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J. Jose et al.
63. Solomon M.Just a paradigm: evidence-based medicine in epistemological context. Eur J Philos Sci.
2011;1(3):451–66.
64. Stegenga J. Down with the hierarchies. Topoi.
2013;33(2):313–22.
65. Bluhm R.From hierarchy to network: a richer view
of evidence for evidence-based medicine. Perspect
Biol Med. 2005;48(4):535–47.
66. Baron JA, Sandler RS, Bresalier RS, Lanas A,
Morton DG, Riddell R, Iverson ER, DeMets
DL. Cardiovascular events associated with rofecoxib: nal analysis of the APPROVe trial. Lancet.
2008;372(9651):1756–64.
67. Pitrou I, Boutron I, Ahmad N, Ravaud P.Reporting
of safety results in published reports of randomized controlled trials. Arch Intern Med.
2009;169(19):1756–61. https://doi.org/10.1001/
archinternmed.2009.306.
68. Onakpoya IJ, Heneghan CJ, Aronson JK. Postmarketing withdrawal of 462 medicinal products because of adverse drug reactions: a
systematic review of the world literature. BMC
Med. 2016;14:10. https://doi.org/10.1186/
s12916- 016- 0553- 2.
69. Aronson JK, Hauben M. Anecdotes that provide
denitive evidence. BMJ. 2006;2006(333):1267.
https://doi.org/10.1136/bmj.39036.666389.94.
70. Scheife RT, Hines LE, Boyce RD, Chung SP,
Momper JD, Sommer CD, Abernethy DR, Horn
JR, Sklar SJ, Wong SK, Jones G, Brown ML,
Grizzle AJ, Comes S, Wilkins TL, Borst C, Wittie
MA, Malone DC. Consensus recommendations
for systematic evaluation of drug-drug interaction evidence for clinical decision support. Drug
Saf. 2015;38(2):197–206. https://doi.org/10.1007/
s40264- 014- 0262- 8.
71. Ventola CL. Big data and pharmacovigilance: data
mining for adverse drug events and interactions. P T.
2018;43(6):340–51.
72. Dimbil M, Kyle R, Brown JS, Aldairy W. Using
real-world data for rapid safety investigations: value
of near-real-time clinical data querying. Drug Saf.
2022;45(10):1251–2.
73. Lieu TA, Kulldorff M, Davis RL, Lewis EM,
Weintraub E, Yih K, Yin R, Brown JS, Platt R,
Vaccine Safety Datalink Rapid Cycle Analysis
Team. Real-time vaccine safety surveillance for
the early detection of adverse events. Med Care.
2007;45:S89–95.
74. Bate A, Hornbuckle K, Juhaeri J, et al. Hypothesisfree signal detection in healthcare databases: nding
its value for pharmacovigilance. Ther Adv Drug Saf.
2019;10:2042098619864744.
75. Gatto NM, Sobel RE, Geier J, Mo J, Bate A,
Reynolds RF.The role of pharmacoepidemiology in
industry. In: Pharmacoepidemiology. Wiley; 2019.
p.98–125.
76. Talbot JC, Nilsson BS. Pharmacovigilance in the
pharmaceutical industry. Br J Clin Pharmacol.
1998;45(5):427.
77. Hartford CG, Petchel KS, Mickail H, PerezGutthann S, McHale M, Grana JM, Marquez
P. Pharmacovigilance during the pre-approval
phases: an evolving pharmaceutical industry model
in response to ICH E2E, CIOMS VI, FDA and
EMEA/CHMP risk-management guidelines. Drug
Saf. 2006;29:657–73.
78. Bahri P. Public pharmacovigilance communication:
a process calling for evidence-based, objectivedriven strategies. Drug Saf. 2010;33:1065–79.
79. Ricci JR, etal. Prescriber compliance with black box
warnings in older adult patients. Am J Manag Care.
2009;15(11):e103–883.
80. Forbes N, Cooray M, etal. Changes in domperidone
prescribing practices after a “Black Box” warning:
are we exposing inpatients to unnecessary cardiac
risk? Am J Gastroenterol. 2013;108:S476.
81. Hollingsbee D, Maskrey N, Hutchinson A, Underhill
J, Bowes A. Changing current practice—the prescribing of NSAIDs. Prescriber. 2011;22:45–8.
https://doi.org/10.1002/psb.795.
82. Chinchilla K, Matos C, Hall V, van Hunsel F.Patient
organizations’ barriers in pharmacovigilance and
strategies to stimulate their participation. Drug
Saf. 2021;44(2):181–91. https://doi.org/10.1007/
s40264- 020- 00999- 0.
