Drug allergy: Principles and Updates

Reviewed by
Wat Mitthamsiri, MD

• Definitions
• Effects to human health
• Classifications of adverse drug reactions
• Chronological classification
• Clinical classification
• Mechanisms of drug allergy
• General approach
• Future of drug allergy prediction
• Future of drug allergy diagnosis
• Conclusion
Outline

Adverse Event (AE)
= Medical occurrence temporally associated with the
use of a medicinal product, but not necessarily causally
related.
Definitions
Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden, glossary, http://www.who-
umc.org/graphics/8321.pdf, p. 1.

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.
Definitions
US FDA, 2013, Good Review Practice: Clinical Review of Investigational New Drug Applications
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079753.pdf

Adverse Reaction (AR)
=A response to a drug which is noxious and
unintended, and which occurs at doses normally used
in man for the prophylaxis, diagnosis, or therapy of
disease, or for the modifications of physiological
function
Definitions
Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden, glossary, http://www.who-
umc.org/graphics/8321.pdf, p. 1.

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.
Definitions
US FDA, 2013, Good Review Practice: Clinical Review of Investigational New Drug Applications
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079753.pdf

• Type A—Exaggerated pharmacological response
• Pharmacodynamic (e.g., bronchospasm from beta-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
Classification of adverse drug reaction
World Health Organization. 2007. Drug and Therapeutics Committee Training Course. Session 4. Assessing and Managing Medicine Safety

• Type D—Delayed (lag time)
• Teratogenic effects with anticonvulsants or lisinopril
• Type E—Ending of use (withdrawal)
• Withdrawal syndrome with benzodiazepines
• Type F—Failure of efficacy (no response)
• Resistance to antimicrobials
World Health Organization. 2007. Drug and Therapeutics Committee Training Course. Session 4. Assessing and Managing Medicine
Safety

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

Drug hypersensitivity 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.
Drug allergy
= Drug reactions resulting from consequences of a drug-specific
immune response
Definition
Gomes ER, Demoly P., Curr Opin AllergyClin Immunol 2005;5:309-16.

• IPD: 10-20% of patients
• OPD: 25% of patients
• Type A reactions : About 85-90% of all ADRs.
• Type B reactions : About 10-15% of all ADRs.
• Immune-mediated (drug allergy) : About 6-10% of ADRs.
Epidemiology
Gomes ER, Demoly P., Curr Opin Allergy Clin Immunol 2005;5:309-16.

• Most common drug groups causing hypersensitivity reactions
• β-lactam antibiotics
• Nonsteroidal antiinflammatory drugs (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)
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 is significant
• 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 be substantial.
Epidemiology
Ratajczak HV, Toxicol Rev. 2004;23(4):265-80.

• 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
Epidemiology: Global scale monitoring
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

• VigiBase
• Maintained and developed on behalf ofWHO 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.
http://www.who-umc.org/DynPage.aspx?id=98080&mn1=7347&mn2=7252&mn3=7322&mn4=7324

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

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

Epidemiology
Health Product Vigilance Center (HPVC), กองแผนงานและวิชาการ อย., Spontaneous Reports of Adverse Drug Reaction 2012
http://thaihpvc.fda.moph.go.th/thaihvc/Public/Webpage/main.jsf

Chronological classification

Clinical classification
Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725

Agents
Immune
system
Effector
functions
General concept of immune response

Agents
Immune
system
Effector
functions
General concept of immune response
???

• 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
Can drug be antigen?
Coulter EM, et al. J Pharmacol Exp Ther 2007;320:885-92.

AK Abbas., et al. Cellular and Molecular Immunology 7th edition, 2012,109-138
8-11 peptide rersidues 10-30 peptide rersidues

AK Abbas., et al. Cellular and Molecular Immunology 7th edition, 2012,139-172
B cell receptor complex T cell receptor complex

Image from: AK Abbas., et al. Cellular and Molecular Immunology 7th edition, 2012,89-108
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.
Celik G., et al. Middleton’sAllergy 8th edition,
2013,1274-1295

• Being complete allergen by itself
• Foreign macromolecules
• Insulin and other hormones
• Enzymes and protamine
• Antisera
• Recombinant proteins
• Vaccines
• Functionally multivalent chemical
• Succinylcholine
• Other quaternary ammonium compounds
How can drug get its antigenicity?

