behzad shakerian md - may be cutaneous, - organ-specific, - or systemic 3
TRANSCRIPT
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به نام خدا
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CLINICAL ANALYSIS OF DRUG ALLERGY
Behzad Shakerian MD
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CLINICAL FEATURES OF DRUG HYPERSENSITIVITY
- May be cutaneous,- organ-specific,- or systemic
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CLASSIFICATION - SEVERITY
Severity of reaction:• Mild
bothersome but requires no change in therapy• Moderate
requires change in therapy, additional treatment, hospitalization
• Severe disabling or life-threatening
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PERTINENT PATIENT/DISEASE FACTORS
Demographics • age, race, ethnicity, gender, height, weight
Medical history and physical exam• Concurrent conditions or special circumstances
e.g., dehydration, autoimmune condition, HIV infection, pregnancy, dialysis, breast feeding
• Recent procedures or surgeries and any resultant complications e.g., contrast material, radiation treatment, hypotension, shock, renal
insufficiency
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CLASSIFICATION OF ADVERSE DRUG REACTIONS
Type A: predictable; strictly dose dependent 80% of all side effects Pharmacological side effects (e.g. gastrointestinal bleeding
under treatment with NSAID)
Type B: not predictable; usually not dose dependent, and sometimes reactions to very small amounts15-20% of all side effects Immunologic/allergic Non-immune mediated, “pseudoallergic” Idiosyncratic
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HAPTEN, PROHAPTEN AND P-I CONCEPT Hapten
chemically reactive drugable to bind covalently to proteins
Prohaptenchemically non reactive drugbecomes reactive upon metabolism (transformation of
prohapten hapten)
p-i conceptparent, chemically non reactive drugunable to bind covalently to proteinscan nevertheless interact with “immune receptors” like T-cell
receptors for antigen and elicit an immune response
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HOW CAN DRUGS STIMULATE THE IMMUNE SYSTEM (I)?
Hapten/prohapten concept The hapten-carrier complex (e.g. penicillin covalently
bound to albumin) leads to formation of neoantigens: these will be recognized by the immune system (hapten-specific Ig on B-cells and by T-cells)
The binding of haptens to cellular structures may be associated with stimulation of the innate immune system. This provides “danger signals”, e.g. leading to upregulation of CD40/CD86 on Dendritic Cells
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NOMATURE
Immune mediated drug hypersensitivity (drug allergy) Clinical symptoms due to different types of specific immune
reactions (T-cell & B-cell/Ig mediated) Non immune mediated drug hypersensitivity (non-allergic drug
hypersensitivity) Symptoms and signs similar to immune mediated hypersensitivity,
but failure to demonstrate a specific immune process to the drug Older term: “pseudoallergy”
Idiosyncrasy symptoms and signs due to some genetic alterations, e.g. an enzyme
deficiency: e.g. hemolytic anaemia due to certain drugs in patients with G-6-P-deficiency
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NOMENCLATURE
Drug hypersensitivity
Drug allergy Non-allergic hypersensitivity
IgE-mediated Non IgE mediated
drug allergy drug allergy
-6
eg: Non-specific histamine release,Arachidonic acid pathway activation,Bradykinin pathway alteration,Complement activation
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EPIDEMIOLOGY Adverse drug reactions (ADRs) have been reported to account for 3 to 6%
of all hospital admissions and occur in 10 to 15% of hospitalized patients.
Drug allergy has been estimated to account for up to a third of all ADRs.
Most epidemiologic studies have dealt with ADRs or adverse drug events, with few focusing on drug allergy alone.
In hospitalized patients, the incidence of cutaneous allergic reactions from the rates of hospitalization for ADRs, disclosed an estimated rate of 2.2 per 100 patients and 3 per 1,000 courses of drug therapy.
The true incidence of drug-induced anaphylaxis is also unknown, as most studies have been based on all causes of anaphylaxis or all causes (both allergic and nonallergic) of ADRs.
The estimated incidence of Stevens-Johnson Syndrome (SJS), which may occur secondary to ADR, is 0.4 to 1.2 per 1 million people per year; the estimated incidence for TEN is 1.2 to 6 per 1 million people per year.
