Hypersensitivity reactions (HRs) to nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently reported reactions to drugs, followed by reactions to beta-lactam antibiotics, and less frequently to other drugs.1,2 The prevalence varies in the different published series; ranging from about 0.6% to 5.7% in the general population, with no data published for the paediatric age group. According to the nomenclature of the EAACI-WAO, HS reactions to NSAIDs may be classified into allergic (mediated by an immunological mechanism) and non-allergic (non-immunological mechanism),3 with the latter being more frequent. The mechanism of action of NSAIDs involves inhibition of cyclooxygenase 1 (COX-1) and/or cyclooxygenase 2 (COX-2), depending on the group they belong to, and it has been proposed that the mechanism underlying reactions to NSAIDs is an impairment in the inhibition of COX-1 that results in the low production of prostaglandin E2 and an associated increase in the synthesis and release of cysteinyl leukotrienes, the latter of which would be responsible for the clinical and histological manifestations observed in these patients.4 Reactions can be classified based on the onset time after drug intake into immediate or delayed,3 and based on the chemical group to which the NSAIDs belong into selective HS when the reaction is elicited by one or several chemically related NSAIDs, and multiple HS when the reaction is elicited by at least two NSAIDs belonging to different chemical groups.2

The aim of this study was to determine the frequency of children that receive a diagnosis of HS to NSAIDs and to analyse their clinical features, type of HS, and tolerance to alternative drugs.

We analysed a total of 93 patients in whom HS to NSAIDs was suspected, out of which the diagnosis was confirmed in 26 (28%), while 66 (71%) tolerated the suspected drug in the DPT. One patient was excluded from the study because he had poorly controlled asthma.

Of the 26 patients with HS, 42% were female and 58% male; their mean age was 12 years (range, 4–17 years); 17 reported having had some type of reaction after intake of a single NSAID and nine to two or more NSAIDs; ibuprofen was involved in all reactions, in addition, four patients reported having reacted to ASA, three to metamizole, one to dexketoprofen and one to ASA and metamizole.

In this study, we found that only 28% of the children that were assessed for a suspected HS to NSAIDs received such a diagnosis. Prior to the assessment, 30% reported having had reactions to more than one NSAID, yet 50% received a diagnosis of multiple HS after testing, which demonstrates the importance of performing DPTs not only as a means of confirming the diagnosis, but also to determine potential cross-reactivity and tolerance to other NSAIDs.3,5

Ibuprofen was the culprit drug in all reactions, consistent with other studies performed in children1,6; this finding may be due to the fact that this is one of the most frequently used NSAIDs in the paediatric age group.

All patients tolerated paracetamol except for one patient diagnosed with multiple HS. Other studies on children have also demonstrated that this drug is well tolerated, and consider it a safe alterantive5,7; however, a clinical phenotype of patients with multiple HS to NSAIDs has been described in the literature in which up to 25% may not tolerate weak COX-1 inhibitors, especially at high doses,3 so it is important to ascertain that the patient can tolerate low as well as high doses. One study of 24 Asian children with a previous history of atopy and a diagnosis of multiple HS to NSAIDs found that 25% could not tolerate paracetamol.8 There seems to be an association between multiple HS with a history of atopy and poor tolerance to paracetamol, and it is believed that genetic factors may be at play in its pathogenesis.2 In our study, 42% of patients had a previous history of atopy, especially of allergic respiratory disease, with a mild predominance of patients with multiple HS.

Other drugs that were evaluated as alternatives for patients with multiple HS were selective COX-2 inhibitors; studies conducted in adults have demonstrated that they are well tolerated by most patients and that they can be considered as an alternative for those that do not tolerate paracetamol9; one study in forty-one children aged 9–14 years assessed tolerance to meloxicam and found reactions in two patients.10 In our study, nine out of thirteen patients with multiple HS underwent a DPT with meloxicam, and two could not tolerate it; while there is still insufficient evidence for the paediatric age group, meloxicam could be considered an alternative in patients with multiple HS that cannot tolerate paracetamol.

Another drug that we evaluated as an alternative for a patient that did not tolerate meloxicam was nabumetone; a study in adults found that it was tolerated by 93% of patients with multiple HS,11 although there are no studies on its use in children.

Angioedema was the most common clinical reaction observed during the provocation tests, consistent with similar findings in other published case series.1,8

To conclude, 28% of the sample under study was diagnosed with HS to NSAIDs, and, of those, 50% had multiple HS. Paracetamol may be considered a safe alternative, as it was tolerated by 96.2% of the children; however, tolerance to it must be confirmed by a DPT. Meloxicam may be an option in patients that do not tolerate paracetamol; however, we must note that its use is not indicated in children younger than 15 years. While HS reactions to NSAIDs are the most frequent adverse reactions in the general population, they tend to be underestimated in everyday practice, as they may be attributed to antibiotics that are being used concomitantly or even to some infectious agents, resulting in the delayed referral of these patients for assessment after having had more than one episode caused by a single drug. This was corroborated by our study, in which 73% of the patients diagnosed with HS to a NSAID had had more than one episode with the same drug and a clear reaction history; for this reason, we propose a simple practical algorithm in case HS to a NSAID is suspected that may be helpful to primary care physicians (Fig. 1).

Figure 1.

Practical algorithm for suspected NSAID hypersensitivity.

(0.39MB).

At present there are not enough studies on HS to NSAIDs in children and on safe alternatives, so the management of these patients remains a challenge.

The authors have no conflicts of interest to declare.