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

• Metabolism to haptenic form
• Sulfonamides*
• Acetaminophen†
• Phenacetin*
• Phenytoin‡
• Procainamide*
• Halothane§
• *Postulated intermediate: hydroxylamine.
• †Postulated intermediate: quinone imine.
• ‡Postulated intermediate: arene oxide.
• §Postulated intermediates: radicals, acylhalides.
Drug antigenicity

Drug antigenicity

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 drug forms

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

P-i concepts
1, The drug fits into someTCR with 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 HLA molecule, and the new drug-HLA
complex stimulatesT cells

P-i concepts
Schaerli P, et al. J Exp Med 2004; 199:1265-75.
• It can explain “bizarre features” of drug hypersensitivity
• Rapid flow of symptoms at the first encounter with the drug, notably
without a sensitization phase
• 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 ofT cells, many of which are effector
memoryT cells that react rapidly if immunogenic agents penetrate the skin
barrier.

Modified Gell and Coombs classification
Pichler et al., Med Clin N Am 94 (2010) 645–664

Differences from immunologic form

Shock after radiocontrast media
• Iodine sensitivity?

Shock after radiocontrast media
• Iodine sensitivity?
• Contrast media reactors tolerate iodine-containing surgical
scrubs, and vice versa
• Its hypertonicity augments basophil and mast cell histamine
release
• Some nonionic contrast agents’ reaction may be IgE mediated
Schabelman E, Witting M. J Emerg Med 2010;39: 701-7.
Stellato C, et al. J Allergy Clin Immunol 1996;97:838-50.
Stellato C, Adkinson NF Jr., Allergy 1998; 53:1111-3.

Risk factors for contrast media reactions
• Atopic background (relative risk: 3 to 5)
• Female gender
• Underlying severe cardiovascular disease
• History of radiocontrast reactions
• History of drug allergy in general
Stellato C, et al. J Allergy Clin Immunol 1996;97:838-50.
Stellato C, Adkinson NF Jr., Allergy 1998; 53:1111-3.

Prevention: premedication
Tramèr MR, et al., BMJ 2006;333:675.

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

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.

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

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

Flushing during vancomycin infusion
Wallace MR, et al., J Infect Dis. 1991 Dec;164(6):1180-5.
Dormis MJ, Moritz ML, Front Pediatr. 2014 Jun 5;2:55.
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

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

Drug-related factors
• Polymerization or macromolecular contamination
• 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 acetylsalicylic acid)
• Concomitant medications (e.g., allopurinol, amoxicillin)

Patient’s disease
K Scherer, AJ Bircher, Med Clin N Am 94 (2010) 681–689
• Need for prolonged or repeated courses of therapy (e.g.,
cystic fibrosis, chronic sinusitis, immunodeficiencies)
• Dose and duration of therapy
• Frequency of drug treatment
• Route of administration
• Immunogenicity: High Low
• Concomitant diseases (e.g., EBV infections and amoxicillin;
AIDS and sulfonamides)
Topical SC IM Oral IV

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-mediated reactions)
• Multiple drug allergy syndromes
• Persistence of drug-specific immune response
• Female sex in certain reactions (gemifloxacin rash)
• HLA class I (B and A) allele

Gathering information
• Assemble clinical data set.
• Complete drug reaction history
• 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)
• Clinical syndrome diagnosis
• Detect danger signs and internal organs involvement

Danger sign
For severe immediate-type reactions
• 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

Danger sign
For severe delayed-type reactions
• Centrofacial edema (diffuse erythematous swelling)
• 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

Danger sign

Internal organs involvement
• Sudden onset of unexplained high fever (>39OC)
• Disseminated lymphadenopathy
• Arthralgias, and arthritides
• Hepatopathy
• Nephropathy
• Pneumonitis
• Abnormal laboratory:
• Eosinophilia
• Activated (atypical) lymphocytes
• Cytopenia

Clinical syndrome diagnosis
Bircher A. and Scherer K. Med Clin N Am 94 (2010) 711–725
Type I hypersensitivity Type II & III hypersensitivity Type IV hypersensitivity

Immediate types
Urticaria
Angioedema
Anaphylaxis

Anaphylaxis diagnostic criteria
Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.