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DRUG ALLERGY Maculopapular exanthem
(MPE) Bullous exanthem Stevens-Johnson Syndrom
(SJS), toxic-epidermal necrolysis (TEN)
Acute generalized exanthematous pustulosis (AGEP)
Drug induced hypersensitivity syndrome (DiHS), or drug reaction with eosinophilia and systemic symptoms (DRESS)
(Interstitial) nephritis, pancreatitis, colitis, pneumonitis, hepatitis
Urticaria, angioedema, anaphylaxis, bronchospasm
Blood cell dyscrasia, hemolytic anaemia, thrombocytopenia, agranulocytosis
Vasculitis Drug induced
autoimmunity (SLE, pemphigus ...)
IgE
IgG&Compl.
T-cell
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ANTIBODY MEDIATED HYPERSENSITIVITY REACTIONS (I-III) AND DELAYED TYPE HYPERSENSITIVITY REACTIONS (IV A-D)
Type I Type II Type IIIType IV a Type IV b Type IV c
Type IV d
Immune reactant
IgE IgG IgGIFN, TNFα(TH1 cells)
IL-5, IL-4/IL-13(TH2 cells)
Perforin/GranzymeB
(CTL)
CXCL-8. GM-CSF, IL-17
(?) (T-cells)
Antigen Soluble antigenCell- or matrix-
associated antigen
Soluble antigen
Antigen presented by
cells or direct T cell stimulation
Antigen presented by
cells or direct T cell stimulation
Cell-associated antigen or direct T cell stimulation
Antigen presented by cells or direct T cell stimulation
EffectorMast-cell activation
FcR+ cells (phagocytes, NK
cells)
FcR+ cellsComplement
Macrophage activation
Eosinophils T cells Neutrophils
Example of hypersen-sitivity reaction
Allergic rhinitis, asthma, systemic anaphylaxis
Some drug allergies (e.g., penicillin)
Serum sickness, Arthus reaction
Tuberculin reaction, contact dermatitis (with IVc)
Chronic asthma, chronic allergic rhinitis, maculo-papular exanthema with eosinophilia
Contact dermatitis,maculopapular and bullous exanthema,hepatitis
AGEP,Behçet disease Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003
Ag
platelets
blood vessel
immune complex
TH1
chemokines, cytokines, cytotoxins
cytokines, inflammatory
mediators
CTL
cytokines, inflammatory
mediators
IFN-TH2
IL-4IL-5 eotaxin PMNCXCL8
GM-CSF
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DRUG ALLERGY: HETEROGENEOUS CLINICAL MANIFESTATIONS & PATHOPHYSIOLOGY
Urticaria, anaphylaxis Blood cell dyscrasia Vasculitis Maculopapular exanthem Bullous or pustular exanthems
(AGEP) Stevens-Johnson Syndrome
(SJS), toxic-epidermal necrolysis (TEN)
Hepatitis, interstitial nephritis, pneumopathy
Drug induced autoimmunity (SLE, pemphigus ...)
Drug induced hypersensitivity syndrome (DiHS/DRESS)
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ALLERGIC VS NON-ALLERGIC DRUG HYPERSENSITIVITY
Allergic
Immune reactions (T-cells, IgE,IgG against a drug/metabolitewith exanthema, urticaria, etc.) Highly specific Dependent of structure Can be dangerous, severe (IgE
& T cell reactions!) Cross-reactions to structurally
related compounds IgE to drug occasionally
detectable (skin tests, IgE-serology)
Non-allergic
No immune reaction against thedrug detectable, symptoms canoccur at the first contact Activation of immunological
effector cells (mast-cells, basophil leukocytes, etc)
Cross-reactions due to function of drug, not structure
Skin tests and serology negative
Drug provocation tests can be positive in allergic and non allergic reactions
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DELAYED REACTIONS: DANGER SYMPTOMS AND SIGNS
Extensive, confluent infiltrated exanthema Bullae, pustules Nikolsky sign Erythrodermia Painful skin Mucosal affection Facial oedema Lymphadenopathy Constitutional symptoms (higher fever, malaise,
fatigue): Look carefully if any of these signs is present. Stop all ongoing drugs. Do liver, renal and blood tests.
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MORTALITY IN SEVERE, DELAYED DRUG HYPERSENSITIVITY REACTIONS
Stevens - Johnson Syndrome (SJS) & toxic epidermal necrolysis (TEN): bullous exanthema and mucosal affection
DRESS (DHiS): Drug reaction with eosinophilia and systemic symptoms (often hepatitis, sometimes pancreatitis, interstitial lung disease, colitis, myocarditis, pleuritis, pericarditis, nephritis …)
AGEP (acute generalized exanthematous pustulosis)
Isolated hepatitis, interstitial nephritis, interstitial lung disease, pancreatitis
Mortality
10 – 30 %
10 %
5 %
?
