Beta-lactam allergy and drug challenge test in children: a systematic review and meta-analysis

Kuniyoshi, Yasutaka; Tsujimoto, Yasushi; Banno, Masahiro; Taito, Shunsuke; Ariie, Takashi; Kubota, Takafumi; Takahashi, Natsuki; Tokutake, Haruka

doi:10.1038/s41390-022-02076-x

Cited by 9 publications

(19 citation statements)

References 43 publications

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“…The frequency with which DH is confirmed in these populations is low, generally below 10% for penicillins and around 20% for NSAIDs. [10][11][12][13][14][15][16][17]36,37 These percentages may be similar to the prevalence of the disease in that population (pre-test probability), conditioning the positive PV of any test, however precise, which decreases markedly when the prevalence is very low (Figure 1). This problem also affects penicillin skin tests to a greater extent, as they are likely to be less sensitive and less specific than DPT, which increases the proportion of false positives, that is, incorrect diagnoses based on skin tests.…”

Section: Pred I C Tive Value Of Dp Tmentioning

confidence: 85%

“…Several studies have proven the excellent negative PV of DPT, 85.3% or 89.1% in some reports, 12,17 but usually over 95% in most papers, regardless of the class of drug tested and the duration of the test. 22,23,[33][34][35][36] The few falsenegative results could be due to a temporary decrease in hypersensitivity due to time elapsed, an insufficient dose administered during the DPT (single dose, cumulative dose, or duration of treatment), or differences in the circumstances of the original reaction because of the absence of cofactors such as infection, exercise, other concomitant drugs assumption, or exposure to allergens. 20 It is generally assumed that the positive PV of an open DPT is also high, although no studies have specifically assessed this.…”

Section: Pred I C Tive Value Of Dp Tmentioning

confidence: 99%

“…61,62 Drug provocation test has a good safety profile, and positive tests usually produce only mild symptoms. 20,36,37,63 While this is reassuring for pediatric allergy units, it may also reflect a very low threshold for considering a test as positive, leading to prompt discontinuation of the test when the observed symptoms are attributed to the drug administered. Although the risk of a serious and potentially life-threatening reaction is very low, performing a DPT generates a certain degree of anxiety and alertness in healthcare staff, which may F I G U R E 1 Graphical representation of the variation in positive and negative predictive value (e.g., of an open DPT with drugs), as a function of disease prevalence, assuming a sensitivity and specificity of 98% each.…”

Section: Interpre Tati On Of a P Os Itive Dp T: Obs Erver B Ia Smentioning

confidence: 99%

“…Open DPT is particularly reliable for ruling out drug hypersensitivity, as the negative PV of a test is high when the sensitivity of the test is also high and the prevalence of disease is low (Figure 1). Several studies have proven the excellent negative PV of DPT, 85.3% or 89.1% in some reports, 12,17 but usually over 95% in most papers, regardless of the class of drug tested and the duration of the test 22,23,33–36 . The few false‐negative results could be due to a temporary decrease in hypersensitivity due to time elapsed, an insufficient dose administered during the DPT (single dose, cumulative dose, or duration of treatment), or differences in the circumstances of the original reaction because of the absence of cofactors such as infection, exercise, other concomitant drugs assumption, or exposure to allergens 20 …”

Section: Predictive Value Of Dptmentioning

confidence: 99%

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Drug provocation tests in children: All that glitters is not gold

Moral,

Mori

2023

Pediatric Allergy Immunology

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A proper allergy work‐up, based on the gold standard drug provocation test (DPT), usually rules out suspected drug hypersensitivity in children. These tests are generally open, given their high efficiency compared with double‐blind placebo‐controlled DPTs. Although their negative predictive value is excellent, no studies have calculated their positive predictive value, highly dependent on the prevalence of the disease. Most studies have found a rate of <5%–10% of true beta‐lactam hypersensitivity in children. Given this low prevalence (pre‐test probability), a few false‐positive results can significantly reduce the estimated positive predictive value. False positives may arise from the nocebo effect during the test, including nocebo by proxy, or from observer bias, which depends on professional expertise and organizational circumstances. Some studies have found a high rate of tolerance on a second DPT in children who failed the first, but these results may be affected by the interval between the two tests, of a year or more in most cases, reflecting a loss of hypersensitivity over time. Taking into account the low rate of positive DPTs, with commonly mild reactions, we suggest confirming nonsevere positive DPTs with a second provocation performed soon after the first, especially in the case of beta‐lactam antibiotics, in order to improve the diagnostic accuracy, de‐label more patients, and achieve a better estimation of true drug hypersensitivity prevalence. In case of mild immediate reactions, the potential benefits of a second DPT should be carefully weighed against the risk of anaphylaxis.

