American Academy of Allergy

Prior high-risk penicillin reactions should not prevent provocation challenges in children

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Factors considered high risk for penicillin allergy should not preclude children from undergoing reevaluation, according to a study presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting.

“Children with penicillin allergy labels should be referred to and evaluated by an allergist for potential delabeling, even if they had traditionally ‘high-risk’ histories of anaphylaxis, serum sickness-like reactions or prior positive penicillin allergy testing,” lead study author Susan S. Xie, MD, clinical fellow in the division of allergy and immunology at Cincinnati Children’s Hospital, told Healio.

Penicillin allergy
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Xie and colleagues reevaluated 1,553 risk-stratified children (median age at reaction, 1.8 years) listed in the penicillin allergy registry at Cincinnati Children’s Hospital Medical Center to characterize higher risk vs. lower risk and determine which children should be eligible for drug provocation challenges and allergy delabeling.

Susan Xie, MD

Susan S. Xie

“Large studies from multiple countries have already established tolerance rates of greater than 90% in children with penicillin-associated rashes when they are re-challenged to the culprit penicillin,” Xie said. “Our study found similar tolerance rates in children with higher-risk histories such as anaphylaxis and serum sickness-like reactions, who traditionally may have been excluded from referral or routine allergy testing.”

In all, 66.3% of children were categorized as having no risk, indicating they had an unknown family allergy history and had experienced a rash or hives more than 1 year before registry or other mild somatic symptoms; 27.3% were categorized as low risk, which included those who experienced a rash or hives within 1 year of registry, as well as swelling, difficulty breathing and reactions to all penicillins or cephalosporins; and 6.4% were categorized as high risk, indicating they had experienced serum sickness-like reactions, anaphylaxis, severe cutaneous reaction and prior positive penicillin skin testing or drug provocation challenges.

“We found that while only 31% of children classified as high-risk underwent challenges, 94% were tolerant. These nonallergic high-risk patients included 22 who originally had serum sickness-like reactions, three with anaphylaxis, four with prior positive skin testing and one with a prior allergic challenge. The two high-risk patients with allergic outcomes had histories of serum sickness-like reaction and possible anaphylaxis, but solely developed delayed-onset hives after their challenges,” Xie said.

“In comparison, patients classified as low risk and no risk in our registry were challenged at higher rates, 59% in both groups, and had similar tolerance rates of 92% in the low-risk group and 96% in the no-risk group,” Xie added.

Certain systemic symptoms likely deterred patients or providers from proceeding with challenges, Xie said. Specifically, patients with hand or foot swelling, vomiting or diarrhea, joint symptoms or fever were less likely to undergo drug challenges.

“However, children who experienced any systemic symptom still had a tolerance rate of 89% overall,” Xie said.

Future research will be aimed at guiding appropriate risk stratification of penicillin-allergic children, with the goal of being more inclusive with safely delabeling pediatric patients and preventing unnecessary avoidance of penicillin, Xie said.

“Given the small number of allergic outcomes even in reaction phenotypes deemed ‘high risk’ in children, we will continue to collect data in this population, and multicenter collaborations would be helpful,” Xie said.

PERSPECTIVE

 Jumy (Olajumoke) Fadugba, MD, FAAAAI)

Jumy (Olajumoke) Fadugba, MD, FAAAAI

This study was interesting because it sought to investigate a group of children with history of “high-risk” penicillin reactions; these are patients who are often not assessed. It was a retrospective study with the goal of identifying the characteristics of patients who underwent a direct oral challenge to penicillin (DPC) without a preceding skin test.

It was interesting to note that 32 “high-risk” patients did undergo DPC. However, as expected, fewer high-risk patients underwent DPC than those who had low-risk history.

The researchers found that most of the “high-risk” children (94%) did tolerate the DPC, a similar tolerance rate as those with low-risk history.

These are promising initial data, but further investigation of these “high-risk” patients would better guide how we should manage these patients. For example, some high-risk reactions (such as serum sickness, Stevens-Johnson syndrome and DRESS, or drug rash with eosinophilia and systemic symptoms) require several days of antibiotic use before they manifest; therefore, one could consider several days of an oral challenge to really determine whether there is tolerance.

In addition, it is possible that the providers felt that the challenged high-risk patients were more likely to tolerate DPC than the nonchallenged high-risk patients. A future goal might be a prospective study that identifies specific high-risk categories of patients who will undergo DPC in order to determine outcome.

