Background
Methods
Search Strategy/Key Words/Databases
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Cochrane Central Register of Controlled Trials = CENTRAL (the last available issue)
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ClinicalTrials.gov (up to present)
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Conference Proceedings Citation Index-Science = CPCI-S (1990–present)
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Embase via Ovid SP (1974–present)
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ISRCTN.com (up to present)
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MEDLINE via Ovid SP (1946–present)
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WHO ICTRP (up to present)
Inclusion/Exclusion Criteria
Population
Intervention
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Laboratory or in vitro diagnostics (measuring tryptase or specific IgE antibodies, and cellular in vitro testing)
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Penicillin skin testing (PST) (patch test, the skin prick test, and the intradermal test) can detect the presence/absence of specific anti-penicillin IgE antibodies against minor (benzylpenicillin, benzylpenicilloate, and benzylpenilloate) or major determinants (penicilloyl-polylysine). During this test, the healthcare worker administers the test solution to the skin with a tiny needle. A positive reaction presents as redness, itchiness, and a raised bump. A positive result indicates a high likelihood of penicillin allergy. However, due to the high rate of positive tests of routine testing, which can be as high as 5% [31], the possibility of a false positive penicillin skin test also has to be considered. False-positives can be due to test (e.g., 3-mm wheal threshold, higher concentrations of reagents, or improper preparation or storage) or patient factors (e.g., female sex) [24].
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Drug challenge (DC), or graded challenge, or test dosing, can be performed following a negative lab or skin test and will exclude or confirm a penicillin allergy diagnosis. This consists of the administration of penicillin under strict clinical supervision, starting with a very low dose, and subsequently administering more drug [32].
Comparator
Types of Studies
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Cohort studies
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Cross-sectional studies with a control group
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Case–control studies
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Randomized controlled trials (RCTs)
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Controlled clinical trials
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Non-randomized clinical trials
Primary Outcome
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Allergic reactions to penicillin
Secondary Outcomes
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Anaphylactic shocks
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Vasovagal reactions
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Arrhythmia rate as defined and reported based on the study protocol
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Treatment adherence: We will report this outcome as a percentage of those who received 100% of their prescribed BPG or as a percentage of the total number of recommended injections administered relative to the study population
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Acceptability to provider and patient as defined in the study protocol
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Adverse events (any)
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Serious adverse events (any)
How Studies Were Selected Based on Titles and Abstracts/Full Papers
Data Extraction
Quality Assessment
Risk of Bias Assessment
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Random sequence generation (selection bias)
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Allocation concealment (selection bias)
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Blinding of participants and personnel (performance bias)
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Blinding of outcome assessment (detection bias)
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Incomplete outcome data (attrition bias)
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Selective reporting (reporting bias)
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Other biases
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Selection bias
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Study design
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Confounders
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Blinding
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Data collection methods
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Withdrawals and drop-outs
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Intervention integrity
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Analyses
Assessment of Reporting Biases
GRADE Methodology
Data Synthesis Incl. Meta-analyses
Assessment of Heterogeneity
Subgroup Analysis
Changes from the Protocol
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Population: patients with suspected penicillin allergy (self-reported by the patient or their guardian, or patient history);
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Intervention: as before (laboratory investigations, PST, or direct DC).
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Comparator: different approach to the one used in the intervention group.
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Outcomes: as before (primary endpoint: allergic reactions to penicillin; secondary endpoints: anaphylactic shocks, vasovagal reactions, arrhythmias, treatment adherence, acceptability and adverse events).