83. Dal Pan GJ. Ongoing challenges in pharmacovigilance. Drug Saf. 2014;37(1):1–8. https://doi.
org/10.1007/s40264- 013- 0123- x.
84. Seselja Perisin A, Bukic J, Rusic D, Leskur D,
Bozic J, Mihanovic A, Vilovic M, Cohadzic T,
Modun D. Teaching pharmacovigilance to healthcare students: identifying gaps and opportunities
for improvement. Pharmacy (Basel, Switzerland).
2021;9(3):147. https://doi.org/10.3390/
pharmacy9030147.
85. Beckmann J, Hagemann U, Bahri P, Bate A, Boyd IW,
Dal Pan GJ, Edwards BD, Edwards IR, Hartigan-Go
K, Lindquist M, McEwen J, Moride Y, Olsson S, Pal
SN, Soulaymani-Bencheikh R, Tuccori M, Vaca CP,
Wong IC. Teaching pharmacovigilance: the WHOISoP core elements of a comprehensive modular curriculum. Drug Saf. 2014;37(10):743–59. https://doi.
org/10.1007/s40264- 014- 0216- 1.
86. Cox AR, Marriott JF, Wilson KA, Ferner
RE. Adverse drug reaction teaching in UK undergraduate medical and pharmacy programmes. J Clin
Pharm Ther. 2004;29:31–5.
87. Comoglio RH. Undergraduate and postgraduate
pharmacovigilance education: a proposal for appropriate curriculum content. Br J Clin Pharmacol.
2020;86(4):779–90. https://doi.org/10.1111/
bcp.14179.
88. Hartman J, Härmark L, van Puijenbroek E.A global
view of undergraduate education in pharmacovigilance. Eur J Clin Pharmacol. 2017;73(7):891–9.
https://doi.org/10.1007/s00228- 017- 2237- z. Epub
2017 Mar 17.
89. Jose J, van Eekeren R, Jimmy B.Medication safety
education through games: a potential approach to
1 Introduction toDrug Safety andPharmacovigilance
29
educate healthcare students on adverse drug reactions. Int J Pharm Pract. 2021;29(1):91–2. https://
doi.org/10.1111/ijpp.12657.
90. Schutte T, Tichelaar J, Reumerman MO, van Eekeren
R, Rolfes L, van Puijenbroek EP, Richir MC, van
Agtmael MA. Feasibility and educational value of
a student-run pharmacovigilance programme: a prospective cohort study. Drug Saf. 2017;40(5):409–18.
https://doi.org/10.1007/s40264- 016- 0502- 1.
91. Reumerman M, Tichelaar J, Piersma B, Richir
MC, van Agtmael MA. Urgent need to modernize
pharmacovigilance education in healthcare curricula: review of the literature. Eur J Clin Pharmacol.
2018;74(10):1235–48. https://doi.org/10.1007/
s00228- 018- 2500- y.
92. van Eekeren R, Rolfes L, Koster AS, Magro L,
Parthasarathi G, Al Ramimmy H, Schutte T,
Tanaka D, van Puijenbroek E, Härmark L.What
future healthcare professionals need to know
about pharmacovigilance: introduction of the
WHO PV core curriculum for university teaching with focus on clinical aspects. Drug Saf.
2018;41(11):1003–11. https://doi.org/10.1007/
s40264- 018- 0681- z.
93. Jose J. Communication on drug safety-related
matters to patients: is it even more signicant in this digital era? Ther Adv Drug Saf.
2020;11:2042098620915057. https://doi.
org/10.1177/2042098620915057.
94. Steurbaut S, Hanssens Y. Pharmacovigilance:
empowering healthcare professionals and patients.
Int J Clin Pharm. 2014;36(5):859–62. https://doi.
org/10.1007/s11096- 014- 0004- 0.
95. Panagioti M, Khan K, Keers R N, Abuzour A, Phipps
D, Kontopantelis E et al. Prevalence, severity, and
nature of preventable patient harm across medical
care settings: systematic review and meta-analysis
BMJ 2019;366:l4185. https://doi.org/10.1136/bmj.
l4185.
96. Reeve E, Gnjidic D, Long J, Hilmer S.A systematic
review of the emerging denition of ‘deprescribing’ with network analysis: implications for future
research and clinical practice. Br J Clin Pharmacol.
2015;80(6):1254–68. https://doi.org/10.1111/
bcp.12732.