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 >/= 1 of the following:
• Respiratory compromise
• e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia
• Reduced BP or associated symptoms of end-organ dysfunction
• e.g., hypotonia [collapse], syncope, incontinence

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 of skin-mucosal tissue
• e.g., generalized hives, itch-flush, swollen lips-tongue-uvula
• Respiratory compromise
• e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia
• Reduced BP or associated symptoms of end-organ dysfunction
• e.g., hypotonia [collapse], syncope, incontinence
• Persistent gastrointestinal symptoms
• e.g., crampy abdominal pain, vomiting

Anaphylaxis: Diagnostic criteria
One of these:
3) Reduced BP after exposure to known allergen for that
patient (minutes to several hours):
• Infants and children:
• Low systolic BP (age specific) or greater than 30% decrease in systolic BP*
• Adults:
• Systolic BP less than 90 mm Hg or greater than 30% decrease from their baseline

Delayed types
• Exanthematic manifestations
• Macular/maculopapular/papular exanthem
• Symmetrical drug-related intertriginous flexural exanthema
(SDRIFE, former Baboon syndrome)
• 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 Drug Allergy InterestGroup.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

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

AGEP: Diagnostic scoring system
A. Sidoroff., et al., J Cutan Pathol 2001; 28: 113–119.

DRESS: Diagnostic criteria (RegiSCAR)
Kardaun SH, et al. Response Br J Dermatol 2007; 156: 609–10.
• 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 laboratory limits
• Platelets below the laboratory limits
• *3 of these 4 criteria are required for diagnosis

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

DRESS/DiHS: Diagnostic criteria
ShioharaT, et al.. Br J Dermatol 2007; 156: 1045–92.
• 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.

DRESS: Diagnostic criteria
ศรีศุภลักษณ์ สิงคาลวณิช, และคณะ, แนวทางการดูแลรักษากลุ่มอาการ Drug hypersensitivity syndrome
Bocquet H, et al.,. Semin Cutan Med Surg 1996;1:250–7.
อาศัยเกณฑ์การวินิจฉัยทั้ง 3 ข ้อ ดังต่อไปนี้
1. อาการแสดงทางผิวหนัง ส่วนใหญ่เป็ นผื่นแดงราบ (macule/ patch) หรือนูน (papule/
plaque) แต่อาจพบตุ่มน้าหรือเป็ นตุ่มหนองได ้
2. CBC พบ eosinophil >/= 1,500 เซลล์/ลบ.มม. หรือพบ atypical lymphocyte
3. มีอาการตามระบบต่างๆ อย่างน้อย 1 อาการได ้แก่
a. ต่อมน้าเหลืองโต >2 ซม.
b. ตับอักเสบ โดยพบมีระดับเอนไซม์ transaminase >/= 2 เท่า
c. Interstitial nephropathy
d. Interstitial lung disease
e. Myocardial involvement
ในกรณีที่มีประวัติการใช ้ยาที่มีความเสี่ยงสูงต่อการเกิด DHS/DRESS แม ้พบ
เกณฑ์การ วินิจฉัยเพียงข ้อ 1 และข ้อ 3 ก็สมควรหยุดยาและให ้การรักษา

DRESS/DiHS: Dx criteria comparison
Z Husain, et al., J Am Acad Dermatol 2013;68:693.e1-14.

SJS/TEN
M Mockenhaupt, Seminars in Cutaneous Medicine and Surgery,Vol. 33, March 2014, 10-16
• No consensus diagnostic criteria
• But there is severity classification system

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

SJS/TEN:The SCORTEN
S Bansal, et al., International Journal of Dermatology 2015, 54, e18–e26
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

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

Tools for culprit drug identification
DJ Doherty, Respiratory Medicine CME 2 (2009) 63–67
• A number of algorithms or decision aids have been published
• Jones’ algorithm
• Naranjo algorithm -> More commonly used
• Yale algorithm
• Karch algorithm
• Begaud algorithm
• The ADRAC
• WHO-UMC
• Quantitative approach algorithm

Naranjo CA, et al. Clin. Pharmacol.Ther. (1981). 30 (2): 239–45.
• The Naranjo adverse drug reaction probability scale
• 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.
Questions Yes No Unknown
1. Are there previous conclusive reports on this reaction?
2. Did the adverse event occur after the suspected drug was administered?
3. Did the adverse reaction improve when the drug was discontinued or a specific
antagonist was administered?
4. Did the adverse reaction reappear when the drug was re-administered?
5. Are there alternative causes (other than the drug) that could caused the reaction?
6. Did the reaction reappear when a placebo was given?
7. Was the drug detected in the blood (or other fluids) in toxic-level concentrations?
8. Was the reaction more severe with higher dose or less severe with lower dose?
9. Did the patient have similar reaction to the same or similar drugs previously?
10. Was the adverse event confirmed by any objective evidence?
+1
+2
+1
+2
-1
-1
+1
+1
+1
+1
0
-1
0
-1
+2
+1
0
0
0
0
0
0
0
0
0
0
0
0
0
0

