Around 10% of people avoid some type of medication due to fear of allergic reactions.1 Suspicion of drug allergy has a great impact in clinical practice.2 However, only a small percentage of patients are confirmed to have drug HSR in subsequent work-up. This over-diagnosing is particularly frequent among children1,3–8 and allergy “mislabelling” often persists into adulthood.

In children, beta-lactam antibiotics (BL) are the most common medications suspected of being involved in drug HSR and can mediate all ‘Gell and Coombs’ types of HSR.9 Most suspected HSR to BL in children are mild non-immediate skin eruptions occurring in the context of treatment for infection.10,11 Viral infections are the most common cause of maculopapular or urticarial eruptions in children, leading to frequent misdiagnosis of HSR to concurrent BL treatment.4,6,12

It is generally agreed that drug provocation tests (DPT) with the culprit antibiotic are the “gold standard” for the diagnosis of non-immediate HSR to BL.13,14 Clinical history criteria cannot accurately predict BL allergy15 whereas blood allergy tests16 and other allergy in vivotests, such as intradermal testing or patch testing, have low sensitivity in this clinical context7,8,10,12,17,18 and may be difficult to implement in young children. Recent evidence suggests that, after a careful clinical history, non-immediate mild cutaneous eruptions in children should be investigated by “up-front” DPT with the culprit drug,12,19–22 and such an approach has been included in some guidelines.23

The negative predictive value (NPV) of DPTs for non-immediate HRS to BL has been reported to be as high as 90–98%4,8,24 with some variation attributable to differences in the populations tested and DPT protocols. However, some patients do have HSR after negative DPT, and no current method can further identify which patients are at risk of HSR on re-exposure. Some DPT modifications were proposed to improve accuracy, including:

• 1.

  Extended DPT protocols,17,24–27 as it has been argued that one-day (“short”) DPT protocols might provide an exposure that is too small to elicit a full non-immediate HSR. It is also well known that, after a negative DPT, some patients, carers or attending physicians remain reluctant to use or prescribe the previously suspected medication.28 Extended protocols were proposed to also increase patients/physicians’ confidence in subsequent use of the drug.29

• 2.

  Retesting after a first negative DPT with the culprit drug. However, recent evidence suggests that retesting adds little diagnostic benefit.30,31

Data directly comparing short DPT versus extended DPT protocols in the context of non-immediate HSR in children is scarce. The primary aim of this study is to compare the NPV of one-day (short) DPT versus 3–7 days (extended) DPT protocols for the diagnosis of non-immediate cutaneous HSR to BL in paediatric age. A secondary aim is to compare the frequency of drug use (re-exposure) after short and extended negative DPTs. We did not intend to compare the performance of the two protocols in terms of diagnostic sensitivity.

We retrospectively collected data from 212 children and adolescents with a negative diagnostic DPT performed between 2007 and 2015 as part of the investigation of non-immediate cutaneous HSR to BL in two Hospitals in Portugal (Centro Hospitalar do Porto, CHP, in Porto, and Hospital Dona Estefânia, HDE, in Lisbon), and completed telephone questionnaires to the carers of the patients between 2015 and 2017.

A total of 212 patients were included: 151 in CHP and 61 in HDE, 86 females, 126 males, average age at DPT 5.52 years (median four years, p25–p75: 3–7.25 years). Sixty-nine (32.5%) patients were tested with short DPT and 143 (67.5%) with extended DPT. No significant differences in age, sex, type of reaction or DPT antibiotic were observed between the groups (Table 1).

Short and extended DPTs have similar negative predictive value

One hundred and four of the 212 patients (49.1%) were re-exposed to beta-lactams months to years after the negative DPT (Fig. 1): 40/69 (58%) in the short DPT group and 64/143 (44.8%) in the extended DPT group (p=0.071). Many factors may have contributed to the frequency of subsequent antibiotic use, e.g., time interval between DPT and telephone interview, rate of infections, age of the patient, among others. Carer/assistant physician refusal of subsequent use will be analysed below. Among the patients re-exposed to BL after negative DPT, 5/104 patients reported a suspected HSR on re-exposure (NPV was 95.2%, when both DPT protocols were analysed together).

Figure 1.

Patient distribution in the two study groups and questionnaire results. DPT: drug provocation test; AB: antibiotic; HS: hypersensitivity.

(0.14MB).

On re-exposure, only 1/40 patients in the short DPT group developed a suspected HSR (NPV: 97.5%) compared to 4/64 patients in the extended DPT group (NPV: 93.75%), p=0.419 (Table 2). All five patients who developed HSR on re-exposure had maculopapular exanthema (MPE) on the HSR index and again presented MPE on re-exposure. All five were male, average age at DPT was five years and the BL involved were amoxicillin/clavulanate in three patients and amoxicillin in two.

Table 2.

Negative predictive value of the DPT and antibiotic refusal after negative DPT.