97. Swen JJ, van der Wouden CH, Manson LE,
Abdullah- Koolmees H, Blagec K, Blagus T,
Böhringer S, Cambon-Thomsen A, Cecchin E,
Cheung KC, Deneer VH, Dupui M, IngelmanSundberg M, Jonsson S, Joeeld-Roka C, Just
KS, Karlsson MO, Konta L, Koopmann R, Kriek
M, etal. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster- randomised crossover
implementation study. Lancet (London, England).
2023;401(10374):347–56. https://doi.org/10.1016/
S0140- 6736(22)01841- 4.
98. World Health Organization. Medication without harm. 2017. https://www.who.int/initiatives/
medication- without- harm. Accessed 8 Nov 2023.
99. Seden K, Kirkham JJ, Kennedy T, et al. Crosssectional study of prescribing errors in patients
admitted to nine hospitals across North West
England. BMJ Open. 2013;3:e002036. https://doi.
org/10.1136/bmjopen- 2012- 002036.
100. Nuckols TK, Smith-Spangler C, Morton SC, Asch
SM, Patel VM, Anderson LJ, et al. The effectiveness of computerized order entry at reducing
preventable adverse drug events and medication
errors in hospital settings: a systematic review and
meta-analysis. Syst Rev. 2014;3:56. https://doi.
org/10.1186/2046- 4053- 3- 56.
101. Schwartzberg D, Ivanovic S, Patel S, Burjonrappa
SC. We thought we would be perfect: medication errors before and after the initiation of computerized physician order entry. J Surg Res.
2015;198(1):108–14.
102. Jose J. Pharmacovigilance: basic concepts and
application of pharmacoinformatics. In: Gasmelseid
TG, editor. Pharmacoinformatics and drug discovery technologies: theories and applications. 1st ed.
Pennsylvania: IGI Global; 2012. p.322–43.
103. Frontiers in Pharmacology. Pharmacoinformatics:
new developments and challenges in drug
design. Available at: https://www.frontiersin.org/
research- topics/50433/pharmacoinformatics- newdevelopments- and- challenges- in- drug- design.
Accessed 23 Sept 2023.
104. Lewis DJ, McCallum JF. Utilizing advanced technologies to augment pharmacovigilance systems:
challenges and opportunities. Ther Innov Regul Sci.
2020;54(4):888–99. https://doi.org/10.1007/s43441- -
019- 00023- 3. Epub 2019 Dec 28.
105. Ball R, Dal Pan G. “Articial intelligence” for
pharmacovigilance: ready for prime time? Drug
Saf. 2022;45(5):429–38. https://doi.org/10.1007/
s40264- 022- 01157- 4.
106. Hauben M. The potential of articial intelligence
in pharmacovigilance. J Faculty Pharm Med.
2020. Available at: https://www.fpm.org.uk/jour-
nals/the- potential- of- artificial- intelligence- inpharmacovigilance/. Accessed 21 Sept 2023.
107. Google Cloud. Articial intelligence (AI) vs.
machine learning (ML). https://cloud.google.com/
learn/artificial- intelligence- vs- machine- learning.
Accessed 24 Sept 2023.
108. Bate A, Stegmann J.Articial intelligence and pharmacovigilance: what is happening, what could happen and what should happen? Health Policy Technol.
2023;12(2):2023.
109. Painter JL, Raymond K, Bate A. An industry perspective on the use of machine learning in drug and vaccine safety. Front Drug Saf
Regul. 2023b;3:1110498. https://doi.org/10.3389/
fdsfr.2023.1110498.
110. Comfort S, Dorrell D, Meireis S, Fine J.MOdied
NARanjo Causality Scale for ICSRs (MONARCSi):
a decision support tool for safety scientists. Drug
Saf. 2018;41(11):1073–85. https://doi.org/10.1007/
s40264- 018- 0690- y.
30
J. Jose et al.
111. Ghosh R, Kempf D, Pufko A, Barrios Martinez
LF, Davis CM, et al. Automation opportunities in
pharmacovigilance: an industry survey. Pharmaceut
Med. 2020;34:7–18.
112. Salas M, Petracek J, Yalamanchili P, Aimer O,
Kasthuril D, Dhingra S, Junaid T, Bostic T. The
use of articial intelligence in pharmacovigilance:
a systematic review of the literature. Pharm Med.
2022;36(5):295–306. https://doi.org/10.1007/
s40290- 022- 00441- z.
113. Alowais SA, Alghamdi SS, Alsuhebany N, Alqahtani
T, Alshaya AI, Almohareb SN, Aldairem A, Alrashed
M, Bin Saleh K, Badreldin HA, Al Yami MS, Al
Harbi S, Albekairy AM.Revolutionizing healthcare:
the role of articial intelligence in clinical practice. BMC Med Educ. 2023;23(1):689. https://doi.
org/10.1186/s12909- 023- 04698- z.
