Introduction
About 10% of the population report an adverse reaction to
“penicillin” (1). While the term “penicillin” in common language is
often misused as a representant for the large group of β-lactam
antibiotics including cephalosporins (common structure see supplementary
Figure 1) or more general as a synonym for “antibiotic”, the word
“allergy” in this context commonly represents various sorts of drug
hypersensitivity reactions (DHR). “Drug allergy” entries appear as red
flags in electronic health records of up to 35% of patients upon which
“penicillin” is the most frequently mentioned suspected drug (2).
However, only 4% of these patients will show positive reactions when
tested with penicillin either by skin, blood or provocation tests (3).
There are several reasons to explain this high rate of obviously false
histories:
- Although a DHR may have been caused by a drug, the pathophysiological
mechanism may not be an immunological one. Most adverse reactions are
caused by the specific pharmacological mechanism of the antibiotic and
are classified as non-allergic type A reactions. Antibiotics
not only kill the pathogenic but also – as an obligatory side effect
– the essential symbiotic bacteria leading to e.g. gastrointestinal
malfunction. Type A reactions comprise more than 80% of all DHR and
are no contraindication for a future reintroduction of the suspected
drug even without testing (4, 5).
- A true allergic reaction (also referred as B-type DHR(4)) is
usually regarded as a contraindication for future use. It may be of
the immediate, anaphylactic type I (IgE-mediated), of the delayed type
IV allergy (T-cell mediated), and rarely of the type II (IgG mediated)
or type III (IgG/IgM mediated). Still, also immunological memory may
diminish and even completely disappear over the years (6).
- Differential diagnoses such as urticaria/angioedema driven by
infection for immediate type reactions (7) and viral exanthema for
delayed reactions are much more frequent than DHRs (8). Infections can
frequently result in a prescription of an antibiotic, which in turn
may easily be misinterpreted as being the cause of the DHR.
This situation bears considerable risks not only to the patient, who may
be prescribed unnecessary alternative, sometimes less effective
antibiotics, but also to society because the overuse of alternative
antibiotics can propagate antibiotic resistance (9, 10). Hence, current
guidelines on the management on DHRs demand an allergy workup for a
“de-labelling” of false histories of DHR in the case of important
drugs and β-lactam antibiotics are generally regarded as belonging to
such a kind (4, 11).
About how to reach this goal, there seems to be some disagreement on
both sides of the Atlantic (12). While Europeans and US experts agree on
the importance of skin testing, there are different views on the
usefulness of in vitro tests (13). Skin tests offer the advantage
of giving an immediate result and are cheap for the healthcare system
(14). While their sensitivity is limited their specificity is high (15).In vitro tests are the safest test for patients. Unfortunately,
there are not many marketed, standardized tests except for drug-specific
IgE (sIgE) to β-lactam antibiotics including the cephalosporin cefaclor.
Measurement of sIgE has a low sensitivity but at a high specificity
(16).
In 2018, a basic DHR test without drug provocation tests (DPT) was
calculated causing costs of US$ 220 for the US healthcare system.
Including DPTs increased the price to at least US$ 359 (17).
Nevertheless, in recent times some US experts have gone even one step
further and started propagating DPTs for mild reactions even without a
prior skin or in vitro tests (10, 18-20).
With this study we wanted to take a step back and ask, how many cases of
suspected DHRs to β-lactams could be solved by applying simple, broadly
available methods causing only limited costs without the resource of
performing DPTs. We report the results of a retrospective chart review
of a cohort of 932 patients with a history of DHRs to β-lactam from the
years 2016 to 2017 from a single centre outpatient clinic. The patients
underwent the following algorithm: 1) DHR-specific history, 2)
drug-specific IgE test (depending upon availability), 3) a series of
skin prick, intradermal and patch tests.