Results
Study Selection
Routine Penicillin Allergy Testing for Patients Prescribed Penicillin for Secondary Prevention of RHD
Systematic Reviews and Studies with Broader Population
Confirmation or Delabeling of Patients with Suspected Penicillin Allergy
Study | Country | Study design | Number of patients | Study period | Setting | Patient selection (random/consecutive) | Patient type and exclusion criteria |
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Iammatteo et al. (2019) [25] | USA | Single-arm trial with historical controls | 321 | DC: January 2016 to December 2017 PST: October 2010 to November 2015 | Outpatient drug allergy clinic | DC: consecutive patients with reported penicillin allergy were screened for enrollment PST: retrospective chart review of all patients with a reported beta-lactam allergy | Aged ≥ 7 with historical non-life-threatening reactions to penicillin Excluded: pregnancy and antihistamine use within 3 days |
Mustafa et al. (2019) [26] | USA | RCT | 159 | April to August 2018 | Outpatient allergy practice | 363 consecutive patients with reported penicillin allergy were approached and 185 (51%) completed the evaluation Reasons for deferral: - Patient time constraint—39 - Fear of needles/other—23 - Delabeled on history alone or family history only—25 - Provider time constraint—12 - Medication—16 | Aged 5–17 with a history of cutaneous-only reaction to penicillin > 1 year ago, or aged ≥ 18 with a history of cutaneous-only reaction > 10 years ago Excluded: pregnancy, severe cutaneous non-IgE mediated reactions or serum-sickness-like reaction |
Stevenson et al. (2019) [27] | Australia | Retrospective study | 447 | February 2016 to May 2018 | Seven immunology outpatient clinics | All patients, aged ≥ 16 years who underwent PST and/or OPC for penicillin allergy assessment were included | Aged ≥ 16 years Some patients (n = 203) were classified as “high-risk”: index reaction < 1 year, or mucosal and/or systemic involvement Excluded: non-IgE mediated reactions, pregnancy, and significant cardiorespiratory comorbidities |
Copaescu et al. (2023) (PALACE) [28] | USA, Canada, and Australia | RCT | 382 | June 2021 to December 2022 | Six allergy outpatient clinics | Out of 446 consecutive patients labeled with a penicillin allergy referred to an allergy clinic meeting eligibility criteria, 382 were randomized Reasons for not being randomized: - Refusal of consent—21 - Reason not recorded—43 | Aged ≥ 18 PEN-FAST score < 3 Excluded: drug-related anaphylaxis, chronic spontaneous urticaria or mast-cell disease, non-IgE-mediated severe reactions, and on antihistamine therapy |
Ramsey et al. (2023) [29] | USA | RCT | 38 | N.A | N.A | N.A | Pregnant patients with a history of cutaneous-only or mild reactions to penicillin > 5 years ago Excluded: N.A |
Study | Treatment arm | Comparator arm | Female sex | Age | Condition requiring penicillin |
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Iammatteo et al. (2019) [25] | 2-step direct DC to oral amoxicillin (n = 155) | PST followed by a challenge to amoxicillin (n = 142) or cephalexin (n = 37) (n = 170; some patients were tested with both amoxicillin and cephalexin) | DC: 77.4% (120) PST: 80% (136) | DC: 50.1 ± 2.4 PST: 52.1 ± 1.5 | Not specified |
Mustafa et al. (2019) [26] | 2-step direct DC to oral amoxicillin (n = 79) | PST followed by challenge to amoxicillin (n = 80) | 69.8% (111) | 38.2 ± 25.0 | Not specified |
Stevenson et al. (2019) [27] | 1 or 2-step direct DC to oral amoxicillin or culprit penicillin (n = 167) | PST followed by challenge to amoxicillin or culprit penicillin (n = 280) | DC: 55.7% (93) PST: 68.6% (192) | DC: 42.4 ± 19.5 PST: 47.0 ± 18.3 | Not specified |
Copaescu et al. (2023) (PALACE) [28] | 1 or 2-step direct DC with oral amoxicillin, penicillin V, or flucloxacyllin (n = 188) | PST followed by 1-step oral challenge (n = 190) | 65.5% (247) | 51 (35-66) | Not specified |
Ramsey et al. (2023) [29] | 2-step direct DC with oral amoxicillin (n = 16) | PST followed by a challenge to amoxicillin (n = 22) | 100% (38) | 28.4 (25.2–30.8) | Peripartum prophylaxis in group B strept-colonized women |
Study | Drug-challenge | Skin test | Timing of outcome assessment |
