Corresponding author:
Maria Jose Torres, Research Unit for Allergic Diseases.
UMA-IBIMA–Hospital Regional Universitario de Málaga. Pl. Hospital
Civil, 29009 Malaga, Spain. mjtorresj@uma.es. Phone +34
951290224. FAX +34 951290302.
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Abbreviations: AX: Amoxicillin; CLV: Clavulanic acid; COVID-19:
Coronavirus disease 2019; DHR: Drug hypersensitivity reactions; DPT:
Drug provocation tests; DRESS: Drug reaction with eosinophilia and
systemic symptoms; ELISpot: enzyme-linked immunospot; LTT: Lymphocyte
transformation tests; MPE: Maculopapular exanthema.
Drug hypersensitivity reactions (DHRs) represent a global threat to
healthcare systems due to their incidence, with a significant increase
over last years1. DHR figures are overestimated in the
general population since less than 40% of cases initially labelled as
allergic can be confirmed as such when evaluated in an allergy
unit2. Achieving an accurate diagnosis is complex and
time consuming; besides, tests must be tailored to specific clinical
manifestations and underlying mechanisms and will depend on the culprit
drugs. Diagnosis often requires performing drug provocation tests
(DPTs), which are especially problematic for severe reactions, making
management of these patients challenging and expensive for the health
care system.
Clinically, DHRs are classified into immediate and non-immediate, based
on the time interval between drug exposure and onset of the
symptoms3. The most severe immediate reaction is
anaphylaxis. This issue of the journal has been dedicated o drug
hypersensitivity, which is becoming a major public health issue during
the last decade, especially with the introduction of biologicals to
medicine. Bilo et al. 4 evaluated the
anaphylaxis mortality rate in Italy from 2004 to 2016 and found an
average mortality rate for definite anaphylaxis (ICD-10 code) of 0.51
per million population per year, mostly due to the use of medications
(73.7%), although in 98% of the cases culprit drugs were not
identified. Regarding non-immediate reactions, one of the most
challenging diagnoses is drug reaction with eosinophilia and systemic
symptoms (DRESS), which is sometimes difficult, at an early stage, due
to overlapping clinical symptoms with maculopapular exanthema (MPE).
Pedruzzi et al. 5 identified 7 microRNAs
(miRNAs) that correctly classified DRESS or MPE patients and were
associated with keratinocyte differentiation/skin inflammation, type I
IFN pathway viral replication, ATP-binding cassette transporters, and T
lymphocyte polarisation, being all of them potential biomarkers.
Non-immunologically mediated adverse reactions, such as
attention-deficit/hyperactivity disorder (ADHD) are reported by Fuhrmannet al. 6 in association with systemic
H1-antihistamines administration in school-age children, especially the
1st generation agents.
The mechanism underlying DHR and the reason why patients treated with
the same drug develop a tolerance response or an immediate or
non-immediate DHR is not completely understood (Figure 1). Therefore,
the prediction of who may experience a DHR, and if so, in what form,
remains clinically obscure for most drugs. Goh SJR et
al. 7 elegantly analyse this complexity, using
non-immediate reactions to penicillins as a model. They focus on the
understanding of the role of nature of the lesional T cells, the
characterisation of drug-responsive T cells isolated from patient blood,
and the potential mechanisms by which penicillins enter the
antigen-processing and presentation pathway to stimulate these
deleterious responses.
Regarding specific drugs involved in allergy, betalactam antibiotics
(BL) are the most frequent culprit, being many reactions mediated by
IgE. This type of reaction varies among patients, with some reacting
only to one BL and others to several of them; it tends to change over
time and differs between European countries, depending on BL
consumption. Nowadays, amoxicillin (AX), alone or in combination with
the β-lactamase inhibitor clavulanic acid (CLV), is the most often
prescribed BL worldwide (Figure 2) and the most common elicitor of
reactions in both children and adults. It is unclear why patients after
the administration of AX-CLV develop selective hypersensitivity to AX,
while tolerating CLV and vice-versa. Ariza et
al. 8 generated drug-specific T-cell clones from AX-
or CLV-selective immediate hypersensitivity patients and found that both
AX- and CLV-specific clones were generated irrespective of whether AX or
CLV was the culprit, although a higher secretion of Th2 cytokines (IL-13
and IL-5) was detected when clones were activated with the culprit BL
compared with clones stimulated with the tolerated BL, in which higher
secretion of Th1 cytokines (IFN-γ) was observed. Regarding selective
non-immediate reactions to CLV, Copaescu A et
al. 9 report on a cohort of patients with a history of
non-immediate reaction to CLV, who demonstrated a delayed intradermal
skin test response to CLV, 17% were allergic to both CLV and
ampicillin, and 83% were selective reactors with good tolerance to AX.
IFN-γ release enzyme-linked immunospot (ELISpot) was performed giving a
sensitivity of 33%. Other drugs such as sulphonamides, either
antibiotic or non-antibiotics are important triggers of non-immediate
DHRs. Vilchez-Sanchez et al. 10 showed that
lymphocyte transformation tests (LTT) can help avoid the performance of
DPT with a sensitivity of 75%, a specificity of 100%, and negative and
positive predictive values of 72.7% and 100%, respectively.
There has been a great expansion in the use of biological agents (mainly
monoclonal antibodies (mAbs)), and they have greatly improved the
treatment landscape of hemato-oncologic, autoimmune, inflammatory and
rheumatologic diseases. In parallel, the incidence rate of reported DHRs
associated with these products has increased considerably within the
last years, ranging from mild to life-threatening. Yang BC et
al. 11 recommend risk stratification as the first step
for managing patients with DHRs to these drugs. In cases with negative
skin test and mild reactions, DPT is an option, and in moderate or
severe reactions, desensitisation becomes the preferred approach. In
cases with positive skin test, desensitisation is the recommended course
of action, especially when there is no alternative medication.
Desensitisation is also widely used in the management of immediate
hypersensitivity reactions to chemotherapy agents, such as platinums.
There is suspicion about the presence of a longer memory of tolerance in
subsequent desensitisation protocols partially resembling the regulatory
tolerance mechanisms induced by allergen immunotherapy. Tüzer et
al. 12 demonstrate the possible role of IL-10 in
desensitisation with platinums, as they found a dynamic change in serum
IL-10 levels observed as an increase during desensitisation and a
decrease in between the protocols.
Finally, a wide spectrum of drugs has been considered for treatment of
coronavirus disease 2019 (COVID-19) and all of them can potentially
induce DHRs. Gelincik A et al .13 reviewed DHRs
in COVID-19 times to these drugs, with knowledge mainly coming from
previous clinical experience in patients not infected with COVID-19. As
in other viral infections, skin symptoms, including exanthemas, may
appear during the evolution of the disease, leading to differential
diagnosis with DHRs. Whether COVID-19 can aggravate T–cell mediated
DHRs reactions as some viruses is at present unknown.
We can conclude that new drugs are continuously introduced into the
markets and confirmed as inducers of hypersensitivity reactions. We
still do not completely understand the mechanisms underlying many of
these reactions and further studies for improving diagnostic and
management are needed even in classic and well-studied drugs as BLs.