INTRODUCTION
Penicillin “allergy” is the most common drug-class allergy identified
in electronic medical records of large healthcare
systems.1-3 Specifically, penicillin allergy was
reported by 12.8% of the entire patient population (n = 1,766,328) of a
study by Zhou et al.2 Urticaria (hives) and rash are
the reactions most commonly reported by patients presenting for a
penicillin allergy evaluation.4,5 In fact, natural
penicillins (i.e., penicillin G and penicillin V) and aminopenicillins
(i.e., ampicillin and amoxicillin) were the causative drugs counting for
100,943 (37.5%) of 269,493 “rash/dermatitis” cases and for 61,457
(40.8%) of 150,450 “hives/urticaria” instances listed in a US-based
electronic-health-record analysis.6
Based on their chronology, hypersensitivity reactions to penicillins are
classifiable as immediate or nonimmediate (also called
delayed).7,8 The former occurs within 6 hours after
the last drug administration, though typically within one hour after the
first dose of a new treatment course.7,8 They usually
manifest as isolated symptoms, such as urticaria, angioedema,
bronchospasm, and hypotension, or as anaphylaxis, and are mostly
associated with an IgE-mediated pathogenic mechanism. Nonimmediate
reactions occur more than one hour after the initial drug
administration, commonly after many days of
treatment7-9, are more frequent than immediate
reactions6 and are characterized by a wide range of
clinical manifestations, including severe ones such as
Stevens-Johnson syndrome/toxic
epidermal necrolysis, drug reaction (or rash) with eosinophilia and
systemic symptoms (DRESS), and acute generalized exanthematous
pustulosis (AGEP). Maculopapular exanthema (MPE) and delayed-appearing
urticaria are the most common clinical presentations of nonimmediate
reactions.7,8 In some nonimmediate reactions,
especially DRESS, AGEP, and MPE, a T-cell-mediated pathogenic mechanism
has been demonstrated on the basis of positive responses to patch tests
and/or delayed-reading intradermal tests.8,10
Despite a high prevalence of nonimmediate reactions to penicillins,
little is known about the influence of genetic determinants, in contrast
to the pharmacogenetic data published on immediate
reactions.11-14 An Italian case-control study by
Romano et al. 15 assessed the HLA-A2 and
HLA-DRw52 alleles in 24 patients with MPE caused by delayed
hypersensitivity to aminopenicillins compared to 522 subjects from the
general population and found that they were significantly more prevalent
among the former. However, it is noteworthy that no
genome-wide association study
(GWAS) or HLA genotyping with next-generation sequencing (NGS) has been
performed to evaluate the contribution of the genetic
determinants.14,15 To address this issue, we evaluated
the influence of HLA genetic determinants on the risk of nonimmediate
reactions to penicillins by performing HLA NGS genotyping/ NGS-based HLA
typing in 24 patients with delayed hypersensitivity and 20 patients with
immediate hypersensitivity to penicillins recruited in Italy. Then we
performed NGS-based HLA typing for a case-control study to estimate the
association between the potentially enriched HLA alleles obtained and
the risk of nonimmediate hypersensitivity to penicillins. We
subsequently replicated the results using in silico data from the
Illumina Immunochip genotyping array that covered the HLA loci in 98
Spanish patients with delayed hypersensitivity compared to 1,308
controls.