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Iammatteo et al. (2019) [25] | All graded challenges were single-blind (patient) and placebo-controlled Patients informed they would receive a placebo, but not told when it would be administered. All patients first received placebo followed by a 30-min observation period. Oral challenge was subsequently performed with 80 mg (1 mL of 400 mg/5 mL suspension) of amoxicillin followed by 30-min observation and subsequent administration of full therapeutic dose (500 mg) of amoxicillin. Patients were observed for 60 min after that. Amoxicillin was supplied in liquid formulation and mixed in the same yogurt and pharmaceutical sweetener used for placebo | PST were performed when appropriate before challenges according to published guidelines. Patients with PST positive for benzylpenicilloyl polylysine, penicillin G, piperacillin, or ampicillin but negative for cephalosporins underwent cephalexin graded challenges. In patients with positive cephalosporin skin testing but negative PST, graded challenges to amoxicillin were subsequently performed single-blind. All graded challenges were single-blind (patient) and placebo-controlled | DC: 120 min PST: not specified 61.9% (n = 96) patients were contacted within one month to assess for delayed reactions 44.5% (n = 69) patients were eligible for 1-year follow-up phone calls, and 19 were reached |
Mustafa et al. (2019) [26] | Oral DC: 1/10 of the target dose of amoxicillin + monitoring for 30 min, and then full-dose amoxicillin + monitoring for 30 min Adults 40 and 400 mg; children 20 and 200 mg, or adult-dose depending on age, weight, and provider preference | PST: skin prick test to volar forearm using the Quintip testing device with benzylpenicilloyl polylysine as the major determinant, penicillin G 10,000 U/mL as the minor determinant, histamine 6 mg/mL as the positive control, and sodium chloride 0.9% as the negative control Negative skin prick testing was followed by intradermal testing administered on the upper arm with the same materials except a histamine concentration of 0.02 mg/mL | DC: 66.7 ± 4.8 min PST: 72.7 ± 5.3 min |
Stevenson et al. (2019) [27] | Oral amoxicillin challenge was performed for patients with unspecified penicillin allergies. When the implicated penicillin was known, it was used. Challenge was performed with 1 or 2 doses (10% or full dose), with minimum 30-min observation between doses, and min 1 h after the final dose. Patients with history of anaphylaxis initially received 1% dose at some centers. Patients who tolerated the direct OPC were discharged on a course of penicillin (i.e., extended challenge) to assess for delayed reactions | PST was selected for each patient according to site-specific protocols, comprising benzylpenicillin (6 mg/mL), amoxicillin (20 mg/mL), and (where specified) the culprit penicillin(s); 5 sites also performed neat penicilloyl polylsysine and minor determinant mixture skin testing | DC: 60 to 90 min PST: not specified Phone follow-up 3 to 7 days after |
Copaescu et al. (2023) (PALACE) [28] | Oral DC: lowest available therapeutic dose at each site of oral penicillin: Amoxicillin 250–500 mg in 85%, amoxicilin 400 mg 2-step in 6%, and penicillin VK 250–500 mg in 9%, and flucloxacillin 250 mg in 1% 60-min observation | PST: skin prick test with benzylpenicilloyl polylysine as the major determinant, ampicillin 25 mg/mL or Penicillin G 10,000 U/mL as minor determinants, histamine 10 mg/mL as positive control, and sodium chloride 0.9% as negative control. Test was read at 15 min Negative skin prick testing was followed by intradermal testing 0.02 mL with same materials 15 min later, and read after 15 min | DC: 1.8 h (IQR 1.3–3.7) PST: 2.3 (IQR 1.7–5.5) All patients contacted at 5 days for delayed adverse events |
Ramsey et al. (2023) [29] | N.A | N.A | DC 70 min PST 72 min |
Immediate allergic reaction | |||||
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Sensitivity/subgroup analysis | % | RR | 95%CI | P | I2 |
RCTs only (3 studies) | DC 4/282 PST 13/292 | 0.36 | 0.12–1.04 | 0.06 | 0% |
Non-RCTs (2 studies) | DC 10/322 PST 72/450 | 0.24 | 0.10–0.56 | 0.001 | 37% |
Pregnancy (1 study) | DC 0/16 PST 2/22 | 0.27 | 0.01–5.28 | 0.39 | N.A |
Children and adults (3 studies) | DC 13/401 PST 82/530 | 0.24 | 0.13–0.43 | < 0.00001 | 0% |
Adults only (2 studies) | DC 1/203 PST 3/212 | 0.55 | 0.07–4.16 | 0.56 | 0% |
Allergic reaction at longest available follow-up | |||||
Sensitivity/subgroup analysis | % | OR | 95%CI | P | I2 |
RCTs only (3 studies) | DC 11/282 PST 16/292 | 0.66 | 0.15–2.91 | 0.58 | 61% |
Non-RCTs (2 studies) | DC 24/322 PST 72/450 | 0.52 | 0.34–0.80 | 0.003 | 0% |
Pregnancy (1 study) | DC 0/16 PST 2/22 | 0.27 | 0.01–5.28 | 0.39 | N.A |
Children and adults (3 studies) | DC 27/401 PST 82/530 | 0.49 | 0.32–0.74 | 0.0006 | 0% |
Adults only (2 studies) | DC 8/203 PST 6/212 | 1.19 | 0.21–6.90 | 0.85 | 35% |