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Reviewed by

Wat Mitthamsiri, MD
Outline
• Definitions
• Effects to humanhealth
• Classifications of adverse drugreactions
• Chronological classification
• Clinical classification
• Mechanisms of drugallergy
• General approach
• Future of drug allergy prediction
• Future of drug allergy diagnosis
• Conclusion
Definitions
Adverse Event (AE)

= Medical occurrence temporally associated with the


use of a medicinal product, but notnecessarily causally
related.

Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden, glossary, http://www.who-
umc.org/graphics/8321.pdf, p. 1.
Definitions
Adverse Event (AE)
=Any untoward medical occurrence associated with the use of
a drug in humans, whether or not considered drug-related.
Any unfavorable and unintended sign (e.g., an abnormal
laboratory finding), symptom, or disease temporally associated
with the use of a drug, without any judgment about causality.
Can arise from any use of the drug (e.g., off-label use, use in
combination with another drug) and from any route of
administration, formulation, or dose, including an overdose.

US FDA, 2013, Good Review Practice: Clinical Review of Investigational New Drug Applications
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm 079753.pdf
Definitions
Adverse Reaction (AR)

=A response to a drug which is noxious and


unintended, and which occurs at doses normallyused
in man for the prophylaxis, diagnosis, or therapy of
disease, or for the modifications of physiological
function

Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden, glossary, http://www.who -
umc.org/graphics/8321.pdf, p. 1.
Definitions
Adverse Reaction (AR)
= An undesirable effect, reasonably associated with use
of a drug, that may occur as part of the
pharmacological action of the drug or may be
unpredictable in its occurrence.

Not include all adverse events, only those for which


there is some basis to believe there is a causal
relationship between the drug and the occurrence of
the adverse event.
US FDA, 2013, Good Review Practice: Clinical Review of Investigational New Drug Applications
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm 079753.pdf
Classification ofadverse drug reaction
• Type A—Exaggerated pharmacological response
• Pharmacodynamic (e.g., bronchospasm frombeta-blockers)
• Toxic (e.g., deafness from aminoglycoside overdose)

• Type B—Nonpharmacological, often allergic,response


• Medicine-induced diseases (e.g., antibiotic-associated colitis)
• Allergic reactions (e.g., penicillin anaphylaxis)
• Idiosyncratic reactions (e.g., aplastic anemia with chloramphenicol)

• Type C—Continuous or long term (time related)


• Osteoporosis with oral steroids

World Health Organization. 2007. Drug and Therapeutics Committee Training Course. Session 4. Assessing and Managing Medicine Safety
Classification ofadverse drug reaction
• Type D—Delayed (lag time)
• Teratogenic effects with anticonvulsants orlisinopril

• Type E—Ending of use(withdrawal)


• Withdrawal syndrome with benzodiazepines

• Type F—Failure ofefficacy (no response)


• Resistance to antimicrobials

World Health Organization. 2007. Drug and Therapeutics Committee Training Course. Session 4. Assessing and Managing Medicine
Safety
Classification ofadverse drug reaction

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Definition
Drughypersensitivity reactions (DHRs)
=Adverse effects of pharmaceutical formulations (including active
drugs and excipients) that clinically resemble allergy
Drug allergy
= DHRs for which a definite immunological mechanism (either drug-
specific antibody or T cell) is demonstrated.
Gomes ER, Demoly P.,Curr OpinAllergy Clin Immunol 2005;5:309-16.

Drug allergy
= Drug reactions resulting from consequences of a drug-specific
immune response

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Epidemiology
• IPD: 10-20% of patients
• OPD: 25% of patients

• TypeA reactions : About 85-90% of all ADRs.


• Type B reactions : About 10-15% of allADRs.
• Immune-mediated (drug allergy) :About 6-10% of ADRs.

Gomes ER, Demoly P., Curr Opin Allergy Clin Immunol 2005;5:309-16.
Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295
Epidemiology
• Most common drug groups causing hypersensitivity reactions
• β-lactam antibiotics
• Nonsteroidal antiinflammatorydrugs (NSAIDs)

• Cutaneous reactions are most common clinical


manifestations, but SJS/TEN and DIHS/DRESS are rare

• Mortality rate: In USA, about 1 of every 300 hospitalized


patients (amounting to 106,000 estimated deaths in 1994)

Gomes ER, Demoly P., Curr Opin Allergy Clin Immunol 2005;5:309-16.
Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295
Epidemiology
• Immune-mediated drug hypersensitivity
• Accounts for 6-10% of the adverse drug reactions
• Rank 5th leading causes of death in the US.
• With <10% of all adverse drug reactions reported, the magnitude of
the problem issignificant
• Estimates of costs >$US30 billion annually in the US (1995 value)

• Hypersensitivity: The leading reason for taking drugs off the


market, so the costs of not determining the potential of a
drug to produce hypersensitivity in the pre-clinical phase of
drug development can besubstantial.

Ratajczak HV, Toxicol Rev.2004;23(4):265-80.


Epidemiology: Globalscale monitoring
• The WHO International Drug Monitoring Programme
• Started in 1968
• Main objectives: To identify the earliest possible
pharmacovigilance signals
• Currently 120 official member countries from all parts of the
world contributing individual case safety reports (ICSRs) to
the WHO Global ICSR Database System, VigiBase.