114. Smith MJ, Komparic A, Thompson A.Deploying the
precautionary principle to protect vulnerable popu-
lations in Canadian post-market drug surveillance.
Can J Bioethics. 2020;3(1):110–8.
115. Edwards IR. The future of pharmacovigilance: a personal view. Eur J Clin Pharmacol.
2008;64(2):173–81.
116. Trirò G, Sultana J, Bate A.From big data to smart
data for pharmacovigilance: the role of healthcare
databases and other emerging sources. Drug Saf.
2018;41:143–9.
117. Painter JL, Mahaux O, Vanini M, Kara V, Roshan C,
Karwowski M, Chalamalasetti VR, Bate A.Enhancing
drug safety documentation search capabilities with
large language models: a user- centric approach. In:
2023 International conference on computational science and computational intelligence (CSCI). IEEE
CPS proceedings; 2023a. (in press).
118. Edwards IR. Spontaneous reporting—of what?
Clinical concerns about drugs. Br J Clin Pharmacol.
1999;48(2):138.
An Overview of Immunological
Reactions to Drugs
SowmyaNagarajan, BernardYu-HorThong,
RashmeetBhogal,
andMamidipudiThirumalaKrishna
2
Abstract
Drug hypersensitivity reactions (DHRs) are
immunologically mediated responses and a
part of the spectrum of adverse drug reactions
(ADRs). ADRs account for about 5–7% of all
hospital admissions, and DHRs constitute
about <10% of all ADRs. Detailed history,
physical examination, and review of hospital
records relating to an index episode are key to
DHR workup. Skin tests and invitro tests for
immediate and non-immediate DHRs are useful although positive and negative predictive
values have not been elucidated for the major-
S. Nagarajan (*)
Paediatric Allergy and Immunology, Sanjeevini
Specialist Clinic and Kanagaroo Care Hospitals,
Bangalore, India
e-mail: dr.sowmya.nagaraj@gmail.com
B. Y.-H. Thong
Division of Medicine, Department of Rheumatology,
Allergy and Immunology, Tan Tock Seng Hospital,
Singapore, Singapore
R. Bhogal
Clinical Pharmacy, Institute of Clinical Sciences,
Robert Aitken Institute for Clinical Research, College
of Medical and Dental Sciences, Birmingham, UK
M. T. Krishna
Allergy, Clinical Immunology and Global Health,
Institute of Immunology and Immunotherapy,
University of Birmingham, Birmingham, UK
University Hospitals Birmingham NHS Foundation
Trust, University of Birmingham, Birmingham, UK
ity of drugs. Hence, these tests must be carefully interpreted by an experienced specialist
in drug allergy in the context of clinical presentation. Drug eruptions may resemble viral
exanthemata, making diagnosis particularly
challenging in children. A drug provocation
test is the “gold standard” in the diagnosis of
DHRs although this intervention is mainly
employed to demonstrate clinical tolerance
and is undertaken after performing a careful
risk–benet analysis. Management of DHRs
involves immediate cessation of exposure to
possible culprit/s and supportive management.
When an alternative drug is under consideration for clinical use, potential cross-reactivity
needs to be considered. Rapid drug desensitization is an intervention employed to induce
temporary immunological tolerance in
patients with an immediate DHR and where
there are no suitable alternatives. This procedure must only be undertaken under the guidance of a specialist allergist in a safe clinical
environment with immediate access to critical
care management.
Keywords
Desensitization · Drug allergy · Drug
hypersensitivity reaction · Drug provocation
test · Immunological reactions
© 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_2
31
32
S. Nagarajan et al.
Learning Objectives
• To provide an overview of drug hypersensitivity reactions, including classication,
mechanism, clinical manifestations, and
diagnosis.
• To understand the clinical implications of true
and inaccurate drug allergy labels.
• To offer an understanding of the clinical
approach applied to a patient with a suspected
drug hypersensitivity reaction.
Key Points
• Skin manifestations are the common
clinical presentation of a drug hypersensitivity reaction.
• Diagnosis is dependent on a robust clin-
ical history and scrutiny of clinical
records, and there are limitations surrounding drug allergy tests.
• The gold standard of establishing clinical
tolerance involves a supervised drug
provocation test (a challenge test) and
must be conducted only after performing
a careful risk–benet analysis and in a
safe clinical environment. This intervention is usually employed when “true”
drug hypersensitivity is the most unlikely.
regarding ADRs and have guided the former to
document ADRs on prescribing systems, e.g.,
electronic medical records (EMRs) [6]. EMRs
may be linked to electronic decision support
systems to prevent accidental prescribing of
the same or potentially cross-reacting medications that patients with drug allergies should
avoid.
