Predominant patterns of β-lactam hypersensitivity in a single German Allergy Center: exanthem induced by aminopenicillins, anaphylaxis by cephalosporins

We retrospectively evaluated 800 patients referred to our Allergy Center from January 2009 to December 2019 for diagnostic work-up of an immediate-type or delayed-type hypersensitivity reaction attributed to a β-lactam antibiotic by the treating physician. The severity of immediate reactions (i.e. anaphylaxis) was classified as mild, moderate or severe as specified in Additional file 1 [7]. Delayed reactions included measles-like (maculo-papular) exanthem, symmetrical drug-related intertriginous and flexural exanthem (SDRIFE), fixed drug eruption (FDE), and drug reaction with eosinophilia and systemic symptoms (DRESS). The institutional review board of the University Hospital Würzburg consented to the retrospective review and publication of anonymized data.

Immunoglobulin E binding to benzyl penicilloyl, phenoxymethyl penicilloyl, amoxicilloyl, ampicilloyl, and cefaclor was determined by ImmunoCAP (Thermo Fisher Scientific, Freiburg, Germany) [8]. A value of > 0.35 kU_A/L was considered significant only in patients with a convincing history of an IgE-mediated reaction, i.e. the anaphylaxis spectrum.

Skin testing was performed according to international guidelines and included reading at 15 min in suspected immediate reactions and additional readings on days two, three, and four in delayed reactions [9]. Patients were tested with a series of different penicillins and cephalosporins; the concentrations used for patch, prick, and intradermal skin testing are detailed in Additional file 2. Test concentrations for intradermal testing are within the range recommended in guidelines, for prick and patch testing comparatively high concentrations were used in our Allergy Center (Additional file 2). At the 15 min reading, a wheal of more than 3 mm in diameter with surrounding erythema was considered a positive prick test result, and a wheal of at least 6 mm was assessed as positive in intradermal testing. An erythematous and infiltrated plaque or eczematous lesion, clearly visible and palpable on days two, three, and four was interpreted as a positive delayed-type skin test reaction [10].

Patients with negative β-lactam-specific IgE and negative skin test results underwent diagnostic challenge. Challenge testing was also performed to identify an alternative tolerated β-lactam antibiotic in patients with proven β-lactam allergy. General principles of our protocol are based on guideline recommendations [11]: (i) Provocation testing was performed after a minimum of 6 weeks following a delayed reaction, and a minimum of 2 weeks following an immediate reaction. (ii) β-lactam doses were incrementally increased to an average daily dose and adapted to age, kidney function or weight if necessary (Additional file 2). (iii) Intervals of 30 min were kept between individual doses. (iv) Patients were observed for at least four hours after the last dose and were advised to present for objective examination if any symptoms developed within the next hours or days. Primary aim of the prolonged monitoring was not only to observe a reaction (IgE-mediated anaphylaxis will develop within 30 min, a delayed-type reaction at earliest after several hours) but rather to calm down the oftentimes quite anxious patient before he leaves definitely the Allergy Center.

Out of 205 cases with β-lactam hypersensitivity, an immediate-type (presumably IgE-mediated) reaction was diagnosed in 70 (34.1%) (Table 1, Fig. 1). Diagnosis was based on positive testing (i.e. prick testing, intradermal testing, serum IgE) together with a convincing history in 65 cases (92.9%), in two on a positive challenge and in the remaining three on history alone. Twenty-six patients developed predominantly urticaria/angioedema with negligible to minor systemic signs; 44 moderate to severe anaphylaxis. Fifty-nine out of the 70 immediate reactions were induced by a cephalosporin (84.3%) (Table 1). In 34 cases with immediate-type β-lactam hypersensitivity, the β-lactam antibiotic was administered intravenously; 24 out of these developed an intraoperative anaphylactic incident during general anesthesia.

Out of 205 cases, delayed-type β-lactam hypersensitivity was diagnosed in 135 patients (65.9%). Out of these, 117 developed a measles-like exanthem (86.7%) and 12 a SDRIFE reaction pattern (8.9%) (Table 1). A comparatively small number of cases were diagnosed as FDE (n = 3) or DRESS (n = 3). Diagnosis of these forms of a drug hypersensitivity reaction was based on established clinical and laboratory criteria [12‐14]. The three DRESS cases developed a skin eruption compatible with acute generalized exanthematous pustulosis (AGEP), but due to accompanying hepatitis the reaction had to be classified finally as DRESS [13]. Most delayed reactions (n = 127, 94.1%) were caused by the aminopenicillins amoxicillin or ampicillin. Thirty-six out of the 127 patients (28.3%) with delayed-type aminopenicillin hypersensitivity were concomitantly sensitized to benzyl penicillin (Table 1).

Test results are depicted in detail in Table 2 and are summarized in Fig. 1. In 24 out of 70 cases (34.3%) with immediate-type β-lactam hypersensitivity, the prick test was clearly positive after 15 min. Thirty-four (48.6%) cases of immediate-type β-lactam hypersensitivity could only be detected by intradermal testing, the prick test yielded a (false) negative result (Table 2). In seven cases, the diagnosis of IgE-mediated allergy was based on the detection of β-lactam-specific serum IgE together with a convincing history (Table 2, Fig. 1). One-hundred-fifteen out of 135 patients (85.2%) with delayed-type hypersensitivity had a positive intradermal test. Skin prick testing was also positive in 68 of 115 intradermal test-positive individuals (59.1%) with delayed-type hypersensitivity.

Both, prick and intradermal testing were false negative in only 2 out of 70 cases of immediate-type β-lactam hypersensitivity (2.9%), and the diagnosis was confirmed by challenge which triggered an anaphylactic reaction (Table 2, Fig. 1). In 17 skin test-negative patients, delayed-type hypersensitivity was confirmed by positive challenge; thirteen patients developed measles-like exanthem, three a SDRIFE, and one FDE.

In 177 out of 205 cases with β-lactam hypersensitivity (86.3%), we identified at least one tolerated alternative β-lactam antibiotic by challenge testing (Fig. 1). Patients with delayed-type aminopenicillin hypersensitivity tolerated at least one, mostly two or three alternative cephalosporins without an aminobenzyl R1 side chain, i.e. cefuroxime, cefazolin, and ceftriaxone (Table 1). In patients with immediate-type cephalosporin hypersensitivity, challenge testing proved regularly tolerance of another cephalosporin carrying a different R1 side chain, phenoxymethyl penicillin, and aminopenicillins (Table 1).

Data were retrospectively extracted from patient records, resulting in a certain methodological inhomogeneity, e.g. not all patients were examined with all skin test methods. The frequency of certain β-lactam antibiotics as a trigger of an allergic reaction depends on general usage and prescription rate. Consequently, our data from a single German Allergy Center may not be generalizable to other regions or study centers.