• Thailand is one of an official members since 1984

M. Lindquist, Drug Information Journal, Vol. 42, pp. 409–419, 2008 • 0092-8615/2008
http://www.who-umc.org/DynPage.aspx?id=98080&mn1=7347&mn2=7252&mn3=7322&mn4=7324
Epidemiology: Globalscale monitoring
• VigiBase
• Maintained and developed on behalf of WHO by the Uppsala
Monitoring Centre (UMC), situated in Uppsala, Sweden.
• A web-based reporting tool
• An automated signal detection process using advanced data
mining
• Search facilities, available to the official staff of national centers of
member countries and, on request, to other stakeholders.

M. Lindquist, Drug Information Journal, Vol. 42, pp. 409–419, 2008 • 0092-8615/2008
http://www.who-umc.org/DynPage.aspx?id=98080&mn1=7347&mn2=7252&mn3=7322&mn4=7324
Epidemiology: Globalscale monitoring

M. Lindquist, Drug Information Journal, Vol. 42, pp. 409–419, 2008 • 0092-8615/2008
Epidemiology: Globalscale monitoring

http://www.who-umc.org/graphics/28351.gif
Epidemiology

https://open.fda.gov/drug/event/
Epidemiology

Health Product Vigilance Center(HPVC), กองแผนงานและวช ิ าการอย.,Spontaneous Reports of Adverse Drug Reaction2012
http://thaihpvc.fda.moph.go.th/thaihvc/Public/Webpage/main.jsf
Epidemiology

Health Product Vigilance Center(HPVC), กองแผนงานและวช ิ าการอย.,Spontaneous Reports of Adverse Drug Reaction2012
http://thaihpvc.fda.moph.go.th/thaihvc/Public/Webpage/main.jsf
Chronological classification

Gomes ER, Demoly P., Curr Opin Allergy Clin Immunol 2005;5:309-16.
Clinical classification

BircherA. and Scherer K. Med Clin N Am 94 (2010) 711–725


General concept of immune response

Immune Effector
Agents
system functions
General concept of immune response

Immune Effector
Agents
system functions
General concept of immune response

Immune Effector
Agents
system functions

???
Can drug beantigen?
• Innate immune recognition
• Danger hypothesis
• Evidence: contact sensitizers can cause upregulation of costimulatory
molecules such as CD86 or CD40 and phosphorylation of signaling
molecules in dendritic cells exposed in vitro
• The data are less clear for drugs causing systemic reactions.

• Adaptive immune recognition


• Discussed later

Coulter EM, et al. J Pharmacol Exp Ther 2007;320:885-92.


Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295
Can drug beantigen?
8-11 peptide rersidues 10-30 peptide rersidues

AK Abbas., et al. Cellular and Molecular Immunology 7th edition, 2012,109-138


Can drug beantigen?
B cell receptorcomplex T cell receptorcomplex

AK Abbas., et al. Cellular and Molecular Immunology 7th edition, 2012,139-172


Can drug beantigen?

With few exceptions, an


antigen must be presented to
the immune system in
multivalent form to elicit a
specific immune response
(i.e., sensitization) and to
activate immunopathologic
mechanisms.

CelikG., et al. Middleton’sAllergy 8th edition,


2013,1274-1295

Image from: AK Abbas., et al. Cellular and Molecular Immunology 7th edition, 2012,89-108
How can drug get its antigenicity?
• Being completeallergen by itself
• Foreign macromolecules
• Insulin and otherhormones
• Enzymes and protamine
• Antisera
• Recombinant proteins
• Vaccines
• Functionally multivalent chemical
• Succinylcholine
• Other quaternary ammoniumcompounds

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Drug antigenicity
• Direct haptenation
• β-Lactam antibiotics
• Quinidine
• Cis-platinum
• Penicillamine
• Barbiturates
• Antithyroid drugs
• Heavy metals (gold)

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Drug antigenicity
• Metabolism to haptenicform
• Sulfonamides*
• Acetaminophen†
• Phenacetin*
• Phenytoin‡
• Procainamide*
• Halothane§

• *Postulated intermediate: hydroxylamine.


• †Postulated intermediate: quinoneimine.
• ‡Postulated intermediate: areneoxide.
• §Postulated intermediates: radicals,acylhalides.

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Drug antigenicity

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Factors involve drug haptens antigenicity
• Genetic factors
• Haptenation (MHC presentation or augmentation of response)
• Acetylator phenotype
• Metabolic factors
• Rate of haptenation
• Hapten inhibition
• Dehaptenation
• Glutathione levels
• Preformed multivalent drugforms

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


Factors involve drug haptens antigenicity
• Adjuvants
• Benzathine penicillin
• Oil-emulsified penicillins,
• Occult exposure to native or cross-reactive epitopes
• Quaternary ammonium epitope in muscle relaxant drugs is widely
distributed in a variety of foods and cosmetics
• Concomitant infections
• High rate of putatively immunologic dermatologic reactions to
sulfonamides and other drugs in patients infected with HIV

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


P-i concepts

1,The drug fits into someTCRwith sufficient affinity to cause a signal.


2, This drug-TCR interaction is supplemented by a MHC interaction

T cells react and proliferate. No metabolism of drugs required. The reactiveT cell
is probably preactivated and has an additional peptide specificity.
Alternatively, the drug binds first to the HLAmolecule, and the new drug-HLA
complex stimulatesT cells
Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295
P-i concepts
• It can explain “bizarre features” of drug hypersensitivity

• Rapid flow of symptoms at the first encounter with the drug, notably
without a sensitizationphase

• Drug hypersensitivity in patient with condition that lowerT cell reactivity


threshold
• During some generalized viral infections: EBV, CMV, HHV6,HIV
• During exacerbations of autoimmune diseases

• Preferential involvement of the skin in drug allergy.