	Total	Short Protocol	Extended Protocol	p-value
HSR on re-exposureNegative predictive value	5/10495.2%	1/4097.5%	4/6493.75%	NSp=0.419
Antibiotic refusal after negative DPT	18/12214.75%	3/436.98%	15/7918.99%	NSp=0.074

HSR: hypersensitivity reaction; DPT: drug provocation test; NS: non-significant.

In this study we aimed to determine whether prolonging the exposition to the antibiotic improved the negative predictive value of DPTs for the diagnosis of mild non-immediate HSR to beta-lactams in children. This is a relevant question because several alterations to the DPT protocols have been suggested and implemented but few data have been published directly comparing the two methods to confirm additional benefits. We evaluated both the recurrence of HSR symptoms on re-exposure, and drug refusal after negative one-day DPTs versus longer DPTs.

Our results confirm the high NPV of diagnostic DPTs in non-immediate HSR to beta-lactams in children (95.2%, both DPT protocols together). Similar values were reported in other studies (Table 3) despite differences in methodologies, type of HSR and populations enrolled. When comparing the NPV of short versus extended DPTs, we found no differences between protocols, although there were more suspected false negatives in the extended group (NPV short DPT 97.6% vs. NPV extended DPT 93.8%). Such a small difference is likely clinically irrelevant.

Refusal of the suspected drug after negative DPT remains a significant issue. In our study, a total of 14.75% of patients were refused BL after a negative DPT. In our sample, extended protocols did not increase confidence in subsequent use and, in fact, drug refusal was higher in the extended DPT group. The reasons for this are unclear and were not explored in our study. We may speculate that psychological factors, such as a “backfire effect”,32 may have played a role. We noted that refusal was more frequent in children tested with amoxicillin/clavulanate and we speculate that perhaps some non-allergic side effects of longer treatments with amoxicillin/clavulanate, such as digestive symptoms, may have influenced subsequent decision to use this antibiotic.

Altogether, our results showed no benefit in prolonging administration to test non-immediate HSR to beta-lactams in children in the parameters analysed. Previously published literature argued for the safety of extended DPTs and reported that some patients developed HSR symptoms only after several days of drug administration during extended DPTs (in adults).25–27 It is however unclear whether these patients would have developed these delayed symptoms if a short DPT had been performed. Data directly comparing sensitivity, NPV and re-exposure confidence of short versus extended DPTs protocols is generally lacking and our study addresses the latter two questions.

Our study included a large number of children with similar characteristics in both groups (e.g., age, type of HSR or suspected antibiotic). Both DPT protocols were performed in the two hospitals to mitigate differences in procedures, personal recommendations or regional differences. In our study, a large number of patients (104/212, 49.1%) were re-exposed to the culprit drug subsequent to negative DPT. A wide variation on re-exposure rates has been reported (Table 3) and the reasons for avoidance have been explored elsewhere.33 The high percentage of re-exposure in our study may, at least in part, be explained by the long period between the DPT and the questionnaire in some patients, and the young age of the patients (e.g., children have more frequent infections providing more possibilities of antibiotic prescription, parents are possibly more abiding to physicians’ prescriptions than adult individuals deciding on their own health).

We are aware of some limitations in our study. We used a questionnaire to evaluate re-exposure and drug refusal. Some carers were interviewed several years after DPT and re-exposure, and this might introduce some recall bias. Although we tried to confirm that patients reporting HSR on re-exposure were indeed describing HSR symptoms, no additional allergological workup was performed to confirm true sensitisation. It has been suggested that, as with index event, some subsequent HSR reports on re-exposure are not “real” HSR4,24 and this might have underestimated the NPV in our study (however, at an expected rate in the two protocols). The presence of non-allergic side-effects, likely arising more frequently during extended DPT, was not evaluated in our study and this might influence willingness to use the same drug besides fear of the HSR. The hypothetical influences of the time intervals between HSR and DPT and also between DPT and re-exposure were not analysed. However, these putative effects are mitigated by the fact that, analysing a paediatric population (average age at DPT=5.52 years), these intervals were never very long.

In conclusion, we did not find additional benefits in prolonging DPT both in terms of NPV and confidence for antibiotic use. However intuitive, any modifications of DPT protocols should be adequately compared with previous standard practice for sensitivity, specificity, predictive values, side-effects and, importantly, patients/carers adhesion to the DPT result. Given the low event rate of HSR on re-exposure after negative DPT, studies in large populations are required to determine the optimal length of DPT. Finally, the diagnostic performance of DPTs is always limited by the incomplete mimicking of all “real-life” conditions: DPTs are usually performed in “controlled” settings, whereas some HSR symptoms may only arise in the presence of co-factors occurring in “real-life” situations, e.g. during infection, after physical exercise, or NSAIDs intake. Other issues under investigation, such as the development of drug resistance or drug sensitisation during diagnostic procedures, might also contribute to determine the risk/benefit of prolonged exposition.

The authors declare that no funding was received for the present study.

The authors declare that they have no conflicts of interest.