Drug allergy labels are often challenging in
any health-care setting and require the prescriber’s expertise to source a suitable alternative
medication, which will meet the criteria of good
therapeutic benet, availability, safety prole,
and minimal drug interactions.
Beta-lactam antibiotics are the most common
drugs involved in drug hypersensitivity reactions
(DHRs). Penicillin “allergy labels” enhance the
risk of antimicrobial resistance (AMR). Research
conducted in high-income countries have
reported that 90–95% of penicillin allergy labels
are inaccurate. The global increase in AMR is a
threat to public health, as it accounts for nearly 5
million deaths every year [7]. Penicillin and other
antibiotic allergy labels adversely impact the
global campaign to improve antimicrobial stewardship and tackle AMR.Furthermore, antibiotic
allergy labels increase the risk of infections resistant to broad-spectrum antibiotics, increase
health-care costs, and result in the use of expensive third- or fourth-line antibiotics to treat AMR
[8–10].
1 Introduction
Adverse drug reactions (ADRs) are a burden to
patients and health-care systems as they are associated with increased health-care costs and delays
in delivering treatment. Depending on the severity, they are also associated with an enhanced risk
of morbidity and mortality [1–5]. In addition,
ADRs may potentially affect the relationship
between prescribers and patients, thus impacting
future adherence [3].
Pharmacovigilance, patient safety, and governance policies have helped raise awareness
among health-care professionals and patients
2 Classication
ADRs can be broadly classied into type A (predictable) and B (unpredictable, idiosyncratic)
reactions [1–4, 6, 11]. Table2.1 outlines the main
classication of ADRs.
The initial classication was suggested by
Rawlins and Thompson in 1977. The letters A
and B in these reactions represent “augmented”
and “bizarre,” respectively.
Up to 20% of ADRs are type B reactions [1],
which can be subcategorized into immunological
and non-immunological [1, 6]. Immunological
2 An Overview of Immunological Reactions to Drugs
33
reactions are often referred to as hypersensitive
reactions or drug allergy, affect approximately
10% of all ADRs, and are a growing public health
concern [6]. Patient factors that increase the likelihood of a type A reaction include age, gender,
genetics, concomitant diseases, nutrition, immunological status, level of physical activity, and
concomitant medications [11]. The properties of
a drug that increase the likelihood of a type B
reaction include the drug metabolism pathway
and the presence of toxic metabolites [11].
DHRs or drug allergies are usually either
immunoglobulin E (IgE)- or T-cell-mediated [2].
Coombs classication into types I–IV reactions
[2, 12]. A type I reaction is immediate and IgEmediated, and a type IV hypersensitivity reaction is non- immediate or delayed (usually
48–72 h after exposure) and is mediated by T
cells. Type IV DHRs are subclassied as per
T-cell subtype involvement by Pichler [2, 12,
13]. While types I and IV DHRs lend themselves
to skin tests, types II and III DHRs remain a clinical diagnosis and require a high index of clinical
suspicion.
Table 2.2 summarizes the characterization of
types I–IV DHRs.
These are categorized as per the Gell and
Table 2.1 Classication of adverse drug reactions (type A and type B)
ADR Mechanism Examples: clinical presentation
Type A:
Predictable
Type B:
Unpredictable
Related to the drugs’ mechanism
of action
Dose-dependent
Independent of the drugs’
mechanism of action and dose
Infections as a result of immunosuppressant treatment
Alopecia with chemotherapy
Anaphylaxis with penicillin antibiotics
Stevens–Johnson syndrome with allopurinol, phenytoin,
phenobarbitone, and sulfamethoxazole
Table 2.2 Characterization of various types ofdrug hypersensitivity reactions [2, 12, 13]
Hypersensitivity
reaction Mechanism of reaction Clinical presentation
Type I IgE-mediated Urticaria, angioedema, bronchospasm,
anaphylaxis
Type II IgG-/IgM-mediated Anemia, cytopenia, thrombocytopenia
Type III IgG-/IgM-mediated Vasculitis, lymphadenopathy, fever,
arthropathy, rashes, serum sickness
Type IV(a) Th1 cells rely on IFN and TNF pathways to
activate monocytes and macrophages
Type IV(b) Th2 cells rely on activation of IL-5, IL-4, IL-13,
and eotaxin to facilitate eosinophilic inammation
Type IV(c) CD4/CD8 cytotoxic T cells use perforin, granzyme
B, and FasL pathways to kill targets
Type IV(d) Neutrophil activation via T cells by CXCL and
GM-CSF pathways
Abbreviations: IFN interferon, TNF tumor necrosis factor, IgG immunoglobulin G, IgM immunoglobulin M, Th1 T
helper cell type 1, Th2 T helper cell type 2, IL interleukin, CD4/8 cluster of differentiation 4/8, CXCL chemokine
