Behzad Shakerian MD

- May be cutaneous, - organ-specific, - or systemic 3

 Severity of reaction: Mild bothersome but requires no change in therapy Moderate requires change in therapy, additional treatment, hospitalization Severe disabling or life-threatening 4

 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 5

 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 amounts  15-20% of all side effects  Immunologic/allergic  Non-immune mediated, “pseudoallergic”  Idiosyncratic 6

 Hapten  chemically reactive drug  able to bind covalently to proteins  Prohapten  chemically non reactive drug  becomes reactive upon metabolism (transformation of prohapten  hapten)  p-i concept  parent, chemically non reactive drug  unable to bind covalently to proteins  can nevertheless interact with “immune receptors” like T-cell receptors for antigen and elicit an immune response 7

 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 8

 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 9

Drug hypersensitivity Drug allergyNon-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 10

 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. 11

 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 12

Type IType IIType IIIType IV a Type IV b Type IV c Type IV d Immune reactant IgEIgG IFN , TNFα (T H 1 cells) IL-5, IL-4/IL-13 (T H 2 cells) Perforin/ GranzymeB (CTL) CXCL-8. GM-CSF, IL-17 (?) (T-cells) Antigen Soluble antigen Cell- or matrix- associated antigen Soluble antigen 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 Effector Mast-cell activation FcR + cells (phagocytes, NK cells) FcR + cells Complement Macrophage activation EosinophilsT cellsNeutrophils 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 TH1TH1 chemokines, cytokines, cytotoxins cytokines, inflammatory mediators CTL cytokines, inflammatory mediators IFN-  TH2TH2 IL-4 IL-5 eotaxin PMN CXCL8 GM-CSF 13

 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) 14

Allergic Immune reactions (T-cells, IgE, IgG against a drug/metabolite with 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 the drug detectable, symptoms can occur 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 15

 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. 16

 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 % ? 17

 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 18

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 19

 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 20

 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 21

Discontinue the offending agent if: it can be safely stopped the event is life-threatening or intolerable there is a reasonable alternative continuing the medication will further exacerbate the patient’s condition  Continue the medication (modified as needed) if: it is medically necessary there is no reasonable alternative the problem is mild and will resolve with time 22

 Discontinue non-essential medications  Administer appropriate treatment e.g., atropine, benztropine, dextrose, antihistamines, epinephrine, naloxone, phenytoin, phytonadione, protamine, sodium polystyrene sulfonate, digibind, flumazenil, corticosteroids, glucagon  Provide supportive or palliative care e.g., hydration, glucocorticoids, warm / cold compresses, analgesics or antipruritics  Consider rechallenge or desensitization 23

Patient’s progress Course of event Delayed reactions Response to treatment Specific monitoring parameters 24

What to check History PE PE-Nikolsky’s sign PE Labs--LFTs, Creatinine/UA. H&P for pleuritis/carditis/cerebritis Labs--CBC with differential ___ Signs of a serious drug rash: Painful skin Fever Loss of skin integrity/blistering Facial edema Mucosal involvement Palm/sole involvement Lymphadenopathy Systemic involvement Marked peripheral eosinophilia 25

 Aka maculopapular or “morbilliform”  ~90% of cutaneous drug reactions.  Type IV (T-cell mediated) hypersensitivity reaction.  Starts 7-14d after start of drug  Stops up to 7d after stopping drug 27

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WBC 16K +reactive lymphocytes AST/ALT 110/134 INR 2.1 BUN/Cr 20/0.8 29

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Stevens- Johnson SJS/TEN overlap TEN Skin rash + 2 or more mucosal sites <10%10-30%>30% BSA: Mortality:30-50%5-10% 31

 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!! 32

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