B Sassolas, et al., Clin PharmacolTher. 2010 Jul;88(1):60-8.
• For SJS/TEN: ALDEN (algorithm of drug causality for
epidermal necrolysis) score

B Sassolas, et al., Clin PharmacolTher. 2010 Jul;88(1):60-8.
• For SJS/TEN: ALDEN (algorithm of drug causality for
epidermal necrolysis) scoer

Intevention/investigation
• Stop and/or substitute all candidate drugs with good temporal
relationship to syndrome and known allergic potential.
• Observe consequences of stopping medications.
• Consider skin testing if suspected drug is clinically imperative
to assess IgE response.
• Disregard negative results within 28 days of acute anaphylaxis
(i.e., false negative), and for all haptenic drugs without
validated negative predictive value.
• Laboratory investigations (in-vitro tests)?

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

Management algorithm (General)

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

*Currently available biological tests lack sensitivity.
**In the absence of contraindications (In next slide)
***If no alternative is available (e.g., NMBA, chemotherapeutic drugs), readministration of the drug is
allowed under close surveillance,considering premedication and/or desensitization.

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 indicated when:
• 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)
• 3 DPTs 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

Management algorithm (Specific)
Romano A. and Caubet J. J Allergy Clin Immunol Pract 2014;2:3-12
Beta lactam antibiotics (immediate reactions)

Beta lactam antibiotics (nonimmediate reactions)

Non-beta lactam antibiotics

Adapted from M. L. Kowalski., et al., Position paper, Allergy 2013; 68: 1219–1232.
Latest classification of NSAID hypersensitivity reactions

M. L. Kowalski., et al., Position paper, Allergy 2013; 68: 1219–1232.
NSAIDs (Acute form of reaction)

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

NSAIDs (Delayed reaction)

K. Brockow, et al,. an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013; 68: 702–712.
Drugs that value of skin tests has not adequately been
demonstrated
• Antihypertensive drugs
• Biologicals other than anti-TNF preparations and omalizumab
• Hormones, corticosteroids and insulins
• Nonbetalactam antibiotics
• Nonplatinum chemotherapeutics
• NSAIDs other than pyrazolones for immediate reactions
• Opioids
• Sera, immunoglobulins and vaccines

Provocative tests (gradual dose escalation)
• Very few subjects with a positive history have positive drug
challenge results
• 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
Lammintausta K, Kortekangas-Savolainen O. Acta Derm Venereol 2005;85:491-6.

• Relatively contraindicated in
• Patients with Hx ofTEN, SJS, DRESS, DiHS, AGEP, or severe organ-
specific involvements.
• Do not perform if:
• 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.
Aberer W, et al. European Network for Drug Allergy (ENDA); EAACI interest group on drug hypersensitivity. Allergy 2003;58:854-63.

NSAIDs (acute reaction)

Nizankowska-Mogilnicka et al. EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy 2007;62:1111-8.
Single-blinded 3-days NSAIDs oral challenge protocol for AERD
The Lysine-ASA Bronchoprovocation Test Protocol
Berges-Gimeno M, et al. Ann Allergy Asthma Immunol 2002;89:474-8.

A White, et al., Ann Allergy Asthma Immunol. 2006;97:190–195.
Nasal ketorolac challenge

RU Lee, et al., Ann Allergy Asthma Immunol. 2010;105:130 –135.
Comparison of standard oral ASA and modified nasal ketorolac challenge

NSAIDs (Dalayed reaction)

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

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 intravenous infusion.
• 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 severe reactions)
• If the skin test result is positive, begin 100-fold below dose
that produces midpoint reaction (5- to 8-mm wheal).

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 for parenteral doses
• 20-30 minutes for oral dosing
• Repeat dose for mild to moderate systemic reactions
• Drop back 2 doses for any reaction causing hemodynamic changes
• Dose escalation: 2x increments

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 therapeutic doses.
• 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.