(C–X–C motif) ligand 1, GM-CSF granulocyte macrophage colony-stimulating factor
Contact dermatitis, bullous exanthema
Maculopapular and bullous rashes
Contact dermatitis, maculopapular,
pustularand bullous exanthemata
Pustular exanthemata
34
S. Nagarajan et al.
3 The Mechanism ofReaction
IgE-mediated reactions are a consequence of
drug antigen antibody cross-linking on the surface of mast cells followed by activation and
degranulation, resulting in the release of histamine, cytokines, and other vasoactive amines
[14]. Mast cell activation may also occur without
involvement of allergen-specic IgE, i.e., nonIgE- mediated mast cell degranulation caused by
activation of the members of the Mas-related
G-protein coupled receptors (MRGPRs)
[14–18].
4 Diagnosis
4.1 History
A diagnosis of a DHR is underpinned by a careful
and detailed evaluation of the temporal association based on the chronology of symptoms and
signs following exposure to culprit drug/s. This
involves scrutiny of the clinical, prescription, and
laboratory records related to the index episode.
This may be particularly challenging in low- and
middle-income countries where there may be limited or no EMRs. The important principles in the
diagnosis of a DHR are as follows [19–23]:
1. A DHR usually occurs in the context of previous exposure resulting in sensitization. It
remains to be established why only some
patients become sensitized, whereas the vast
majority is not.
2. Most DHRs are relatively mild, nonimmediate, or delayed and are limited to the
cutaneous compartment.
3. Life-threatening systemic DHRs are relatively
rare events and include severe immediate DHRs
(anaphylaxis) or severe systemic delayed reactions such as Stevens–Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN).
Table 2.3 summarizes the characterization of
DHRs based on the time of presentation while
Tables2.4 and 2.5 listtips for history taking and
early warning signs of DHRs, respectively.
Table 2.3 Classication of common drug hypersensitivity reactions based on time of presentation
Immediate DHRs
(IgE-mediated)
Urticaria Stevens–Johnson syndrome
Bronchospasm Toxic epidermal necrolysis
Hypotension Drug reaction with eosinophilia
Angioedema Acute interstitial nephritis
Table 2.4 Useful clinical tips for history taking in the
evaluation of drug hypersensitivity reactions
History and extraction of clinical information from
patient records
1. Capture information regarding names, dose, time,
and route of administration ofdrugs used prior to the
onset of the reaction
2. Note the temporal association between
administration of the drug and the onset of reaction
3. Can other drugs administered concurrently
contribute to the reaction?
4. Is there a history of similar reaction previously?
What treatment was given?
5. Did the patient have concurrent infection during or
prior to the suspected reaction?
6. Does the patient have a genetic predisposition to
non-immediate or delayed systemic DHRs?
Non-immediate severe systemic
DHRs (non-IgE-mediated)
and systemic symptoms
(DRESS)
Pulmonary/hepatic/renal
involvement
Vasculitis
Hemolytic anemia
Thrombocytopenia
Eosinophilia
Lymphocytosis
4.2 Physical Examination
Physical examination is an important step in the
evaluation of an acute episode, specically describing characteristics of skin lesions alongside systemic involvement. The majority of cutaneous
lesions are usually benign and relatively mild, with
generalized maculopapular exanthema being the
most common manifestation. Therefore, it is prudent to consider a differential diagnosis of an underlying infection in all cases of a suspected DHR.
It is important to evaluate (consider) for systemic involvement, specically the liver, kidneys,
lungs, and heart with relevant laboratory workup,
including a complete hemogram, liver/renal
2 An Overview of Immunological Reactions to Drugs
35
Table 2.5 Early warning signs in drug hypersensitivity
reactions
Reactions Manifestations
Immediate Pruritis around the mouth and on the
Non-immediate
or delayed
palms and soles
Erythema, urticaria, angioedema
Rhinoconjunctivitis
Respiratory distress
Gastrointestinal manifestations such
as vomiting and diarrhea
Fever, malaise
Lymphadenopathy
Mucosal involvement
Maculopapular or exanthematous
rash
Bullous lesions, epidermal separation
(Nikolsky’s sign)
Conuent lesions in extensive skin
areas
Angioedema and diffuse
erythematous swelling
Eosinophilia (>1.5×10
Hepatic involvement
Renal involvement
Lung involvement
Cardiac involvement
Peripheral and/or central nervous
system involvement
9
/L)
function, urine dipstick examination, skin biopsy
(including direct immunouorescence for complement and immunoglobulin deposition), and,
where deemed necessary, imaging and electrophysiological studies for lung and cardiac
involvement.
