Serum sickness-like reactions to amoxicillin in children: Drug provocation test duration, recurrence, cross-reactivity.

BackgroundSkin rash often occurs upon oral administration of amoxicillin in children, due to non-immediate hypersensitivity. However, information on delayed hypersensitivity to amoxicillin is scarce. Moreover, the appropriate diagnostic method and actual diagnostic rate of delayed hypersensitivity to amoxicillin among Japanese children are unclear. We conducted intradermal tests (IDTs) and drug provocation tests (DPTs) and retrospectively investigated the proportion of children with a definitive diagnosis of non-immediate hypersensitivity to amoxicillin. We then evaluated the characteristics of patients with a positive allergic workup. MethodsWe enrolled children referred for suspected findings of mild or moderate non-immediate hypersensitivity to amoxicillin between August 2018 and March 2020. If the IDT in the delayed phase was negative, DPT with amoxicillin (60–90 mg/kg/day) was performed for 7 days. Non-immediate hypersensitivity to amoxicillin was defined when IDT or DPT was positive. We evaluated the potential of the drug-induced lymphocyte stimulation test (DLST) to reveal hypersensitivity to amoxicillin. ResultsThis study enrolled 27 children. Fourteen children (52%) had hypersensitivity to amoxicillin, of whom 12 had positive IDTs and two had positive DPTs. No differences in age, sex, history of allergic disease, days from oral use to symptom onset, type of rash at symptom onset, generalized rash, and DLST results were observed between the hypersensitivity and non-hypersensitivity groups. ConclusionsExamination should be performed for children with mild or moderate reactions because positive cases have no significant features and half of the suspected cases are negative.

BackgroundMild non‐immediate reactions (NIR) to beta‐lactams (βLs) are the most common manifestation of adverse drug reactions in children, and the drug provocation test (DPT) remains the gold standard for diagnosis. However, there are still controversies about the protocol that should be used, especially regarding the administration of doses and the DPT length.ObjectiveThis study aimed to evaluate a pediatric population with a history of mild NIR to amoxicillin (AMX) or to amoxicillin‐clavulanic acid (AMX/CL) who underwent a diagnostic workup including a DPT with the culprit drug, to understand if a graded DPT or, instead, a single full dose could be the most appropriate way of administration in clinical practice.MethodsThe data of children were retrospectively analyzed for a 5‐year period, with demographic and clinical characteristics collected. We reported the allergy workup and the results of the DPT performed with the administration of incremental doses and a prolonged DPT at home for a total of 5 days.ResultsThree hundred fifty‐four patients were included. Overall, 23/354 (6.5%) DPTs were positive: 11/23 patients showed a reaction after 2–8 h after the last dose on the 1st or 2nd day (1 reacted 30 min after the last dose), 1/23 reacted with urticaria 30 min after the first dose, 11/23 reacted at home on the 5th day of the DPT.ConclusionThis paper indirectly suggests that a single therapeutic dose administered on the 1st day of a DPT could be safe in the diagnostic workup of mild NIR to AMX/CL. Moreover, this could be less time‐consuming as patients would spend less time in the hospital, also considering the public health restrictions imposed during the COVID‐19 pandemic.

Review for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Author response for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Review for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Decision letter for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Decision letter for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Review for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Review for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Author response for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

Decision letter for "Serum sickness-like reactions to amoxicillin in children: drug provocation test duration, recurrence, cross-reactivity"

BackgroundMany children present to emergency departments (EDs) with a reported allergy to penicillin.1 There is growing data to support key historical features to accurately stratify patients into low and high-risk...

Simplifying The Drug Provocation Test in Non-Immediate Hypersensitivity Reactions to Amoxicillin in Children: The Experience of a Tertiary Care Allergy Unit.