• Skin is a repository for an enormous number of T cells, many of which are effector
memory T cells that react rapidly if immunogenic agents penetrate the skin
barrier.
Schaerli P, et al. JExp Med 2004; 199:1265-75.
Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295
Modified Gell and Coombs classification

Pichler et al., Med Clin N Am 94 (2010) 645–664


“Idiosyncratic mechanism”
Differences from immunologicform

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Shock after radiocontrastmedia
• Iodine sensitivity?
Shock after radiocontrastmedia
• Iodine sensitivity?

• Contrast media reactors tolerate iodine-containing surgical


scrubs, and vice versa
Schabelman E, WittingM. JEmerg Med 2010;39: 701-7.

• Its hypertonicity augments basophil and mast cell histamine


release
Stellato C, et al. JAllergy Clin Immunol 1996;97:838-50.

• Some nonionic contrast agents’ reaction may be IgE mediated


Stellato C, Adkinson NF Jr.,Allergy 1998; 53:1111-3.
Risk factors for contrast media reactions
• Atopic background (relative risk: 3 to5)
• Female gender
• Underlying severe cardiovasculardisease
• History of radiocontrastreactions
• History of drug allergy in general

Stellato C, et al. JAllergy Clin Immunol 1996;97:838-50.


Stellato C, Adkinson NF Jr.,Allergy 1998; 53:1111-3.
Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295
Prevention: premedication

Tramèr MR, et al., BMJ2006;333:675.

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


ASA and NSAIDs
• Aspirin-induce acute bronchospasm/rhinosinusitis = AERD.
• Other NSAIDs, except COX-2 inhibitors, exhibit virtually complete
cross-reactivity in thissyndrome
• Common functional property of COX inhibition (especially COX-1) is
involved in thepathogenesis

• ASA-induced urticarial reactions (most common)


• In patients with U/D chronic urticaria: Found 30%
• Cross-reactivity among COX-1 inhibitors is very likely
• In patients without U/D chronic urticaria
• Cross-reactivity with other NSAIDs is less likely

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Taxanes
• Taxanes can lead to mast cell degranulation by nonimmune
mechanisms
• Commonly occur with the first infusion
• Slowing the infusion and pretreatment with corticosteroids
and antihistamines can prevent hypersensitivity reactions in
most cases.

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Hemolytic anemia
• Hemolytic anemia can be immunologic:penicillins
Dern RJ, Beutler E,Alving AS. J Lab Clin Med 1981;97:750-9.

• And also idiosyncratic: primaquine-sensitive anemia


• G6PD deficiency renders erythrocytes sensitive to the metabolic
consequences of drugs with antioxidant properties
• Clinical phenotype is similar to immune hemolysis except for the
absence of drugantibodies

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Local Anesthetics
• Vasovagal syncope (mimic anaphylaxis)
• Paresthesias and lightheadedness
• Pharmacologic toxicity
• Symptoms are more common in drug-intolerant patients
• Episodes of anxiety or panic associated with a procedure
• Rare IgE responses
• Rare antibody-mediated reactions

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Flushing during vancomycininfusion
Red man syndrome (RMS)
• Most common toxicity of intravenous vancomycin therapy
• Associated with rapid infusion of large doses of vancomycin
• Occurs secondary to histamine release from mast cells
• Manifestations
• Generalized flushing
• Pruritus
• Erythematous rash
• Chest pain
• Dyspnea
• Hypotension Wallace MR, et al., JInfect Dis. 1991 Dec;164(6):1180-5.
Dormis MJ, Moritz ML, Front Pediatr. 2014 Jun 5;2:55.
Biological agents
• Adverse reactions at the first exposure are not uncommon
with biological agents and reflect a variety of mechanisms
• Acute induction or release of cytokines
• Protein infusion reactions
• Secondary toxicities of the product
• Carbohydrate epitopes such as α-galactose added by bacteria
during recombinant synthesis are the object of IgE-dependent
reactions

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Recognize the risk factors
Drug-related factors
• Polymerization or macromolecularcontamination
• Multivalency of drug epitopes -> risk of IgE-mediated reaction
• Protein reactivity
• Cross-reactive epitopes
• Impurity of the preparation (e.g., containing acetylsalicylic
acid-anhydride in acetylsalicylicacid)
• Concomitant medications (e.g., allopurinol,amoxicillin)

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Patient’s disease
• Need for prolonged or repeated courses of therapy (e.g.,
cystic fibrosis, chronic sinusitis,immunodeficiencies)
• Dose and duration of therapy
• Frequency of drugtreatment
• Route of administration
• Immunogenicity: High Low
Topical SC IM Oral IV

• Concomitant diseases (e.g., EBV infectionsand amoxicillin;


AIDS and sulfonamides)

K Scherer, AJ Bircher, Med Clin N Am 94 (2010) 681–689


Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295
Patient’s individual
• Prior reaction history (both related and unrelated drugs)
• Family history of drug allergy
• Prior unrecognized exposure eg.in-utero/in breast milk drug
exposure of fetus
• Atopy (IgE-mediatedreactions)
• Multiple drug allergy syndromes
• Persistence of drug-specific immune response
• Female sex in certain reactions (gemifloxacin rash)
• HLA class I (B andA) allele

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Establishing diagnosis
Gathering information
• Assemble clinical data set.
• Complete drug reactionhistory
• Atopic history
• List of concomitant medications, with chart of starts, stops, and
dose changes
• Previous exposures to same or cross-reacting drugs
• Chronology of all drug reactions: attributable signs and symptoms,
useful nonspecific laboratory tests (e.g., eosinophilia, ESR, tryptase,
proteinuria)
Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295