Table 2.6 describes the systemic manifestationsof DHRs [2, 24–26].
4.2.1 Dierential Diagnosis
The common differentials to consider include
viral infection, allergic contact dermatitis,
chronic urticaria, erythema nodosum, lymphoproliferative disorder, and clonal mast cell disorders based on the clinical scenario. Contact
dermatitis has a predilection to the areas of direct
contact with the drug and resolves following cessation of exposure. Chronic spontaneous urticaria
is characterized by a history of recurrent “hives,”
usually associated with angioedema, and systemic involvement is rare.
Table 2.6
S.
No. Manifestations Clinical symptoms Drugs commonly involved
1. DRESS
Systemic manifestations of drug hypersensitivity reactions
syndrome
DRESS syndrome is an acronym for drug reaction with
eosinophilia and systemic symptoms. It is also known as
drug-induced pseudo-lymphoma and drug hypersensitivity
syndrome.
The symptoms of DRESS syndrome usually begin
1–8weeks after exposure to the offending drug
Symptoms: Fever, extensive rash (morbilliform,
erythroderma), lymphadenopathy, hepatocellular injury,
acute kidney injury, peripheral blood eosinophilia, atypical
lymphocytes, other hematological abnormalities, cardiac
involvement (myocarditis, pericarditis), neurological
involvement (meningitis, encephalitis, polyneuritis),
pneumonitis, myositis, etc.
Carbamazepine,
phenobarbital, phenytoin,
terbinane, and valproic acid
(continued)
36
Table 2.6 (continued)
S.
No. Manifestations Clinical symptoms Drugs commonly involved
2. Stevens–Johnson
syndrome(SJS)
3. Toxic epidermal
necrolysis
(TEN)
4. Fixed drug
eruption(FDE)
5. Lupus
erythematosus
Severe and occasionally fatal form of erythema multiforme,
accompanied by any or all of the following:
– Fever, myalgia, malaise, headache, arthralgia, and
ocular involvement, with bullae (positive Nikolsky’s
sign) and erosions covering less than 10% of the body
surface
– Painful stomatitis is an early and conspicuous
symptom. Hemorrhagic bullae may appear over the
lips, mouth, and genital mucous membranes. Patients
are often acutely ill with high fever. The course from
eruption to the healing of the lesions may extend up to
6weeks
– Peripheral blood eosinophilia and atypical
lymphocytes absent (in comparison to DRESS)
Also known as Lyell’s syndrome, it is a rare and serious
acute exfoliative, bullous eruption of the skin and mucous
membranes that usually develops as a reaction to diverse
drugs. TEN can also be the result of a bacterial or viral
infection and can develop after radiation therapy or
vaccinations. Skin biopsy shows cleavage of the epidermis
from the dermal layer and is associated with necrosis.
The clinical picture resembles an extensive second-degree
burn; the patient is acutely ill. Fatigue, vomiting, diarrhea,
and angina are prodromal symptoms. In a few hours, the
condition becomes grave.
TEN is a medical emergency and unless the offending agent
is discontinued immediately, the outcome may be fatal in
the course of a few days.
Fixed drug eruption is an unusual hypersensitivity reaction
characterized by one or more well-demarcated
erythematous plaques that recur at the same cutaneous (or
mucosal) site/s following each one’s exposure to the
offending drug.
The size of the lesions vary from a few millimeters to
20cm in diameter.
Itusually develops 30min to 8h following the
administration of a drug and mainly affects the hands, legs,
and groin.
A reaction, clinically and pathologically resembling
idiopathic systemic lupus erythematosus (SLE), has been
reported in association with a large variety of drugs. These
symptoms recede within days or weeks following
discontinuation of the drug responsible.
Allopurinol, barbiturates,
carbamazepine, estrogens/
progesterone, gold,
lamotrigine, non-steroidal
anti-inammatory drugs
(NSAIDs), penicillamine,
phenytoin, sulfonamides,
tetracycline, tolbutamide, and
valproic acid
Allopurinol, ampicillin,
amoxicillin, carbamazepine,
phenobarbital, pentamidine,
phenytoin, pyrazolones,
sulfonamides, NSAIDs
Ampicillin, aspirin,
barbiturates, NSAIDs, oral
contraceptives, phenytoin,
quinine, sulfonamides, and
tetracyclines
Beta-blockers, carbamazepine,
chlorpromazine, estrogens,
isoniazid, lithium, minoxidil,
andoral contraceptives
S. Nagarajan et al.
4.2.2 Diagnostic Tests
Tests used for the assessment of DHRs are limited and must be employed and interpreted in
conjunction with theclinical situation. Table2.7
lists the points to be considered prior to a DHR
evaluation.
