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From the Journals

Is Penicillin Allergy Overdiagnosed? Meta-Analysis Questions Prevalence

Direct penicillin challenges led to reactions in only 3.5% of 9,225 patients across 56 studies, raising doubts about the perceived prevalence of penicillin allergies.

Conexiant

A systematic review and meta-analysis found that direct penicillin challenges are safe and effective for penicillin allergy delabeling across diverse populations and clinical settings.

In the study, published in JAMA Internal Medicine, investigators included data from 56 primary studies involving 9,225 participants. They conducted a comprehensive search of MEDLINE, Web of Science, and Scopus databases up to July 19, 2023, focusing on studies that reported the frequency of immunologically mediated reactions following direct penicillin challenges in patients with penicillin allergy labels.

The investigators utilized Bayesian meta-analytic methods to synthesize the data, a technique that effectively manages rare events such as those with zero-cell data. Heterogeneity was assessed using the I² statistic, and the team conducted subgroup analyses and meta-regression to examine potential risk factors for reactions​.

 The investigators revealed that the overall frequency of reactions to direct penicillin challenges was 3.5% (95% credible interval [CrI] = 2.5%–4.6%). The reaction rate was 2.2% (95% CrI = 1.2%–3.2%) among adults and 6.6% (95% CrI = 4.6%–9.5%) among children. Notably, only five severe reactions occurred, none of which were fatal. The findings suggested that concerns about the risks of direct penicillin challenges may be overstated, particularly in lower-risk populations.

Detailed results:

  • Geographic Variations: North American studies (n = 4,861) had a reaction frequency of 2.3% (95% CrI = 1.5%–3.1%), while European studies (n = 3,051) showed a higher rate of 5.9% (95% CrI = 3.4%–9.0%).
  • Challenge Protocols: Single-dose challenges (n = 1,821) resulted in reactions in 1.6% (95% CrI = 0.7%–2.6%) of patients, whereas graded challenges (n = 4,650) had a higher rate of 4.2% (95% CrI = 2.3%–6.5%). Prolonged challenges (n = 1,310) had the highest rate of 7.1% (95% CrI = 3.5%–11.8%).
  • Patient Settings: Reaction rates were lower in inpatient settings (2.3%, 95% CrI = 1.1%–3.6%) compared with outpatient settings (4.2%, 95% CrI = 2.8%–6.0%).
  • Drug Selection: Direct challenges with the suspected culprit drug led to a reaction frequency of 4.1% (95% CrI = 2.5%–6.5%), whereas challenges using an alternative β-lactam had a lower rate of 1.6% (95% CrI = 0.7%–2.9%).

The analysis identified several risk factors associated with increased reaction rates, including:

  • A lower risk in North American studies (odds ratio [OR] = 0.36, 95% CrI = 0.20–0.61).
  • A higher risk in children (OR = 3.37, 95% CrI = 1.98–5.98).
  • A higher risk in outpatient settings (OR = 2.19, 95% CrI = 1.08–4.75).
  • A higher risk with graded (OR = 3.24, 95% CrI = 1.50–7.06) or prolonged challenges (OR = 5.45, 95% CrI = 2.38–13.28).

The investigators highlighted substantial statistical heterogeneity across the studies, which could affect the generalizability of the results. Additionally, the exclusion of participants with severe index reactions may have resulted in an underestimation of reaction rates in the general population. Most studies also had inconsistent definitions of low-risk allergy, further contributing to variability in findings. The certainty of the evidence was downgraded to very low because of these factors​

The lead author reported receiving grants from a medical diagnostics company unrelated to the current study. Another author reported leadership roles in guideline development groups. No other conflicts of interest were disclosed by the study team.