• Clinical syndrome diagnosis


• Detect danger signs and internal organs involvement
Danger sign
For severe immediate-typereactions
• Sudden onset of extensive pruritus, in particular palmoplantar
and scalp
• Flush on face and neck with conjunctivitis and rhinitis
• Angioedema of the oral mucosa, in particular pharynx and
larynx
• Severe urticaria
• Dyspnea and bronchospasm, especially in known asthmatics
• Hypotension

K Scherer,AJ Bircher, Med Clin N Am 94 (2010) 681–689


Danger sign
For severe delayed-typereactions
• Centrofacial edema (diffuse erythematousswelling)
• Involvement of large body surfaces or erythroderma
• Painful skin, skin tender to touch
• Atypical target lesions
• Nikolsky sign positive, vesiculobullous lesions,epidermolysis
• Erosive stomatitis; mucositis, especially if affecting more than
one mucosa
• Hemorrhagic necrotizing lesions
• Purpura
K Scherer,AJ Bircher, Med Clin N Am 94 (2010) 681–689
Danger sign

Gomes ER, Demoly P., Curr Opin Allergy Clin Immunol 2005;5:309-16.
Internal organsinvolvement
• Sudden onset of unexplained high fever (>39OC)
• Disseminated lymphadenopathy
• Arthralgias, and arthritides
• Hepatopathy
• Nephropathy
• Pneumonitis
• Abnormal laboratory:
• Eosinophilia
• Activated (atypical) lymphocytes
• Cytopenia
K Scherer,AJ Bircher, Med Clin N Am 94 (2010) 681–689
Clinical syndrome diagnosis

Type I hypersensitivity Type II &III hypersensitivity Type IV hypersensitivity

BircherA. and Scherer K. Med Clin N Am 94 (2010) 711–725


Immediate types

Urticaria

Angioedema

Anaphylaxis
Anaphylaxis diagnostic criteria

Sampson HA et al.. JAllergy Clin Immunol 2006;117: 391-7.


Anaphylaxis diagnostic criteria
One of these:
1)Acute onset of an illness (minutes to several hours)
• With involvement of the skin, mucosal tissues, or both
• e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula

• And >/= 1of the following:


• Respiratory compromise
• e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia
• Reduced BPor associated symptoms of end-organ dysfunction
• e.g., hypotonia [collapse], syncope, incontinence

Sampson HA et al.. JAllergy Clin Immunol 2006;117: 391-7.


Anaphylaxis diagnostic criteria
One of these:
2) >/=2 of the following that occur rapidly after exposure to a
likely allergen for that patient (minutes to several hours):
• Involvement ofskin-mucosal tissue
• e.g., generalized hives, itch-flush, swollen lips-tongue-uvula
• Respiratory compromise
• e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF,hypoxemia
• Reduced BPor associated symptoms of end-organ dysfunction
• e.g., hypotonia [collapse], syncope, incontinence
• Persistent gastrointestinal symptoms
• e.g., crampy abdominal pain, vomiting

Sampson HA et al.. JAllergy Clin Immunol 2006;117: 391-7.


Anaphylaxis: Diagnostic criteria
One of these:
3) Reduced BP after exposure to known allergen for that
patient (minutes to several hours):

• Infants andchildren:
• Low systolic BP(age specific) or greater than 30% decrease in systolic BP*

• Adults:
• Systolic BPless than 90 mm Hg or greater than 30% decrease from their baseline

Sampson HA et al.. JAllergy Clin Immunol 2006;117: 391-7.


Delayed types
• Exanthematic manifestations
• Macular/maculopapular/papular exanthem
• Symmetrical drug-related intertriginous flexuralexanthema
(SDRIFE, former Baboonsyndrome)
• Acute generalized exanthematous pustulosis(AGEP)
• Drug rash with eosinophilia and systemic symptoms
(DRESS)/drug hypersensitivity syndrome (DHS)
• Severe cutaneous adverse reactions (SCAR)
• Erythema multiforme (EM)
• Stevens–Johnson Syndrome (SJS)
• Toxic epidermal necrolysis(TEN)

K. Scherer , et al., an EAACI position paper of the DrugAllergy Interest Group.Allergy 2013; 68: 844–852.
Delayed types
• Dermatitis
• Fixed drug eruption
• Others
• Cutaneous vasculitis
• Autoimmune skin disorders, for example drug-induced
pemphigus or pemphigoid
• Stomatitis

K. Scherer , et al., an EAACI position paper of the DrugAllergy Interest Group.Allergy 2013; 68: 844–852.
Delayed types
• Internal organ manifestations (isolated or in the context
of complex exanthems)
• General symptoms:malaise, eosinophilia, fever, arthritis,
lymphadenopathy
• Organ involvement: hepatitis, pneumonitis, nephritis,
nephrotic syndrome, myocarditis
• Blood cell dyscrasias: neutropenia,thrombocytopenia,
anemia
• Systemic vasculitis
• Systemic autoimmune disorders, for example drug-induced
lupus erythematosus

K. Scherer , et al., an EAACI position paper of the DrugAllergy Interest Group.Allergy 2013; 68: 844–852.
AGEP: Diagnostic scoring system

A. Sidoroff., et al., JCutan Pathol 2001; 28: 113–119.


DRESS: Diagnostic criteria (RegiSCAR)
• Hospitalization
• Reaction suspected to be drug-related
• Acute rash
• Fever > 38 OC*
• Enlarged lymph nodes at a minimum of 2 sites*
• Involvement of at least one internal organ*
• Blood count abnormalities*
• Lymphocytes above or below normal limits
• Eosinophils above the laboratorylimits
• Platelets below the laboratory limits
• *3 of these 4 criteria are required for diagnosis
Kardaun SH, et al. Response Br J Dermatol 2007; 156:609–10.
DRESS: Diagnostic validation score

Kardaun SH, et al. Response Br J Dermatol 2007; 156:609–10.