Peripheral blood eosinophilia is a characteris-
tic feature of DRESS and may be associated with
Table 2.7
sensitivity reaction evaluation [27–29]
The history of the DHR and the implicated drug is
required. An equally effective, structurally unrelated
alternative drugis not available.
A risk benet assessment is favorable for investigation
if the patient can benet from de-labeling
The patient (where relevant, the carer) has the capacity
to give informed consent
Points to be considered prior to a drug hyper-
2 An Overview of Immunological Reactions to Drugs
37
atypical lymphocytes. Biopsy and histopathological evaluation is useful in the assessment of
severe skin lesions. Coombs test is employed in
the diagnosis of immune-mediated hemolytic
anemia. A negative test, however, does not
exclude the diagnosis. Liver function tests are
useful for evaluating the presence of hepatocellular damage and urine examination and renal
function tests for acute kidney injury, in all cases
of suspected systemic DHRs.
Serial serum total tryptase measurements are
indicated in the assessment of anaphylaxis. Three
samples are recommended: the rst one as soon
as possible following clinical stabilization of the
patient, the second within 1–2h after the onset of
the reaction, and the third comprising a baseline
sample at ≥24h. A threshold for a signicant rise
to indicate mast cell degranulation has been proposed and validated as ≥2 mcg/L+1.2×baseline
serum total tryptase [30]. A baseline serum total
tryptase ≥20 mcg/L indicates a diagnosis of systemic mastocytosis.
Skin Tests
The same diagnostic algorithms and techniques
are employed in children and adults, assuming
that the immune system reacts in the same way at
any given point in life. Skin tests include prick
tests and intradermal tests. Skin tests remain the
main tool for evaluation of immediate (type I) and
non-immediate (type IV) DHRs. It is important to
note that positive and negative predictive values
of skin tests have not been established for most
drugs, although nonirritant concentrations have
been published for commonly evaluated drugs
[31]. These data must be interpreted in conjunction with clinical presentation, and the yield of
these tests is superior in experienced hands when
a pretest probability has been duly considered
prior. It is not within the scope of this chapter to
provide details of the practical steps involved in
conducting and interpreting skin tests.
Patch Tests
Patch tests are an alternative to intradermal
tests in the evaluation of type IV DHRs.
However, they are less frequently employed in
routine clinical practice, as they are less sensi-
tive than intradermal tests. They may be preferred to intradermal tests in the context of
severe cutaneous adverse reactions such as
DRESS and TEN.
In Vitro Tests
A basophil activation test (BAT) involves assessment of activation markers such as CD63 and
CD203c on the surface of basophils by ow
cytometry, following incubation of peripheral
blood with the relevant drug. A lymphocyte
transformation test (LTT) might serve as a useful
adjunct in the assessment of type IV DHRs. Both
BAT and LTT are resource-dependent, expensive,
and require a specialist laboratory and personnel.
Further research is needed to validate the performance characteristics of these tests for various
drug classes before their place is considered in
the routine investigation pathway for DHRs.
Drug Provocation Tests
A drug provocation test (DPT) is the gold standard in the diagnosis of DHRs. However, in routine clinical practice, it is mainly employed to
exclude DHRs and demonstrate clinical tolerance
rather than clinical reactivity. The decision to
conduct a DPT therefore requires careful assessment by an experienced specialist in allergy. A
DPT is conducted when the likelihood of a DHR
is extremely low based on clinical presentation
with or without undertaking skin tests (a direct
DPT). There is mounting evidence regarding the
utility and safety of a direct DPT for de-labeling
patients with inaccurate penicillin allergy labels
[32–34]. A direct DPT is undertaken in “lowrisk” patients, i.e., in those where the clinical presentation and/or prescription records suggest that
a DHR to penicillin is most unlikely. A number of
protocols, including single and graded challenges, have been proposed for DPTs, although
none has been validated [35]. A prolonged DPT
is undertaken to exclude type IV DHRs in those
where the index clinical episode is either indeterminate or suggestive of a delayed or nonimmediate reaction. A DPT is conducted in a
hospital setting with immediate access to management of anaphylaxis and critical care facility.
Details regarding patient selection for a DPT are
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