Overall, this study should encourage providers to not simply dismiss patients with “high-risk” histories, but rather to probe histories further and, if appropriate, administer DPC.

Jumy (Olajumoke) Fadugba, MD, FAAAAI

Associate professor of clinical medicine
Chief, section of allergy & immunology
Fellowship program director of allergy & immunology
Perelman School of Medicine, University of Pennsylvania

AAAAI: Penicillin Allergy Label Linked to MRSA, C. difficile

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Increase attributable to use of alternative antibiotics

Patients with general practitioner-reported penicillin allergies had an increased risk for developing methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. difficile) infections mediated by increased use of beta-lactam alternative antibiotics, researchers reported here.

Findings from the newly reported study suggest that addressing patient over-reporting of penicillin allergies could prove to be an effective strategy for reducing MRSA and C. difficile incidence, researchers say.

Kimberly Blumenthal, MD, of Massachusetts General Hospital in Boston, reported the study findings during a presentation at a joint meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the World Allergy Organization (WAO).

Blumenthal and colleagues used mediation analysis to estimate the impact of a new penicillin allergy documentation by a general physician on the use of alternative antibiotics and risk of MRSA and C. difficile over 6 years of patient follow-up.

“We found that over a quarter to half of the risk of new infection was attributable to the alternative antibiotics,” Blumenthal told MedPage Today, adding that the study is the first to show a link between new-onset use of antibiotics and a first documentation of MRSA or C. difficile.

Since the patients did not undergo formal testing to confirm their penicillin allergy, many may have needlessly been taking the alternative antibiotics, she said.

Asked for his perspective, David Lang, MD, chairman of the Department of Allergy and Clinical Immunology and director of the Allergy/Immunology Fellowship Training Program at the Cleveland Clinic, who was not involved with the study, told MedPage Today that there is growing evidence that patient over-reporting of penicillin allergy has very real clinical consequences.

While approximately one in 10 people self-report having a penicillin allergy, studies suggest that only perhaps one in 20 actually have a clinically confirmable intolerance to the drug, he said. “As many as 19 in 20 people avoiding penicillin are doing so needlessly. These people are given alternative antibiotics that are more costly, have more side effects, and predispose them to untoward outcomes.”

Lang said the newly reported research provides further evidence that a label of penicillin allergy is not clinically benign: “A large focus of the antibiotic stewardship initiative is to limit the use of these broad-spectrum antibiotics when we can. It is clear that the low-hanging fruit of antibiotic stewardship is de-labeling these people who believe they have penicillin allergy, but don’t.”

For the study, Blumenthal and colleagues used a general practice database in the United Kingdom with patient data spanning 1995 through 2015, and studied a matched cohort of adults without prior MRSA or C. difficile.

Patients with incident penicillin allergy, as reported in their medical records, were matched with up to five penicillin users without allergy by age, sex, and index date.

The researchers calculated relative risks (RRs) for the association of penicillin allergy with incident MRSA and C. difficile, adjusting for potential confounders, and also examined beta-lactam alternative antibiotic use to determine whether it was a mediator for MRSA/C. difficile incidence.

Over a mean follow-up of 6 years, among 64,141 penicillin allergy patients and 237,258 matched comparators, 1,345 developed MRSA and 1,688 developed C. difficile.

Among the main study findings:

  • The adjusted RRs among penicillin allergy patients were 1.62 (95% CI, 1.42-1.85) for MRSA and 1.27 (95% CI, 1.13-1.43) for C. difficile
  • The adjusted RRs for antibiotic use among penicillin allergy patients were 4.08 (95% CI, 4.05-4.10) for macrolides, 3.73 (95% CI, 3.51-3.97) for clindamycin, and 2.13 (95% CI, 2.10- 2.16) for fluoroquinolones
  • Increased beta-lactam alternative antibiotic use accounted for 53% of the increased MRSA risk and 25% of the increased C. difficile risk

“The message from this research and other research to general practitioners, medical specialists, and surgeons is that when they see a patient with a label of penicillin allergy, send them to us to confirm or disprove this label,” Lang said. “Nine out of 10 — or even 19 of 20 — times we will be able to reduce the patient’s risk for bad outcomes by removing this label.”