DRESS/DiHS: Diagnostic criteria
• MP rash developing > 3 wk after starting of the suspected drug
• Prolonged clinical symptoms 2 weeks after drug discontinuation
• Fever (> 38 OC)
• Liver abnormalities (ALT > 100 U ⁄ L)*
• Leucocyte abnormalities
• Leucocytosis (> 11 x 109 ⁄ L)
• Atypical lymphocytosis (>5%)
• Eosinophilia (> 1.5 x 109 ⁄ L)
• Lymphadenopathy
• Human herpesvirus 6 reactivation
• Dx: 7 criteria = typical DIHS, first 5 criteria = atypical DIHS
• *This can be replaced by other organ involvement such as renal involvement.

ShioharaT, et al.. Br J Dermatol 2007; 156: 1045–92.


DRESS: Diagnostic criteria
อาศิยเกณฑก์ ารวน จฉยทง ้ 3 ขอ ้ ดงตอ่ ไปน ้
1. อาการแสดงทางผว หนง สวิ ่ นใหญ่เปนผน่ื แดงราบ(macule/ patch)หรอ ื นูน(papule/
plaque) แตอ่ าจพบตมุ่ น
าิ ้ หรอ ื เป็ นตมุ่ หนองได
2. CBC พบeosinophil >/= 1,500 เซลล/ิ ์ ลบ.มม. หรอ ื พบatypical lymphocyte
3. มอี าการตามระบบตาิ ่ ๆงอยาิ ่ งนอ ้ ย1 อาการไดแิ ้ ก
a. ตอ่ มนิ เห
้าลอื งโต>2 ซม.
b. ตบอกเสบโดยพบมรี ะดบเอนไซม์ transaminase >/= 2 เท

c. Interstitial nephropathy
d. Interstitial lungdisease
e. Myocardial involvement
ในกรณีทม่ี ปี ระวตก ารใชยิ ้ าทม่ี คี วามเส
ยิิ
่ ี งสงู ตอ่ การเกด DHS/DRESS แมพ ้
บเกณฑก์ารวน จ ฉยเพยี งขอ ้ 1 และขอ ้ 3 ก็สมควรหยุดยาและใหก ้ าร กษา

ุ ลกษณ์ สงิ คาลวณช,และคณะ,แนวทางการดแ


ศรีศภ ู ลรกษากล่ิม
ุ อาการ Drug hypersensitivitysyndrome
Bocquet H, et al.,. Semin Cutan Med Surg 1996;1:250–7.
DRESS/DiHS: Dx criteria comparison

Z Husain, et al., JAm Acad Dermatol 2013;68:693.e1-14.


SJS/TEN
• No consensus diagnostic criteria
• But there is severity classification system

M Mockenhaupt, Seminars in Cutaneous Medicine and Surgery, Vol. 33, March 2014, 10-16
SJS/TEN
• And there is a mortality risk score:The SCORTEN

M Mockenhaupt, Seminars in Cutaneous Medicine and Surgery, Vol. 33, March 2014, 10-16
SJS/TEN: TheSCORTEN

Left: Serial analysis is better performed only on day 1


Right: Mortality is underestimated for scores of 2 and 3, and overestimated for
scores of 4 and 5

S Bansal, et al., International Journal of Dermatology 2015, 54, e18–e26


Consolidation of possible culprit
• Narrow candidate list by focusing on the following.
• Temporal association between drug starts and stops and onset
• Intensification and waning of signs and symptoms of reactions

• Consider pharmaco-epidemiology of the candidate list, and


rank candidates by allergenic potential from published data

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Tools for culprit drug identification
• A number of algorithms or decision aids have been published
• Jones’algorithm
• Naranjo algorithm -> More commonly used
• Yale algorithm
• Karch algorithm
• Begaud algorithm
• TheADRAC
• WHO-UMC
• Quantitative approachalgorithm

DJ Doherty, Respiratory Medicine CME 2 (2009)63–67


Tools for culprit drug identification
• The Naranjo adverse drug reaction probability scale
Questions Yes No Unknown
1. Are there previous conclusive reports on this reaction? +1 0 0
2. Did the adverse event occur after the suspected drug wasadministered? +2 -1 0
3. Did the adverse reaction improve when the drug was discontinued ora specific +1 0 0
antagonist was administered? +2 -1 0
4. Did the adverse reaction reappear when the drug wasre-administered? -1 +2 0
5. Are there alternative causes (other than the drug) that could caused thereaction? -1 +1 0
6. Did the reaction reappear when a placebo wasgiven? +1 0 0
7. Was the drug detected in the blood (or other fluids) in toxic-level concentrations? +1 0 0
8. Was the reaction more severe with higher dose or less severe with lower dose? +1 0 0
9. Did the patient have similar reaction to the same or similar drugs previously? +1 0 0
10. Was the adverse event confirmed by any objective evidence?

• Interpretration: >9 = definite ADR, 5-8 = probable ADR, 1-4 = possible ADR, 0 = doubtful ADR

• The Naranjo criteria do not take into account drug-drug


interactions.

Naranjo CA, et al. Clin. Pharmacol.Ther. (1981). 30 (2): 239–45.


