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38
S. Nagarajan et al.
Table 2.8 Common clinical scenariosand contraindicationsfor a drug provocation test
Common clinical scenarios
To exclude an allergy: history suggests that it is
unlikely
Examples: local anesthesia-related reactions, vague
childhood penicillin reactions, vasovagal episode,
benign skin rash, etc.
Conrm/exclude allergy: skin tests negative,
inconclusive or not available, and clinical presentation
suggests “drug DHR unlikely”
Exclude an allergy in simultaneous exposures
Perioperative reactions, skin tests negative (not to be
undertaken for neuromuscular blocking drugs or other
general anesthetic agents)
Exclude cross-reactivity after demonstrating negative
skin tests
Example: Beta-lactams
Contraindications
Index episode suggestive of severe life-threatening
DHRs
Index episode suggestive of severe cutaneous reactions,
e.g., SJS, TEN, DRESS, vasculitis, acute generalized
exanthematous pustulosis (AGEP)
Patient declines to give informed consent forthe
procedure
Safe alternatives and comparable efcacious options
are available
Severe concurrent illness or pregnancy (unless the drug
is essential for the concurrent illness or required during
pregnancy or delivery)
summarized in Table2.8 [25, 26, 36, 37]. A case
report of a DPT is provided separately in a clinical scenario under the section of case studies.
able therapeutic alternatives and after undertaking a careful risk–benet analysis [38–42]. As
desensitization is a means of inducing temporary
immunological tolerance, the allergy label must
not be removed. This is in contrast to “delabeling” for an inaccurate allergy label and negative DPT [43].
RDD requires one-to-one clinical supervision of patients, preferably in an intensive care
unit or a high dependency unit where there is
immediate access to critical care management.
This procedure must be carried out only under
expert supervision and with input from a clinical pharmacist for preparing drug dilutions. It
can be delivered via intravenous or oral routes,
with the latter being relatively safer. In principle, it involves 12–16 steps, starting at an
extremely minute dose with dose escalations at
an interval of 15–30min in between steps. An
important caveat is that immunological tolerance lasts as long as the patient is receiving
regular daily therapy and that tolerance status is
lost following cessation of treatment or if there
is a break in the treatment schedule [44–46].
A written informed consent must be obtained
in all cases after counseling the patient regarding the possibility ofallergic reactions, including anaphylaxis. The common indications for
desensitization are summarized in Table2.9 [27,
43–53].
5 Drug Desensitization
Rapid drug desensitization (RDD) is a therapeutic intervention undertaken to induce temporary
immunological tolerance, usually in the context
of type I DHRs. It is also undertaken in patients
with aspirin-exacerbated respiratory disease
(AERD) and recurrent nasal polyps, and in those
requiring dual antiplatelet therapy following coronary stent procedure in the context of AERD or
aspirin intolerance. There is also some evidence
regarding use of desensitization in patients with a
relatively mild-type IV DHR. Desensitization
should only be considered in the absence of suit-
Table 2.9 Common indications for rapid drug desensitization (drugs involved)
Bacterial endocarditis (penicillin)
Syphilis in pregnancy (penicillin)
Neurosyphilis (penicillin)
Tuberculosis
Chemotherapeutic drugs
Biologics
Cystic brosis (penicillin, cephalosporins,
carbapenems)
Aspirin-sensitive asthma
AERD with recurrent nasal polyposis (aspirin)
Coronary stent procedure in a patient with aspirininduced allergic reaction
AERD aspirin-exacerbated respiratory disease
2 An Overview of Immunological Reactions to Drugs
39
6 Future Directions in Drug
Hypersensitivity Reaction
Diagnosis and Management
Precision and personalized medicine is already
being practiced in drug allergy in the following
way:
• Human leukocyte antigen (HLA) genotyping
prior to initiation of drugs at “high risk” of
causing severe cutaneous adverse reactions,
e.g., HLA-B*1502 (carbamazepine), HLAB*5701 (abacavir), and HLAB*5801(allopurinol) [54].
• Drug allergy “alert cards” and applications to
empower individual patients to be aware of
their drug allergies and potentially crossreactive drugs to avoid [55].
• Clinical decision support within EMR systems at the point of medication orders to prevent accidental prescription [56, 57].
• Medication safety tools and enablers at the
point of medication administration and
dispensing.
• “Direct” DPT in “low-risk” patients with an
inaccurate penicillin allergy label to improve
antimicrobial stewardship and reduce the risk
of AMR.
• Education of health-care professionals and
patients regarding drug allergies. A list of
drugs to be avoided should be given to
patients/parents (To Whom It May Concern
Letter), including medications that can be
used as safe alternatives.
• Pathways for referral to an allergy specialist.
