibuprofen was the most common culprit. Immediate reactions were reported in 31 children (55.4%) and delayed/late reactions in 25 (44.6%). Previous allergy history was a significant risk factor (p = 0.001). Vitamin D deficiency was associated with a higher risk of confirmed NSAID hypersensitivity (OR = 5.76). Hypersensitivity to NSAIDs is a difficult diagnostic problem in paediatric patients.
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| Tekcan et al. [23], 2025, Turkey | Retrospective, observational study of patients with a history of NSAID and paracetamol hypersensitivity, comparing NPV of single vs. 2-day DPTs for NSAID and paracetamol hypersensitivity | 104 patients—53.8% boys, age 1–18 | Rash, gastrointestinal symptoms, respiratory symptoms with angioedema | 104–116 negative DPT for suspected agents. 67 (57.7%) in the single-day group, 49 (42.2%) in the extended DPT group. NPV 100% in both groups. 93 children reused the suspected agent without any reaction at follow-up. Single-day DPT is sufficient to exclude NSAID hypersensitivity in children.
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| Uluc et al. [24], 2025, Turkey | Prospective study evaluating the development of tolerance in children with a confirmed diagnosis of NSAID-H | 34 cases confirmed NSAID-H, 23 (67.65%) were included in study. Median age 16.5 (last DPT). Tolerance was developed in 12/23 (52.1%). Median duration to tolerance development: 6.16 years. | Urticaria most common symptom at DPT in the tolerant group. In the persistent group, reactions occurred at significantly lower cumulative doses | Younger age at time of initial reaction (particularly < 11.75 years old) led to a higher chance of developing tolerance. Potential predictors of persistence include initial reaction at low dose to diagnostic DPT.
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| Yilmaz Topal et al. [14], 2020, Turkey | Retrospective observational diagnostic study with oral DPT in children | 243 patients with suspected NSAID-H (median age ~84 months; including both < 10 years and older children) were evaluated with 238 provocation tests | HSR to NSAIDs with mainly isolated skin manifestations (e.g., urticaria/angioedema); classified according to the EAACI position paper; classification | 47 of 231 children (20.3%) were diagnosed with confirmed NSAID-H. Ibuprofen was the most commonly implicated in 168/243 of children (69.1%), 90 children with paracetamol (37.0%). Isolated skin symptoms (urticaria, maculopapular, exanthema, angioedema) were the most frequent clinical feature (86%). 12 families refused further testing, limiting diagnostic classification. Difficulty in classifying reactions was highlighted due to overlapping symptoms and the need for multiple tests. Characterising reactions in children can be difficult due to the coexistence of indistinguishable symptoms in their history.
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