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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

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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