Tools for culprit drug identification
• For SJS/TEN:ALDEN (algorithm of drug causality for
epidermal necrolysis) score

B Sassolas, et al., Clin PharmacolTher. 2010 Jul;88(1):60-8.


Tools for culprit drug identification
• For SJS/TEN:ALDEN (algorithm of drug causality for
epidermal necrolysis) scoer

B Sassolas, et al., Clin PharmacolTher. 2010 Jul;88(1):60-8.


Intevention/investigation
• Stop and/or substitute all candidate drugs with good temporal
relationship to syndrome and known allergic potential.
• Observe consequences of stoppingmedications.
• Consider skin testing if suspected drug is clinically imperative
to assess IgEresponse.
• Disregard negative results within 28 days of acute anaphylaxis
(i.e., false negative), and for all haptenic drugs without
validated negative predictive value.
Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295

• Laboratory investigations (in-vitrotests)?


Diagnosis and management
• Readminister incriminated drugs as clinically indicated.
• Use gradual dose escalation if skin test negative
• Use desensitization protocol if reaction IgE dependent or skin
test positive

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Management algorithm (General)

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Management algorithm (General)

P. Demoly, et al., International Consensus on drug allergy.Allergy 2014; 69: 420–437.


Management algorithm (General)

*Currently available biological tests lack sensitivity.


**In the absence of contraindications (In next slide)
* * * I f no alternative is available (e.g., NMBA, chemotherapeutic drugs), readministration of the drug is
allowed under close surveillance,considering premedication and/or desensitization.
P. Demoly, et al., International Consensus on drug allergy.Allergy 2014; 69: 420–437.
Management algorithm (General)
Precautions and contraindications of performing DPTs

• 1 Noncontrollable and/or severe life-threatening DHRs:


• Severe cutaneous reactions (SJS,TEN, DRESS, vasculitis,AGEP)
• Systemic reactions eg.DRESS, any internal organ involvement, hematological
reactions
• Anaphylaxis may be tested after risk/benefit analysis

• 2 DPTs are not indicatedwhen:


• The offending drug is unlikely to be needed and several alternatives exist
• Severe concurrent illness or pregnancy (unless the drug is essential for the concurrent
illness or required during pregnancy or delivery)

• 3DPTs should be performed under the highest safety conditions:


• Trained staff: aware of the tests, ready to identify early signs of a positive reaction,
and ready to manage a life-threatening reaction
• With emergency resuscitative equipment available

P. Demoly, et al., International Consensus on drug allergy.Allergy 2014; 69: 420–437.


Management algorithm (Specific)
Beta lactam antibiotics (immediate reactions)

RomanoA. and Caubet J. JAllergy Clin Immunol Pract 2014;2:3-12


Management algorithm (Specific)
Beta lactam antibiotics (nonimmediate reactions)

RomanoA. and Caubet J. JAllergy Clin Immunol Pract 2014;2:3-12


Management algorithm (Specific)
Non-beta lactam antibiotics

RomanoA. and Caubet J. JAllergy Clin Immunol Pract 2014;2:3-12


Management algorithm (Specific)

Latest classification of NSAID hypersensitivity reactions

Adapted from M. L. Kowalski., et al., Position paper, Allergy 2013; 68: 1219–1232.
Management algorithm (Specific)
NSAIDs (Acute form ofreaction)

M. L. Kowalski., et al., Position paper,Allergy 2013; 68: 1219–1232.


Skin tests for drug allergy

K. Brockow, et al,. an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy 2013; 68: 702–712.
Skin tests for drug allergy

K. Brockow, et al,. an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy 2013; 68: 702–712.
Skin tests for drug allergy

K. Brockow, et al,. an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy 2013; 68: 702–712.
Skin tests for drug allergy
NSAIDs (Delayed reaction)

M. L. Kowalski., et al., Position paper,Allergy 2013; 68: 1219–1232.


Skin tests for drug allergy
Drugs that value of skin tests has not adequately been
demonstrated
• Antihypertensive drugs
• Biologicals other than anti-TNF preparations and omalizumab
• Hormones, corticosteroids andinsulins
• Nonbetalactam antibiotics
• Nonplatinum chemotherapeutics
• NSAIDs other than pyrazolones for immediate reactions
• Opioids
• Sera, immunoglobulins and vaccines

K. Brockow, et al,. an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy 2013; 68: 702–712.
Provocative tests (gradual dose escalation)
• Very few subjects with a positive history have positive drug
challenge results
Lammintausta K, Kortekangas-Savolainen O. Acta Derm Venereol 2005;85:491-6.

• Provocative drug tests should be implemented only…


• After consideration of risk-benefit ratio for each patient
• Performed by experienced personnel in an appropriate setting
• Informed consent can be obtained from the patient before the
procedure

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Provocative tests (gradual dose escalation)
• Relatively contraindicated in
• Patients with Hx of TEN, SJS,DRESS, DiHS,AGEP, or severe organ-
specific involvements.
Aberer W, et al. European Network for Drug Allergy (ENDA); EAACI interest group on drug hypersensitivity. Allergy 2003;58:854-63.

• Do not performif:
• An acute reaction occurred within the last 4-weeks
• Antihistamines or oral steroids are being used
• There are active signs of U/D
• Urticaria, uncontrolled asthma, or uncontrolled cardiac, renal, or
hepatic disease or current upper airway infection.
• For IgE-dependent reactions, the principal concern is
anaphylaxis, and lower initial doses are warranted.
Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295
Provocative tests (gradual dose escalation)
NSAIDs (acute reaction)

M. L. Kowalski., et al., Position paper,Allergy 2013; 68: 1219–1232.


Provocative tests (gradual dose escalation)
Single-blinded 3-days NSAIDs oral challenge protocol for AERD

Berges-Gimeno M, et al. Ann Allergy Asthma Immunol 2002;89:474-8.