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Section: Pred I C Tive Value Of Dp Tmentioning

confidence: 85%

Section: Pred I C Tive Value Of Dp Tmentioning

confidence: 99%

Section: Interpre Tati On Of a P Os Itive Dp T: Obs Erver B Ia Smentioning

confidence: 99%

Section: Predictive Value Of Dptmentioning

confidence: 99%

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Drug provocation tests in children: All that glitters is not gold

Moral,

Mori

2023

Pediatric Allergy Immunology

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“…For delabelled children who were subsequently exposed to β-lactams, this review found that a high percentage (94.8%) of children tolerated it. A recent meta-analysis of PAT in children 56 showed that the rate of false negatives (positive second challenge after a negative first challenge) was 2.8%. Although our review found that a median 5.2% of children did not tolerate a subsequent course of penicillin, it may be an overestimation as this outcome was patient-reported or carer-reported in most studies.…”

Section: Discussionmentioning

confidence: 99%

Health outcomes of penicillin allergy testing in children: a systematic review

Kwok

Heard

May

et al. 2023

Journal of Antimicrobial Chemotherapy

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Background Penicillin allergy labels are commonly acquired in childhood and lead to avoidance of first-line penicillin antibiotics. Understanding the health outcomes of penicillin allergy testing (PAT) can strengthen its place in antimicrobial stewardship efforts. Objectives To identify and summarize the health outcomes of PAT in children. Methods Embase, MEDLINE, Web of Science, Cochrane Library, SCOPUS and CINAHL were searched from inception to 11 Oct 2021 (Embase and MEDLINE updated April 2022). Studies that utilized in vivo PAT in children (≤18 years old) and reported outcomes relevant to the study objectives were included. Results Thirty-seven studies were included in the review, with a total of 8411 participants. The most commonly reported outcomes were delabelling, subsequent penicillin courses, and tolerability to penicillin courses. Ten studies had patient-reported tolerability to subsequent penicillin use, with a median 93.6% (IQR 90.3%–97.8%) of children tolerating a subsequent course of penicillins. In eight studies, a median 97.3% (IQR 96.4%–99.0%) of children were reported as ‘delabelled’ after a negative PAT without further definition. Three separate studies verified delabelling by checking electronic or primary care medical records, where 48.0%–68.3% children were delabelled. No studies reported on outcomes relating to disease burden such as antibiotic resistance, mortality, infection rates or cure rates. Conclusions Safety and efficacy of PAT and subsequent penicillin use was the focus of existing literature. Further research is required to determine the long-term impact of delabelling penicillin allergies on disease burden.

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Reaction Risk to Direct Penicillin Challenges

Blumenthal,

Smith,

Mann

et al. 2024

JAMA Intern Med

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ImportanceWhile direct penicillin challenges might support the expansion of penicillin allergy delabeling efforts, the perceived risk of reactions remains a key barrier.ObjectiveTo evaluate the frequency of reactions to direct penicillin challenges in individuals with penicillin allergy labels and to identify factors associated with such reactions.Data SourcesThree electronic databases were searched (MEDLINE, Web of Science, and Scopus) from inception to July 19, 2023, for primary studies assessing patients undergoing direct penicillin challenges. Articles were included regardless of publication year, language, status, or definition of allergy risk.Study SelectionTwo reviewers independently selected original studies reporting the frequency of immunologically mediated reactions following a direct penicillin challenge in patients reporting a penicillin allergy.Data Extraction and SynthesisTwo reviewers independently extracted data and independently assessed the quality of each primary study using a risk-of-bias tool for prevalence studies.Main Outcomes and MeasuresThe primary outcome was the frequency of reactions to direct penicillin challenges as calculated using random-effects bayesian meta-analysis of proportions. Secondary outcomes included risk factors for reactions and the frequency of severe reactions.ResultsA total of 56 primary studies involving 9225 participants were included. Among participants, 438 experienced reactions to direct penicillin challenges without prior testing, corresponding to an overall meta-analytic frequency of 3.5% (95% credible interval [CrI], 2.5%-4.6%). Meta-regression analyses revealed that studies performed in North America had lower rates of reaction to direct challenges (odds ratio [OR], 0.36; 95% CrI, 0.20-0.61), while studies performed in children (OR, 3.37; 95% CrI, 1.98-5.98), in outpatients (OR, 2.19; 95% CrI, 1.08-4.75), and with a graded (OR, 3.24; 95% CrI, 1.50-7.06) or prolonged (OR, 5.45; 95% CrI, 2.38-13.28) challenge had higher rates of reaction. Only 5 severe reactions (3 anaphylaxis, 1 fever with rash, and 1 acute kidney injury) were reported, none of which were fatal.Conclusions and RelevanceThis systematic review and meta-analysis found that reactions to direct penicillin challenges are infrequent, with rates comparable to indirect challenges after allergy testing. These findings suggest that direct challenges are safe for incorporation into penicillin allergy evaluation efforts across age groups and clinical settings.

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Beta-lactam allergy and drug challenge test in children: a systematic review and meta-analysis

Cited by 9 publications

References 43 publications

Drug provocation tests in children: All that glitters is not gold

Drug provocation tests in children: All that glitters is not gold

Health outcomes of penicillin allergy testing in children: a systematic review

Reaction Risk to Direct Penicillin Challenges

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