Beta-lactam Hypersensitivity Remains Baffling

Heidi Splete

December 03, 2021

Approximately 75% of skin-test results among individuals with allergic reactions to beta-lactams were negative, based on data from 175 patients.

The World Allergy Organization distinguishes between allergy and nonallergic hypersensitivity, which may be useful in advising patients with drug hypersensitivity reactions (DHR), wrote Lukas Joerg, MD, from University Hospital of Zurich, Switzerland, and colleagues. "In the case of allergy to beta-lactam antibiotics (BL), the chemical structure plays a key role," they wrote.

The current diagnostic approach for a suspected allergic DHR is based primarily on history, clinical signs, skin tests, in vitro tests, and drug provocation tests, the researchers noted. Although skin tests are effective for immediate reactions, their negative predictive value has shown less reliability for delayed DHR, and "transferring predictive values to a population with a different prevalence of drug allergy can lead to wrong conclusions," the researchers said.

To determine the value of positive skin tests for predicting beta-lactam allergies, the researchers conducted a cross-sectional study of 175 individuals with a history of DHR to a penicillin or cephalosporin antibiotic who were referred for workups at two university centers. Of these, 152 had a suspected DHR to penicillins and 23 to cephalosporins. The median age of the patients was 47 years, and 63% were female. Maculopapular exanthema was present in 71 patients, and 45 had an immediate DHR reaction.

In the study, published in the World Allergy Organization Journal, a total of 44 patients (25.1%) had positive skin tests, including 37% of those with immediate DHR and 20.0% of those with delayed DHR. The positivity of the skin prick or intradermal test (IDT) decreased over time, from 47.8% to 23.5% in immediate DHR and from 23.0% to 12.9% in delayed DHR after 3 years.

Patients with more severe forms of delayed DHR had a higher proportion of positive skin-test results, with the highest rates for patients with macular exanthema (20.9%), drug reaction with eosinophilia and systemic symptoms (DRESS; 75%), and both pustular and bullous exanthema (50% for both). However, no sensitization was found in patients with delayed urticaria or unspecified delayed exanthem, the researchers noted.

Positive skin-test results also were more common in patients with shorter latency period to onset of symptoms after drug exposure; 29.5% for 0 - 3 days vs 11.6% for greater than 3 days.

Skin tests for areas outside the area of involvement were negative. Although a combination of patch testing and IDT identified an additional positive result in 2/77 patients, further in vitro testing reduced the overall proportion of negative test results from 75% to 72%.

"Overall, even with the inclusion of additional in vitro tests, we were still unable to make a conclusive diagnosis in 27/45 patients," the researchers wrote in their discussion of the findings. They hypothesized that skin-test results for patients with delayed reactions might be improved if performed in areas affected in the index reaction, which yielded positive results in 31% of cases vs no positives from tests in areas outside of the index area. "This difference may be due to a presumably more pronounced index reaction with spreading also to the forearms (usual test area in IDT)," they said. "However, it may indicate that the sensitivity of these tests could be improved if performed in skin areas affected in the index reaction," they added.

In the study, the researchers acknowledged that they were not usually able to distinguish between the reasons for negative test results. "In the case of anamnestically moderate or severe reactions, we therefore recommended not only the avoidance of the triggering agent, but also the avoidance of potentially cross-reactive beta lactams (as in the case of skin test positive patients)," they said. However, the team has planned a larger, longitudinal study "with defined recommendations regarding drugs to be avoided or allowed," with patients interviewed at 2-year intervals to assess the further course of disease, they added.

The study findings were limited by several factors, including the relatively small study population, a short follow-up period, and potential overestimation of skin-test positivity, the researchers noted.

"A larger patient cohort and a longer observation period of these study patients with systematic evaluation on drug exposure could improve the recommendations, especially in those subjects with negative test results," they said.

The results suggest that drug provocation tests might be appropriate for immediate DHR, but may be unnecessary in those with delayed DHR, they concluded.

Confirming Allergies Will Improve Care

"We are in a place right now where understanding beta lactam antibiotic allergies is very important, because they are such a large number of antibiotics, and the workhorses of many of our first-line infection treatments," Kimberly G. Blumenthal, MD, MSc, from Massachusetts General Hospital, Boston, said in an interview with Medscape Medical News. "Beta lactams include the penicillins and cephalosporins, and are the most commonly reported drug allergies, so it is important to know who truly is or is not allergic," because choosing alternatives to these drugs can be harmful.

The current study findings confirm much of the data that have been published, although it is important for different countries to do their own assessments of their own epidemiology with regard to confirmed allergies, Blumenthal added. The current study, conducted in Switzerland, "used more extensive testing than what we use in the United States," including blood tests, skin tests, and patch tests. The results add to the collective knowledge of the value of these tests, she said.

Blumenthal highlighted the researchers' table of late-reading skin-test results in patients with delayed drug-hypersensitivity reactions. The table is useful to see what value the testing had in the researchers' evaluations, she said. For example, the study population had only four cases of DRESS, but three of these had a positive patch test. Although this is a small number, it suggests possible value in doing some tests not routinely conducted in the United States.

Overall, the study highlights the need for more training of personnel to conduct more extensive drug-allergy testing, Blumenthal said. More testing to confirm allergies can promote the correct diagnosis and affect care, and even if testing in the United States is less extensive than elsewhere, "there is some beta-lactam allergy testing that could be done in primary care" and other settings, she noted.

World Allergy Organ J. Published online November 5, 2021. Full text

The study was funded by the Ulrich-Mueller-Gierok Allergy Foundation, Bern, Switzerland, and CK-Care (Christine Kühne – Center for Allergy Research and Education), Davos, Switzerland. The researchers and Blumenthal disclosed no relevant financial relationships.  

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