Current recommendations for the management of penicillin allergy are to perform penicillin skin testing (PST) with penicilloyl-polylysine (PPL) and benzylpenicillin (BP) prior to drug challenge with amoxicillin. However, the role of PST is increasingly questioned in the pediatric setting. To resolve the question of PST’s diagnostic accuracy, consecutive children with a history of non-life-threatening penicillin allergy referred to a tertiary-care allergy center were recruited to undergo double-blinded PST with PPL and BP prior to drug provocation to amoxicillin. Five of 158 participants (3.2%) presented with an immediate or accelerated reaction upon amoxicillin challenge, none of which were severe. Only one of these had positive PST (20%), compared to 15 of 153 amoxicillin tolerant participants (9.8%). The sensitivity and specificity of PST with PPL and BP for reacting upon amoxicillin challenge were 20% (95% CI: 0.5–71.6%) and 90% (95% CI: 84.4–94.4%), respectively. These results argue against the routine use of PST as a preliminary step to drug provocation with amoxicillin in this population, as it is unlikely to significantly alter pre-test probability of reacting to challenge.

We have read the manuscript about codeine (3-methylmorphine) anaphylaxis by Hey-Soo Yoo et al.1 with great interest and would like to take the opportunity to raise some issues and communicate our experience. As recently reviewed, despite their frequent and ubiquitous use, genuine IgE-mediated allergy to opiates remains exceedingly rare. Also, correct diagnosis is not straightforward, mainly because of uncertainties associated with measurement of drug-specific IgE antibodies and skin testing.2 Actually, the key to correct diagnosis of opiate allergy lies in elucidating the clinical significance of positive specific IgE (sIgE) results and distinguishing skin test responsiveness resulting from direct histamine release from a true IgE-mediated activation of cutaneous mast cells. From investigations about morphine and pholcodine (3-[2-morpholinyl-ethyl] morphine)-reactive IgE antibodies it is clear that positive IgE results towards these compounds cannot be considered as a proof for opiate allergy. As a matter of fact, sIgE reactivity to opiates has been observed in up to 10% of the general population and over 80% of patients allergic to rocuronium.3,4,5 Mutatis mutandis, this observation applies to skin testing with these potent histamine releasers that, for years, have been used as a positive control in skin testing (for review2). In contrast, opiates seem not to trigger histamine release from human basophils,6,7,8 making these cells highly attractive as a complementary diagnostic instrument to discriminate non-immunologic hypersensitivity reactions from genuine allergy with an underlying IgE-mediated mechanism (for review2). In their manuscript the authors describe a patient who suffered from anaphylaxis due to oral intake of codeine and document their diagnosis with a drug provocation and histamine release tests. However, due to the unavailability of codeine-sIgE tests, they were unable to establish a potential IgE-mediated mechanism. However, several points might be addressed here. First, measurement of pholcodine and morphine sIgE antibodies, that are readily available from Phadia Thermo Fisher Scientific, might have proven to be useful. As a matter of fact, these three opiates are structurally almost identical, except the substituent in position 3. At this position codeine has a methoxy group, morphine a hydroxyl group, and pholcodine a 2-morpholinoethyl group. Second, mutatis mutandis, the recommendation also applies to histamine release and drug provocation tests. Recently, we have described three patients with immediate hypersensitivity reactions to pholcodine in who measurement of drug-specific IgE and basophil activation tests (Figure) lead to the diagnosis of an IgE-mediated pholcodine allergy.9 Because these patients demonstrated a positive sIgE to morphine but negative basophil activation and provocation tests with the closely related structures morphine and pholcodine, the conclusion seems inescapable that the currently available quantification of opiate-sIgE tests should not be used to diagnose or predict clinical outcomes. Moreover, these observations seem to indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, the position 3 substituent. Figure Representative plot CD63 appearance and histamine release in response to buffer, anti-IgE as a positive control, pholcodine 10 µg/mL (top), and the structurally almost similar opiates codeine 100 mg/mL and morphine 100 µg/mL (both bottom) ...