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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)
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)
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.
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
World Health Organization. 2007. Drug and Therapeutics Committee Training Course. Session 4. Assessing and Managing Medicine
Safety
Classification ofadverse drug reaction
Drug allergy
= Drug reactions resulting from consequences of a drug-specific
immune response
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)
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)
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
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.
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
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
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
Urticaria
Angioedema
Anaphylaxis
Anaphylaxis diagnostic criteria
• 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
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
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
• Interpretration: >9 = definite ADR, 5-8 = probable ADR, 1-4 = possible ADR, 0 = doubtful ADR
Adapted from M. L. Kowalski., et al., Position paper, Allergy 2013; 68: 1219–1232.
Management algorithm (Specific)
NSAIDs (Acute form ofreaction)
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)
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.
• 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)
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
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?