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DRUGS WITH POTENTIAL FOR SERIOUS ALLERGIES
Immediate reactions (anaphylaxis) -lactam-antibiotics, pyrazolone, neuromuscular blocking
agents, radiocontrast media
Delayed reactions (drug-induced hypersensitivity syndromes) Antiepileptics: carbamazepine, lamotrigine, phenobarbital Allopurinol Sulfonamide/Sulfasalazine Nevirapine, Abacavir Certain quinolones Minocyclin, diltiazem
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PERTINENT PATIENT/DISEASE FACTORS
• End-organ function • Review of systems• Laboratory tests and diagnostics• Social history
tobacco, alcohol, substance abuse, physical activity, environmental or occupational hazards or exposures
• Pertinent family history• Nutritional status
special diets, malnutrition, weight loss
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PERTINENT MEDICATION FACTORS Medication history
• Prescription medications• Non-prescription medications• Alternative and investigational therapies• Medication use within previous 6 months• Allergies or intolerances• History of medication reactions• Adherence to prescribed regimens• Cumulative mediation dosages
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PERTINENT MEDICATION FACTORS
Medication• Indication, dose, diluent, volume
Administration • Route, method, site, schedule, rate, duration
Formulation• Pharmaceutical excipients
e.g., colorings, flavorings, preservatives• Other components
e.g., DEHP, latex
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MANAGEMENT OPTIONS
Discontinue the offending agent if: it can be safely stopped the event is life-threatening or intolerable there is a reasonable alternativecontinuing the medication will further exacerbate
the patient’s conditionContinue the medication (modified as needed) if:
it is medically necessary there is no reasonable alternative the problem is mild and will resolve with time
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MANAGEMENT OPTIONSDiscontinue non-essential medicationsAdminister appropriate treatment
e.g., atropine, benztropine, dextrose, antihistamines, epinephrine, naloxone, phenytoin, phytonadione, protamine, sodium polystyrene sulfonate, digibind, flumazenil, corticosteroids, glucagon
Provide supportive or palliative caree.g., hydration, glucocorticoids, warm / cold
compresses, analgesics or antipruriticsConsider rechallenge or desensitization
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• Patient’s progress • Course of event• Delayed reactions • Response to treatment• Specific monitoring parameters
FOLLOW-UP AND RE-EVALUATION
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What to check HistoryPEPE-Nikolsky’s signPEPEPEPELabs--LFTs, Creatinine/UA. H&P for pleuritis/carditis/cerebritisLabs--CBC with differential
________________________
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Signs of a serious drug rash:
Painful skinFever
Loss of skin integrity/blisteringFacial edema
Mucosal involvementPalm/sole involvement
LymphadenopathySystemic involvement
Marked peripheral eosinophilia
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TYPICAL BENIGN DRUG EXANTHEM
Aka maculopapular or “morbilliform”
~90% of cutaneous drug reactions.
Type IV (T-cell mediated) hypersensitivity reaction.
Starts 7-14d after start of drugStops up to 7d after stopping drug
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DAY 1
WBC 16K +reactive lymphocytesAST/ALT 110/134INR 2.1BUN/Cr 20/0.8
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DAY 3
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WHAT IS IT, AND IS THEIR SKIN GOING TO FALL OFF?
Stevens-Johnson
SJS/TENoverlap
TEN
Skin rash + 2 or more mucosal sites
<10% 10-30% >30%BSA:
Mortality: 30-50%5-10%
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STEVENS-JOHNSON SYNDROME (SJS)& TOXIC EPIDERMAL NECROLYSIS (TEN)
Rare; 1-2 cases per million person years
Occurs 1-3 weeks after starting drug; sooner if rechallenged
URI-prodrome 1-2 weeks before rash
fever (universal), conjunctivitis, pharyngitis, pruritis and PAINFUL SKIN!!
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SJS
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TEN
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ACUTE EXANTHEMATOUS GENERALIZED PUSTULOSIS (AGEP)
http://dermatology.cdlib.org/126/case_presentations/agep/teixeira.html
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PHOTOTOXIC REACTION
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DRUG INDUCED LUPUS
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DRUG INDUCED VASCULITIS
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FIXED DRUG ERUPTION
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THE END