The Lysine-ASA BronchoprovocationTest Protocol

Nizankowska-Mogilnicka et al. EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy 2007;62:1111-8.
Provocative tests (gradual dose escalation)
Nasal ketorolac challenge

AWhite, et al., Ann Allergy Asthma Immunol. 2006;97:190–195.


Provocative tests (gradual dose escalation)
Comparison of standard oralASA and modified nasal ketorolac challenge

RU Lee, et al., Ann Allergy Asthma Immunol. 2010;105:130 –135.


Provocative tests (gradual dose escalation)
NSAIDs (Dalayed reaction)

M. L. Kowalski., et al., Position paper,Allergy 2013; 68: 1219–1232.


Drug desensitization in IgE-type reaction
Procedure
• Obtain a skin test to determine the patient’s degree of
sensitivity (if available).
• Dilute available drug solution or suspension to 1-3 mg/mL.
• Prepare three tenfold dilutions.
• Perform prick or puncture testing with a 1: 1000 dilution.
• If the result is negative, perform serial intradermal tests, using 0.02
mL (3- to 4-mm bleb) in duplicate, up to and including 3 mg/mL
stock; discontinue testing when >8 mm wheal is observed.
• Positive result = both duplicate wheals increase significantly (>2-3
mm) 20 minutes after placement compared with diluent control.
• Prepare sufficient quantities of drug solution or suspension
for desensitization regimen in 10x dilutions from full
therapeutic dose
Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295
Drug desensitization in IgE-type reaction
Preparation
• Establish baseline monitoring in a medical setting appropriate
for patient’s clinical conditions and the nature or severity of
prior reaction.
• Start a secure intravenousinfusion.
• Starting dose:
• If the skin test result negative and the test is unvalidated,
begin with 0.1 mL of a 1:100 dilution (start with a 1:1000
dilution in severereactions)
• If the skin test result is positive, begin 100-fold below dose
that produces midpoint reaction (5- to 8-mm wheal).

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Drug desensitization in IgE-type reaction
Preparation
• Route:
• Oral by ingestion or nasogastric tube in 30 mL of water
• Parenteral by intradermal(<0.2 mL)
• Subcutaneous (0.2-0.6 mL)
• Intramuscular (>0.6 mL)injection
• Dosing interval
• 15-20 minutes forparenteral doses
• 20-30 minutes fororal dosing
• Repeat dose for mild to moderate systemic reactions
• Drop back 2 doses for any reaction causing hemodynamic changes
• Dose escalation: 2x increments
Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295
Drug desensitization in IgE-type reaction
Follow up
• If iv therapy follows desensitization, continuous 24-hour drug
infusion is preferable if feasible.
• If not, avoid rapid infusion of intermittent drug doses.
• If drug skin test result was positive, repeat after
desensitization to document shift in skin sensitivity.
• Avoid lapses in therapeuticdoses.
• Treat through selected mild to moderate reactions (e.g.,
urticaria) to avoid need to repeat desensitization.
• Before subsequent courses of therapy, repeat desensitization
if skin test results remain positive
• Desensitization therapy is dose and drug dependent.
Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295
Drug desensitization in delayed reaction
Criteria for desensitization
• Drug therapy isessential
• Drug is irreplaceable, more effective than alternatives, or it
has a unique mechanism
• Unavailability of a non-cross-reactingdrug
• Previous reaction is well documented and not severe,
preferably, the mechanism is known after allergologic workup
• Potential benefits outweigh the potential risks

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization in delayed reaction
Absolute contraindications of drugdesensitization
• Severe or life-threateningdrug-induced diseases
• Such as SJS/TEN, DHS/DIHS/DRESS, cutaneous or systemic
vasculitis, severe mucosalulcerations
• Drug-induced autoimmune disorders
• Drug-induced severe generalsymptoms
• Such as drug fever, arthritis, generalized lymphadenopathy
• Drug-induced organ involvement
• Such as hepatitis, nephritis, pneumonitis, or cytopenias, or
severe eosinophilia

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization in delayed reaction
Relative contraindications of drugdesensitization
• AGEP
• Underlying autoimmune disorders
• Pre-existing severe renal or hepatic impairment
• Severe cardiac disease/hemodynamicallyunstable
patient
• Simultaneous treatment with potentially interfering
drugs

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization in delayed reaction
Recommendation
• Things to consider before start
• Characterize patient
• Check criteria andcontraindications
• Assess clinical manifestation of previous reaction as detailed
as possible
• Possibly on the basis of allergological tests
• Possibly confirm diagnosis by provocation tests
• Affirm comorbidities, comedications, and risk factors
• Obtain written informedconsent

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization in delayed reaction
Recommendation
• Choose appropriate protocol
• Check whether protocol for the culprit drug exists
• Check for clinical description of patients, soundness of the
protocol, and successrate/outcome
• If there exists, no appropriate protocol check below

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization in delayed reaction
Recommendation
• Prior to starting theprocedure
• Assess complete clinical status
• Document skin, mucous membranes, internal organs, lymph nodes
• Laboratory as appropriate, but at least CBC,LFT, BUN/Cr,CRP
• Decide on starting dose, dose increments, and dose intervals

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization in delayed reaction
Recommendation
• During and after desensitization
• Apply chosen protocol, modify according to criteria below
• Check skin and mucous membranes, lymph nodes, body
temperature, atregular intervals
• Recommended at leastdaily
• Laboratory parameters asappropriate
• Monitorthe underlying disease appropriately
• In case ofan adverse event:
• Adjust the protocol or stop the procedure
• Administer symptomatic treatment

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization protocols
Beta lactam antibiotic

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Drug desensitization protocols
Non-beta lactam antibiotic

K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group.Allergy 2013; 68: 844–852.
Prediction of high-risk population
Who is at risk?

