به نام خدا

1. به نام خدا

2. Clinical Analysis of Drug Allergy Behzad Shakerian MD

3. Clinical features of drug hypersensitivity - May be cutaneous, - organ-specific, - or systemic

4. 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

5. 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

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

7. Hapten, prohapten and p-i concept • 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 covalentlyto proteins • can nevertheless interact with “immune receptors” like T-cell receptors for antigen and elicit an immune response

8. 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

9. 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

10. Nomenclature Drug hypersensitivity Drug allergy Non-allergic hypersensitivity IgE-mediated Non IgE mediated drug allergy drug allergy eg: Non-specific histamine release, Arachidonic acid pathway activation, Bradykinin pathway alteration, Complement activation -6

11. 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.

12. Drug allergy • Maculopapularexanthem (MPE) • Bullousexanthem • 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

13. immune complex blood vessel TH2 platelets TH1 IFN- Ag IL-4IL-5 eotaxin CXCL8GM-CSF PMN CTL cytokines, inflammatory mediators chemokines, cytokines, cytotoxins cytokines, inflammatory mediators Antibody mediated hypersensitivity reactions (I-III) and delayed type hypersensitivity reactions (IV a-d) Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003

14. Drug allergy: Heterogeneous clinical manifestations & pathophysiology • Urticaria, anaphylaxis • Blood cell dyscrasia • Vasculitis • Maculopapularexanthem • Bullous or pustularexanthems (AGEP) • Stevens-Johnson Syndrome (SJS), toxic-epidermal necrolysis (TEN) • Hepatitis, interstitial nephritis, pneumopathy • Drug induced autoimmunity (SLE, pemphigus ...) • Drug induced hypersensitivity syndrome (DiHS/DRESS)

15. Allergic vs non-allergic drug hypersensitivity 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

16. 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.

17. 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 % ?

18. 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

19. 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

20. 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

21. 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

22. Management Options • 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

23. Management Options • 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

24. Follow-up and Re-evaluation • Patient’s progress • Course of event • Delayed reactions • Response to treatment • Specific monitoring parameters

25. 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 What to check History PE PE-Nikolsky’s sign PE PE PE PE Labs--LFTs, Creatinine/UA. H&P for pleuritis/carditis/cerebritis Labs--CBC with differential ___ ___ ___ ___ ___ ___ ___ ___ ___

27. 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 drug • Stops up to 7d after stopping drug

29. Day 1 • WBC 16K +reactive lymphocytes • AST/ALT 110/134 • INR 2.1 • BUN/Cr 20/0.8

30. Day 3

31. Stevens- Johnson SJS/TEN overlap TEN What is it, and is their skin going to fall off? Skin rash + 2 or more mucosal sites BSA: <10% 10-30% >30% Mortality: 5-10% 30-50%

32. 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!!

33. SJS

34. TEN

35. Acute Exanthematous Generalized Pustulosis (AGEP) http://dermatology.cdlib.org/126/case_presentations/agep/teixeira.html

36. Phototoxic reaction

37. Drug induced Lupus

38. Drug induced vasculitis

39. Fixed Drug Eruption

40. THE END