The following e-tools for predicting drug
allergy remain investigational:
• Phenotyping and endotyping DHRs according
to the different patterns of biomarkers/cytokines released [28, 58].
• Multidimensional approaches including predictive analytics, articial intelligence techniques, and “point-of-care” clinical decision
tools [29].
• Machine learning (e.g., articial neural networks) to predict beta-lactam DHRs [59],
nonsteroidal anti-inammatory drug-exacerbated respiratory disease [60], and diagnosis
of early SJS/TEN [61].
7 Summary andConclusions
DHRs are mediated by the immune system.
Broadly, they are classied as either immediate
or non-immediate reactions. Most reactions are
relatively mild and involve the skin, although
rarely, serious multisystem presentations can
occur. Prompt recognition is paramount to keeping patients safe. Evaluation of suspected drug
hypersensitivity involves a thorough clinical history, scrutiny of clinical/prescription records,
skin tests, and DPTs to establish clinical tolerance and insert appropriate “allergy alerts” in
clinical records. DPTs must be carried out by an
experienced clinician, in a safe clinical environment, and after a careful risk–benet analysis.
Rapid drug desensitization is a specialist intervention employed to induce temporary immune
tolerance in a patient with type I hypersensitivity
to a certain drug and is undertaken when there are
no suitable alternatives.
8 Case Studies
8.1 Case Study 1: Case Report of a
Drug Provocation Test
A 45-year- old male patient with a label of penicillin allergy requires penicillin prophylaxis prior
to a dental procedure. He has a prosthetic mitral
valve and hence requires penicillin prophylaxis
to prevent bacterial endocarditis.
The index history dates back to his childhood.
He was informed by his parents that he had a
mild “whole body rash” when he took a penicillin
antibiotic for glandular fever, although this did
not require hospitalization. The family physician
advised avoiding exposure to penicillin in future.
40
S. Nagarajan et al.
1. What investigations can be conducted for
evaluation of this patient?
A skin prick test, an intradermal test for
penicillin major and minor determinants, benzyl penicillin, and amoxicillin, and a serumspecic IgE for penicillin V, penicillin G, and
amoxicillin can be conducted.
The skin prick test and intradermal tests for
penicillin major and minor determinants, benzylpenicillin, and amoxicillin were negative
for immediate and non-immediate hypersensitivity response. Serum-specic IgE was also
negative for penicillin V, penicillin G, and
amoxicillin.
2. What further investigation can be conducted
in the index patient?
A drug provocation test with oral amoxicillin can be carried out.
The patient underwent a supervised DPTwith a
single oral dose of amoxicillin (500mg) followed
by 250mg twice daily for 3days. There was no
evidence of type I and type IV hypersensitivity
reaction.
3. How would you proceed after the patient
passed the drug provocation test?
He was counseled regarding the de-labeled
status, and his family physician was informed
accordingly. His clinical records were updated
regarding the de-labeled status as follows:
(a) Communicate the outcome of the DPT to
the patient and provide written communication in relation to this. Counsel the
patient about which antibiotics the patient
can now receive and check the patient’s
understanding of this.
(b) Tell the patient to inform all health-care
professionals that are responsible for their
care, e.g., their general practitioner, local
pharmacy, cardiologist or secondary care
clinical team, nurse, etc.
(c) Send written communication to primary
and secondary care or equivalent to
inform them of the outcome of the
DPTand to encourage them to update the
patient’s allergy status.
(d) Encourage the patient to inform their next
of kin in case of an emergency.
(e) It is also advisable to follow-up the
patient after a period of time to check that
all the above was understood and that all
relevant records have been updated (helps
prevent relabeling).
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Predisposing Factors forAdverse
Drug Reactions
JimmyJose andFranciscoJ.de Abajo
3
Abstract
Adverse drug reactions (ADRs) are multifactorial phenomena, and predisposing factors
for ADRs can beconsidered components of a
constellation of causes, including the drug,
needed for an ADR to be induced. The identication of the predisposing factors for ADRs
is an important task of pharmacovigilance, as
it may contribute to prevent the occurrence of
ADRs. There are four types of predisposing
factors: (1) those related to patient characteristics (e.g., age, sex, ethnicity, genetics); (2)
those related to the underlying diseases or
comorbidities (e.g., renal failure, liver disorders, metabolic disorders); (3) those related to
environmental and lifestyle factors (e.g.,
smoking, alcohol consumption, caffeine use);
and (4) those related to the concomitant use of
other drugs (e.g., drug–drug interactions,
polypharmacy). Predisposing factors interact
with the drug to increase the risk of presenting
J. Jose (*)
Pharmacy Practice, School of Pharmacy, College of
Health Sciences, University of Nizwa, Nizwa, Oman
e-mail: jimmy.jose@unizwa.edu.om
F. J. de Abajo
Department of Biomedical Sciences (Pharmacology),
University of Alcalá (IRYCIS),
Alcalá de Henares, Madrid, Spain
Unit of Clinical Pharmacology, University Hospital
Príncipe de Asturias,
Alcalá de Henares, Madrid, Spain
an ADR, and the best tools to identify them
are analytical epidemiological studies.