Celik G., et al. Middleton’sAllergy 8th edition, 2013,1274-1295


Why they are at risk?
Why they are at risk?
Why they are at risk?
Why they are at risk?
Finding genetic factors of ADRs
Pharmacogenetics
• Study of the affects of genetic factors on the inconsistency
of drug response by assessing the extent of the contribution
of variant forms of human genes to the observed variability
in drug disposition, drug action or drug toxicity
• Goal: to identify the right dose of the right drug for a given
individual
• Typically, genotyping or phenotyping strategies focus on a
single gene

JS Leeder, Drug Discovery Today,Vol. 9, No. 13 July 2004, page 567-573


Finding genetic factors of ADRs
Pharmacogenomics
• Investigations use constantly emerging and evolving
genomic technologies to encompass comprehensive,
genome-wide strategies targeted at identifying all factors
that influence the response of a patient to small
molecules that have been administered with therapeutic
intent.
• Goal:To identifying (developing) the right drug for a given
disease in the context of complex genomic factors.

JS Leeder, Drug Discovery Today,Vol. 9, No. 13 July 2004, page 567-573


Example of currentknowledge

SC Su, et al., Biomed Res Int. 2014;2014:824343.


Example of currentknowledge

SC Su, et al., Biomed Res Int. 2014;2014:824343.


Example of currentknowledge

Chonlaphat Sukasem, et al., Asian Pac JAllergy Immunol 2014;32:111-23


Example of currentknowledge

Chonlaphat Sukasem, et al., Asian Pac JAllergy Immunol 2014;32:111-23


More diagnostic tools should be made
available
What else? (Apart from skin/provocative tests)
Better validation algorithm/scoringsystems

S Bansal, et al., International Journal of Dermatology 2015, 54, e18–e26


What else? (Apart from skin/provocative tests)
Better validation algorithm/scoringsystems

S Bansal, et al., International Journal of Dermatology 2015, 54, e18–e26


What else? (Apart from skin/provocative tests)
Better validation algorithm/scoringsystems

S Bansal, et al., International Journal of Dermatology 2015, 54, e18–e26


What else? (Apart from skin/provocative tests)
Laboratory (in-vitro) tests
• For immediate reactions
• Solid-phase immunoassays forspecific IgE
• Only with penicillin allergy have in vitro test results been
systematically compared with those of skin tests
• Sensitivity for penicilloyl-IgE
• 65-85% compared with PPL skin tests
• 32-50%compared with skin test+provocative test
• Minor determinant penicillin IgE antibodies are not reliably
detected by available allergosorbent-typeimmunoassays.
Blanca M, et al. Allergy 2001;56:862-70.
Fontaine C, Mayorga C, Bousquet PJ, et al. Allergy 2007; 62:47-52.

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


What else? (Apart from skin/provocative tests)
Laboratory (in-vitro) tests
• For immediate reactions
• Solid-phase immunoassays forspecific IgE
• Immunoassays for documenting IgE antibodies to quinolone
antibiotics, rocuronium, and other drugs have been reported,
but their validity is unknown.

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


What else? (Apart from skin/provocative tests)
Laboratory (in-vitro) tests
• For immediate reactions
• Flow cytometry to detect drug-induced basophil activation by
means of increased surface markers such asCD63 and CD203c
• Cysteinyl leukotrienes released from blood leukocytes after
drug incubation
These tests remain investigational.

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


What else? (Apart from skin/provocative tests)
Laboratory (in-vitro) tests
• For delayed reactions
• Lymphocyte transformation tests(LTT)
• Positive in 78% of patients classified as highly likely to be drug allergic on
clinical grounds
• Overall specificitywas 85%
• False-positive results were observed, especially with NSAIDs.
• Flow cytometric lymphocyte activation test (LAT)
• T cell assays eg. drug-stimulated cytokines such as IL-5, IFN-γ,
and IL-2

Szebeni J. Crit RevTher Drug Carrier Syst 2001;18:567-606.


Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295
What else? (Apart from skin/provocative tests)
Laboratory (in-vitro) tests
• For delayed reactions
• Immunoassays for IgG, IgM, or IgA responses to drug allergens
 not useful.
• CH50, C3and C4 levels are useful indicators of the presence
and severity of complement activation in immune complex
disorders such as serum sicknesssyndromes
• Diagnostic utility of anaphylatoxin measurements (C3a,C4a,
and C5a) remains to be defined

Celik G., et al. Middleton’s Allergy 8th edition, 2013,1274-1295


• Drug hypersensitivity reactions (DHRs) is one of major
problem in modernmedicine
• DHRs can mediated by both immunologic and non-
immunologic mechanism and multiple mechanisms can
concurrently occur at the same time
• Clinical presentations of DHRs have high heterogeniety. To
make a diagnosis and identify the culprit drug needs multiple
aspects to consider. Currently, only in-vivo tests are validated
for somedrugs
• Prervention of DHRs might include genetic screening
• Management must be individualized and based on risk vs
benefit judgement.
• If drug provocation or desensitization is chosen, the
procedure must be run at maximal available safety measures.

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