Drug desensitization in delayed reaction
K. Scherer , et al., an EAACI position paper of the Drug Allergy Interest Group. Allergy 2013; 68: 844–852.
Criteria for desensitization
• Drug therapy is essential
• Drug is irreplaceable, more effective than alternatives, or it
has a unique mechanism
• Unavailability of a non-cross-reacting drug
• Previous reaction is well documented and not severe,
preferably, the mechanism is known after allergologic workup
• Potential benefits outweigh the potential risks

Absolute contraindications of drug desensitization
• Severe or life-threatening drug-induced diseases
• Such as SJS/TEN, DHS/DIHS/DRESS, cutaneous or systemic
vasculitis, severe mucosal ulcerations
• Drug-induced autoimmune disorders
• Drug-induced severe general symptoms
• Such as drug fever, arthritis, generalized lymphadenopathy
• Drug-induced organ involvement
• Such as hepatitis, nephritis, pneumonitis, or cytopenias, or
severe eosinophilia

Relative contraindications of drug desensitization
• AGEP
• Underlying autoimmune disorders
• Pre-existing severe renal or hepatic impairment
• Severe cardiac disease/hemodynamically unstable
patient
• Simultaneous treatment with potentially interfering
drugs

Recommendation
• Things to consider before start
• Characterize patient
• Check criteria and contraindications
• 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 informed consent

Recommendation
• Choose appropriate protocol
• Check whether protocol for the culprit drug exists
• Check for clinical description of patients, soundness of the
protocol, and success rate/outcome
• If there exists, no appropriate protocol check below

Recommendation
• Prior to starting the procedure
• 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

Recommendation
• During and after desensitization
• Apply chosen protocol, modify according to criteria below
• Check skin and mucous membranes, lymph nodes, body
temperature, at regular intervals
• Recommended at least daily
• Laboratory parameters as appropriate
• Monitor the underlying disease appropriately
• In case of an adverse event:
• Adjust the protocol or stop the procedure
• Administer symptomatic treatment

Drug desensitization protocols
Beta lactam antibiotic

Drug desensitization protocols
Non-beta lactam antibiotic

Prediction of high-risk population

Who is at risk?

Finding genetic factors of ADRs
• 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
Pharmacogenetics
JS Leeder, Drug DiscoveryToday,Vol. 9, No. 13 July 2004, page 567-573

Finding genetic factors of ADRs
• 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.
Pharmacogenomics
JS Leeder, Drug DiscoveryToday,Vol. 9, No. 13 July 2004, page 567-573

Example of current knowledge
SC Su, et al., Biomed Res Int. 2014;2014:824343.

Example of current knowledge
Chonlaphat Sukasem, et al., Asian Pac J Allergy Immunol 2014;32:111-23

More diagnostic tools should be made
available

What else? (Apart from skin/provocative tests)
S Bansal, et al., International Journal of Dermatology 2015, 54, e18–e26
Better validation algorithm/scoring systems

Blanca M, et al. Allergy 2001;56:862-70.
Fontaine C, Mayorga C, Bousquet PJ, et al. Allergy 2007; 62:47-52.
Laboratory (in-vitro) tests
• For immediate reactions
• Solid-phase immunoassays for specific 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-type immunoassays.

• Solid-phase immunoassays for specific IgE
• Immunoassays for documenting IgE antibodies to quinolone
antibiotics, rocuronium, and other drugs have been reported,
but their validity is unknown.

• Flow cytometry to detect drug-induced basophil activation by
means of increased surface markers such as CD63 and CD203c
• Cysteinyl leukotrienes released from blood leukocytes after
drug incubation
These tests remain investigational.

Szebeni J. Crit Rev Ther Drug Carrier Syst 2001;18:567-606.
• For delayed reactions
• Lymphocyte transformation tests (LTT)
• Positive in 78% of patients classified as highly likely to be drug allergic on
clinical grounds
• Overall specificity was 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

• For delayed reactions
• Immunoassays for IgG, IgM, or IgA responses to drug allergens
 not useful.
• CH50, C3 and C4 levels are useful indicators of the presence
and severity of complement activation in immune complex
disorders such as serum sickness syndromes
• Diagnostic utility of anaphylatoxin measurements (C3a, C4a,
and C5a) remains to be defined

• Drug hypersensitivity reactions (DHRs) is one of major
problem in modern medicine
• 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 some drugs
• 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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