Clinical data of the subjects confirmed as DHR
The 662 subjects confirmed as of DHR to APs had a median age at diagnosis of 38 [interquartile range (IR): 26–49] years, and 402 (60.73%) were female. A total of 284 had underlying rhinitis (42.9%); 161 had asthma (24.32%); 61 had nasosinusal polyposis (9.21%); 49 CSU (7.4%), and 24 food allergy (3.63%) (3 to nuts, 7 to shellfish, 6 to melon, 5 to peach, 2 to apple, 1 to kiwi, and 1 to banana). The percentage of rhinitis, asthma, nasosinusal polyposis, and CSU was higher in CRs compared with SRs (Table 1). A total of 440 patients were atopic (66.46%), being most frequently detected sensitisations toDermatophagoides pteronyssinuss (264; 39.87%), Olea europaea (217; 32.77%), and Lolium perenne (175; 26.43%) No differences were observed comparing CRs and SRs (Table 1 and Supplemmentary Table 1).
Patients confirmed as blended were the youngest (p=0.01), being the percentage of females higher in NERD and SNIDR (p=0.01). The percentage of cases with underlying rhinitis, asthma, and nasosinusal polyposis was higher in NERD cases, followed by blended cases (p<0.0001, respectively). The percentage of atopy was higher in NIUA, NECD, blended, and SNIUAA (p<0.0001), being the percentage of sensitisations to D. pteronyssinus higher in NIUA and SNIUAA (p=0.0003) and to Alternaria and Pru p 3 in blended (p<0.0001 and p=0.01, respectively) compared with the other clinical entities (Table 2 and Supplemmentary Table 2).
Cases reported a total of 1946 episodes induced by NSAIDs, being 1341 induced by APs, with a median of 2 [IR: 1-2] episodes induced by APs intake per patient, being the median higher in SRs compared with CRs (2 [IR: 2-3] vs 1 [IR: 1-2]; p<0.0001). In most subjects (601; 90.78%), reported reactions were induced by ibuprofen, followed by dexketoprofen (96; 14.5%), naproxen (64; 9.66%), and ketoprofen (9; 1.35%). In 100 cases (73 CRs and 27 SRs), 2 different APs were involved in the reactions, and in 4 cases 3 different APs were reported, all of them CRs. Comparing CRs and SRs, the percentage of subjects reporting reactions induced by ibuprofen (CR: 453 (92.63%) vs SR: 148 (85.54%); p=0.005) and dexketoprofen (CR: 81 (16.56%) vs SR: 15 (8.67%), p=0.01) was higher in CRs, and patients reporting reactions induced by naproxen (CR: 37 (7.15%) vs SR: 29 (16.76%); p=0.0002) and ketoprofen (CR: 1 (1.84%) vs SR; 8 (4.62%); p=0.00001) were more frequent in SRs. All APs were administered orally, except for 27 cases in which dexketoprofen was administered by parenteral route (intravenous and intramuscular) and 6 cases in which ketoprofen were administered topically. In 147 cases confirmed as CRs, 605 episodes were induced by others NSAIDs different from APs: 180 (36.8%) cases reported reactions induced by pyrazolones (175 by metamizol and 5 by propifenazone), 164 (33.53%) by ASA, 82 (16.76%) by arylacetic acid derivatives (73 by diclofenac, 6 by ketorolac and 3 by aceclofenac), 66 (13.49%) by paracetamol, 9 (1.84%) by oxicams (7 by meloxicam and 2 by piroxicam), 5 (1.02%) by lysine clonixinate, 2 (0.4%) by etoricoxib, 2 (0.4%) by indomethacin, and 1 (0.2%) by nimesulide.
According to the clinical entity, a total of 225 cases were confirmed as NIUA (33.98%), 150 as SNIUAA (22.65%), 110 as blended (16.61%), 105 as NERD (15.86%), 49 as NECD (7.4%), and 23 as SNIDR (3.47%) (Figure 1). Ibuprofen and dexketoprofen induced NIUA more commonly than other APs (34.8%, p<0.0001; and 42.7%, p=0.02, respectively), whereas naproxen induced more frequently SNIUAA (34.4%, p=0.0004), and ketoprofen induced SNIDR (77.8%, p<0.0001) (Table 3).
The most frequent symptoms induced by ibuprofen, dexketoprofen, and naproxen were isolated AE and urticaria combined or not with AE in both NIUA and SNIUAA, and the most frequent ones induced by ketoprofen were contact eczema and maculopapular exanthema (MPE) in SNIDR (Table 4). No differences were found in the percentage of atopic patients comparing the clinical symptoms induced by each AP (data not shown).
The time interval between the AP intake and the onset of the reaction was shorter for NERD (30 [IR:15-50] minutes), blended (30 [IR: 10-60] minutes), and SNIUAA (30 [IR: 30-120] minutes, respectively) compared with NECD (60 [IR: 30-120] minutes), NIUA (60 [IR: 15-120] minutes) and SNIDR (2160 [IR: 510-7200] minutes) (p<0.0001). No differences were found comparing the APs involved in each clinical entity (data not shown).