Drug Allergy: Understanding Hypersensitivity Reactions

1. Author: Netherlands Pharmacovigilance Centre Lareb Version date: 14 Nov 2017 Content: This lecture describes Drug allergy, by R. van Eekeren, PharmD, The Netherlands. This lecture can be used for teaching key aspect 2,3,4: preventing, recognizing, managing ADRs.

2. Drug allergy Pharmacovigilance course 2017 University of Groningen, The Netherlands Drs R. (Rike) van Eekeren Pharmacist

3. Hypersensitivity? Allergy? Intolerance? Idiosyncrasy? Side effect?

4. Learning objectives • Knowing the meaning of terms like allergy, hypersensitivity and intolerance • Explain differences in immunological reaction according to the Gell and Coombs classification and give some examples • Be able to discuss if a drug should be considered as contra-indicated and what consultation with other health care providers is necessary

5. Content ∙ Terminology • Various types of hypersensitivity • Some diagnostics • Recordings and actions • Exam question examples

6. Terminology

7. Examples Side-effect (collateralUnknownmechanism Pseudo-allergyIntolerance AllergyIdiosyncrasy Hypersensitivity

8. Examples Side-effect (collateral)Unknownmechanism Pseudo-allergyIntolerance AllergyIdiosyncrasy Hypersensitivity

9. Content • Terminology • Various types of hypersensitivity • Some diagnostics • Recording and actions • Exam question examples

10. Allergichypersensitivity • A specific unwanted immune-mediated allergic reaction, resulting in tissue damage • As a rule, previous contact with the allergy inducing substance (allergen) is necessary (sensitization) • Risk of recurrence on repeated exposure with a risk of an increasing severity of the reaction • Cross-reaction based on drug structure may occur

12. Naissbitt et al. Drug Saf 2000; 23 (6):483-507

13. ClassificationaccordingtoGell & Coombs Four different type of allergicreactions: • Type I: Immediatehypersensitivity, IgEmediated. e.g. urticaria (hives), anaphylacticreaction • Type II: Antibody-dependentcytotoxichypersensitivity. e.g. disorder of production of blood • Type III: Immune complex disease, e.g. serum sickness • Type IV: Delayed T-cellmediatedhypersensitivity, e.g. cutaneousreactions

14. Type I allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

15. Urticaria (hives, galbulten) Wheal flare Van den Bemt et al. Pharm Weekbl 1998; 133(32):1183-92

16. Case report type I • Female, 56 years • Hypertension for a couple years, causing abnormalities of the retinal vessels (retinophaty) • Medication - Betahistine - Furosemide, Felodipine, Metoprolol Because of decreased vision, consultation of an ophthalmologist - Decision to fluorescence angiography - IV administration fluorescein 100mg / ml;

17. Case report • After administration fluorescein i.v. suddenly unwell- Flushing- Low blood pressure- Treatment with epinephrine, clemastine and dexamethasone, • Died within minutes after administration of fluorescein • A known but very rare side effect fluorescein- Previous exposure to fluorescein- Influence of metoprolol?

19. Anaphylaxis (2)

20. Anaphylacticreactionand - shock • Anaphylactic reaction- At least two “organ systems” involved- Symptoms can vary considerably • Anaphylactic shock- Anaphylactic reaction in combination with very low blood pressure- Immediate treatment is required- High risk of death • Anaphylactic reaction may precede an anaphylactic shock

21. Type II allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

22. Type II reactions Timing : > 5-8 days to weeks after exposure (sometimes asymptomatic at first)

23. Type III allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

24. Case report type III • Male, 35 years • Bupropion 150 mg for smoking cessation • One week after starting bupropion complaints- Fever, Fatigue- Rash on forearms- Lymph node swelling- Upper abdominal pain- Arthralgia • Increased markers for inflammation, decrease in renal and liver function • Referred to an internist; diagnosis “serum sickness like reaction”

25. Serum sickness like Reaction • Type III reaction- Formation of immune complexes between antibodies and drug- Precipitation of antibodies in various organs • Inflammation- Usually within 2-3 weeks after starting- Upon re-exposure occur within a week • Rare, serious side effect, which should be recongnized in time and treated. • Drugs: antibiotics, bupropion

26. Type IV allergy Naisbitt et al. Drug Saf 2000; 23 (6):483-507

27. Example of contact dermatitis after ingestion of a herbal drug Van den Bemt et al. Pharm Weekbl 1998; 133(32):1183-92

28. Case report type IV • Female 88 years, amputation of lower leg in the past • Medication- Carbamazepine- Oxazepam- Lactulose- Nitrofurantion • Eczema of- Hands and feet- Head

29. Case Eczema • Carbamazepine is replaced by oxcarbazepine • Complaints are gradually worse • After discontinuation only gradual improvement • Treatment with tropical steriods • Note: cross hypersensitivity Carbamazepine Oxcarbazepine

30. Clinical presentations type IV • Contact dermatitis • Maculopapular eruptions • Drug fever • Acute generalized exanthematous pustolosis (AGEP) • Stevens-Johnsom syndrome and toxic epidermal necrolysis (SJS / TEN) • Drug-induced hypersensitivity syndrome (DRESS) • Interstitial pneumonitis • Granulomatous hepatitis

32. Non-allergic hypersensitivity • Pseudo-allergy- Signs and symptoms that mimic immunologic drug allergies- No immunological mechanism • Idiosyncrasy- Unknown mechanism- Genetic predisposition

33. Pseudo-allergy • Direct mastcell stimulation- Opiates  pruritus, urticaria- Vancomycin  flushing during infusion (red man synd)- Ciprofloxacin  urticaria • Alteration in immunological mediators- Aspirin, NSAIDs  exacerbation asthma, rhinitis  urticaria, angioedema- ACE inhibitors  angioedema • Direct complement activation- Radio contrast media  anaphylaxis, shock

34. Idiosyncrasy (example) Hemolytic anaemia caused by nitrofurantion, sulfasalzine, hydroxychloroquine, glibenclamide, ..., in patients with G6PD deficiency

35. Idiosyncrasy / Risk factors

36. Content • Terminology • Various types of hypersensitivity • Some diagnostics • Recording and actions • Exam question examples

37. Diagnosis • Correct anamnese- Symptoms- Time relationship- Changes in the use of drugs- Prior exposure to drugs • Physical examination- Additional diagnostics (lab, skin testing)- Specific IgE to penicillin allergy (RAST)- Skin prick- Proofs (oral challenge; patch in type IV)- Specific parameters - histamine and tryptase in type I, - complement in type III - eosinophils in type IV

39. Afbeelding: website LUMC

40. Content • Terminology • Various types of hypersensitivity • Some diagnostics • Recording and actions • Exam question examples

41. Which information shouldberecorded?

42. Which information should be recorded?

43. To avoid, or? • Should a drug that has caused a true immunologic reaction always be avoided in future? • Should a drug that has caused a pseudo allergic reaction always be avoided in future?

44. Learning objectives • Knowing the meaning of terms like allergy, hypersensitivity and intolerance • Explain differences in immunological reaction according to the Gell and Coombs classification and give some excamples • Be able to discuss if a drug should be considered as contra-indicated and what consultation with other health care providers is necessary

45. Exam question (1) Urticaria (hives) is a sign of a specific type of allergic reaction.Do you know which one? a. Type I, immediate type b. Type II, cytotoxic reaction c. Type III, immune complex reaction d. Type IV, delayed type

46. Exam question (2) Give an example of a non-allergic hypersensitivity reaction of enalapril (ACE-inhibitor) a. Postural hypotension b. Dry cough c. Angioedema d. Rash