Through them, it is possible to estimate the
measures of a drug–event association and then
assess which factors may strengthen such an
association. Once a predisposing factor has
been identied, it is necessary to translate this
information into appropriate regulatory measures in order to minimize the risk of ADRs.
In this context, health-care professionals play
a crucial role in implementing risk minimization measures, informing patients, and monitoring the results.
Keywords
Adverse drug reactions · Predisposing factors ·
Risk factors · Multicausality · Effect modiers ·
Risk management · Risk minimization ·
Interactions · Clinical practice · Regulatory
Learning Objectives
• To understand the concept and importance of
predisposing factors for adverse drug reactions (ADRs).
• To learn the main types of predisposing fac-
tors for ADRs.
• To learn how researchers can identify predis-
posing factors for ADRs.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
J. Jose et al. (eds.), Principles and Practice of Pharmacovigilance and Drug Safety,
https://doi.org/10.1007/978-3-031-51089-2_3
45
46
J. Jose and F. J. de Abajo
• To know how predisposing factors for ADRs
are managed in both drug regulation and clinical practice settings.
Key Points
• Predisposing factors for ADRs can be
conceptualized as components of a sufcient cause that, along with the drug,
can lead to an adverse event.
• Identication of predisposing factors is
important to reduce the burden of ADRs.
• Predisposing factors can be grouped
into four categories: (1) those related to
patient characteristics; (2) those related
to the underlying diseases; (3) those
related to environmental factors; and (4)
those that are drug-related.
• Analytical epidemiological studies are
the main tool for the identication and
evaluation of predisposing factors for
ADRs.
• Predisposing factors should be managed
at both regulatory and clinical practice
levels to effectively minimize the risk
posed by ADRs to patients.
1 Introduction
The ultimate objective of pharmacovigilance is to
prevent or minimize the risks associated with the
use of drugs. To this end, it is important to know
thatnot only the drug’s effects and its pharmacological characteristics but also the factors that
interact with it canincrease the risk of a specic
adverse drug reaction (ADR). Broadly speaking,
these are called “predisposing factors.” Many
risk minimization measures address such predisposing factors, and their prompt identication is
crucial to adopt regulatory measures tooptimize
the benet–harm ratio of the drug. At the clinical
level, a better understanding of predisposing factors will facilitate more individualized drug use
and thereby improve patient safety. As the amount
of information available on drug safety is limited
when rst introduced in the market, information
regarding the predisposing factors for ADRs
increases with general use of the drugs. Various
tools are available to obtain and increase the
knowledge database of the predisposing factors
for individual drug use. This chapter will introduce to the readers the concept of predisposing
factors, their different types, the available methods to identify them, and, nally, how they are
managed in pharmacovigilance and clinical
practice.
2 Conceptual Framework
andDenition
It is a common observation that, fortunately, not
all patients who use a drug present a specic
ADR. In addition, among those presenting the
same ADR, not all experience it with the same
seriousness, the same intensity (severity), at the
same time, or with the same drug posology (dose,
frequency, duration). This variability occurs
regardless of the type of ADR, either type A
(related to the pharmacological action of the
drug) or type B (unrelated to the pharmacological
action), though it is often stated that all patients
could experience an ADR of type A provided that
the drug used is over a certain dose threshold.
However, the dose threshold can vary between
patients. What is the reason for such variability?
The answer comes from the consideration of
ADRs as multifactorial or multicausal phenomena. Following the “causal pie model” proposed
by Rothman [1] (Fig. 3.1), we can accept that
drugs never behave as a “sufcient cause” of a
disease or an event and other components have to
be present. In other words, an event is set off
when the “causal pie” is complete and the drug is
just a piece of that pie. In a few cases, the event
only occurs when the drug is present; in this
sense, the drug can be considered as a “necessary
cause” of such an event. Some examples include
oculomucocutaneous syndrome, a disease that
has only been described to be associated with the
use of practolol [2], malignant neuroleptic syndrome, or serotonin syndrome induced by serotonergic drugs. Much more often, nevertheless, a
Sufficient cause 1 Sufficient cause 2 Sufficient cause 3
y
Component cause
AE
3 Predisposing Factors forAdverse Drug Reactions
47
A
CD
Fig. 3.1 The “causal pie model” proposed by Rothman
[1]. A disease or event can be developed by different “sufcient causes,” which are made up of different “compo-
B
drug is just a “component cause” and the event
may occur even in its absence (e.g., myocardial
infarction and coxibs). Irrespective of whether
the drug is a necessary or a component cause, an
event is not triggered until all the components
conforming to the “sufcient cause” are present,
often appearing at different points in time.
Admittedly, an ADR is a special type of event
because, by denition, a drug should always be
present and, in this sense, drugs can always be
considered as the necessary causes of ADRs, but
it is just a terminology question with no biological substrate because, biologically speaking, as
mentioned above, a drug is rarely a necessary
cause of a disease and, likely, is never a sufcient
cause.
Once the sufcient cause is completed, the dis-
ease (the ADR, in our case) starts, and, after a
latency or subclinical period, the disease turns up
clinically. This latency period may last for minutes, as in the case of immediate allergic reactions, or for years, as in the case of breast cancer
associated with hormone replacement therapy.
The latency period is conceptually different from
the induction period, with the latter being the time
span since the exposure to a particular cause until
the start of the disease, but often they are erroneously mixed up. The induction period is not an
attribute of the disease, but it is specic to each
cause and can differ considerably from one component cause to another: for instance, diethylstilbestrol taken by pregnant women had a long
induction period (around 15years) for the vaginal
E
ZDFD
nent causes.” When a component cause is present in all
sufcient causes, it can be considered as a “necessary
cause” (D, in this example)
Y
Necessar
cause
cancer that developed in their daughters, whereas
the hormonal explosion in puberty, among other
component causes, showed a much shorter induction period (a few years) for the same event.
Therefore, the presence of causal components,
different from the drug itself, actually determines
whether the ADR appears or not, and when, being
actually the reason for the observed interindividual variability. Obviously, the features of the drug
(pharmacological actions, dose, duration, pharmaceutical form, route of administration, etc.)
also count, but they are not enough.
The set of component causes of an ADR, different from the drug itself, can be considered,
broadly speaking, as “predisposing factors.”
Depending on the timing of the causal components with respect to the drug administration, we
can classify them into three categories: (1) pure
predisposing factors, when they precede the
drug administration; (2) triggering factors,1
when they are subsequent to the drug administration; and (3) co-inducers or cooperators when
they are simultaneous with the drug use (coinducers having an independent effect, whereas
cooperators do not). An explanatory depiction is
shown in Fig.3.2, and examples are described in
Table3.1. Finally, the factors that block or reduce
1
Sometimes these factors are also referred to as “catalysts,” as they shorten the induction time of the disease to
occur or be diagnosed. Drugs may act as catalysts themselves (some drugs with some antidopaminergic activity
may unmask the diagnosis of Parkinson’s disease rather
inducing parkinsonism).
48
Component causes
Pu
III III
or (T):
J. Jose and F. J. de Abajo
re predisposing factors (A, B, E ):
Present before drug use (D)
D
E
A
B
Fig. 3.2 Depiction of the conceptual framework for pure
predisposing factors, co-inducers/cooperators, and triggering factors. (I) When the drug use (D) is the last component cause that completes the pie, all others (A, B, and
E) precede the drug and can be considered as pure predisposing factors. (II) When the component cause (C) occurs
Co-inducer or Cooperators (C): Triggering fact
Appearing at the same time
the expression of the component causes, different
from the drug itself, would act as preventive or
minimizing factors of the ADR, whereas those
blocking the action of the drug itself can be specically considered as antagonists (though,
practically speaking, they also behave as preventive factors).
Putting the timing aside, we can pragmatically dene a predisposing factor for a specic
ADR as “a third variable, different from the
drug itself and the indication for which the drug
is taken that, when present, increases the risk of
suffering an ADR, including the probability of
its occurrence, its seriousness or its severity
of drug use (D)
C
D
B
A
at the same time as the drug use (D), it can be considered
a co-inducer (if it has an independent effect) or a cooperator (if it has no independent effect per se and only acts as
a cause when the drug is present). (III) The drug (D) and
other component causes (A and B) are present, but the
disease does not start until T shows up
Appearing after
drug use (D)
T
B
D
A
(understood as intensity).” In other words, a
predisposing factor is a “component cause” of a
constellation of causes that, along with the drug,
conform to the sufcient cause that induces the
event that we consider an ADR. As we will
explain later on, a predisposing factor may have
an independent effect (given other component
causes), which is added to the drug effect (given
other component causes) or, more often, its
combination with the drug may give rise to an
overall effect that is stronger than the mere addition of their independent effects. When the latter
occurs, we call such a phenomenon “effect
modication” or “interaction” (see Sect. 5).
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